Consumer medicine information

Estraderm MX

Estradiol

BRAND INFORMATION

Brand name

Estraderm MX

Active ingredient

Estradiol

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Estraderm MX.

SUMMARY CMI

ESTRADERM MX

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.

WARNING: Important safety information is provided in a boxed warning in the full CMI. Read before using this medicine.

1. Why am I using ESTRADERM MX?

ESTRADERM MX contains the active ingredient estradiol. ESTRADERM MX is used for the treatment of menopausal symptoms due to estrogen deficiency during menopause or after a surgical procedure, where estrogen production is decreased.

For more information, see Section 1. Why am I using ESTRADERM MX? in the full CMI.

2. What should I know before I use ESTRADERM MX?

Do not use if you have ever had an allergic reaction to estradiol or any of the ingredients listed at the end of the CMI.

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 2. What should I know before I use ESTRADERM MX? in the full CMI.

3. What if I am taking other medicines?

Some medicines may interfere with ESTRADERM MX and affect how it works.

A list of these medicines is in Section 3. What if I am taking other medicines? in the full CMI.

4. How do I use ESTRADERM MX?

ESTRADERM MX patches are usually worn continuously, and replaced every 3-4 days. You should only wear one patch at a time, unless your doctor tells you otherwise.

The best place to apply ESTRADERM MX patches is on your lower abdomen or buttocks. Never put ESTRADERM MX patches on your breasts.

More instructions can be found in Section 4. How do I use ESTRADERM MX? in the full CMI.

5. What should I know while using ESTRADERM MX?

Things you should do
  • Remind any doctor, dentist or pharmacist ESTRADERM MX.
  • If you become pregnant while taking this medicine, tell your doctor immediately.
Things you should not do
  • Do not stop Do not take ESTRADERM MX to treat any other complaints unless your doctor tells you to.
  • Do not give your medicine to anyone else, even if they have the same condition as you.
Driving or using machines
  • Be careful before you drive or use any machines or tools until you know how ESTRADERM MX affects you.
  • ESTRADERM MX may cause dizziness in some people.
Drinking alcohol
  • Tell your doctor if you drink alcohol.
  • Excess intake of alcohol during use of HRT has an influence on the treatment.
Looking after your medicine
  • Do not remove the patch from the protective pouch until you are ready to apply it.
  • Keep your patches in a cool dry place below 25°C.

For more information, see Section 5. What should I know while using ESTRADERM MX? in the full CMI.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention. Ask your doctor or pharmacist if you have any further questions about side effects.

For more information, including what to do if you have any side effects, see Section 6. Are there any side effects? in the full CMI.

WARNING: The Women's Health Initiative (WHI) trial examined the health benefits and risks of combined estrogen plus progestogen therapy (n=16,608) and estrogen-alone therapy (n=10,739) in postmenopausal women aged 50 to 79 years.
The estrogen plus progestogen arm of the WHI trial indicated an increased risk of myocardial infarction (MI), stroke, invasive breast cancer, pulmonary embolism and deep vein thrombosis in postmenopausal women receiving treatment with combined conjugated equine estrogens (CEE, 0.625 mg/day) and medroxyprogesterone acetate (MPA, 2.5 mg/day) for 5.2 years compared to those receiving placebo.
The estrogen-alone arm of the WHI trial indicated an increased risk of stroke and deep vein thrombosis in hysterectomized women treated with CEE-alone (0.625 mg/day) for 6.8 years compared to those receiving placebo.
Other doses of oral conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestogens were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar.
Therefore, the following should be given serious consideration at the time of prescribing:
• Estrogens with or without progestogens should not be prescribed for primary or secondary prevention of cardiovascular diseases.
• Estrogens with or without progestogens should be prescribed at the lowest effective dose for the approved indication.
• Estrogens with or without progestogens should be prescribed for the shortest period possible for the approved indication.
• For the prevention of osteoporosis, estrogen treatment should be considered in light of other available therapies.



FULL CMI

ESTRADERM MX

Active ingredient(s): Estradiol hemihydrate

Consumer Medicine Information (CMI)

This leaflet provides important information about using ESTRADERM MX. 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 ESTRADERM MX.

Where to find information in this leaflet:

1. Why am I using ESTRADERM MX?
2. What should I know before I use ESTRADERM MX?
3. What if I am taking other medicines?
4. How do I use ESTRADERM MX?
5. What should I know while using ESTRADERM MX?
6. Are there any side effects?
7. Product details

1. Why am I using ESTRADERM MX?

ESTRADERM MX contains the active ingredient estradiol. ESTRADERM MX is an adhesive patch, which delivers estradiol through the skin and into the blood stream.

ESTRADERM MX is used for the treatment of menopausal symptoms due to estrogen deficiency during menopause or after a surgical procedure, where estrogen production is decreased. ESTRADERM MX is only intended for short term use.

ESTRADERM MX releases estradiol in a continuous and controlled way just as your ovaries were doing before.

Because the medicine does not have to pass through your stomach and liver, it allows you to take a much lower dose of estrogen than would be needed in a tablet. The estradiol in ESTRADERM MX can replace the estrogen in the body.

During menopause, the estradiol production of the ovaries declines. Although menopause is natural, it often causes distressing symptoms, which are connected with the gradual loss of the hormones produced by the ovaries.

ESTRADERM MX provides estrogen, which the body is no longer making, to prevent or relieve menopausal symptoms such as hot flushes (night sweats), sleep disturbances, vaginal dryness, depression, nervousness, irritability, headache, dizziness.

ESTRADERM MX can also be used to prevent bone mineral density loss (where the bones become weaker, more brittle and likely to break) during menopause.

Calcium, vitamin D and regular exercise are some other factors that may help to prevent thinning of the bones.

You should include foods that are good sources of calcium and vitamin D in your daily diet and exercise regularly.

Your doctor can advise you on which foods and types of exercise are best for you.

ESTRADERM MX is not a contraceptive. It will not prevent you from falling pregnant.

2. What should I know before I use ESTRADERM MX?

Warnings

Do not use ESTRADERM MX if you have:

  • an allergy to estradiol, or any of the ingredients listed at the end of this leaflet. Always check the ingredients to make sure you can use this medicine.
  • severe uncontrolled high blood pressure
  • severe liver disease such as jaundice (signs of liver problems such as yellowing of skin and/or eyes) or persistent itching during a previous pregnancy
  • a history of or existing liver tumours
  • suspected or existing tumours in the uterus, ovaries or breast
  • known or suspected tumours influenced by sex hormones
  • endometriosis (the presence of tissue of the lining of the womb in places in the body where it is not usually found)
  • a history of or existing blood clot in the blood vessels (such as blood clots in the legs)
  • if you recently had a heart attack and/or stroke
  • if you have a high risk of venous or arterial thrombosis (blood clot)
  • severe diabetes
  • sickle-cell anaemia (inherited disorder which causes the red blood cells to change shape)
  • disturbances of fat metabolism
  • a history of herpes during pregnancy
  • hearing loss (otosclerosis) that worsens during pregnancy
  • undiagnosed abnormal vaginal bleeding

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 you have not had your uterus (womb) removed (hysterectomy), do not use ESTRADERM MX unless your doctor has prescribed another hormone progestogen to take with ESTRADERM MX.

The use of estrogens alone and over a prolonged period can lead to excessive development of the lining of the womb and this can increase the incidence of cancer of the womb. This risk can be avoided by the additional administration of a progestogen. The general result of this is regular shedding of the lining of the womb and, therefore, menstruation-like bleeding. If you have not had a hysterectomy (your uterus/womb removed) your doctor should prescribe a progestogen for you to take and you should discuss this with your doctor before using ESTRADERM MX.

Before you start to use it

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

Check with your doctor if you:

  • have any are overweight.
  • smoke.
  • or anyone in your immediate family has had blood clots (thrombosis).
  • have systemic lupus erythematosus (SLE, a chronic inflammatory disease).
  • have any planned hospitalisation, surgery or prolonged immobilisation.

Studies have suggested that HRT may be associated with an increased risk of developing blood clots. You have an increased risk of a blood clot if you have any of the above risk factors. In addition to these, there may be other risk factors. In the case of a combination of factors, the risk may be higher than simply adding two individual risks. Talk to your doctor if you have any concerns.

Using ESTRADERM MX may also increase your risk of coronary heart disease. Tell your doctor if you experience chest pain or discomfort.

Using ESTRADERM MX may increase your risk of gall bladder disease. This is because estrogen stimulates the liver to remove more cholesterol from blood and divert it to the gall bladder.

Before being prescribed ESTRADERM MX, your doctor should perform a thorough medical and gynaecological examination (including the breasts and a pap smear). Your doctor will also note your family medical history and exclude pregnancy.

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

  • diabetes
  • high blood pressure
  • varicose veins
  • otosclerosis (a type of hearing loss)
  • endometriosis (the presence of tissue of the lining of the womb in places in the body where it is not normally found)
  • multiple sclerosis
  • epilepsy
  • porphyria (inherited or acquired disorder of certain enzymes)
  • tetany (mineral imbalance in the body that results in severe muscle spasms)
  • chorea minor (disorder characterised by irregular and involuntary muscles)
  • kidney or heart disease
  • tumours in the pituitary gland
  • yellowing of the skin and/or eyes (cholestatic jaundice) with previous estrogen use or during pregnancy
  • migraine
  • a high level of triglycerides (fats) in the blood
  • high or low calcium levels in the blood
  • an underactive thyroid gland (hypothyroidism)
  • an abnormal build-up of blood vessels in the liver (hepatic haemangioma)
  • chloasma (yellowish brown pigmentation patches on the skin, particularly of the face); if so, avoid too much exposure to the sun or ultraviolet radiation
  • asthma
  • systemic lupus erythematosus (SLE; a disease affecting the skin all over the body)
  • tumours in the womb or liversystemic lupus
  • hereditary angioedema, an inherited disorder where repeated episodes of severe swelling occur

Tell your doctor if you are 65 years or older when HRT is initiated. The reason is that there is limited evidence from clinical studies that hormonal treatment may increase the risk of significant loss of intellectual abilities such as memory capacity (dementia).

If ESTRADERM MX is used in the presence of any of the conditions listed above you will need to be kept under close observation. Your doctor can explain this to you. Therefore, if any of these apply to you, tell your doctor before starting to use ESTRADERM MX.

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 6. Are there any side effects?

Pregnancy and breastfeeding

Do not use this medicine if you are pregnant. It may affect your developing baby if you use it during pregnancy.

Do not breast-feed if you are using this medicine. The active ingredient in ESTRADERM MX passes into breast milk and there is a possibility that your baby may be affected.

HRT and cancer

Endometrial cancer

The risk of cancer of the lining of the womb (endometrial cancer) increases when estrogens are used alone for prolonged periods. Taking a progestogen in addition to the estrogen lowers this risk.

Please inform your doctor if you frequently have bleeding irregularities or persistent bleeding during the treatment with ESTRADERM MX.

Breast cancer

Tell your doctor if you have suffered from fibrocystic disease of the breasts (lumps in the breast) or if you have first degree relatives (mother, sisters, daughters) who have had breast cancer.

Breast cancer has been diagnosed slightly more often in women who use hormone replacement therapy (HRT) than in women of the same age who do not use HRT. If you are concerned about this information you should discuss this with your doctor. It is recommended that yearly breast examinations are conducted and regular breast self-examination (monthly) should be carried out.

HRT has been reported to result in an increased number of abnormal mammograms requiring further evaluation.

Ovarian cancer

Some observational studies show a slightly increased overall risk of developing ovarian cancer in women who have used HRT compared to women who have never used HRT. In women currently using HRT, this risk was further increased. These associations have not been shown in all studies. There is no consistent evidence that the risk of developing ovarian cancer is related to the duration of use of HRT. However, the risk may be more relevant with longterm use (for several years).

Liver tumour

During or after the use of hormones such as those that are contained in ESTRADERM MX, benign liver tumours have rarely occurred, and malignant liver tumours even more rarely. In isolated cases, bleeding has occurred from such tumours into the abdominal cavity. Although such events are rare, you should inform your doctor about any pain in your upper abdomen that does not disappear within a short time.

3. 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 ESTRADERM MX may interfere with each other. These include:

  • medicines to treat high blood pressure, chest pain and/or irregular heart beat such as ACE inhibitors, verapamil, diltiazem
  • macrolide antibiotics (e.g. clarithromycin, erythromycin)
  • medication used to treat epilepsy, such as hydantoins, barbituates, primidone, carbamazepine
  • rifampicin for the treatment of tuberculosis
  • herbal medicines containing St John's Wort
  • medicines used to treat HIV such as ritonavir or nevirapine
  • some medicines used to treat Hepatitis C Virus (HCV) such as boceprevir, telaprevir
  • medicines used to treat fungal infections such as ketoconazole, itraconazole, voriconazole, fluconazole
  • grapefruit juice
  • medicines used to treat diabetes, such as insulin or
  • anti-diabetic medications

These medicines may be affected by ESTRADERM MX or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while using this medicine.

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

4. How do I use ESTRADERM MX?

How much to use

  • The amount of estrogen you need will depend upon your body's requirements. Your doctor may adjust this amount by changing the size of the patch you use.
  • Follow the instructions provided and use ESTRADERM MX until your doctor tells you to stop.

When to use ESTRADERM MX

  • ESTRADERM MX patches are usually worn continuously, and replaced every 3-4 days. You should only wear one patch at a time, unless your doctor tells you otherwise.
  • Your doctor will explain when to start using the patch and if you should use it any other way (for example, for 3 weeks out of 4).

How to use ESTRADERM MX

A leaflet in the carton contains pictures and information on how to apply the patch properly.

The best place to apply ESTRADERM MX patches is on your lower abdomen or buttocks. Never put ESTRADERM MX patches on your breasts.

Do not put the patch on your waistline where tight clothes may rub it. Avoid putting the patch on areas where the skin is hairy or folded.

Before applying an ESTRADERM MX patch, make sure your skin is clean and dry. Do not apply the patch to oily, broken or irritated skin.

  1. Remove ESTRADERM MX from the pouch
The ESTRADERM MX patch is packed in a protective pouch. Tear open the pouch at the notched corner and remove the patch. Do not use scissors as you may accidentally cut the patch. Dispose of the pouch once the ESTRADERM MX patch has been applied.
  1. Take the backing off the patch
A clear plastic protective backing which is slightly larger than the patch itself covers the sticky side of the patch. The backing must be removed before you apply the patch to your skin. Remove the backing by holding the edge of the patch in one hand and peeling the backing off with the other hand from the crease line. Half of the backing will come off, exposing part of the patch. As you apply the patch to your skin, peel off the rest of the backing. Do not touch the sticky side of the patch. Apply the patch immediately after opening the pouch and removing the backing. Throw away the backing.
  1. Apply the patch to your skin
Place the sticky side of the patch on a clean, dry area of skin. Press the patch firmly in place for about 10 seconds. Make sure the patch sticks well, especially around the edges.
  1. Changing ESTRADERM MX patches
Change the patch once every 3-4 days. Remove the old patch and discard it, out of the way of children. Apply your new patch to a different area of clean, dry skin. Do not put the patch on the same area of skin each week.
  1. What to do if your patch comes off
ESTRADERM MX patches are unlikely to fall off. But if the patch does fall off put a new patch on for the rest of the 3-4 days.

How long to use ESTRADERM MX

Your doctor will advise you on how long to use ESTRADERM MX. Your doctor should discuss with you the risks and benefits with extended use of this product and your treatment with hormone therapy should also be reevaluated at regular intervals.

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

You may have an increased risk of developing breast cancer, heart disease, stroke, blood clots on the lungs and dementia. On the other hand, the risk of hip fractures and bowel cancer may be reduced. Your doctor can discuss these risks and benefits with you, taking into account your particular circumstances

If you forget to use ESTRADERM MX

Apply a new patch as soon as you remember, and then go back to your usual schedule.

If you have trouble remembering when to use or replace your patches, ask your pharmacist for some hints.

If you use too much ESTRADERM MX

Estrogen overdose is unlikely with this type of application. In the event of accidental overdose, remove the patch.

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

You should immediately:

  • phone the Poisons Information Centre
    (by calling 13 11 26), 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. Symptoms of an overdose may include nausea, vomiting, breast discomfort, breakthrough bleeding, fluid retention and bloating.

5. What should I know while using ESTRADERM MX?

Things you should do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are using ESTRADERM MX.

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

Call your doctor straight away if you:

Tell your doctor immediately if you become pregnant while using ESTRADERM MX. The use of ESTRADERM MX should be stopped immediately.

If you are still able to fall pregnant, barrier methods of contraception should be practised (such as condoms or a diaphragm). If there is a chance that pregnancy has occurred, stop using the patch until it has been ruled out.

If you are going to have surgery, tell the surgeon or anaesthetist well in advance that you are using this medicine. ESTRADERM MX should not be used at least four to six weeks before surgery.

If irregular menstrual bleeding occurs repeatedly during the use of ESTRADERM MX or if the bleeding in the treatment free weeks is unusually heavy, tell your doctor.

See your doctor at least once a year for a check-up. Some women will need to go more often. Your doctor will check your breasts and order a mammogram at regular intervals, check your uterus and cervix and do a pap smear at regular intervals, and monitor your blood pressure.

Check your breasts each month and report any changes promptly to your doctor. Your doctor or nurse can show you how to check your breasts properly.

Stop using ESTRADERM MX immediately if:

You should stop treatment at once and consult your doctor if you have any of the following conditions:

  • your very first attack of migraine (typically a throbbing headache and nausea preceded by visual disturbances)
  • worsening of pre-existing migraine, any unusually frequent or unusually severe headaches
  • sudden disturbances of vision or hearing
  • swollen veins (thrombophlebitis),
  • itching of the whole body
  • unusual upper abdominal pains that do not disappear within a short period of time
  • planned operations/surgery or immobilisation
  • seizures
  • increase in blood pressure

If you get a blood clot while you are using ESTRADERM MX or there is a suspicion of this you should stop using it immediately and contact your doctor. Warning signs to look out for are:

  • coughing blood
  • unusual pains or swelling of your arms or legs
  • sudden shortness of breath, pain or tightness in the
  • chest
  • fainting

ESTRADERM MX must also be stopped at once if you develop jaundice (yellowing of the skin and/or eyes). Tell your doctor immediately if either occurs.

Remind any doctor, dentist or pharmacist you visit that you are using ESTRADERM MX.

Things you should not do

Do not use ESTRADERM MX to treat any other complaints unless your doctor tells you to.

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

Do not stop using your medicine or lower the dosage without checking with your doctor. If you stop using it suddenly, your condition may worsen or you may have unwanted side effects.

Other things to know

  • You can bathe, shower or swim when wearing a ESTRADERM MX patch. The patch might, however, become detached from the skin in very hot water or in the sauna.
  • If there are, repeatedly, persistent skin irritations (e.g. persistent reddening or itching at the application site) even if the application site is changed according to the directions given, you should consider stopping treatment.

Driving or using machines

Be careful before you drive or use any machines or tools until you know how ESTRADERM MX affects you.

ESTRADERM MX may cause dizziness in some people.

Drinking alcohol

Tell your doctor if you drink alcohol.

Excess intake of alcohol during use of HRT has an influence on the treatment. Your doctor will advise you.

Looking after your medicine

Do not use this medicine if the packaging is torn or shows signs of tampering.

  • Keep your patches in the pack until it is time to use them.
  • Do not remove the patch from the protective pouch until you are ready to apply it.
  • Keep your patches in a cool dry place below 25°C.

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.

Getting rid of any unwanted medicine

If you no longer need to use this medicine or it is out of date, take it to any pharmacy for safe disposal.

When disposing of patches, make sure children cannot reach them.

Do not use this medicine after the expiry date.

6. Are there any side effects?

All medicines can have side effects. If you do experience any side effects, most of them are minor and temporary. However, some side effects may need medical attention.

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

Skin disorders have been reported in women receiving HRT. Tell your doctor if you notice itchy, reddish, painful lumps (erythema nodosum, erythema multiforme, haemorrhagic dermatitis) or yellowish brown pigmentation on the skin (chloasma).

Less serious side effects

Less serious side effectsWhat to do
General disorders and application skin conditions:
  • redness, rash, itching, stinging and blisters on the skin after the patch has been removed
  • fluid retention (bloating or swelling in the arms, ankles or feet)
  • unusual tiredness
  • pain (including back and pelvic pain)
Reproductive:
  • tender or painful breasts, breast enlargement
  • irregular menstrual bleeding
  • vaginal itching, burning or discharge
Central and peripheral nervous system:
  • headache
  • dizziness
  • leg cramps
Autonomic nervous system:
  • increased sweating
Gastrointestinal system:
  • nausea
  • stomach pain, cramps or wind
Metabolic and nutritional:
  • changes in body weight
Psychiatric:
  • nervousness or depressive moods
Skin and appendages:
  • rash or itching
  • acne
Speak to your doctor if you have any of these less serious side effects and they worry you.

Serious side effects

Serious side effectsWhat to do
Immune system disorders:
  • signs of allergy such as rash, itching or hives on the skin, swelling of the face, lips, tongue, or other parts of the body, shortness of breath, wheezing, or trouble breathing
Gastrointestinal system:
  • list as yellowing of the skin and/or eyes (cholestatic jaundice)
General disorders
  • coughing blood, unusual pains or swelling of your arms or legs, sudden shortness of breath, fainting of the skin and/or eyes
Call your doctor straight away, or go straight to the Emergency Department at your nearest hospital if you notice any of these serious side effects.

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.

7. Product details

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

What ESTRADERM MX contains

Active ingredient
(main ingredient)		Estradiol hemihydrate
Other ingredients
(inactive ingredients)		isopropyl palmitate
acrylate
methacrylate
polyethylene terephthalate
ethylene/vinylacetate copolymer
silicone coating on the release liner

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

What ESTRADERM MX looks like

Estraderm MX patches come in four strengths: 25, 50, 75 and 100. They are thin, flat, square patches with rounded corners, sealed in individual pouches.

Estraderm MX 25 patches are marked CG GRG (AUST R 67089).

Estraderm MX 50 patches are marked CG GSG (AUST R 56658).

Estraderm MX 75 patches are marked CG HKH (AUST R 76117).

Estraderm MX 100 patches are marked CG GTG (AUST R 67090).

Estraderm MX patches are made up of three layers:

  • a waterproof transparent backing film
  • a sticky layer containing the active ingredient, estradiol (as hemihydrate)
  • a protective liner (to be removed before use)

Each carton contains 8 patches (enough for 4 weeks of treatment).

Who distributes ESTRADERM MX

Juno Pharmaceuticals Pty Ltd
15-17 Chapel Street,
Cremorne,
VIC 3121
Australia
www.junopharm.com.au

This leaflet was prepared in November 2024.

Published by MIMS February 2025

BRAND INFORMATION

Brand name

Estraderm MX

Active ingredient

Estradiol

Schedule

S4

 

1 Name of Medicine

Estradiol.

2 Qualitative and Quantitative Composition

Estraderm MX contains 0.75 mg, 1.5 mg, 2.25 mg or 3.0 mg estradiol (as hemihydrate) in a transdermal therapeutic system.
A drug/ adhesive matrix which is laminated to a polyester backing film is directly in contact with the skin. The active substance penetrates the skin from the adhesive and passes directly into the bloodstream for up to four days after application.
Estraderm MX overcomes the problems of the short half-life and extensive first pass metabolism of estradiol.
Estraderm MX 25, 50, 75 and 100 have a nominal in vivo release rate of 25, 50, 75 and 100 micrograms/24 h, respectively. Estraderm MX 25, 50, 75 and 100 contain 0.75 mg, 1.5 mg, 2.25 mg and 3.0 mg estradiol and have drug releasing areas of 11 cm2, 22 cm2, 33 cm2 and 44 cm2, respectively.

3 Pharmaceutical Form

Estraderm MX is thin flat multilaminate sheet composed of three layers. Proceeding from the visible outer surface towards the inner surface, next to the skin, the layers are:
1. An impermeable, transparent backing film.
2. A drug/ adhesive matrix containing estradiol.
3. A protective liner (to be removed prior to use).

Estraderm MX 25.

A translucent, colourless system, about 3.5 cm square, with rounded corners, on an oversized, transparent protective liner. The code CG GRG is heat-stamped on the backing film of the patch.

Estraderm MX 50.

A translucent, colourless patch, about 4.9 cm square with rounded corners, on an oversized, transparent protective liner. The code CG GSG is impressed on the backing side of the patch.

Estraderm MX 75.

A translucent, colourless system, about 6.1 cm in diameter, square, with rounded corners, on an oversized transparent protective liner. The backing film is imprinted with code "CG HKH".

Estraderm MX 100.

A translucent, colourless system, about 7.0 cm square with rounded corners, on an oversized, transparent protective liner. The code CG GTG is heat-stamped on the backing film of the patch.

4 Clinical Particulars

4.1 Therapeutic Indications

Menopausal symptoms.

Short-term treatment of signs and symptoms of estrogen deficiency due to the menopause, whether natural or surgically induced. In women with intact uteri, estrogen should always be opposed by progestogen in an adequate dosage regimen to ensure secretory transformation of the endometrium at regular intervals (see Section 5.1 Pharmacodynamic Properties, Clinical trials; Section 4.2 Dose and Method of Administration).

Prevention of postmenopausal bone mineral density loss.

Estraderm MX 50, 75 and 100 may be used for prevention of postmenopausal bone mineral density loss in women with an increased risk of future osteoporotic fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of bone mineral density loss. When prescribed solely for the prevention of postmenopausal bone mineral density loss, therapy should only be prescribed for women who are at high risk of future fracture and who are intolerant of, or contraindicated for, nonestrogen products approved for prevention of bone mineral density loss. Lifestyle modifications and the risk/ benefit profile of Estraderm MX should be taken into careful consideration and discussed with the patient to allow the patient to make an informed decision prior to prescribing (see Section 4.4 Special Warnings and Precautions for Use; Section 4.2 Dose and Method of Administration).
Estraderm MX 25 is not indicated for the prevention of postmenopausal bone mineral density loss.
Combination HRT should not be used in hysterectomised women because it is not needed in these women and it may increase the risk of breast cancer.

4.2 Dose and Method of Administration

Initiation of therapy.

Based on relief of menopausal symptoms, doses of Estraderm and Premarin1 (conjugated estrogens) which have been shown to produce the same effect are: Estraderm 25: Premarin 0.3 mg; Estraderm 50: Premarin 0.625 mg; Estraderm 100: Premarin 1.25 mg.
Estraderm 50 has also been shown to be clinically equivalent to 20 micrograms/day ethinylestradiol.
In women who are not currently taking oral estrogens, treatment with Estraderm MX can be initiated at once. In women who are currently taking oral estrogens, treatment with Estraderm MX can be initiated on reappearance of symptoms, following discontinuation of oral therapy (generally within 5 to 7 days).
For all therapeutic indications, the lowest effective dose should be used and consideration should be given to the shortest duration of use. A careful appraisal of the risks and benefits should be undertaken over time in women treated with HRT and the need for treatment re-evaluated periodically. Treatment should only be continued for as long as the benefits outweigh the risks for the individual (see Section 4.4 Special Warnings and Precautions for Use).
1 Premarin is a registered trademark of Ayerst Laboratories Division of Wyeth Pharmaceuticals Pty Ltd.

Signs and symptoms of estrogen deficiency due to the menopause.

Treatment is normally initiated with Estraderm MX 50. Thereafter, the dosage should be adapted to the needs of the individual; breast discomfort, breakthrough bleeding, water retention or bloating (if persisting for more than 6 weeks) are generally signs that the dose is too high and needs to be lowered. If, however, the dose selected fails to eliminate the signs and symptoms of estrogen deficiency, a higher dose should be given. For maintenance therapy the lowest effective dose should always be used (see Section 4.4 Special Warnings and Precautions for Use).

Prevention of postmenopausal bone mineral density loss.

The mainstays for decreasing the risk of postmenopausal osteoporosis are weightbearing exercise, adequate calcium and vitamin D intake and, when indicated, pharmacological therapy. Postmenopausal women require an adequate daily intake of elemental calcium. Therefore, when not contraindicated, calcium supplementation may be helpful for women with suboptimal dietary intake. Vitamin D supplementation may also be required to ensure adequate daily intake in postmenopausal women.
Estraderm MX 50, 75 and 100 prevent the accelerated loss of bone density due to estrogen deficiency and may be used for prevention of postmenopausal bone mineral density loss (see Section 4.1 Therapeutic Indications). Estraderm MX 25 is insufficient to prevent postmenopausal bone mineral density loss. The effect is seen only while estrogen replacement therapy continues and discontinuation may re-establish the natural rate of bone loss. The optimal duration of use to prevent fractures has not yet been determined. In patients with established bone mineral density loss and evidence of fracture, therapy should be initiated with Estraderm MX 100. For maintenance therapy the lowest effective dose should always be used (see Section 4.4 Special Warnings and Precautions for Use).

Continuous treatment.

Continuous therapy is usually recommended. Estraderm MX should be applied twice weekly, i.e. the system should be changed once every 3 or 4 days. Each pack contains information on Estraderm MX and how to use it.

In women with intact uteri.

A progestogen should be administered sequentially for the first 10-14 (preferably 12) days of each calendar month to avoid overstimulation of the endometrium (see Section 5.1 Pharmacodynamic Properties, Clinical trials). The addition of sufficient progestogen to induce secretory transformation of the endometrium is strongly recommended. Consideration should be given to a minimum progestogen dose of medroxyprogesterone acetate 10 mg for at least 10 days of the month as a means of achieving endometrial transformation.

Cyclic treatment.

If required, Estraderm MX can be applied in a cyclic manner. In such cases, the progestogen should be taken on the last 12 days of each 3 week period of estradiol administration, so that the 4th week of each cycle remains without any treatment.
In either case, i.e. continuous or cyclic treatment, a withdrawal bleed usually occurs following the progestogen administration.

In hysterectomised women.

Estraderm MX can be applied continuously without the coadministration of a progestogen.

Method of administration.

Remove Estraderm MX from the sachet and peel off the protective release liner. Apply the system to an area of clean, dry, intact skin on the buttocks.
The area of skin should be free from oil and from signs of irritation. Apply the adhesive side of the patch to the chosen spot and press firmly in place for at least 10 seconds.
Water contact (bathing, swimming or showering) should not affect the patch, although very hot water or steam may loosen it. In the unlikely event that a patch should fall off, it can be reapplied.
If it fails to adhere, a new system may be applied. In either case, the original treatment schedule should be continued.
Estraderm MX must not be applied to the breasts.
The patch should not be affixed twice in succession to the same site.
The applied patch should not be directly exposed to sunlight or worn in a solarium. Immediately after removal from the pouch, Estraderm MX should be applied to skin sites which will be covered by clothes.
The patch must not be cut or torn.

4.3 Contraindications

Estraderm MX should not be used by women with any of the following conditions:
Known hypersensitivity to estrogens or to any of the excipients.
Known, past or suspected cancer of the breast.
Known or suspected estrogen dependent neoplasia, including cancer of the endometrium.
Undiagnosed abnormal vaginal bleeding.
Severe hepatic impairment.
History of, or current, venous thromboembolism (VTE) (e.g. deep vein thrombosis, pulmonary embolism).
Known thrombophilic disorders or thrombophlebitis.
History of, or current, arterial thromboembolic disease (e.g. coronary heart disease, stroke).
Porphyria.
Acute liver disease, or a history of liver disease as long as liver function tests have failed to return to normal.
Untreated endometrial hyperplasia.
Known or suspected pregnancy.
Breast-feeding.

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.
When initiating estrogen/ progestogen therapy for the prevention of postmenopausal bone mineral density loss in women, careful consideration should be given to the benefits versus the risks for the individual. Potential alternative therapies should be considered if the risks outweigh the benefits. Periodic re-evaluation of continuing treatment is recommended.

Cardiovascular disorders.

Estrogen/ progestogen therapy should not be used for the prevention of cardiovascular disease.
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).
In the estrogen plus progestogen substudy of WHI, an increased risk of coronary heart disease (CHD) events (defined as nonfatal myocardial infarction and CHD death) was observed in women receiving CE + 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.
In the same estrogen plus progestogen substudy of WHI, an increased risk of stroke was observed in women receiving CE + MPA 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 + MPA demonstrated no cardiovascular benefit. During an average follow-up of 4.1 years, treatment with CE + 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 CE + MPA 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 CE + MPA group and the placebo group in HERS, HERS II and overall.

Venous thromboembolism (VTE).

Estrogen-only and combined estrogen-progestogen HRT are associated with a higher risk of developing venous thromboembolism (VTE), e.g. deep vein thrombosis or pulmonary embolism.
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.)
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 + MPA compared to women receiving placebo. The rate of VTE was 34 per 10,000 women-years in the CE + MPA 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.
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.
Generally recognised risk factors for VTE include a personal history (see Section 4.3 Contraindications), a family history of thromboembolic disease (the occurrence of VTE in a direct relative at a relatively early age may indicate genetic predisposition), severe obesity (body mass index > 30 kg/m2) and systemic lupus erythematosus (SLE). The risk of VTE also increases with age. There is no consensus about the possible role of varicose veins in VTE. 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.
A history of recurrent spontaneous abortions should be investigated to exclude thrombophilic predisposition. In patients in whom this diagnosis is confirmed, the use of Estraderm MX is contraindicated.
Patients should be told to contact their doctor immediately if they become aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).
If VTE develops after initiating HRT, the drug should be discontinued.

Ischaemic stroke.

Combined estrogen-progestagen and estrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. 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)).

Malignant neoplasms.

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 estrogen 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 or spotting, and treatment should be re-evaluated. 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.
The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.
Breast cancer. The overall evidence shows an increased risk of breast cancer in women taking combined estrogen-progestagen or estrogen-only HRT, 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 sub study 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. HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer. 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.
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.

Dementia.

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.
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 2.05 (95% CI: 1.21-3.48). The absolute risk of probable dementia for CE + MPA 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.)

Gall bladder disease.

A 2- to 4-fold increase in the risk of gall bladder 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 papilledema or retinal vascular lesions, estrogens should be discontinued.

General precautions.

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 and impairment of glucose tolerance.
Hysterectomised women who require postmenopausal hormone therapy should receive estrogen only hormone replacement therapy unless otherwise indicated (e.g. endometriosis).

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. These patients should be monitored closely.

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.

Angioedema.

Estrogens may induce or exacerbate symptoms of angioedema, in particular in women with hereditary angioedema.

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 progestogen should be considered.

Exacerbation of other conditions.

Estrogen therapy may cause an exacerbation of asthma, diabetes mellitus, epilepsy, migraine or severe headache, porphyria, systemic lupus erythematosus and hepatic hemangiomas and should be used with caution in women with these conditions.
The patient should also be closely monitored if any of the following conditions are present or have occurred previously (including during pregnancy or a previous hormone treatment): leiomyomas (uterine fibroids) or endometriosis, renal or hepatic disorders (e.g. liver adenoma), thromboembolic disorders, heart failure, hypertension, diabetes mellitus with or without vascular involvement, migraine or severe headache, systemic lupus erythematous, past endometriosis, endometrial hyperplasia, epilepsy, asthma, otosclerosis, gall bladder disease, estrogen related jaundice and pruritus.
It should be taken into account that these conditions may recur or be aggravated during treatment with estrogens. If worsening of any of the above conditions is diagnosed or suspected during HRT, the benefits and risks of continuing HRT should be reassessed.
Caution is advised when risk factors for estrogen dependent tumours (e.g. first degree blood relatives who have ever had breast cancer) are present.
Treatment with HRT should be stopped in the following situations: an increase in epileptic seizures, jaundice or deterioration in liver function, a significant increase in blood pressure, new onset of migraine type headache, pregnancy or if a condition described under Section 4.3 Contraindications develops.

Contact sensitisation.

Contact sensitisation is known to occur with all topical drug applications. Although contact sensitisation to any components of the patch is extremely rare, patients who develop it should be warned that a severe hypersensitivity reaction may occur with subsequent exposure to the causative agent.

Severe anaphylactic/ anaphylactoid reactions and angioedema.

Cases of anaphylactic/ anaphylactoid reactions, which developed anytime during the course of Estraderm treatment and required emergency medical management, have been reported in the post-marketing setting. Involvement of skin (urticaria, pruritus, swelling of the face, throat, lips, tongue, skin and periorbital oedema) and either respiratory tract (respiratory compromise) or gastrointestinal tract (abdominal pain, vomiting) has been noted. Angioedema requiring medical intervention involving the eye/ eyelid, face, larynx, pharynx, tongue and extremity (hands, legs, ankles and fingers) with or without urticaria requiring medical intervention has occurred in the post-marketing experience of using Estraderm. If angioedema involves the tongue, glottis, or larynx, airway obstruction may occur. Patients who develop angioedema after treatment with Estraderm should not receive Estraderm again.

Precautions prior to initiation of Estraderm MX therapy.

Before initiating or re-instituting HRT, a complete personal and family medical history, and an appropriate physical (including pelvic and breast) examination should be performed (see Section 4.3 Contraindications; Section 4.4 Special Warnings and Precautions for Use).
Consideration should be given to the lowest dose and the shortest duration of use. Hysterectomized women who require postmenopausal hormone replacement therapy should receive estrogen-only replacement therapy unless otherwise indicated (e.g. endometriosis).
Women should be advised that Estraderm MX is not a contraceptive, nor will it restore fertility.

Monitoring during Estraderm MX therapy.

During treatment, periodic check ups of a nature and frequency adapted to the individual woman are recommended. A careful appraisal of the risks and benefits should be undertaken over time in women treated with HRT and the need for HRT should be re-evaluated periodically.
If any of the following conditions are present or have occurred previously (including during pregnancy or a previous hormone treatment), the woman should be closely monitored, in particular: leiomyoma (uterine fibroids) or endometriosis, thromboembolic disorders, heart failure, hypertension, renal or hepatic (e.g. liver adenoma) disorders, diabetes mellitus with or without vascular involvement, cholelithiasis, migraine or severe headache, systemic lupus erythematosus, endometrial hyperplasia, epilepsy, asthma, otosclerosis, gallbladder disease, estrogen-related jaundice and pruritus.
It should be taken into account that these conditions may recur or be aggravated during treatment with estrogens.
If worsening of any of the above-mentioned conditions is diagnosed or suspected during HRT, the benefits and risks of HRT should be reassessed on an individual basis.
Estrogens may cause fluid retention, and therefore women with cardiac or renal dysfunction should be carefully monitored.
Women with hypertriglyceridaemia should be monitored closely during HRT, since rare cases of large increases in plasma triglycerides leading to pancreatitis have been reported with oral estrogen therapy in these women.
Exogenous estrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
Although observations to date suggest that estrogens, including transdermal estradiol, do not impair carbohydrate metabolism, diabetic women should be monitored during initiation of therapy until further information is available.
Thyroid function should be monitored regularly in patients who require thyroid hormone replacement therapy and who are also taking estrogen in order to ensure that thyroid hormone levels remain within an acceptable range.
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.
Physical (including pelvic and breast) examination should be guided by this and by the contraindications and warnings for use. Women should be advised what changes in their breasts should be reported to their doctor or nurse (see 'Breast cancer' above). 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.

ALT (alanine aminotransferase) 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 combined hormonal contraceptives (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 estrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of women taking these other estrogens, 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).

Discontinuation of Estraderm MX therapy.

Therapy should be discontinued in the following situations: jaundice or deterioration of liver function, a significant increase in blood pressure, new onset of migraine-type headache and pregnancy, or if a condition described under Section 4.3 Contraindications develops.

Use in hepatic impairment.

No studies were performed in patients with hepatic impairment.

Use in renal impairment.

No studies were performed in patients with renal impairment.
All estrogen preparations are contraindicated in patients with severe hepatic impairment (see Section 4.3 Contraindications).

Use in the elderly.

Of the total number of subjects in the estrogen alone substudy of the Women's Health Initiative (WHI) study, 46% (n = 4,943) were 65 years and over, while 7.1% (n = 767) were 75 years and over. There was a higher relative risk (CE vs placebo) of stroke in women less than 75 years of age compared to women 75 years and over.
In the estrogen alone substudy of the 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 alone group, after an average follow-up of 5.2 years, the relative risk (CE versus placebo) of probable dementia was 1.49 (95% CI: 0.83-2.66).
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. There was a higher relative risk (CE + MPA vs placebo) of stroke and invasive breast cancer in women 75 and over compared to women less than 75 years of age.
In the estrogen plus progestogen substudy of WHIMS, a population of 4,532 postmenopausal women, aged 65 to 79 years, was randomised to CE + MPA or placebo. In the estrogen plus progestogen group, after an average follow-up of 4 years, the relative risk (CE + MPA versus placebo) of probable dementia was 2.05 (95% CI: 1.21-3.48).
Pooling the events in women receiving CE or CE + MPA in comparison to those in women on placebo, the overall relative risk for probable dementia was 1.76 (95% CI: 1.19-2.60). 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, Dementia.)

Paediatric use.

Estraderm MX is not to be used in children.

Effects on laboratory tests.

Some laboratory tests may be influenced by estrogen therapy, such as tests for glucose tolerance or thyroid function.

4.5 Interactions with Other Medicines and Other Forms of Interactions

Metabolism of estrogens and progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. carbamazepine, phenytoin, phenobarbital), meprobamate, phenylbutazone and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).
Estradiol is predominantly metabolised by CYP3A4; concomitant administration of inhibitors of CYP3A4 such as ketoconazole, erythromycin or ritonavir may therefore result in an increase of approximately 50% in estradiol exposure.
Caution should be used if the patient is receiving protease inhibitors (e.g. ritonavir and nelfinavir), which are known as strong inhibitors of cytochrome P450 enzymes, and 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 and progestogens.
Clinically, increased metabolism of estrogens and progestogens may lead to decreased effects, and changes in the uterine bleeding profile.

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.

Pharmacodynamic 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 estrogens other than ethinylestradiol, such as estradiol, had a rate of ALT elevation similar to those not receiving any estrogens; however, due to the limited number of women taking these other estrogens, 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).
With transdermal HRT administration, the first-pass effect in the liver is avoided and thus transdermally applied estrogens may be less affected by enzyme inducers than are oral hormones.
Some laboratory tests may be influenced by estrogen therapy, such as tests for glucose tolerance or thyroid function.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

No data available.
(Category B1)
Estrogens must not be used during pregnancy (see Section 4.3 Contraindications). Estrogens may cause foetal harm when administered to pregnant woman. If pregnancy occurs during medication with Estraderm MX treatment should be withdrawn immediately.
 Estraderm MX must not be used while breastfeeding.

4.7 Effects on Ability to Drive and Use Machines

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of this registration.

4.8 Adverse Effects (Undesirable Effects)

Adverse drug reactions from multiple sources including clinical trials and post-marketing experience (Table 1) are listed according to the system organ class in MedDRA. Within each system organ class, the adverse drug reactions are ranked by frequency, the most frequent first. Within each frequency grouping, adverse drug reactions are presented in the order of decreasing seriousness. In addition, the corresponding frequency using the following convention (CIOMS III) is also provided for each adverse drug reaction: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ 1/1,000, < 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000), including isolated reports and not known.
The following other adverse reactions have been reported in association with some estrogen-progestogen treatments:
Estrogen dependent neoplasms, benign and malignant, e.g. endometrial cancer.
Venous thromboembolism, e.g. deep leg or pelvic venous thrombosis and pulmonary embolism.
Cerebrovascular accident.
Myocardial infarction.
Dementia.
Dry eyes.
Tear film composition changes.

Breast cancer risk.

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestagen therapy for more than 5 years.
The increased risk in users of estrogen-only therapy is 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).
Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented.
Largest meta-analysis of prospective epidemiological studies are presented in Tables 2-4.

Endometrial cancer risk.

Postmenopausal women with a uterus.
The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.
In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see Section 4.4 Special Warnings and Precautions for Use).
Depending on the duration of estrogen-only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.
Adding a progestagen to estrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).

Ovarian cancer.

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 50-54 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.

Risk of venous thromboembolism.

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 HT (see Section 4.4 Special Warnings and Precautions for Use). Results of the WHI studies are presented in Table 5:

Risk of coronary artery disease.

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).

Risk of ischaemic stroke.

The use of estrogen-only and estrogen + progestagen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.
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. (See Table 6.)

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 http://www.tga.gov.au/reporting-problems.

4.9 Overdose

Intentional overdosage with Estraderm MX is not likely, due to the pharmaceutical form and method of administration. However, if necessary, it can be reversed by removal of the patch(es). Signs of overdosage may be one or more of the following: breast discomfort, breakthrough bleeding, fluid retention and bloating (see Section 4.2 Dose and Method of Administration). Toxicity is unlikely following acute single exposure; ingestion may cause nausea and vomiting.

Safety note concerning children.

Estraderm MX should be kept out of the reach of children both before and after use. Used systems contain residual estradiol.
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.

Like all steroidal hormones, estrogens exert their metabolic effects intracellularly. In the cells of the target organs, estrogens interact with a specific receptor to form a complex which stimulates both DNA and protein synthesis. Such receptors have been identified in various organs, e.g. the hypothalamus, pituitary, vagina, urethra, uterus, breast and liver, and in osteoblasts.
Estradiol, which in women from the menarche to the menopause is produced mainly by the ovarian follicles, is the estrogen most active at the receptor level. After the menopause, when the ovaries have ceased to function, only a little estradiol is still produced, i.e. from aromatisation of androstenedione and, to a lesser extent, of testosterone by the aromatase enzyme, yielding oestrone and estradiol, respectively. Oestrone is further transformed to estradiol by the enzyme 17β-hydroxysteroid dehydrogenase. Both enzymes prevail in fat, liver and muscle tissue.
In many women, cessation of ovarian estradiol production results in vasomotor and thermoregulatory instability (hot flushes), sleep disturbances and progressive atrophy of the urogenital system. These disorders can be largely eliminated by means of estrogen replacement therapy. Owing to the accelerated loss of bone substance induced by postmenopausal estrogen deficiency, women may develop osteoporosis, particularly of the vertebral column, hip and wrist.
Known risk factors for postmenopausal osteoporosis include early menopause or surgical oophorectomy, prolonged secondary amenorrhoea, prolonged systemic steroid use and a family history of osteoporosis. Women especially at risk are those who are Caucasian, small boned, smokers and live a sedentary lifestyle.
Estraderm MX delivers the major estrogenic hormone secreted by the human ovary, estradiol, through the skin directly into the bloodstream in unchanged form. Estraderm MX raises the blood estradiol concentrations to levels similar to those in the early to midfollicular phase of ovulation and maintains them over the application period. In the plasma, the concentration ratio of estradiol (E2) to oestrone (E1) undergoes a corresponding shift from between 1:5 and 1:2 to approximately 1:1, i.e. to values such as are recorded before the menopause in women with normally functioning ovaries.
Since the amount of estradiol absorbed from Estraderm MX is similar to that absorbed from Estraderm and because Estraderm MX has a smoother concentration time curve than Estraderm, it can be concluded that the pharmacodynamic effects described below are comparable for both types of patches.
Short-term treatment with estrogen replacement therapy perimenopausally has been shown to prevent loss of bone density. This effect has also been shown when Estraderm 100, the transdermal estrogen reservoir patch containing alcohol, is started as late as fifteen years after the menopause. One year treatment with Estraderm 100 prevented further loss of bone mass, without restoring it to premenopausal levels, in 32 postmenopausal women already diagnosed as having fractures (see Section 4.1 Therapeutic Indications).
As yet, there is no evidence of the minimum duration of estrogen replacement therapy for the younger postmenopausal woman which will be effective subsequently in reducing fracture at the age of greatest fracture risk of 75 years of age.
No data are available on the effect of Estraderm MX 25 to prevent postmenopausal bone mineral density loss. Estraderm MX 25 should not be used in this indication.
Following the application of Estraderm for 28 days, no effect has been observed on the concentrations or activity of the blood coagulation factors fibrinopeptide A, high molecular weight fibrinogen and antithrombin III. After this period of 28 days, transdermally administered estradiol did not induce any change in the concentrations either of circulating renin substrate or of the sex hormone binding, thyroxine binding or cortisol binding globulins. It has been found, however, that after only 3 weeks administration, transdermally administered estradiol elicits a dose dependent reduction in urinary excretion of calcium and hydroxyproline.
Administration of transdermal Estraderm to postmenopausal women for up to 3 years has been shown to reduce serum total cholesterol, low density lipoprotein (LDL) cholesterol and triglyceride levels. Increases in high density lipoprotein (HDL) cholesterol have been observed in some short-term studies (6-18 months). However, these changes have been shown in robust studies not to be of clinical benefit (see Section 4.4 Special Warnings and Precautions for Use, Cardiovascular disorders).
Estraderm therapy for 3 months has been shown to reduce fasting insulin levels and increase hepatic clearance.
Regardless of the route of administration, estrogen doses required to relieve menopausal symptoms and conserve bone mass are also a potent stimulus for endometrial mitosis and proliferation. Unopposed estrogens increase the incidence of endometrial hyperplasia and the risk of endometrial carcinoma. With 1 year of unopposed estrogen therapy, endometrial hyperplasia has been found in up to 57% of biopsies. Endometrial hyperplasia also occurs with unopposed transdermal estrogen therapy. Specifically with the higher doses of Estraderm, a high rate of endometrial hyperplasia has also been observed.

Clinical trials.

Women's health initiative (WHI) 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 7.
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 8.
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.)
The estrogen plus progestogen 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 oral conjugated estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day (CE + 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

Within 8 hours after application of Estraderm MX 50 to the skin, steady state plasma estradiol concentrations are reached and remain stable during 4 days. The mean E2 concentration during steady state of Estraderm MX 50 is 41 picogram/mL in healthy postmenopausal women, corresponding to a mean increase of 37 picogram/mL over the mean baseline value of 4 picogram/mL (range 2.1-9.0 picogram/mL). The E2:E1 ratio increases from a postmenopausal value of 0.3 to a value of 1.3, similar to the physiological E2:E1 ratio observed before menopause in women with normally functioning ovaries. During continuous treatment of postmenopausal patients with Estraderm MX twice weekly for 12 weeks, mean E2 plasma concentrations rise by 36 picogram/mL above baseline at the end of the treatment phase, without any indication that accumulation of E2 levels occurs.
With Estraderm MX 25, E2 plasma levels half those observed with Estraderm MX 50 are measured, and with Estraderm MX 100 plasma E2 levels are slightly more than double those measured with Estraderm MX 50. A bioavailability study has provided evidence of bioequivalence between Estraderm MX 75 and Estraderm MX 25 plus Estraderm MX 50 applied simultaneously. These studies showed wide variability between subjects.
While Estraderm MX and Estraderm patches are effective, they are not strictly bioequivalent and they may not necessarily be interchangeable.
Plasma estradiol concentrations return to the baseline value within 24 hours after removal of the system.
The elimination half-life of estradiol in plasma is approximately 1 hour. The metabolic plasma clearance rate ranges from 650 to 900 L/(day x m2). Estradiol is mainly metabolised in the liver. Its most important metabolites are oestriol and oestrone and their conjugates (glucuronides, sulphates); these are far less active than estradiol. The bulk of the conjugates are excreted in the urine. Estrogen metabolites are also subject to enterohepatic circulation.

5.3 Preclinical Safety Data

Genotoxicity.

The toxicity profile of estradiol is well established.

Carcinogenicity.

Long-term, continuous administration of natural and synthetic estrogens in certain animal species increases the frequency of carcinomas of the breast, uterus, cervix, vagina, testis, and liver.

6 Pharmaceutical Particulars

6.1 List of Excipients

Isopropyl palmitate, acrylate, methacrylate, polyethylene terephthalate, ethylene/vinylacetate copolymer and a silicone coating on the inner surface of the protective release liner (discarded before use).

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 25°C.

6.5 Nature and Contents of Container

Pack size.

2 sachets and 8 sachets (sachets are made of paper/LDPE/aluminium/sealing layer laminate).

6.6 Special Precautions for Disposal

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

6.7 Physicochemical Properties

The active ingredient is estradiol or oestra-1,3,5 (10)-triene-3, 17β-diol, the major estrogenic hormone produced by the human ovary.

Chemical structure.


CAS number.

50-28-2.

7 Medicine Schedule (Poisons Standard)

S4 - Prescription Only Medicine.

Summary Table of Changes