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.

What is in this leaflet

This leaflet answers some common questions about the menopause ("change of life"), hormone replacement therapy and Estraderm MX.

It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

The information in this leaflet was last updated on the date listed on the final page. More recent information on the medicine may be available.

You should ensure that you speak to your pharmacist or doctor to obtain the most up to date information on the medicine. You can also download the most up to date leaflet from www.novartis.com.au. Those updates may contain important information about the medicine and its use of which you should be aware.

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

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

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

When you must not use Estraderm MX

Do not use Estraderm MX or other oestrogens, with or without a progestogen to prevent heart attacks, stroke or dementia. A study called the Women's Health Initiative indicated increased risk of heart attack, stroke, breast cancer, and blood clots in the legs or lungs in women receiving treatment with a product containing conjugated oestrogens 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. The Women's Health Initiative Memory Study indicated increased risk of dementia in women aged 65-79 years taking conjugated oestrogens and MPA. There are no comparable data currently available for other doses of conjugated oestrogens and MPA or other combinations of oestrogens and progestogens. Therefore, you should assume the risks will be similar for other medicines containing oestrogen and progestogen combinations.

Talk regularly with your doctor about whether you still need treatment with Estraderm MX. Treatment with oestrogens, with or without progestogens should be used at the lowest effective dose and for the shortest period of time.

What Estraderm MX is used for

Estraderm MX is a type of treatment called hormone replacement therapy (HRT). It is a stick-on patch that contains a hormone called estradiol.

Estraderm MX is used for the short-term relief of symptoms of the menopause. It can also be used to prevent thinning of the bones in women with a high risk of fractures due to osteoporosis who cannot use other treatments.

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

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

How it works

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

The menopause occurs naturally in the course of a woman's life, usually between the ages of 45 and 55. It may happen sooner if the ovaries are removed by surgery (e.g. total hysterectomy). After menopause, your body produces much less oestrogen than it did before. 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 dryness of the vagina causing discomfort during or after sex. Oestrogens can be given to reduce or eliminate these symptoms.

After the age of 40, and especially after the menopause, some women develop osteoporosis. This is a thinning of the bones that makes them weaker and more likely to break, especially the bones of the spine, hip and wrist. Exercise, calcium and vitamin D can help reduce the risk of osteoporosis.

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 oestrogen than would be needed in a tablet and helps to avoid some unpleasant side effects.

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

This medicine is available only with a doctor's prescription. It is not habit-forming.

Before you use Estraderm MX

When you must not use it

Do not use Estraderm MX if you have an allergy to:

  • estradiol, the active ingredient, or to any of the other ingredients listed at the end of this leaflet
  • any other medicine containing oestrogen, including the birth control pill

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 had a severe skin reaction in the past, you could have a very serious reaction if you use any type of oestrogen (patch, tablet, cream, etc.) again in the future.

Do not use Estraderm MX if you have:

  • cancer of the breast or uterus (womb) or any other oestrogen dependent cancer, or you have had this condition in the past
  • blood clots in your blood vessels, now or in the past, or a condition or history of a condition that increases your tendency to get blood clots (such as thromboembolic disease, thrombophilia or thrombophlebitis). You may have had painful inflammation of the veins or blockage of a blood vessel in the legs (for example deep vein thrombosis), lungs, brain or heart
  • endometriosis, which is a disorder where tissue grows outside of the uterus that may cause painful periods and abnormal bleeding
  • untreated endometrial hyperplasia, which is where the lining of the uterus becomes thick, often causing heavy periods and vaginal bleeding
  • abnormal vaginal bleeding that has not been investigated
  • severe liver problems
  • a condition called porphyria, which is a disease that results from a build up of chemicals related to red blood cell proteins

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

Do not use Estraderm MX if you are pregnant or breast-feeding. It may affect your baby. If you become pregnant while taking Estraderm MC, you should stop treatment immediately.

If you still have a uterus (womb), do not use Estraderm MX unless you are also taking another medicine called a progestogen. Women who still have a uterus must take both oestrogen and progestogen as part of HRT. This is because oestrogen stimulates the growth of the lining of the uterus (called the endometrium). Before menopause this lining is removed during your period through the action of a natural progestogen. After menopause, taking oestrogen on its own as HRT may lead to irregular bleeding and to a disorder called endometrial hyperplasia. Your doctor will prescribe a progestogen to protect the lining of the uterus from the effects of oestrogen.

Do not use this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering. In that case, return it to your pharmacist.

Before you start to use it

Tell your doctor if you have:

  • a family history of breast cancer
  • a family history of ovarian or endometrial cancer
  • a family history of, or have ever suffered from a stroke
  • nodules, lumps or cysts in your breasts or any other benign breast condition (not cancer)
  • fibroids or other benign tumours of the uterus (not cancer)
  • had one or more pregnancies where you lost the baby before birth
  • high blood pressure
  • heart disease
  • kidney or liver problems
  • diabetes
  • epilepsy
  • migraine or other severe headaches
  • a disease affecting the eardrum and hearing (otosclerosis)
  • ever suffered from dementia, or have a family history of dementia
  • gall bladder disease
  • asthma
  • a high level of triglycerides in the blood
  • a disorder where the immune system can attack its own tissues called systemic lupus erythematosus (SLE)
  • low levels of thyroid hormone
  • a bone disease causing high calcium levels in the blood
  • very low calcium levels in the blood
  • had a problem in the past with jaundice (a liver problem) or itching skin when you took an oestrogen (e.g. the birth control pill or HRT)
  • a skin condition that could be made worse by applying the patch
  • severe allergic reactions
  • hereditary angioedema or if you have had episodes of rapid swelling of the hands, feet, face, lips, eyes, tongue, throat (airway blockage) or digestive tract

Your doctor may want to take special precautions if you have any of the above conditions.

Your doctor will take a complete personal and family medical history and appropriate physical examinations before you start using Estraderm MX.

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 (SLE)

Taking other medicines

Tell your doctor if you are taking birth control pills. Estraderm MX is not a contraceptive. Since pregnancy may be possible early in the menopause while you are still having menstrual periods, you should ask your doctor to suggest another (non-hormonal) method of birth control.

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

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

  • herbal medicines containing St. John's wort
  • some medicines to help you sleep, including barbiturates and meprobamate
  • some medicines for epilepsy, including phenytoin, lamotrigine, phenobarbitol and carbamazepine
  • phenylbutazone, a medicine for pain and inflammation
  • some antibiotics, including rifampicin, erythromycin and rifabutin
  • medicines for HIV infection, such as nevirapine, efavirenz, ritonavir and nelfinavir
  • medicines for Hepatitis C virus, such as combination regimen ombitasvir/paritaprevir/ritonavir with or without dasabuvir as well as a regimen with glecaprevir/pibrentasvir
  • ketoconazole (an antifungal medicine).

You may need to take different amounts of your medicines or to take different medicines while you are using Estraderm MX. Your doctor and pharmacist have more information.

If you have not told your doctor about any of these things, tell him/her before you start using this medicine.

How to use Estraderm MX

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

If you do not understand the instructions on the label, ask your doctor or pharmacist for help.

When to start it

If you are not already using HRT, you can start Estraderm MX at a convenient time for you. If you are already using a different type of HRT, your doctor can advise you when to switch to Estraderm MX.

How much to use

The patches come in three strengths. To reduce symptoms of the menopause, you will usually start with the Estraderm MX 50 patch. Your doctor will check your progress and may change you to a lower or higher strength, depending on your response to treatment. To prevent thinning of the bones, Estraderm MX 50 or 100 may be suitable.

How to use it

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

You will usually have a patch on all the time. You will apply a new patch twice weekly (every 3 or 4 days). There are 8 patches in the carton, enough for a 4-week cycle.

Estraderm MX can also be used in cycles of 3 weeks of patches and then 1 week with no treatment. Your doctor will advise you on the method that is best for you.

If you have not had a hysterectomy (operation to remove the uterus), you must take another type of hormone called a progestogen as well as using the patches. A progestogen helps to protect the lining of the uterus. If you have not been asked to take a progestogen, talk to your doctor.

How long to use it

If you want to continue using HRT for longer than a few months, discuss the possible risks and benefits with your doctor. Depending on your medical history, your doctor will ensure you use the lowest dose 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. If you have had a hysterectomy but still have your ovaries, there may also be a small increase in the risk of developing cancer of the ovaries. Women taking estrogens alone, or in combination with progestogens, may have a higher risk of ovarian cancer that may appear within 5 years of use and slowly diminishes over time after discontinuation. Your doctor will perform periodic check ups and discuss these risks and benefits with you, taking into account your particular circumstances.

If you forget to use it

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 (Overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26) or go to Accident and Emergency at your nearest hospital, if you think that an overdose has happened. Keep the telephone numbers for these places handy.

Because of the way this medicine is used, an intentional overdose is unlikely. Swallowing a patch may cause nausea and vomiting.

While you are using Estraderm MX

Things you must do

If you become pregnant while using Estraderm MX, tell your doctor immediately. It should not be used while you are pregnant.

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

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.

Tell your doctor that you are using Estraderm MX 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 as a result of an operation, serious injury or having to stay in bed for a prolonged period. If possible, this medicine should be stopped at least 4 weeks before surgery and it should not be restarted until you are fully mobile.

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 doctor, dentist or pharmacist who treats you that you are using Estraderm MX.

Things you must not do

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

Do not give it to anyone else, even if their symptoms seem similar to yours.

Side effects

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are using Estraderm MX.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical treatment if you get some of the side effects.

Do not be alarmed by these lists of possible side effects. You may not experience any of them. Ask your doctor or pharmacist to answer any questions you may have.

Stop using Estraderm and tell your doctor straight away if you experience:

  • difficulty breathing or swallowing, tightness of the chest, shortness of breath or difficulty breathing, hives, general rash, swelling, itching, skin redness, dizziness, changes in level of consciousness, light-headedness, hypotension with or without mild generalised itching, vomiting, abdominal pain (possible signs of a severe allergic reaction)
  • swelling of the face, lips, tongue, throat, the area around the eyes and/or extremities (possible signs of angioedema)

Tell your doctor immediately or go to Accident and Emergency at your nearest hospital if you notice any of the following:

  • 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, sudden loss of coordination, blurred vision or sudden loss of vision, slurred speech, numbness or tingling in an arm or leg, painful swelling in the calves or thighs, chest pain, difficulty breathing, coughing blood
  • pain or tenderness in the abdomen, which may be accompanied by fever, loss of appetite, nausea and vomiting
  • a yellow colour to the skin or eyes, itching, dark coloured urine or light-coloured bowel motions.
  • signs of angioedema: swelling of the face, lips, tongue, throat, and/or extremities.

Tell your doctor if you notice any of the following and they worry you:

  • 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
  • redness, irritation or itching under the patch (signs of application site reaction includes bleeding, bruising, burning, discomfort, dryness, skin boils, oedema, erythema, inflammation, irritation, pain, tiny solid skin bumps, rash, skin discolouration, skin pigmentation, swelling, hives and blisters)
  • itching or inflammation of the vagina
  • pain during sex or when urinating (passing water)
  • palpitations (feeling of fast or irregular heartbeat)
  • swelling of the lower legs, ankles, fingers or abdomen due to fluid retention
  • nausea (feeling sick), abdominal cramps, bloating
  • headache, migraine
  • rise in blood pressure
  • dizziness
  • tiredness, nervousness, irritability, depression, reduced sex drive
  • muscle or nerve pain, leg pain
  • worsening of varicose veins
  • ringing in the ears
  • changes in weight
  • reversible skin discolouration

Tell your doctor if you notice anything else that is making you feel unwell. Some people may have other side effects not yet known or mentioned in this leaflet. Some side effects can only be found when laboratory tests are done. Depending on the severity of the side effects, your doctor may decide for you to stop using Estraderm MX.

After using Estraderm MX

Storage

  • Keep your medicine in the original container until it is time to use it.
  • Store it in a cool dry place.
  • Do not store Estraderm MX or any other medicine in the bathroom or near a sink.
  • Do not leave it in the car or on windowsills.

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

Disposal

Fold used patches in half with the sticky side inwards. Dispose of them where children cannot reach them. Used patches still contain some estradiol which could harm a child.

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

Product description

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

  • Estraderm MX 25 patches are marked CG GRG
  • Estraderm MX 50 patches are marked CG GSG
  • Estraderm MX 75 patches are marked CG HKH
  • Estraderm MX 100 patches are marked CG GTG

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)

Ingredients

Estraderm MX patches release approximately 25, 50, 75 or 100 micrograms estradiol in 24 hours.

The following inactive ingredients are also used to make the patch:

  • isopropyl palmitate
  • acrylate
  • methacrylate
  • polyethylene terephthalate
  • ethylene/vinylacetate copolymer
  • silicone coating on the release liner

Sponsor

Estraderm MX is supplied in Australia by:

Juno Pharmaceuticals Pty Ltd
42 Kelso Street,
Cremorne,
VIC 3121.
www.junopharm.com.au

This leaflet was prepared in
September 2023.

Australian Registration Number.

Estraderm MX 25 AUST R 67089

Estraderm MX 50 AUST R 56658

Estraderm MX 75 AUST R 76117

Estraderm MX 100 AUST R 67090

Published by MIMS November 2023

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