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Cyclo-Progynova 2mg


Cyclo-Progynova 2 mg

Please read this leaflet carefully before you start to take your medicine. This leaflet provides a summary of the information known about your medicine. If you have any questions or are not sure about anything, ask your doctor or pharmacist.

Remember this medicine is for you. Only a doctor can prescribe this medicine and it may harm someone else, even if their symptoms are the same as yours.

About your medicine What is your medicine?

The name of your medicine is Cyclo-Progynova 2 mg.

Each strip of Cyclo-Progynova 2 mg has 11 white tablets containing 2 mg estradiol valerate and 10 pale brown tablets each containing 2 mg estradiol valerate and 500 micrograms of norgestrel.

The active ingredient in this medicine is estradiol. This is the new name for oestradiol. The ingredient itself has not changed.

Cyclo-Progynova 2 mg also contains the following inactive ingredients: lactose, maize starch, povidone, magnesium stearate (E 572), sucrose, polyethylene glycol 6000, calcium carbonate (E 170), glycerin (E 422), talc, montan glycol wax, titanium dioxide (E 171), yellow and red/brown ferric oxide pigments (E 172).

Each pack of Cyclo-Progynova 2 mg contains 1 or 3 memo-packs (strips) of 21 tablets.

Who produces your medicine The product licence is held by: MEDA Pharmaceuticals Ltd Skyway House Parsonage Road Takeley Bishop’s Stortford CM22 6PU This product is manufactured by: Bayer Schering Pharma AG D-13342 Berlin GERMANY What your medicine does and what it is used for

Cyclo-Progynova 2 mg is a hormone replacement therapy that contains the female sex hormones oestrogen and progestogen.

These hormones are lost in women during the "change of life" (also known as "the climacteric"). This is a gradual process which usually takes place between the ages of about 45 and 55. Periods usually become irregular, both in timing and amount of blood loss, before they stop altogether, but the time at which the periods finally stop - "the menopause" – is not the end of the change of life, which always continues for some time afterwards.

Although the change of life is natural, it often causes distressing symptoms such as hot flushes. These symptoms are due to the gradual loss of the female sex hormones produced by the ovaries.

Cyclo-Progynova 2 mg is used to treat symptoms associated with "the change of life".

In addition, the loss of these hormones may, in some women, lead to thinning of the bones (osteoporosis) in later life. If you are likely to develop osteoporosis, and are unable to take other medicines which can prevent osteoporosis, you may be prescribed Cyclo-Progynova 2 mg to prevent osteoporosis. Your doctor will be able to advise you further.

Cyclo-Progynova 2 mg will not make you able to have children, but on the other hand Cyclo-Progynova 2 mg will not prevent you becoming pregnant if you are still fertile.

Before taking your medicine You must not take Cyclo-Progynova 2 mg If you have, or have had, cancer of the breast If you have, or have had, cancer of the or womb If you currently have any problems with your liver If you have vaginal bleeding and the cause is not known If you have a condition called endometrial hyperplasia (where the lining of the womb grows more than normal) and if you are not having treatment for it If you have a blood clot in a vein in your leg or anywhere else (a "deep vein thrombosis") or if you have had one of these in the past If you have a blood clot that has travelled to your lung or another part of the body (an "embolus") or if you have had one of these in the past If you have, or have had, a disease related to blood clots such as angina, or a heart attack If you are allergic to any of the ingredients in Cyclo-Progynova If you have the condition known as porphyria. If you are pregnant, suspect that you are pregnant or if you are breast feeding What you should know before using Cyclo-Progynova

As well as benefits, HRT has some risks which you need to consider when you’re deciding whether to take it, or whether to carry on taking it.

Medical Check-ups

Before starting to take hormone replacement therapy you should discuss your personal and family medical history with your doctor.

Your doctor may decide to perform a physical examination of the breasts and/or a pelvic examination before starting this medication - but only if these examinations are necessary for you, or if you have any special concerns.

Once you’ve started on HRT, you should see your doctor for regular check-ups (at least once a year). At these check-ups, your doctor may discuss with you the benefits and risks of continuing to take HRT.

Before starting to take your medicine you must tell your doctor if you have, or have had any of the following as he may decide to alter your treatment or he may ask to see you more often:-

fibroids in your uterus endometriosis (when the lining of the womb grows outside the womb) a family history of cancer of the breast or womb liver disease diabetes gall stones migraine or severe headaches a condition known as systemic lupus erythematosus a condition called endometrial hyperplasia (where the lining of the womb grows more than normal) epilepsy asthma deafness (otosclerosis) hypertension risk factors that indicate you may experience blood clots. These include being seriously overweight, having blood clotting problems or having a blood clot previously. The full list of these risk factors is provided in the section on Blood clotting below.

Be sure to:

go for regular breast screening and cervical smear tests regularly check your breasts for any changes such as dimpling of the skin, changes in the nipple, or any lumps you can see or feel.

Effects On Your Heart or Circulation

Heart Disease

HRT is not recommended for women who have heart disease, or have had heart disease recently. If you have ever had heart disease, talk to your doctor to see if you should be taking HRT.

HRT will not help to prevent heart disease.

Studies with one type of HRT (containing conjugated oestrogen plus the progestogen MPA) have shown that women may be slightly more likely to get heart disease during the first year of taking the medication.

For other types of HRT, the risk is likely to be similar, although this is not yet certain.

If you get: a pain in your chest that spreads to your arm or neck you must see a doctor as soon as possible. Do not take any more HRT until your doctor says you can. This pain could be a sign of heart disease.

Stroke

Recent research suggests that HRT slightly increases the risk of having a stroke. Other things that can increase the risk of stroke include:

getting older high blood pressure smoking drinking too much alcohol an irregular heartbeat

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

Consider the following:

Looking at women in their 50s who are not taking HRT — on average, over a 5-year period, 3 in 1000 would be expected to have a stroke.

For women in their 50s who are taking HRT, the figure would be 4 in 1000.

Looking at women in their 60s who are not taking HRT — on average, over a 5-year period, 11 in 1000 would be expected to have a stroke.

For women in their 60s who are taking HRT, the figure would be 15 in 1000.

If you get unexplained migraine-type headaches (with or without disturbed vision) you must see a doctor as soon as possible. Do not take any more HRT until your doctor says you can. These headaches may be an early warning sign of a stroke.

Blood Clots

HRT may increase the risk of blood clots in the veins (also called deep vein thrombosis, or DVT), especially during the first year of taking it.

These blood clots are not always serious, but if one travels to the lungs, it can cause chest pain, breathlessness, collapse or even death. This condition is called pulmonary embolism, or PE.

DVT and PE are examples of a condition called venous thromboembolism, or VTE.

You are more likely to get a blood clot:

if you are seriously overweight if you have had a blood clot before if any of your close family have had blood clots if you have had one or more miscarriages if you have any blood clotting problem that needs treatment with a medicine such as warfarin if you’re off your feet for a long time because of major surgery, injury or illness if you have a rare condition called SLE

If any of these things apply to you, talk to your doctor to see if you should take HRT.

Consider the following:

Looking at women in their 50s who are not taking HRT — on average, over a 5-year period, 3 in 1000 would be expected to get a blood clot.

For women in their 50s who are taking HRT, the figure would be 7 in 1000.

Looking at women in their 60s who are not taking HRT — on average, over a 5-year period, 8 in 1000 would be expected to get a blood clot.

For women in their 60s who are taking HRT, the figure would be 17 in 1000.

If you get any of the following:

painful swelling in your leg sudden chest pain difficulty breathing

you must see a doctor as soon as possible. Do not take any more HRT until your doctor says you can. These may be signs of a blood clot.

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

Effects on Your Risk of Developing Cancer

Breast Cancer

Women who have breast cancer, or have had breast cancer in the past, should not take HRT

Taking HRT slightly increases the risk of breast cancer; so does having a later menopause. The risk for a post-menopausal woman taking oestrogen-only HRT for 5 years is about the same as for a woman of the same age who’s still having periods over that time and not taking HRT. The risk for a woman who is taking oestrogen plus progestogen HRT is higher than for oestrogen-only HRT (but oestrogen plus progestogen HRT is beneficial for the endometrium, see ‘Endometrial cancer’ below).

For all kinds of HRT, the extra risk of breast cancer goes up the longer you take it, but returns to normal within about 5 years after stopping HRT. Your risk of breast cancer is also higher:

if you have a close relative (mother, sister or grandmother) who has had breast cancer if you are seriously overweight

Consider the following:

Looking at women aged 50 who are not taking HRT – on average 32 in 1000 will have breast cancer diagnosed by the age of 65.

For women who start taking oestrogen-only HRT at age 50 and take it for 5 years, the figure will be between 33 and 34 in 1000 (ie an extra 1-2 cases). If they take oestrogen-only HRT for 10 years, the figure will be 37 in 1000 (i.e. an extra 5 cases).

For women who start taking oestrogen plus progestogen HRT at age 50 and take it for 5 years, the figure will be 38 in 1000 (ie an extra 6 cases). If they take oestrogen plus progestogen HRT for 10 years, the figure will be 51 in 1000 (i.e. an extra 19 cases).

If you notice any changes in your breast, such as:

dimpling of the skin changes in the nipple any lumps you can see or feel

you must make an appointment to see your doctor as soon as possible.

Endometrial cancer (cancer of the lining of the womb)

Taking oestrogen-only HRT for a long time can increase the risk of cancer of the lining of the womb (the endometrium). Taking a progestogen as well as the oestrogen helps to lower the extra risk.

If you still have your womb, your doctor may prescribe a progestogen as well as oestrogen. If so, these may be prescribed separately, or as a combined HRT product.

If you have had your womb removed (a hysterectomy), your doctor will discuss with you whether you can safely take oestrogen without a progestogen.

If you’ve had your womb removed because of endometriosis, any endometrium left in your body may be at risk. If so, your doctor may prescribe HRT that includes a progestogen as well as an oestrogen.

Your product, Cyclo-Progynova 2 mg contains a progestogen.

Consider the following:

Looking at women who still have a uterus and who are not taking HRT – on average 5 in 1000 will be diagnosed with endometrial cancer between the ages of 50 and 65.

For women who take oestrogen-only HRT, the number will be 2 to 12 times higher, depending on the dose and how long you take it.

The addition of a progestogen to oestrogen-only HRT substantially reduces the risk of endometrial cancer.

If you get breakthrough bleeding or spotting, it’s usually nothing to worry about, especially during the first few months of taking HRT.

But if the bleeding or spotting:

carries on for more than the first few months starts after you’ve been on HRT for a while carries on even after you’ve stopped taking HRT

you must make an appointment to see your doctor. It could be a sign that your endometrium has become thicker.

Ovarian cancer

Ovarian cancer (cancer of the ovaries) is very rare, but it is serious.

It can be difficult to diagnose, because there are often no obvious signs of the disease.

Some studies have indicated that taking oestrogen-only HRT for more than 5 years may increase the risk of ovarian cancer. It is not yet known whether other kinds of HRT increase the risk in the same way.

What about other medicines that you may be taking?

Some medicines affect the way that drugs are handled by the liver and may reduce the effectiveness of Cyclo-Progynova 2 mg. These include some epilepsy medicines (for example phenytoin, phenobarbital and carbamazepine), and some antibiotics/anti-infectives (for example rifampicin, rifabutin, nevirapine, efavirenz, ritonavir, nelfinavir) and the herbal preparation, St John’s Wort.

If you are taking oral contraceptives, these should be stopped and other, non-hormonal methods of contraception should be used.

If you are a diabetic on insulin or tablets, your daily dose might need to be changed, your doctor will advise you.

What about food and drink?

Cyclo-Progynova 2 mg is not known to react with any types of food and drink.

What to do if you see a different doctor or have to go to hospital for treatment.

If you see any other doctor or go to hospital for treatment, tell your doctor about all your medicines, including Cyclo-Progynova 2 mg.

Special warnings

Lactose

This product contains lactose. If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.

You should stop taking your tablets and tell your doctor if you:

develop any of the conditions listed in this leaflet under "You must not take Cyclo-Progynova". start developing headaches or migraines develop jaundice or problems with your liver become pregnant experience pain, tingling or numbness in any part of the body experience sudden chest pain

Cyclo-Progynova 2 mg must also be stopped at once if your doctor finds your blood pressure to be significantly raised.

Taking your medicine How to take your Cyclo-Progynova 2 mg

It is usually recommended that Cyclo-Progynova is taken at the lowest dose which is effective and for the shortest time possible.

About the pack:

The pack of Cyclo-Progynova 2 mg is designed to help you take your tablets. To use it you must first know the day of the week on which you will take the first tablet. If you are still having your periods, take the first tablet on the fifth day of your period, whether the period has finished or not. If your periods have become infrequent or have stopped altogether, your doctor may have advised you to start Cyclo-Progynova 2 mg immediately. If you have been taking a continuous HRT product (i.e. you take the same dose each day) you may change to Cyclo-Progynova 2 mg on any day. If you have been taking an HRT product which is followed by a withdrawal bleed, you should complete the cycle of treatment before changing to Cyclo-Progynova 2 mg.

In addition to the memo-pack (which contains the tablets), the outer carton contains a self adhesive blue sticker showing the days of the week. Peel the circular sticker off its backing and stick it in the centre of the memo-pack so that the day on which you start taking the tablets is directly underneath the red segment marked 'Start'.

For instance, if you are to start the tablets on a Wednesday, then stick a 'Wed' directly underneath the red segment marked 'Start'. You can now see on which day you have to take each tablet. Simply take one tablet each day, following the direction of the arrows on the foil, until the pack is empty. This means that you will be taking one white tablet for the first 11 days and then one pale brown tablet daily for the following 10 days. If, at any time, you are in doubt whether you have taken your tablet, a glance at the appropriate day on the memo-pack will tell you.

When you have finished taking your pack, you must leave a tablet free interval of seven days (unless your doctor decides otherwise). During this week, bleeding similar to a period may occur. This is normal.

Start your next pack of Cyclo-Progynova 2 mg immediately after this seven day break, whether the bleeding has stopped or not. You will in fact start on the same day of the week that you started your previous pack and the same will be true for each successive pack.

It is best to take your tablet at the same time each day, preferably after a meal. The tablet should not be chewed or sucked, but swallowed whole with a glass of water.

What to do if you forget to take a tablet

Take it as soon as possible, and take the next one at your normal time. If you are more than twelve hours late, leave the forgotten tablet in the pack. Continue to take the remaining tablets at the usual time on the right days.

You may experience some vaginal bleeding (breakthrough bleeding) if you have missed a tablet. This is normal.

What to do if you take too many tablets at once

There have been no reports of ill effects from taking too many tablets.

You should consult your doctor who will be able to advise you what action, if any, is necessary.

What bleeding to expect (what to do if your bleeding pattern seems different)

Just as with normal periods, the amount of bleeding with Cyclo-Progynova 2 mg varies from woman to woman. Usually the blood loss is not unduly heavy and it may even be rather scanty, but this is not important as far as the treatment is concerned. If you have recently had very light, short periods, you may have rather heavier blood loss with Cyclo-Progynova 2 mg.

If you are still menstruating, you will probably have regular blood loss 2 – 3 days after finishing each pack of Cyclo-Progynova 2 mg. If you miss a period, the possibility of pregnancy should be investigated.

Ask your doctor for advice.

If you have stopped having periods, Cyclo-Progynova 2 mg will probably cause you to experience blood loss again after the end of each pack, but may not always do so.

If blood loss occurs during the three weeks in which you are taking the tablets, let your doctor know. This may be a sign that your endometrium is getting thicker (see section on Endometrial Cancer in this leaflet). It is not necessary to stop taking your tablets unless your doctor tells you to.

After taking your medicine

During the first few months of treatment you may experience some vaginal bleeding at unexpected times (breakthrough bleeding and spotting) and some breast tenderness or enlargement. These symptoms are usually temporary and normally disappear with continued treatment. If they don't, contact your doctor.

All women have a small chance of having a blood clot in the veins of the leg, in the lung or other parts of the body whether or not they take HRT. If you think you have developed a blood clot while you are taking Cyclo-Progynova 2 mg you should stop taking it immediately and contact your doctor. The warning signs to look out for are listed in this leaflet in the section on Blood Clots under What you should know before taking Cyclo-Progynova.

The following symptoms have been reported: indigestion, nausea, vomiting, bloated stomach, increased appetite, increased or reduced weight, leg pains, fluid retention, palpitations, dizziness, anxiety, headaches, depressive moods, rashes, altered sexual interest. Tell your doctor if you have any of these symptoms, or, indeed, any other symptoms while you are taking Cyclo-Progynova 2 mg.

If you have any of the symptoms of heart disease, stroke or blood clots, breast, endometrial or ovarian cancer, as described earlier in this leaflet, tell your doctor.

Dementia: HRT will not prevent memory loss. In one study of women who started using combined HRT after the age of 65, a small increase in the risk of dementia was observed.

How to store your medicine

Keep your medicine in a safe place where children cannot see or reach it. Your medicine could harm them.

Do not use your medicines after the expiry date on the box, even if there is some medicine left after this date. Ask your doctor for a replacement prescription.

This leaflet was amended in November 2007

Cyclo-Progynova is a registered trademark of Schering AG.

© MEDA

United Kingdom 80620633_1107


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Progynova TS 50


Due to regulatory changes, the content of the following Patient Information Leaflet may vary from the one found in your medicine pack. Please compare the 'Leaflet prepared/revised date' towards the end of the leaflet to establish if there have been any changes.

If you have any doubts or queries about your medication, please contact your doctor or pharmacist.

Progynova TS 50 micrograms/24 hours transdermal patch

(estradiol)

Please read all of this booklet carefully before you start taking your medicine Keep this booklet as you may need to read it again. If you have further questions, please ask your doctor or your pharmacist. This medicine has been prescribed for you personally. It is not suitable for all women, so you should not give it to anyone else as it may harm them. This medicine is called ‘Progynova TS 50 micrograms/24 hours transdermal patch’ but will be referred to as ‘Progynova TS 50’ throughout this booklet. Contents What Progynova TS 50 is and what it is used for What does Progynova TS 50 contain? What kind of medicine is Progynova TS 50? What is Progynova TS 50 used for?
Before you use Progynova TS 50
Reasons for not using Progynova TS 50
What you should know before using Progynova TS 50 Medical check-ups Effects on your heart or circulation Effects on your risk of developing cancer Other important information What to do if you are taking other medicines at the same time as Progynova TS 50
How to use Progynova TS 50 To apply Progynova TS 50 What to do if a patch falls off What to do if you forget a patch What to do if you use too many patches
Possible side effects
Reasons for stopping Progynova TS 50
How to store Progynova TS 50 What Progynova TS 50 is and what it is used for

The name of your treatment is Progynova TS 50.

What does Progynova TS 50 contain?

Progynova patches are oval transparent patches with a self-adhesive backing, which can be stuck to the skin.

Progynova TS 50 is a patch with an area of 12.5 square centimetres containing 3.8 milligrams of estradiol, an oestrogen, (formed from 3.9 milligrams estradiol hemihydrate). Your body will absorb about 50 micrograms of estradiol each day whilst you are wearing a Progynova TS 50 patch.

Inactive ingredients: ethyl oleate, isopropyl myristate and glycerol monolaurate. The adhesive system is an acrylate/acrylamide/vinyl acetate copolymer.

Packs containing either 4 or 12 patches are available. Each sealed pouch contains one Progynova TS 50 patch.

What kind of medicine is Progynova TS 50?

Progynova TS 50 patches are a form of oestrogen replacement therapy.

What is Progynova TS 50 used for?

Progynova TS 50 is used to treat symptoms of the menopause in women who are at least one year past their last menstrual period. The patches contain the hormone oestrogen which is absorbed through your skin and into the blood stream. They can therefore relieve the symptoms caused by the loss of your own oestrogen. Your doctor will aim to prescribe the lowest dose that controls your symptoms.

Thinning of the bones (osteoporosis) can occur after the menopause. In some women this can lead to fractures of the wrist, spine or hip in later life. You may be able to use Progynova TS 50 to prevent this if you are unable to take other treatments or they haven’t worked for you. Your doctor will be able to advise you further.

Because it only contains one of the female sex hormones, Progynova TS 50 is not suitable to be used alone for women who have not previously had a hysterectomy. You will need to take another hormone, progestogen, as well as Progynova TS 50 if this is the case. Your doctor will be able to advise you about this. (See “Effects on your risk of developing cancer” for more information).

The product licence for Progynova TS 50 is held by: Bayer plc Bayer House Strawberry Hill Newbury Berkshire RG14 1JA

Product Licence number:

PL 00010/0560

Progynova TS 50 is made by: 3M Pharmaceuticals Northridge California USA

Batch release in the EU by

Schering GmbH and Co. Productions KG Germany Before you use Progynova TS 50 Reasons for not using Progynova TS 50

You must not use Progynova TS 50 if you have any of the following:

a blood clot in a vein in your leg or anywhere else (a “deep vein thrombosis”) or a blood clot that has travelled to your lung or another part of the body (an “embolus”) or have had one of these in the past angina (severe chest pain), or if you have recently had a heart attack the rare inherited disorder porphyria a hormone dependent tumour e.g. cancer of the lining of the womb (endometrial cancer) breast cancer, or have had this in the past if you have an allergy to any of the ingredients. Tell your doctor if: you are pregnant or breast feeding you have liver disease or have had this in the past you have irregular or unusually heavy periods you have endometrial hyperplasia (changes to the lining of the womb which may cause heavy vaginal bleeding) or have had this in the past

as these may mean that Progynova TS 50 is not suitable for you.

What you should know before using Progynova TS 50

As well as benefits, HRT has some risks which you need to consider when you’re deciding whether to take it, or whether to carry on taking it.

Medical check-ups

Before you start taking HRT, your doctor should ask about your own and your family’s medical history. Your doctor may decide to examine your breasts and/or your abdomen, and may do an internal examination — but only if these examinations are necessary for you, or if you have any special concerns.

Once you’ve started on HRT, you should see your doctor for regular check-ups (at least once a year). At these check-ups, your doctor may discuss with you the benefits and risks of continuing to take HRT.

Make sure you:

go for regular breast screening and cervical smear tests regularly check your breasts for any changes such as dimpling of the skin, changes in the nipple, or any lumps you can see or feel.

Certain diseases sometimes get worse when you are taking hormone replacement therapy.

So tell your doctor if you suffer from: fibroids of the womb endometriosis (lining of the womb growing in the wrong place causing pain or bleeding) risk factors for getting blood clots (see “Effects on your heart or circulation – blood clots” for more information) risk factors for hormone dependent tumours (see “Effects on your risk of developing cancer high blood pressure diabetes gall stones migraine or severe headaches systemic lupus erythematosus – SLE (a disease affecting the skin all over the body) epilepsy asthma inherited deafness (otosclerosis) heart or kidney problems a blood-fat disorder called hypertriglyceridaemia hereditary angioedema (episodes of swelling of body parts)

These may mean that your doctor will need to check you more closely.

If you are not sure whether any of these apply to you, ask your doctor. If any of these conditions appear during your use of Progynova TS 50, contact your doctor for advice. Effects on your heart or circulation

Heart disease

HRT is not recommended for women who have heart disease, or have had heart disease recently. If you have ever had heart disease, talk to your doctor to see if you should be taking HRT. HRT will not help to prevent heart disease.

Studies with one type of HRT (containing conjugated oestrogen plus the progestogen MPA) have shown that women may be slightly more likely to get heart disease during the first year of taking the medication. For other types of HRT, the risk is likely to be similar, although this is not yet certain.

If you get:

a pain in your chest that spreads to your arm or neck See a doctor as soon as possible and do not take any more HRT until your doctor says you can. This pain could be a sign of heart disease.

Stroke

Recent research suggests that HRT slightly increases the risk of having a stroke. Other things that can increase the risk of stroke include:

getting older high blood pressure smoking drinking too much alcohol an irregular heartbeat.

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

Compare

Looking at women in their 50s who are not taking HRT — on average, over a 5-year period, 3 in 1000 would be expected to have a stroke.

For women in their 50s who are taking HRT, the figure would be 4 in 1000.

Looking at women in their 60s who are not taking HRT — on average, over a 5-year period, 11 in 1000 would be expected to have a stroke.

For women in their 60s who are taking HRT, the figure would be 15 in 1000.

If you get:

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

Blood clots

HRT may increase the risk of blood clots in the veins (also called deep vein thrombosis, or DVT), especially during the first year of taking it.

These blood clots are not always serious, but if one travels to the lungs, it can cause chest pain, breathlessness, collapse or even death. This condition is called pulmonary embolism, or PE.

DVT and PE are examples of a condition called venous thromboembolism, or VTE.

You are more likely to get a blood clot:

if you are seriously overweight if you have had a blood clot before if any of your close family have had blood clots if you have had one or more miscarriages if you have any blood clotting problem that needs treatment with a medicine such as warfarin if you’re off your feet for a long time because of major surgery, injury or illness if you have a rare condition called SLE.

If any of these things apply to you, talk to your doctor to see if you should take HRT.

Compare

Looking at women in their 50s who are not taking HRT — on average, over a 5-year period, 3 in 1000 would be expected to get a blood clot.

For women in their 50s who are taking HRT, the figure would be 7 in 1000.

Looking at women in their 60s who are not taking HRT — on average, over a 5-year period, 8 in 1000 would be expected to get a blood clot.

For women in their 60s who are taking HRT, the figure would be 17 in 1000.

If you get:

painful swelling in your leg sudden chest pain difficulty breathing. See a doctor as soon as possible and do not take any more HRT until your doctor says you can. These may be signs of a blood clot.

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

Effects on your risk of developing cancer

Breast cancer

Women who have breast cancer, or have had breast cancer in the past, should not take HRT.

Taking HRT slightly increases the risk of breast cancer; so does having a later menopause. The risk for a post-menopausal woman taking oestrogen-only HRT for 5 years is about the same as for a woman of the same age who is still having periods over that time and not taking HRT. The risk for a woman who is taking oestrogen plus progestogen HRT is higher than for oestrogen-only HRT (but oestrogen plus progestogen HRT is beneficial for the lining of the womb (endometrium), see “Endometrial cancer” below).

For all kinds of HRT, the extra risk of breast cancer goes up the longer you take it, but returns to normal within about 5 years after stopping.

Your risk of breast cancer is also higher:

if you have a close relative (mother, sister or grandmother) who has had breast cancer if you are seriously overweight.

Compare

Looking at women aged 50 who are not taking HRT — on average, 32 in 1000 will be diagnosed with breast cancer by the time they reach the age of 65.

For women who start taking oestrogen-only HRT at age 50 and take it for 5 years, the figure will be between 33 and 34 in 1000 (ie an extra 1 – 2 cases).

If they take oestrogen-only HRT for 10 years, the figure will be 37 in 1000 (ie an extra 5 cases).

For women who start taking oestrogen plus progestogen HRT at age 50 and take it for 5 years the figure will be 38 in 1000 (ie an extra 6 cases)

If they take oestrogen plus progestogen HRT for 10 years, the figure will be 51 in 1000 (ie an extra 19 cases).

If you notice any changes in your breast, such as:

dimpling of the skin changes in the nipple any lumps you can see or feel Make an appointment to see your doctor as soon as possible.

Endometrial cancer (cancer of the lining of the womb)

Taking oestrogen-only HRT for a long time can increase the risk of cancer of the lining of the womb (the endometrium). Taking a progestogen as well as the oestrogen helps to lower the extra risk.

If you still have your womb, your doctor may prescribe a progestogen as well as oestrogen. If so, these may be prescribed separately, or as a combined HRT product.

If you have had your womb removed (a hysterectomy), your doctor will discuss with you whether you can safely take oestrogen without a progestogen.

If you’ve had your womb removed because of endometriosis, any endometrium left in your body may be at risk. So your doctor may prescribe HRT that includes a progestogen as well as an oestrogen.

Your product, Progynova TS 50 contains only oestrogen.

Compare

Looking at women who still have a uterus and who are not taking HRT – on average 5 in 1000 will be diagnosed with endometrial cancer between the ages of 50 and 65.

For women who take oestrogen-only HRT the number will be between 10 and 60 in 1000 depending on the dose and for how long it is taken.

The addition of a progestogen to oestrogen-only HRT substantially reduces the risk of endometrial cancer.

If you get breakthrough bleeding or spotting, it’s usually nothing to worry about, especially during the first few months of taking HRT.

But if the bleeding or spotting:

carries on for more than the first few months starts after you’ve been on HRT for a while carries on even after you’ve stopped taking HRT Make an appointment to see your doctor. It could be a sign that your endometrium has become thicker.

Ovarian cancer

Ovarian cancer (cancer of the ovaries) is very rare, but it is serious. It can be difficult to diagnose, because there are often no obvious signs of the disease.

Some studies have indicated that taking oestrogen-only HRT for more than 5 years may increase the risk of ovarian cancer. It is not yet known whether other kinds of HRT increase the risk in the same way.

Other important information

The use of hormone replacement therapy may affect the results of certain laboratory tests. Always tell your doctor or the laboratory staff that you are using hormone replacement therapy.

Brown patches on your face and body (chloasma) may occasionally occur, especially if you experienced this during a previous pregnancy. You can reduce this by not staying in the sun too long and by not using sunbeds or sunlamps.

HRT will not prevent memory loss. A study with one type of HRT (containing conjugated oestrogen plus the progestogen MPA) showed that women who started using this HRT after the age of 65 had a small increase in their risk of developing dementia. It is not known if this applies to other types of HRT or to younger women.

Progynova TS 50 is not a contraceptive. If there is any possibility that you may become pregnant ask your doctor for contraceptive advice. It is important that you use a reliable form of non-hormonal contraception such as a condom or cap plus spermicide. Oral contraceptives should not be used.

What to do if you are taking other medicines at the same time as Progynova TS 50

Some medicines may stop Progynova TS 50 from working properly and other medicines will be affected by Progynova TS 50.

Tell your doctor if you have to take any other medicines regularly, especially: medicines used to treat epilepsy or other illnesses, such as phenobarbitol, phenytoin, carbamazepine medicines used to treat certain infections, such as rifampicin, rifabutin, nevirapine, efavirenz medicines used to treat HIV infections, such as ritonavir, nelfinavir the herbal remedy commonly known as St John’s wort (Hypericum perforatum).

If in doubt about any medicines you are taking, ask your doctor or pharmacist.

How to use Progynova TS 50

If you are not currently using hormone treatment, or you use a type that does not cause a regular monthly bleed, you can start to use Progynova TS 50 immediately.

If you are changing from another type of hormone replacement therapy that causes a monthly bleed, you may be told to start Progynova TS 50 the day after stopping your treatment or when your doctor has told you to.

If you are changing from a 3-week on, 1-week off, type of hormone replacement therapy you may be told to start Progynova TS 50 the day after the treatment-free period (1-week off).

If you have not had a hysterectomy, your doctor may have prescribed a progestogen separately in addition to Progynova TS 50. Follow your doctor’s instructions.

To apply Progynova TS 50: the patch should be applied to a clean, dry area of skin preferably on the stomach or buttocks. Progynova TS 50 must not be applied on or near the breasts. The area chosen should not be oily, damaged or irritated, and the waistline should be avoided since tight clothing may rub the patch off.

Take the patch out of its packaging. Remove the protective liner. The patch should then immediately be pressed firmly in place with the palm of the hand for about 10 seconds. Make sure there is good contact with the skin; especially around the edges.

The patch should be left in place for 7 days, then removed and replaced with a new patch which should be applied to a different area.

Although the patches should usually be applied continuously, your doctor may tell you to apply the patches on a cyclical basis. In this case, a patch should be applied weekly for 3 weeks followed by a 7 day interval without a patch application before the next course.

You will be able to bath or shower as normal while wearing a patch. However, the patch may fall off in very hot water or in a sauna.

After use, Progynova TS 50 patches still contain large amounts of the active ingredient estradiol. Take care when throwing away used and unused patches. Fold patches in half with the sticky sides together and throw away with your dustbin waste. Patches must not be flushed down the toilet.

What to do if a patch falls off

If a patch falls off before 7 days are up, it may be reapplied. If necessary a new patch may be used if it is not possible to reattach the old patch properly. If a new patch is used it should be kept on for the remainder of the 7 days and then changed on your usual day for applying a new patch.

What to do if you forget a patch

If you forget to put a patch on, put it on as soon as you remember and keep it on for 7 days before replacing with a new patch. If you are several days late in changing your patch, you may get some light vaginal bleeding (spotting) at unexpected times.

What to do if you use too many patches

If you use too many patches, it is unlikely to cause you any serious problems but you may feel sick, actually be sick or have some vaginal bleeding. If you are worried, talk to your doctor or pharmacist who can tell you what, if anything, you need to do.

Possible side effects

The most frequently reported reactions during the first few months of treatment are breast tenderness or enlargement or vaginal bleeding at unexpected times (breakthrough bleeding or spotting). These are usually temporary and normally disappear with continued treatment.

Below we list other possible side effects by how likely they are to occur:

Common

Between 1 and 10 in every 100 people are likely to get these:

Pain; excessive gas or belching; feeling sick; swelling caused by build up of fluid in arms, legs or other parts of the body; weight gain; depression; dizziness; nervousness; feeling sluggish; headache; increased sweating; hot flushes; itchy rash which may be around the patch; changes to menstrual bleeding; vaginal discharge; vaginal and genital problems.

Uncommon

Less than 1 in every 100 people are likely to get these:

Feeling weak, tired or generally unwell; abnormal laboratory tests; fever, flu-like symptoms; migraine; fast or irregular heartbeats (palpitations); inflamed and itchy veins, usually in the legs (phlebitis); increased blood pressure; increased appetite; constipation; diarrhoea; back passage problems; high level of blood fats (cholesterol); joint problems and muscle cramps; difficulty breathing; runny nose; trouble sleeping; mood changes; problems concentrating; pins and needles; changes to sex drive; shaking or tremor; loss of hair, excessive hair growth; lumpy, enlarged or tender breasts; skin rashes; acne; dry skin or small skin swelling; nail problems; problems with frequency and control of urine; discoloured urine; blood in urine; changes to the lining of the womb which may cause heavier vaginal bleeding; bladder infections (cystitis); dry eyes; eyesight problems.

Rare

Less than 1 in every 1000 people are likely to get these::

Stomach pain or bloating; yellowing of the skin or eyes (jaundice); inflammatory skin rashes; breast pain; fibroids.

Other side effects reported with HRT include:

The risk of breast cancer increases with the number of years of using HRT. Cancer of the lining of the womb (endometrial cancer) has also been reported. See “Effects on your risk of developing cancer” for more information.

Blood clots, heart attacks and stroke (see “Effects on your heart or circulation” for more information); dementia , increased skin pigment especially on the face (chloasma) (see “Other important information” for more information); some rare skin problems and gall bladder disease.

Worsening of hereditary angioedema with swelling of the skin and/or mucous membranes such as swollen face, lips, tongue and/or throat and/or difficulty swallowing or hives together with difficulty breathing.

Tell your doctor if you have any of the symptoms listed above, or indeed any other new symptoms during treatment. Also tell your doctor if you have any of the symptoms listed under “Reasons for stopping Progynova TS 50”. Reasons for stopping Progynova TS 50 Stop treatment (remove the patch) at once and talk to your doctor immediately if you have any of the following: your very first attack of migraine (typically a throbbing headache and nausea preceded by visual disturbances); if you get a blood clot – see the section “Blood clots” on for warning signs of a blood clot. you have difficulty breathing or have worsening of hereditary angioedema. Stop treatment (remove the patch) at once and talk to your doctor as soon as you can if you have any of the following: if you become pregnant if you develop jaundice (get yellowing of the skin or eyes) if you develop any of the conditions listed under “Reasons for not using Progynova TS 50” . Your doctor may decide that you should stop using Progynova TS 50 if: your liver function tests become abnormal there is a significant rise in your blood pressure you are off your feet for a long time because of major surgery, injury or illness. See also the section “Blood clots” on, especially if you are going to have an operation. How to store Progynova TS 50

Store your patches in the original packaging in order to protect from moisture.Store below 30?C.

Keep your patches in a safe place where children cannot see or reach them.

Do not use the patches after the expiry date that is shown on the box.

Date of last revision of this booklet: May 2008

Progynova is a registered trademark of Bayer Schering Pharma AG (formerly Schering AG).


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Progynova TS 100 micrograms / 24 hours Transdermal Patch


1. Name Of The Medicinal Product

Progynova® TS 100 micrograms/24 hours Transdermal Patch

2. Qualitative And Quantitative Composition

Each 25 cm2 patch contains 7.6 mg estradiol (formed from 7.8 mg estradiol hemihydrate), releasing a nominal 100 micrograms of estardiol per 24 hours.

For excipients, see 6.1.

3. Pharmaceutical Form

Transdermal patch

Oval transdermal patch with a translucent homogenous matrix on a transparent carrier film.

4. Clinical Particulars 4.1 Therapeutic Indications

• Hormone replacement therapy for oestrogen deficiency symptoms in postmenopausal women more than 1 year postmenopause.

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

(See also Section 4.4)

4.2 Posology And Method Of Administration

• Posology

Progynova TS 100 is an oestrogen-only patch applied to the skin once weekly.

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used. Treatment to control menopausal symptoms should be initiated with the lowest Progynova TS patch dose. If considered necessary, a higher dosed patch should be used. Once treatment is established the lowest effective dose patch necessary for relief of symptoms should be used.

For prevention of postmenopausal osteoporosis Progynova TS 50 is recommended. Women receiving Progynova TS 100 for postmenopausal symptoms can continue at this dose.

In women with an intact uterus, a progestogen should be added to Progynova TS 100 for at least 12-14 days each month. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women.

For continuous use: The patches should be applied once weekly on a continuous basis, each used patch being removed after 7 days and a fresh patch applied to a different site.

For cyclical use: The patches may also be prescribed on a cyclical basis. Where this is the preferred option, the patches should be applied weekly for 3 consecutive weeks followed by a 7-day interval, without a patch being applied, before the next course.

• How to start Progynova TS 100

Women who do not take oestrogens or women who change from a continuous combined HRT product may start treatment at any time.

Patients changing from a continuous sequential HRT regimen, should begin the day following completion of the prior regimen.

Patients changing from a cyclic HRT regimen should begin the day after the treatment-free period.

• Missed or lost patch

In the event that a patch falls off before 7 days are up, it may be reapplied. If necessary, a new patch should be applied for the remainder of the 7-day dosing interval.

If the patient forgets to replace a patch, this should be done as soon as possible after she remembers it. The next patch has to be used after the normal 7-day interval.

After several days without replacement of a new patch there is an increased likelihood of breakthrough bleeding and spotting.

• Mode of application

Following removal of the protective liner the adhesive side of Progynova TS patches should be placed on a clean, dry area of the skin of the trunk or buttocks. Progynova TS patches should not be applied to the breasts. The sites of application should be rotated, with an interval of at least one week between applications to a particular site. The area selected should not be oily, damaged, or irritated. The waistline should be avoided since tight clothing may rub the patch off. The patch should be applied immediately after opening the pouch and removing the protective liner. The patch should be pressed firmly in place with the palm of the hand for about 10 seconds, making sure there is good contact, especially around the edges.

The patch should be changed once weekly.

If the patch is applied correctly, the patient can bath or shower as usual. The patch might, however, become detached from the skin in very hot bath water or in the sauna.

Children

Not recommended for children

4.3 Contraindications

• Known, past or suspected breast cancer

• Known or suspected oestrogen dependent malignant tumours, e.g. endometrial cancer

• Undiagnosed genital bleeding

• Untreated endometrial hyperplasia

• Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)

• Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction)

• Acute liver disease, or history of liver disease as long as liver function tests have failed to return to normal

• Porphyria

• Known hypersensitivity to the active substance or any of the excipients

4.4 Special Warnings And Precautions For Use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken al least annually and HRT should only be continued as long as the benefit outweighs the risk.

Medical examination/follow up:

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

Conditions which need supervision

• If any of the following conditions are present, have occurred previously, and/or have been aggravated during pregnancy or previous hormone treatment, the patient should be closely supervised. It should be taken into account that these conditions may recur or be aggravated during treatment with Progynova TS 100, in particular:

- Leiomyoma (uterine fibroids) or endometriosis

- A history of, or risk factors for, thromboembolic disorders (see below)

- Risk factors for oestrogen dependent tumours, e.g. 1 st degree heredity for breast cancer

- Hypertension

- Liver disorders (e.g. liver adenoma)

- Diabetes mellitus with or without vascular involvement

- Cholelithiasis

- Migraine or (severe) headache

- Systemic lupus erythematosus.

- A history of endometrial hyperplasia (see below)

- Epilepsy

- Asthma

- Otosclerosis

- Hereditary angioedema

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contra-indication is discovered and in the following situations:

- Jaundice or deterioration in liver function

- Significant increase in blood pressure

- New onset of migraine-type headache

- Pregnancy

Endometrial hyperplasia

• The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods (see section 4.8). The addition of a progestogen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.

• For Progynova TS 100 (100 ?g/day) the endometrial safety of added progestogens has not been studied.

• Break-through bleeding and spotting may occur during the first months of treatment. If break-through bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

• Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.

Breast cancer

• A randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking oestrogens, oestrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8). For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

• In the MWS, the relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in risk between the different routes of administration.

• In the WHI study, the continuous combined conjugated equine oestrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

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

Venous thromboembolism

• HRT is associated with a higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later.

• Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI > 30 kg/m 2 ) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.

• Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

• The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised.

• If VTE develops after initiating therapy, the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

Coronary artery disease (CAD)

• There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated oestrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS, i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity and mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.

Stroke

• One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated oestrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 women per 1000 women aged 60-69 years. It is estimated that for women who use conjugated oestrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Ovarian cancer

• Long-term (at least 5-10 years) use of oestrogen only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than oestrogen-only products.

Other conditions

• Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Progynova TS is increased.

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

• Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex- hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

• Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation whilst taking HRT.

• There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger postmenopausal women or other HRT products.

4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction

The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamezapine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St. John's wort (Hypericum Perforatum) may induce the metabolism of oestrogens.

At transdermal administration, the first-pass effect in the liver is avoided and, thus, transdermally applied oestrogens might be less affected than oral hormones by enzyme inducers.

Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.

4.6 Pregnancy And Lactation

Pregnancy

Progynova TS is not indicated during pregnancy. If pregnancy occurs during medication with Progynova TS treatment should be withdrawn immediately.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.

Lactation

Progynova TS is not indicated during lactation.

4.7 Effects On Ability To Drive And Use Machines

None known.

4.8 Undesirable Effects

During the first few months of treatment, breakthrough bleeding, spotting and breast tenderness or enlargement can occur. These are usually temporary and normally disappear after continued treatment. The table below lists adverse drug reactions recorded in clinical studies as well as adverse drug reactions reported post-marketing. Adverse drug reactions were recorded in 3 phase III clinical studies (n = 611 women at risk) and were included in the table when considered at least possibly related to treatment with 50 µg/day estradiol or 100 µg/day estradiol, respectively, following transdermal application.

The experience of adverse drug reactions is overall expected in 76% of the patients. Adverse drug reactions appearing in > 10% of patients in clinical trials were application site reactions and breast pain.

Organ system

Adverse events reported in clinical trials

Adverse events reported post marketing

   

Common

(

Uncommon

(

 

BODY AS A WHOLE

Pain.

Fatigue, abnormal laboratory test1, asthenia1, fever1, flu syndrome1, malaise1.

 

CARDIOVASCULAR SYSTEM

-

Migraine, palpitations, superficial phlebitis1, hypertension1.

Cerebral ischaemic events.

DIGESTIVE SYSTEM

Flatulence, nausea.

Increased appetite, constipation, dyspepsia1, diarrhoea1, rectal disorder1.

Abdominal pain, bloating (abdominal distension), cholestatic jaundice

IMMUNE SYSTEM DISORDER

   

Exacerbation of hereditary angioedema

METABOLIC and NUTRITIONAL DISORDER

Oedema, weight gain.

Hypercholesteremia1

 

HAEMATOLOGICAL and LYMPHATIC SYSTEM

-

Purpura1.

 

MUSCULOSKELETAL SYSTEM

-

Joint disorder, muscle cramps.

 

RESPIRATORY SYSTEM

-

Dyspnoea1, rhinitis1.

 

NERVOUS SYSTEM

Depression, dizziness, nervousness, lethargy, headache, increased sweating, hot flushes.

Anxiety, insomnia, apathy, emotional lability, impaired concentration, paraesthesia, libido changed, euphoria1, tremor1, agitation1.

 

SKIN and APPENDAGES

Application site pruritus, rash.

Acne, alopecia, dry skin, benign breast neoplasm, breast enlargement, breast tenderness, nail disorder1, skin nodule1, hirsutism1

Contact dermatitis, eczema, breast pain

UROGENITAL SYSTEM

Menstrual disorder, vaginal discharge, disorder of vulva/vagina.

Increased urinary frequency/urgency, benign endometrial neoplasm, endometrial hyperplasia, urinary incontinence1, cystitis1, urine discoloration1, haematuria1 uterine disorder1.

Uterine fibroids

SPECIAL SENSES

 

Abnormal vision1, dry eye1

 

1 have been reported in single cases. Given the small study population (n=611) it cannot be determined based on these results if the events are uncommon or rare.

Breast cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

For oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was oestrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95% CI 1.21-1.49) and 1.30 (95% CI 1.21-1.40), respectively.

For oestrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone.

The MWS reported that, compared to never users, the use of various types of oestrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95% CI: 1.88-2.12) than use of oestrogens alone (RR = 1.30, 95% CI: 1.21-1.40) or use of tibolone (RR = 1.45, 95% CI 1.25-1.68).

The WHI trial reported a risk estimate of 1.24 (95% CI 1.01-1.54) after 5.6 years of use of oestrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.

The absolute risks calculated from the MWS and the WHI trial are presented below:

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be

• For users of oestrogen-only replacement therapy

o between 0 and 3 (best estimate = 1.5) for 5 years' use

o between 3 and 7 (best estimate = 5) for 10 years' use.

• For users of oestrogen plus progestogen combined HRT,

o between 5 and 7 (best estimate = 6) for 5 years' use

o between 18 and 20 (best estimate = 19) for 10 years' use.

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to oestrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years. According to calculations from the trial data, it is estimated that:

• For 1000 women in the placebo group,

o about 16 cases of invasive breast cancer would be diagnosed in 5 years.

• For 1000 women who used oestrogen + progestogen combined HRT (CEE + MPA), the number of additional cases would be

o between 0 and 9 (best estimate = 4) for 5 years' use.

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) see section 4.4).

Endometrial cancer

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2- to 12-fold greater compared with non-users. Adding a progestogen to oestrogen-only therapy greatly reduces this increased risk.

Other adverse reactions have been reported in association with oestrogen/progestogen treatment:

- Oestrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer.

- Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.

- Myocardial infarction and stroke (see also section 4.4)

- Gall bladder disease.

- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura.

- Probable dementia (see section 4.4).

4.9 Overdose

Overdosage is unlikely with this type of application. Nausea, vomiting and withdrawal bleeding may occur in some women. There is no specific antidote and treatment should be symptomatic. The patch(es) should be removed.

5. Pharmacological Properties 5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Natural and semisynthetic oestrogens, plain.

ATC code: G03CA03

Progynova TS contains synthetic 17?-estradiol, which is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.

• Relief of oestrogen-deficiency symptoms

- Relief of menopausal symptoms was achieved during the first few weeks of treatment.

• Prevention of osteoporosis

- Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of oestrogens on the bone mineral density is dose-dependent. However, in clinical trials, the efficacy of Progynova TS 100 was not significantly better than the efficacy of Progynova TS 50 for the prevention of postmenopausal osteoporosis. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.

- Evidence from the WHI trial and meta-analysed trials shows that current use of HRT alone or in combination with a progestogen – given to predominantly healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.

5.2 Pharmacokinetic Properties

Absorption

After dermal application of Progynova TS, estradiol is continuously released and transported across intact skin leading to sustained circulating level of estradiol during 7-day treatment period as shown in figure 1. The systemic availability of estradiol after transdermal administration is about 20 times higher than that after oral administration. This difference is due to the absence of first pass metabolism when estradiol is given by the transdermal route. The major pharmacokinetic parameters of estradiol are summarized in the following table:

Transdermal Delivery System

Daily Delivery Rate, mg/day

Application Site

AUC(0-tlast)

ngxh/mL / nmolxh/L

Cmax

pg/mL / pmol/L

Cavg

pg/mL / pmol/L

tmax

h

Cmin

pg/mL / pmol/L

Progynova TS 50

0.050

Abdomen

5.44 /20

55 /202

35 /129

26

30 /110

Progynova TS 100

0.100

Abdomen

11.5 /42

110 /404

70 /257

31

56 /206

Figure 1 : Mean baseline uncorrected serum 17 ?-estradiol concentrations vs. time profile following application of Progynova TS 50 and Progynova TS 100

Distribution

The distribution of exogenous oestrogens is similar to that of endogenous oestrogens. The apparent volume of distribution of estradiol after single intravenous administration is about 1 l/kg. Oestrogens circulate in the blood largely bound to serum proteins. About 61 % of estradiol is bound non-specifically to serum albumin and about 37 % specifically to sex hormone binding globulin (SHBG).

Metabolism

After transdermal administration, the biotransformation of estradiol leads to concentrations of estrone and of the respective conjugates within the range as seen during the early follicular phase in the reproductive life period, indicated by an estradiol/estrone serum level ratio of approximately 1. Unphysiologically high estrone levels as a result of the intensive "first pass" metabolism during oral estradiol hormone replacement therapy, reflected in estradiol/estrone ratios as low as 0.1, are avoided.

The biotransformation of the transdermally administered estradiol is the same as that of the endogenous hormone: Estradiol is mainly metabolized in the liver but also extrahepatically e.g. in gut, kidney, skeletal muscles and target organs. These processes involve the formation of estrone, estriol, catecholoestrogens and sulfate and glucuronide conjugates of these compounds, which are less oestrogenic or even nonoestrogenic.

Excretion

The total serum clearance of estradiol following single intravenous administration, shows high variability in the range of 10-30 ml/min/kg. Estradiol and its metabolites are excreted in the bile and undergo a so-called enterohepatic circulation. Ultimately estradiol and its metabolites are mainly excreted as sulfates and glucuronides with the urine.

Steady-state conditions

Accumulation of estradiol and estrone was not observed following multiple 1-week patch applications. Accordingly, steady-state serum levels of estradiol and estrone correspond to those observed after a single application.

5.3 Preclinical Safety Data

The toxicity profile of estradiol is well known. There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SPC.

In primary dermal irritation studies, application of Progynova TS patches resulted in mild irritation related to mechanical trauma at removal. Progynova TS patches had no dermal sensitising potential.

Studies on the components (adhesive matrix, backing and release liner) did not indicate any risk related to the use of the Progynova TS patch.

6. Pharmaceutical Particulars 6.1 List Of Excipients

Isooctyl acrylate/acrylamide/vinyl acetate copolymer, ethyl oleate, isopropyl myristate, glycerol monolaurate, mounted on a polyester release liner and protected with a polyethylene backing film.

6.2 Incompatibilities

Not applicable.

6.3 Shelf Life

3 years.

6.4 Special Precautions For Storage

Store below 30?C.

Store in the original package in order to protect from moisture.

6.5 Nature And Contents Of Container

Each patch is sealed in a multilaminate pouch containing a desccant. The pouch consists of polyester/aluminium/acrylonitril, methyl acrylate copolymer (BAREX210).

The desiccant consists of sodium alumino silicate;

Pack of 4 or 12 patches.

(Not all pack sizes may be marketed).

6.6 Special Precautions For Disposal And Other Handling

After use the patch still contains substantial quantities of estradiol, which may have harmful effects if reaching the aquatic environment. Therefore, the used patch should be discarded carefully. Any used or unused patches should be folded in half, adhesive side together, and disposed of in the solid waste disposal system. Used patches should not be flushed down the toilet nor placed in the liquid waste disposal systems.

7. Marketing Authorisation Holder

Bayer plc

Bayer House

Strawberry Hill

Newbury

Berkshire RG14 1JA

United Kingdom

8. Marketing Authorisation Number(S)

PL 00010/0561

9. Date Of First Authorisation/Renewal Of The Authorisation

1 May 2008

10. Date Of Revision Of The Text

25 November 2011

LEGAL CATEGORY

POM


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