Estradot 25 mikrogram/24 timmar Depotplåster

Sverige - svenska - Läkemedelsverket (Medical Products Agency)

Bipacksedel Bipacksedel (PIL)

08-12-2020

Produktens egenskaper Produktens egenskaper (SPC)

02-04-2019

Aktiva substanser:
estradiolhemihydrat
Tillgänglig från:
2care4 ApS,
ATC-kod:
G03CA03
INN (International namn):
estradiol hemihydrate
Dos:
25 mikrogram/24 timmar
Läkemedelsform:
Depotplåster
Sammansättning:
estradiolhemihydrat 0,4 mg Aktiv substans
Receptbelagda typ:
Receptbelagt
Produktsammanfattning:
Förpacknings: Påse, 24 x 1 depotplåster
Bemyndigande status:
Avregistrerad
Godkännandenummer:
57509
Tillstånd datum:
2018-10-31

Dokument på andra språk

Bipacksedel Bipacksedel - engelska

08-12-2020

Produktens egenskaper Produktens egenskaper - engelska

08-12-2020

Läs hela dokumentet

Package leaflet: Information for the user

Estradot 25 micrograms/24 hours transdermal patch

Estradot 37.5 micrograms/24 hours transdermal patch

Estradot 50 micrograms/24 hours transdermal patch

Estradot 75 micrograms/24 hours transdermal patch

Estradot 100 micrograms/24 hours transdermal patch

(Estradiol (as hemihydrate))

Read all of this leaflet carefully before you start using this medicine

because it contains

important

information for you.

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any side effects talk, to your doctor or pharmacist. This includes any possible side effects not

listed in this leaflet. See section 4.

What is in this leaflet

1.

What Estradot is and what it is used for

2.

What you need to know before you use Estradot

3.

How to use Estradot

4.

Possible side effects

5.

How to store Estradot

6.

Contents of the pack and other information

1.

What Estradot is and what it is used for

Estradot is a Hormone Replacement Therapy (HRT). It contains the female hormone oestrogen. Estradot is

used in postmenopausal women with at least 12 months since their last natural period.

Estradot comes as a patch that is applied to the skin.

Estradot is used for:

Relief of symptoms occurring after menopause

During the menopause, the amount of oestrogen produced by a woman’s body drops. This can cause

symptoms such as hot face, neck and chest ("hot flushes").

Estra

dot alleviates these symptoms after

menopause. You will only be prescribed Estradot if your symptoms seriously hinder your daily life.

Prevention of osteoporosis

(for Estradot 50, 75 and 100 only)

After the menopause some women may develop fragile bones (osteoporosis). You should discuss all

available options with your doctor.

If you are at an increased risk of fractures due to osteoporosis and other medicines are not suitable for you,

you can use Estradot to prevent osteoporosis after menopause.

2.

What you need to know before you use Estradot

Medical history and regular check-ups

The use of HRT carries risks which need to be considered when deciding whether to start using it, or whether

to carry on using it.

The experience in treating women with a premature menopause (due to ovarian failure or surgery) is limited.

If you have a premature menopause the risks of using HRT may be different. Please talk to your doctor.

Before you start (or restart) HRT, your doctor will ask about your own and your family's medical history.

Your doctor may decide to perform a physical examination. This may include an examination of your breasts

and/or an internal examination, if necessary.

Once you have started on Estradot, you should see your doctor for regular check-ups (at least once a year).

At these check-ups, discuss with your doctor the benefits and risks of continuing with Estradot.

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

Do not use Estradot

if any of the following applies to you. If you are not sure about any of the points below,

talk to your doctor

before using Estradot.

Do not use Estradot:

if you have or have ever had

breast cancer

, or if you are suspected of having it;

if you have

cancer which is sensitive to oestrogens

, such as cancer of the womb lining (endometrium),

or if you are suspected of having it;

if you have

unexplained vaginal bleeding

if you have

excessive thickening of the womb lining

(endometrial hyperplasia) that is not being treated;

if you have or have ever had a

blood clot in a vein

(thrombosis), such as in the legs (deep venous

thrombosis) or the lungs (pulmonary embolism);

if you have a

blood clotting disorder

(such as protein C, protein S or antithrombin deficiency);

if you have or recently have had

a disease caused by blood clots in the arteries, such as a

heart attack,

stroke

angina

if you have or have ever had

liver disease

and your liver function tests have

not returned to normal;

if you have

a rare blood problem called “

porphyria

which is passed down in families (inherited);

if you are

allergic

(hypersensitive) to

estradiol

or any of the other ingredients of Estradot (listed in

section 6 Further information).

If any of the above conditions appear for the first time while using Estradot, stop using it at once and consult

your doctor immediately.

When to take special care with Estradot

Tell your doctor if you have ever had any of the following problems, before you start the treatment, as these

may return or become worse during treatment with Estradot. If so, you should see your doctor more often for

check-ups:

fibroids

inside your womb;

growth of womb lining outside your womb (endometriosis) or a history of excessive growth of the womb

lining (endometrial hyperplasia);

increased risk of developing blood clots (see “Blood clots in a vein (thrombosis)”);

increased risk of getting an oestrogen-sensitive cancer (such as having a mother, sister or grandmother

who has had breast cancer);

high blood pressure;

a liver disorder, such as a benign liver tumour;

diabetes;

gallstones;

migraine or severe headaches;

a disease of the immune system that affects many organs of the body

(systemic lupus erythematosus

,

SLE);

epilepsy;

asthma;

a disease affecting the eardrum and hearing (otosclerosis);

a very high level of fat in your blood (triglycerides);

fluid retention due to cardiac or kidney problems;

products containing oestrogens may cause or worsen the symptoms of hereditary angioedema. You

should see your doctor immediately if you experience symptoms of angioedema such as swollen face,

tongue and/or throat and/or difficulty swallowing, or hives together with difficulty breathing.

Stop using Estradot and see a doctor immediately

If you notice any of the following when using HRT:

any of the conditions mentioned in the ‘Do not use Estradot’ section;

yellowing of your skin or the whites

of your eyes

(jaundice).

These may be signs of a liver disease;

a large rise in your blood pressure (symptoms may be headache, tiredness, dizziness);

migraine-like headaches which happen for the first time;

if you become pregnant;

if you notice signs of a blood clot, such as:

painful swelling and redness of the legs;

sudden chest pain;

difficulty in breathing.

For more information, see ‘Blood clots in a vein (thrombosis)’.

Note

: Estradot is not a contraceptive. If it is less than 12 months since your last menstrual period or you are

under 50 years old, you may still need to use additional contraception to prevent pregnancy. Speak to your

doctor for advice.

HRT and cancer

Excessive thickening of the lining of the womb (endometrial hyperplasia) and cancer of the lining of

the womb (endometrial cancer)

Taking oestrogen-only HRT will increase the risk of excessive thickening of the lining of the womb

(endometrial hyperplasia) and cancer of the womb lining (endometrial cancer).

Taking a progestogen in addition to the oestrogen for at least 12 days of each 28 day cycle protects you from

this extra risk. So your doctor will prescribe a progestogen separately if you still have your womb. If you

have had your womb removed (a hysterectomy), discuss with your doctor whether you can safely take this

product without a progestogen.

In women who still have a womb 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 aged 50 to 65 who still have a womb and who take oestrogen-only HRT, between 10 and 60

women in 1000 will be diagnosed with endometrial cancer (i.e. between 5 and 55 extra cases), depending on

the dose and for how long it is taken.

Estradot 75 and 100 contain a higher dose of oestrogens than other oestrogen-only HRT products. The risk of

endometrium cancer when using Estradot 75 or 100 together with a progestogen is not known.

Unexpected bleeding

You will have a bleed once a month (so-called withdrawal bleed) while using Estradot in combination with a

progestagen. But, if you have unexpected bleeding or drops of blood (spotting) besides your monthly

bleeding, which:

carries on for more than the first 6 months;

starts after you have been using Estradot for more than 6 months;

carries on after you have stopped using Estradot;

see your doctor as soon as possible

Breast cancer

Evidence shows that taking combined oestrogen-progestogen or oestrogen-only hormone replacement

therapy (HRT) increases the risk of breast cancer. The extra risk depends on how long you use HRT. The

additional risk becomes clear within 3 years of use. After stopping HRT the extra risk will decrease with

time, but the risk may persist for 10 years or more if you have used HRT for more than 5 years.

Compare

Women aged 50 to 54 who are not taking HRT, on average, 13 to 17 in 1000 will be diagnosed with breast

cancer over a 5-year period.

For women aged 50 who start taking oestrogen-only HRT for 5 years, there will be 16-17 cases in 1000 users

(i.e. an extra 0 to 3 cases).

For women aged 50 who start taking oestrogen-progestogen HRT for 5 years, there will be 21 cases in 1000

users (i.e. an extra 4 to 8 cases).

Women aged 50 to 59 who are not taking HRT, on average, 27 in 1000 will be diagnosed with breast cancer

over a 10-year period.

For women aged 50 who start taking oestrogen-only HRT for 10 years, there will be 34 cases in 1000 users

(i.e. an extra 7 cases).

For women aged 50 who start taking oestrogen-progestogen HRT for 10 years, there will be 48 cases in 1000

users (i.e. an extra 21 cases).

Regularly check your breasts. See your doctor if you notice any changes such as:

dimpling of the skin;

changes in the nipple;

any lumps you can see or feel.

Additionally,

advised

join

mammography

screening

programs

when

offered

you.

mammogram screening, it is important that you inform the nurse/healthcare professional who is actually

taking the x-ray that you use HRT, as this medication may increase the density of your breasts which may

affect the outcome of the mammogram. Where the density of the breast is increased, mammography may not

detect all lumps.

Ovarian cancer

Ovarian cancer is rare - much rarer than breast cancer. The use of oestrogen-only or combined oestrogen-

progestagen HRT has been associated with a slightly increased risk of ovarian cancer.

The risk of ovarian cancer varies with age. For example, in women aged 50 to 54 who are not taking HRT,

about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period. For women who have

been taking HRT for 5 years, there will be about 3 cases per 2000 users (i.e. about 1 extra case).

Effect of HRT on heart and circulation

Blood clots in a vein (thrombosis)

The risk of

blood clots in the veins

is about 1.3 to 3- times higher in HRT users than in non-users, especially

during the first year of taking it.

Blood clots can be serious, and if one travels to the lungs, it can cause chest pain, breathlessness, fainting or

even death.

You are more likely to get a blood clot in your veins as you get older and if any of the following applies to

you. Inform your doctor if any of these situations applies to you:

you are unable to walk for a long time because of major surgery, injury or illness (see also section 3, If

you need to have surgery);

you are seriously overweight (BMI >30 kg/m

you have any blood clotting problem that needs long-term treatment with a medicine used to prevent

blood clots;

if any of your close relatives has ever had a blood clot in the leg, lung or another organ;

you have systemic lupus erythematosus (SLE);

you have cancer.

For signs of a blood clot, see “Stop using Estradot and see a doctor immediately”.

Compare

Looking at women in their 50s who are not taking HRT, on average, over a 5-year period, 4 to 7 in 1000

would be expected to get a blood clot in a vein.

For women in their 50s who have been taking oestrogen-progestogen HRT for over 5 years, there will be 9 to

12 cases in 1000 users (i.e. an extra 5 cases).

For women in their 50s who have had their womb removed and have been taking oestrogen-only HRT for

over 5 years, there will be 5 to 8 cases in 1000 users (i.e. 1 extra case).

Heart disease (heart attack)

There is no evidence that HRT will prevent a heart attack.

Women over the age of 60 years who use oestrogen-progestogen HRT are slightly more likely to develop

heart disease than those not taking any HRT.

For women who have had their womb removed and are taking oestrogen-only therapy there is no increased

risk of developing a heart disease.

Stroke

The risk of getting stroke is about 1.5 times higher in HRT users than in non-users. The number of extra

cases of stroke due to use of HRT will increase with age.

Compare

Looking at women in their 50s who are not taking HRT, on average, 8 in 1000 would be expected to have a

stroke over a 5-year period. For women in their 50s who are taking HRT, there will be 11 cases in 1000

users, over 5 years (i.e. an extra 3 cases).

Other conditions

HRT will not prevent memory loss. There is some evidence of a higher risk of memory loss in

women who start using HRT after the age of 65. Speak to your doctor for advice.

Other medicines and Estradot

Some medicines may interfere with the effect of Estradot. This might lead to irregular bleeding. This applies

to the following medicines:

Medicines for

epilepsy

(such as phenobarbital, phenytoin and carbamazepine);

Medicines for

tuberculosis

(such as

rifampicin, rifabutin);

Medicines for

HIV infection

(such as

nevirapine, efavirenz, ritonavir, nelfinavir);

Herbal remedies containing

St John's Wort

Hypericum perforatum

Other

anti-infective

medicines

(such as ketoconazole, erythromycin).

Please tell your doctor or pharmacist if you are taking or have recently taken any other medicines, including

medicines obtained without a prescription, herbal medicines or other natural products.

Laboratory tests

If you need a blood test, tell your doctor or the laboratory staff that you are using Estradot, because this

medicine can affect the results of some tests.

Pregnancy and breast-feeding

Estradot is for use in postmenopausal women only. If you become pregnant, stop using Estradot and contact

your doctor. You should not use Estradot if you are pregnant or while you are breast-feeding.

Driving and using machines

Estradot has no known effect on the ability to drive and use machines.

3.

How to use Estradot

Always use this medicine exactly as your doctor has told you. Check with your doctor or pharmacist if you

are not sure.

Your doctor will aim to prescribe the lowest dose to treat your symptom for as short as necessary. Speak to

your doctor if you think this dose is too strong or not strong enough.

How long to use Estradot

It is important that you use the lowest possible effective dose and only as long as needed.

From time to time, you should discuss with your doctor whether you still need the treatment.

When to start treatment

If you are currently not using any form of HRT

(patches or tablets), or

if you have been using a

continuous combined HRT product

(where oestrogen and the progestogen are given every day without

interruption), you can start to use Estradot on any convenient day.

If you are changing from a cyclic or sequential HRT treatment

(where the progestogen is added for

12-14 days of the cycle), you should start to use Estradot on the day after you complete your previous

cycle.

When to apply Estradot

An Estradot patch should be replaced twice weekly (every 3 to 4 days). It is best to always replace it on

the same two days of the week (e.g. Monday and Thursday). Your Estradot pack contains a calendar

checklist on the back to help you remember your schedule. Mark the twice-a-week schedule that you

plan to follow. Always change the patch on the two days of the week you have marked.

Estradot should be worn continuously until it is time to replace it with a new patch.

Any adhesive that might remain on your skin can be easily rubbed off. Then place the new Estradot patch

onto a different area of skin.

Women without a uterus

The Estradot patch is applied continuously without a break. Additional use of another type of hormone called

progestogen is not required, unless you have a condition where the lining of the uterus also grows outside the

uterus (

endometriosis

). Check the risks to be aware of with HRT in general in section 2,

When to

take special

care with Estradot

Women with a uterus

Your doctor should give you another hormone called progestogen in addition to Estradot to reduce the risk of

cancer of the uterus. While Estradot is applied continuously without a break, the progestogen tablet should

be taken for at least 12-14 days every month/28 day cycle. Check the risks to be aware of with HRT in

general in section 2

, When to

take special care with Estradot

You may have some irregular bleeding or spotting during the first few months of treatment. If you have

heavy bleeding or continue to have bleeding or spotting after a few months of treatment, tell your doctor so

that the treatment can be re-evaluated if necessary (see section 2,

Unexpected bleeding

Where to apply Estradot

Apply the patch to the lower abdomen, below the waistline. Avoid the waistline itself, since clothing may

cause the patch to rub off. Do not apply the patch to the breasts or any area near to the breasts.

When changing your patch, based on your twice-a-week schedule, apply your new patch to a different site.

Do not apply a new patch to that same area for at least one week.

Before you apply Estradot, make sure that your skin is:

clean, dry and cool,

free of any powder, oil, moisturiser, or lotion,

free of cuts and/or irritation.

How to apply Estradot

Each patch is individually sealed in a protective pouch. Tear open this pouch at the indentation and remove

the patch (do not use scissors to open the pouch as this could damage the patch).

A stiff protective backing covers the sticky side of the patch. This backing must be removed before the patch

is stuck to the skin. Apply the patch immediately after opening the pouch and removing the protective

backing.

Hold the patch with the protective backing facing you. Peel off one side of the protective backing and discard

it. Try to avoid touching the sticky side of the patch with your fingers.

Holding the other half of the backing, apply the sticky side of the patch to a dry area of your lower abdomen.

Press the sticky side to the skin and smooth down. Fold back the remaining side of the patch.

Grasp the straight edge of the protective backing and pull it off the patch.

Press the sticky remaining side of the patch to the skin and smooth down. Press the patch firmly in place with

the palm of your hand for about 10 seconds.

Make sure that the patch sticks properly to your skin and go over the edges with your finger to ensure good

contact between the patch and skin.

When changing the patch, peel it off, fold it in half with the sticky side inwards. Please see section 5,

How to

store Estradot

for instructions on safe disposal of the patch. Do not flush used patches down the toilet.

Further useful information

Bathing, swimming, showering or exercising should not affect the patch if it has been correctly applied. If a

patch falls off, e.g. during bathing or showering, shake it to remove the water. After careful drying and

cooling down of the skin, reapply the same patch on a different area of the lower abdomen (see ‘Where to

apply Estradot’).

If the patch does not stick completely to your skin, use a new patch. No matter what day this happens, go

back to changing this patch on the same days as your original schedule.

When sunbathing or using a solarium, the patch should be covered. When swimming, the patch can be worn

under your bathing suit.

If you need to have surgery

If you are going to have surgery, tell the surgeon that you are using Estradot. You may need to stop using

Estradot about 4 to 6 weeks before the operation to reduce the risk of a blood clot (see section 2, Blood clots

in a vein). Ask your doctor when you can start using Estradot again.

If you use more Estradot than you should

Remove the patch if you have used too much Estradot. Symptoms of overdose are usually tenderness of the

breasts and/or vaginal bleeding. Acute overdose is unlikely due to the way Estradot is used (patch). If

symptoms persist contact your doctor.

If you forget to use Estradot

If you forget to change the patch, change the patch as soon as you remember. No matter what day this

happens, go back to changing the newly applied patch on the same days as your original schedule.

Do not use a double dose to make up for the forgotten patch.

If you stop using Estradot

Stopping use of Estradot may increase the risk of breakthrough bleeding or spotting. Talk to your doctor if

this occurs. After a long break in treatment, consult your doctor before starting to use the patch again.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, this medicine can cause side effects, although not everybody gets them.

The following diseases are reported more often in women using HRT compared to women not using HRT:

breast cancer;

abnormal growth or cancer of the lining of the womb (endometrial hyperplasia or cancer);

ovarian cancer;

blood clots in the veins of the legs or lungs (venous thromboembolism);

heart disease;

stroke;

probable memory loss if HRT is started over the age of 65.

For more information about these side effects, see Section 2.

Some effects could be serious

These symptoms need immediate medical attention:

Sudden chest pain;

Pain in your chest that spreads to your arm or neck;

Difficulty in breathing;

Painful swelling and redness of the legs;

Yellowing of the eyes and face, darkening of urine, itchy skin (

jaundice

Unexpected vaginal bleeding or spotting (breakthrough bleeding) after using Estradot for some time, or

after you stop treatment;

Breast changes, including dimpling of the breast skin, changes in the nipple, lumps that you can see or

feel (

breast cancer

Painful menstrual periods;

Unexplained migraine-like headaches.

Stop using Estradot and tell your doctor immediately

if you get any of the effects mentioned above.

Check the risks to be aware of with HRT in general in section 2,

When to take special care with Estradot

Other side effects

In addition, the following side effects have been reported with Estradot.

If any of these gets severe, tell

your doctor or

pharmacist.

Very common

, may affect more than 1 in 10 people:

Headache, skin reactions at the patch application site (including irritation, burning, rash, dryness,

bleeding, bruising, inflammation, swelling, skin pigmentation, hives, and blisters), breast tension and

pain, menstrual pains, menstrual disorder.

Common,

may affect up to 1 in 10 people:

Depression, nervousness, mood changes, sleeplessness, nausea (feeling sick), indigestion, diarrhoea,

abdominal pain, bloated feeling, acne, rash, dry skin, itching, breast enlargement, heavy menstrual

periods, a white or yellowish discharge from the vagina, irregular vaginal bleeding, severe uterine

contractions, inflammation of the vagina, abnormal growth of the womb lining (endometrial

hyperplasia), pain (e.g. back pain, arms, legs, wrists, ankles), weakness, fluid retention (oedema) in the

extremities (hands and feet), weight changes.

Uncommon,

may affect up to 1 in 100 people:

Migraine, dizziness, increase in blood pressure, vomiting (being sick), skin discoloration, impaired liver

function tests.

Rare,

may affect up to 1 in 1,000 people:

Tingling or numbness of hand and feet, blood clot, gallstones, hair loss, muscular weakness, benign

smooth muscle growth in uterus, cysts close to uterine tubes, polyps (small growths) in the uterine

cervix (neck of the womb), changes in sexual desire, allergic reactions such as rash.

Very rare,

may affect up to 1 in 10,000 people:

Hives, signs of serious allergic reaction (including difficulties to breath; swelling of face, tongue, throat

or skin; dizziness and hives), decreased carbohydrate tolerance, involuntary movements which may

affect the eyes, head and neck, contact lens discomfort, severe skin lesions, excessive hair growth.

Not known

(cannot be estimated from the available data):

Breast cancer, liver function test abnormal, allergic skin inflammation, lumps in the breast (non-

cancerous).

The following side effects have been reported with other HRTs:

gallbladder disease

various skin disorders:

discoloration of the skin especially of the face or neck known as “pregnancy patches”

(chloasma);

painful reddish skin nodules (erythema nodosum);

rash with target-shaped reddening or sores (erythema multiforme).

decline in memory or mental ability (possible

dementia

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist

.

This includes any possible side effects not listed

in this leaflet

.

You can also report side effects directly via [to be completed nationally]. By reporting side

effects you can help provide more information on the safety of this medicine.

5.

How to store Estradot

Keep this medicine out of the sight and reach of children.

Store Estradot in the original package in a cool, dry place. Once opened or once the protective pouch has

been removed, the patch should be applied to the skin immediately.

Do not refrigerate or freeze Estradot.

Do not use this medicine after the expiry date which is stated on the carton and patch after ‘EXP’. The

expiry date refers to the last day of that month.

Do not use this medicine if you notice that the pack is damaged or shows signs of tampering.

After removing a patch, fold it in half with the sticky side inwards and dispose of it safely out of the

reach of children. Any used or unused transdermal patches should be disposed of in accordance with

local requirements or returned to the pharmacy, preferably in the original packaging. Do not throw away

any medicines via wastewater. Ask your pharmacist how to throw away medicines you no longer use.

These measures will help to protect the environment.

6.

Contents of the pack and other information

What Estradot contains

Each 25 micrograms/24 hours patch contains 0.39 mg estradiol (as hemihydrate) and releases about

25 micrograms estradiol per 24 hours.

Each 37.5 micrograms/24 hours patch contains 0.585 mg estradiol (as hemihydrate) and releases about

37.5 micrograms estradiol per 24 hours.

Each 50 micrograms/24 hours patch contains 0.78 mg estradiol (as hemihydrate) and releases about

50 micrograms estradiol per 24 hours.

Each 75 micrograms/24 hours patch contains 1.17 mg estradiol (as hemihydrate) and releases about

75 micrograms estradiol per 24 hours.

Each 100 micrograms/24 hours patch contains 1.56 mg estradiol (as hemihydrate) and releases about

100 micrograms estradiol per 24 hours.

The active substance is estradiol (as hemihydrate).

The other ingredients in the adhesive layer of the patch are acrylic adhesive, silicone adhesive, oleyl

alcohol, dipropylene glycol, povidone (E1201).

The backing layer is an ethylene/vinyl acetate copolymer and vinylidene chloride/methyl acrylate

copolymer laminate.

The release liner (to be removed before application) is a fluoropolymer-coated polyester film.

What Estradot looks like and contents of the pack

Estradot 25 is a 2.5 cm

rectangular patch with rounded corners, comprising a pressure-sensitive adhesive

layer containing estradiol, with a translucent polymeric backing on one side and a protective liner on the

other.

Estradot 37.5 is a 3.75 cm

rectangular patch with rounded corners, comprising a pressure-sensitive adhesive

layer containing estradiol, with a translucent polymeric backing on one side and a protective liner on the

other.

Estradot 50 is a 5 cm

rectangular patch with rounded corners, comprising a pressure-sensitive adhesive layer

containing estradiol, with a translucent polymeric backing on one side and a protective liner on the other.

Estradot 75 is a 7.5 cm

rectangular patch with rounded corners, comprising a pressure-sensitive adhesive

layer containing estradiol, with a translucent polymeric backing on one side and a protective liner on the

other.

Estradot 100 is a 10 cm

rectangular patch with rounded corners, comprising a pressure-sensitive adhesive

layer containing estradiol, with a translucent polymeric backing on one side and a protective liner on the

other.

Estradot is available in five different strengths: 25, 37.5, 50, 75 and 100 micrograms/24 hours. Not all

strengths may be marketed in your country.

Estradot is available in cartons of 2, 8, 24 and 26 patches. Not all pack sizes may be marketed in your

country.

Marketing Authorisation Holder and Manufacturer

<[To be completed nationally]>

{Name and address}

<{tel}>

<{fax}>

<{e-mail}>

This medicinal product is authorised in the Member States of the EEA under the following name:

Austria: Estradot

Belgium: Vivelle dot

Denmark: Vivelle dot

Finland: Estradot

France: Vivelledot

Croatia: Estradot

Germany: Estradot

Iceland: Vivelle dot

Ireland: Estradot

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This leaflet was last revised in 11/2020

<[To be completed nationally]>

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<ESTRADOT 100>

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

Estradot 25 micrograms/24 hours, transdermal patch

Estradot 37.5 micrograms/24 hours, transdermal patch

Estradot 50 micrograms/24 hours, transdermal patch

Estradot 75 micrograms/24 hours, transdermal patch

Estradot 100 micrograms/24 hours, transdermal patch

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

2.5 cm

patch containing 0.39 mg estradiol (as hemihydrate) with a release rate of 25 micrograms

estradiol per 24 hours.

3.75 cm

patch containing 0.585 mg estradiol (as hemihydrate) with a release rate of 37.5 micrograms

estradiol per 24 hours.

5 cm

patch containing 0.78 mg estradiol (as hemihydrate) with a release rate of 50 micrograms estradiol

per 24 hours.

7.5 cm

patch containing 1.17 mg estradiol (as hemihydrate) with a release rate of 75 micrograms

estradiol per 24 hours.

10 cm

patch containing 1.56 mg estradiol (as hemihydrate) with a release rate 100 micrograms

estradiol per 24 hours.

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Transdermal patch.

Rectangular patch with rounded corners, comprising a pressure-sensitive adhesive layer containing

estradiol, with a translucent polymeric backing on one side and a protective liner on the other.

4.

CLINICAL PARTICULARS

4.1

Therapeutic indications

Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women.

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 (for Estradot 50, 75 and 100 only).

The experience treating women older than 65 years is limited.

4.2

Posology and method of administration

Dosage

The transdermal patch is applied twice weekly, i.e. every three to four days.

Oestrogen deficiency symptoms:

Estradot is available in five strengths: 25, 37.5, 50, 75 and 100. 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. Depending on the clinical response the dose can then be adjusted to the

patient’s individual needs. If, after three months, there is insufficient response in the form of alleviated

symptoms, the dose can be increased. If symptoms of overdose arise (e.g. tender breasts) the dose

must be decreased.

Prevention of postmenopausal osteoporosis:

Estradot is available in three strengths: 50, 75 and 100. Treatment must be initiated with an Estradot

50 microgram/24 hours patch. Adjustments can be made by using Estradot 50, 75 and 100 microgram

patches.

General instructions

Estradot is administered as continuous therapy (uninterrupted application twice weekly).

In women with an intact uterus, Estradot should be combined with a progestagen approved for

addition to oestrogen treatment in a continuous sequential dosing scheme: the oestrogen is dosed

continuously. The progestagen is added for at least 12 to 14 days of every 28-day cycle, in a sequential

manner.

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in

hysterectomised women.

In women who are not taking HRT or women transferring from a continuous combined HRT product,

treatment may be started on any convenient day. In women transferring from a sequential HRT regimen,

treatment should begin the day following completion of the prior regimen.

Method of administration

The adhesive side of Estradot should be placed on a clean, dry area of the abdomen.

Estradot should not

be applied to the breasts.

Estradot should be replaced twice weekly. The site of application must be rotated, with an interval of at

least 1 week allowed 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 dislodge the patch. The

patch should be applied immediately after opening the sachet 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.

In the event that a patch should fall off, the same patch may be reapplied. If necessary, a new patch

may be applied. In either case, the original treatment schedule should be continued. The patch may be

worn during bathing.

If a woman has forgotten to apply a patch, she should apply a new patch as soon as possible. The

subsequent patch should be applied according to the original treatment schedule. The interruption of

treatment might increase the likelihood of irregular bleeding and spotting.

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 or current venous thromboembolism (deep venous thrombosis, pulmonary embolism);

Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section

4.4);

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

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

to normal;

Known hypersensitivity to the active substance or to any of the excipients listed in section 6.1;

Porphyria.

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 at least annually and HRT should only be continued as long as the benefit outweighs the

risk.

Estradot 25 and Estradot 37.5 are not indicated for osteoporosis.

Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited.

Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for

these women may be more favourable than in older women.

Medical examination/follow-up

Before initiating or reinstituting HRT, 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 (see ‘Breast cancer’ below). Investigations,

including appropriate imaging tools, e.g. mammography, should be carried out in accordance with

currently accepted screening practices, modified to the clinical needs of the individual.

Conditions which need supervision

If any of the following conditions are present, have occurred previously, and/or have been aggravated

during pregnancy or previous hormone treatment, the patient should be closely supervised. It should

be taken into account that these conditions may recur or be aggravated during treatment with Estradot,

in particular:

Leiomyoma (uterine fibroids) or endometriosis

Risk factors for thromboembolic disorders (see below)

Risk factors for oestrogen-dependent tumours, e.g. 1

-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 (SLE)

A history of endometrial hyperplasia (see below)

Epilepsy

Asthma

Otosclerosis

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contraindication is discovered and in the following

situations:

Jaundice or deterioration in liver function

Significant increase in blood pressure

New onset of migraine-type headache

Pregnancy

Endometrial hyperplasia and carcinoma

In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when

oestrogens are administered alone for prolonged periods .The reported increase in endometrial cancer

risk among oestrogen-only users varies from 2- to 12-fold greater compared with non-users, depending

on the duration of treatment and oestrogen dose (see section 4.8). After stopping treatment risk may

remain elevated for at least 10 years.

The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous

combined oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk

associated with oestrogen-only HRT.

For Estradot 75 or 100 µg/day the endometrial safety of added progestagens 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 progestagens 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

The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen-

progestagen or oestrogen-only HRT, that is dependent on the duration of taking HRT.

Combined oestrogen-progestagen 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 oestrogen-progestagen for HRT that becomes apparent after

about 3 (1-4) years (see section 4.8).

Oestrogen-only therapy

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using

oestrogen-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 oestrogen-progestagen

combinations (see section 4.8).

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.

HRT, especially oestrogen-progestagen combined treatment, increases the density of mammographic

images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer.

Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women

taking oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5

years of use and diminishes over time after stopping.

Some other studies, including the WHI trial, suggest that the use of combined HRTs may be associated

with a similar or slightly smaller risk (see Section 4.8).

Venous thromboembolism

HRT is associated with a 1.3- 3 fold risk of developing venous thromboembolism (VTE), i.e. deep

vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the

first year of HRT than later (see Section 4.8).

Generally recognised risk factors for VTE include use of oestrogens, older age, major surgery,

prolonged immobilisation, obesity (BMI > 30 kg/m

), pregnancy/postpartum period, systemic

lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose

veins in VTE.

Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this

risk. HRT is therefore contraindicated in these patients (see section 4.3).

Women already on chronic anticoagulant treatment require careful consideration of the benefit-

risk of use of HRT.

As in all postoperative patients, prophylactic measures need be considered to prevent VTE

following surgery. If prolonged immobilisation is to follow elective surgery, temporarily stopping

HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is

completely mobilised.

In women with no personal history of VTE but with a first degree relative with a history of

thrombosis at young age, screening may be offered after careful counselling regarding its

limitations (only a proportion of thrombophilic defects are identified by screening). If a

thrombophilic defect is identified which segregates with thrombosis in family members or if the

defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of

defects) HRT is contraindicated.

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 protection against myocardial infarction

in women with or without existing CAD who received combined oestrogen-progestagen or

oestrogen-only HRT.

Combined oestrogen-progestagen therapy

The relative risk of CAD during use of combined oestrogen-progestagen HRT is slightly increased. As

the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due

to oestrogen-progestagen use is very low in healthy women close to menopause, but will rise with

more advanced age.

Oestrogen-only

Randomised controlled data found no increased risk of CAD in hysterectomised women using

oestrogen-only therapy.

Ischaemic stroke

Combined oestrogen-progestagen and oestrogen-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).

Severe anaphylactic/anaphylactoid reactions

Cases of anaphylactic/anaphylactoid reactions, which developed anytime during the course of

estradiol treatment and required emergency medical management, have been reported in the post

marketing setting.

Angioedema

Oestrogens may induce or exacerbate symptoms of angioedema, in particular in women with

hereditary angioedema.

Patients who develop angioedema after treatment with estradiol should not receive Estradot again.

Other conditions

Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction

should be carefully observed.

Women with pre-existing hypertriglyceridaemia should be followed closely during 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).

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 oestrogen-only HRT after the age of 65.

Contact sensitisation is known to occur with all topical applications. Although it is extremely rare,

women who develop contact sensitisation to any of the components of the patch should be warned

that a severe hypersensitivity reaction may occur with continuing exposure to the causative agent.

4.5

Interaction with other medicinal products and other forms of interaction

The metabolism of oestrogens (and progestagens) 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, carbamazepine) 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 (and progestagens).

Estradiol is predominantly metabolized by CYP3A4, hence concomitant administration of inhibitors of

CYP3A4 such as ketoconazole, erythromycin may result in increase in the exposure of estradiol.

At transdermal administration, the first-pass effect in the liver is avoided and, thus, transdermally

applied oestrogens (and progestagens) might be less affected than oral hormones by enzyme inducers.

Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and

changes in the uterine bleeding profile.

Some laboratory tests may be influenced by oestrogen therapy, such as tests for glucose tolerance or

thyroid function.

4.6

Pregnancy and lactation

Pregnancy

Estradot is not indicated during pregnancy. If pregnancy occurs during medication with Estradot,

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.

Breast-feeding

Estradot is not indicated during lactation.

4.7

Effects on ability to drive and use machines

Estradot has no or negligible influence on the ability to drive and use machines.

4.8

Undesirable effects

Mild erythema at the patch application site was the most reported undesirable effect (16.6%). The

erythema was observed after removing the patch by peeling from the skin at the application site. Mild

pruritus and rash were also reported around the application site.

Adverse drug reactions (Table 1) are ranked under headings of frequency, the most frequent first,

using the following convention: very common (≥1/10), common (≥1/100 to <1/10), uncommon

(≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), very rare (<1/10,000), not known (cannot be

estimated from the available data).

Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

The following adverse drug reactions have been reported from clinical trials and from post-marketing

experience with either Estradot or oestrogen therapy in general:

Table 1

Neoplasms benign, malignant and unspecified (including cysts and polyps)

Not known*:

Breast cancer.

Immune system disorders

Rare:

Hypersensitivity.

Very rare:

Urticaria, anaphylactic reaction.

Not known*:

Anaphylactoid reaction.

Metabolism and nutrition disorders

Very rare:

Decreased carbohydrate tolerance.

Psychiatric disorders

Common:

Depression, nervousness, affect liability.

Rare:

Libido disorder.

Nervous system disorders

Very common:

Headache.

Common:

Insomnia.

Uncommon:

Migraine, dizziness.

Rare:

Paraesthesia.

Very rare:

Chorea.

Eye disorders

Very rare:

Contact lens intolerance.

Vascular disorders

Uncommon:

Hypertension.

Rare:

Embolism venous.

Not known*:

Embolism.

Gastrointestinal disorders

Common:

Nausea, dyspepsia, diarrhoea, abdominal pain abdominal distension.

Uncommon:

Vomiting.

Hepatobiliary disorders

Rare:

Cholelithiasis.

Skin and subcutaneous tissue disorders

Very common:

Application site reactions**, erythema.

Common:

Acne, rash, dry skin, pruritus.

Uncommon:

Skin discoloration.

Rare:

Alopecia.

Very rare:

Skin necrosis, hirsutism.

Not known*:

Angioedema, contact dermatitis,

chloasma.

Musculoskeletal and connective tissue disorders

Common:

Back pain.

Rare:

Myasthenia.

Not known*:

Pain in extremity.

Reproductive system and breast disorders

Very common:

Breast tension and pain, dysmenorrhoea, menstrual disorder.

Common:

Breast enlargement, menorrhagia, genital discharge, irregular vaginal bleeding, uterine

spasms, vaginal infection, endometrial hyperplasia.

Rare:

Uterine leiomyoma, fallopian tube cysts, cervical polyps.

Not known*:

Fibrocystic breast disease.

General disorders and administration site conditions

Common:

Pain, asthenia, oedema peripheral, weight fluctuation.

Investigations

Uncommon:

Transaminases increased.

Not known*:

Liver function test abnormal.

(*) Reported in post-marketing experience

(**) Application site reactions includes localized bleeding, bruising, burning, discomfort, dryness, eczema,

edema, erythema, inflammation, irritation, pain, papules, paraesthesia, pruritus, rash, skin discolouration,

skin pigmentation, swelling, urticaria, and vesicles.

Breast cancer risk

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking

combined oestrogen-progestagen therapy for more than 5 years.

The increased risk in users of oestrogen-only therapy is lower than that seen in users of oestrogen-

progestagen combinations.

The level of risk is dependent on the duration of use (see section 4.4).

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 – Estimated additional risk of

breast cancer after 5 years’ use in women with BMI 27 (kg/m

2

)

Age at start

HRT

(years)

Incidence per 1,000 never-

users of HRT over a 5 year

period (50-54 years)*

Risk ratio

Additional cases per 1,000

HRT users after 5 years

Oestrogen only HRT

13.3

Combined oestrogen-progestagen

13.3

* Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of

breast cancer will also change proportionately.

Estimated additional risk of breast cancer after 10 years’ use in women with BMI 27 (kg/m

2

)

Age at start

HRT

(years)

Incidence per 1,000 never-

users of HRT over a 10 year

period (50-59 years)*

Risk ratio

Additional cases per 1,000

HRT users after 10 years

Oestrogen only HRT

26.6

Combined oestrogen-progestagen

26.6

20.8

* Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of

breast cancer will also change proportionately.

US WHI studies - additional risk of breast cancer after 5 years’ use

Age range

(years)

Incidence per 1,000 women in

placebo arm over 5 years

Risk ratio & 95%CI

Additional cases per 1000 HRT

users over 5 years (95%CI)

CEE oestrogen-only

50-79

0.8 (0.7 – 1.0)

-4 (-6 – 0)*

CEE+MPA oestrogen & progestagen‡

50-79

1.2 (1.0 – 1.5)

+4 (0 – 9)

‡When the analysis was restricted to women who had not used HRT prior to the study there was no increased

risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

* WHI study in women with no uterus, which did not show an increase in risk of breast cancer.

Endometrial cancer risk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1,000 women with a uterus not using HRT.

In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk

of endometrial cancer (see section 4.4).

Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of

endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in

every 1,000 women between the ages of 50 and 65.

Adding a progestagen to oestrogen-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 oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly

increased risk of having ovarian cancer diagnosed (see Section 4.4).

A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in

women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-

1.56). For women aged 50 to 54 years taking 5 years of HRT, this results in about 1 extra case per

2000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2000 will be

diagnosed with ovarian cancer over a 5-year period.

Risk of venous thromboembolism

HRT is associated with a 1.3-3-fold increased relative risk of developing venous thromboembolism

(VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more

likely in the first year of using HRT (see section 4.4). Results of the WHI studies are presented:

WHI Studies - Additional risk of VTE over 5 years’ use

Age range (years)

Incidence per 1,000 women in

placebo arm over 5 years

Risk ratio and 95%CI

Additional cases per 1,000 HRT

users

Oral oestrogen-only*

50 - 59

1.2 (0.6 - 2.4)

1 (-3 – 10)

Oral combined oestrogen-progestagen

50 - 59

2.3 (1.2 – 4.3)

5 (1 - 13)

* Study in women with no uterus.

Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined oestrogen-

progestagen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

The use of oestrogen-only and oestrogen + 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.

WHI studies combined - Additional risk of ischaemic stroke* over 5 years’ use

Age range

(years)

Incidence per 1,000 women in

placebo arm over 5 years

Risk ratio and 95%CI

Additional cases per 1,000 HRT

users over 5 years

50 - 59

1.3 (1.1 - 1.6)

3 (1 - 5)

* No differentiation was made between ischaemic and haemorrhagic stroke.

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

Gallbladder disease.

Skin and subcutaneous tissue disorders: chloasma, erythema multiforme, erythema nodosum,

vascular purpura.

Probable dementia over the age of 65

(see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via [to be completed nationally].

4.9

Overdose

Acute overdose is unlikely due to the method of administration. The most common symptoms of

overdose in clinical use are breast tenderness and/or vaginal bleeding. If such symptoms occur, a

reduction in dosage should be considered. The effects of overdose can be rapidly reversed by removal

of the patch.

5.

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Oestrogens, ATC code: G03CA03

The active ingredient in Estradot, synthetic 17β-estradiol, is chemically and biologically identical to

endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women and

alleviates menopausal symptoms.

Relief of oestrogen-deficiency symptoms

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

Prevention of osteoporosis (for Estradot 50, 75 and 100 only)

Oestrogens prevent bone loss following menopause or ovariectomy.

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. 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 progestagen – 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

Transdermal administration of estradiol achieves therapeutic plasma concentrations using a lower total

dose of estradiol than required with oral administration, whereas plasma levels of estrone and estrone

conjugates are lower with the transdermal route.

In studies in postmenopausal women with application of Estradot 25, 37.5, 50, and 100 µg/24 hours

patches, average peak estradiol serum levels (C

) were approximately 25 pg/ml, 35 pg/ml, 50-

55 pg/ml and 95-105 pg/ml, respectively. Linear pharmacokinetics have been demonstrated for

estradiol following transdermal administration.

At steady state, after repeated applications of Estradot 50 µg/24 hours patches, C

and C

values

were 57 and 28 pg/ml for estradiol and 42 and 31 pg/ml for estrone, respectively.

Distribution

Estradiol is more than 50% bound to plasma proteins such as sex hormone binding globulin and

albumin. Only 2% is free and biologically active.

Biotransformation/Metabolism

Transdermally applied estradiol is metabolised in the same way as the endogenous hormone. Estradiol

is metabolised primarily in the liver to estrone, then later to estriol, epioestriol and catechol estrogens,

which are then conjugated to sulphates and glucuronides. Cytochrome 450 isoforms CYP1A2 and

CYP3A4 catalyze the hydroxylation of estradiol forming estriol. Estriol is glucuronidated by UGT1A1

and UGT2B7 in humans. Estradiol metabolites are subject to enterohepatic circulation.

Elimination

The sulphate and glucuronide esters along with a small proportion of estradiol and several other

metabolites are excreted in the urine. Only a small amount is excreted in faeces. Since estradiol has a

short half-life (approximately one hour), serum concentrations of estradiol and estrone returned to

baseline values within 24 hours following removal of the patch.

5.3

Preclinical safety data

The toxicity profile of estradiol has been well established. Long-term continuous administration of

natural and synthetic oestrogens in certain animal species increases the frequency of carcinomas of the

breast, uterus, cervix, vagina, testis, and liver as well as the frequency of lymphoid and pituitary

tumours.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

Adhesive matrix:

acrylic adhesive,

silicone adhesive,

oleyl alcohol,

dipropylene glycol,

povidone (E1201).

Backing layer:

Ethylene/vinyl acetate copolymer and vinylidene chloride/methyl acrylate copolymer laminate

Release liner:

fluoropolymer-coated polyester film.

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

2 years

6.4

Special precautions for storage

Do not refrigerate or freeze.

Store in the original pouch and carton.

6.5

Nature and contents of container

Each Estradot patch is individually sealed in an aluminium laminate sachet.

Sachets may be provided in cartons of 2, 8, 24 and 26.

Not all pack sizes may be marketed.

6.6

Special precautions for disposal

Used transdermal patches should be folded in half with the adhesive side inwards, and discarded safely

and out of the reach and sight of children. Any used or unused transdermal patches should be disposed

of in accordance with local requirements or returned to the pharmacy, preferably in the original

packaging.

7.

MARKETING AUTHORISATION HOLDER

<[To be completed nationally]>

{Name and address}

<{tel}>

<{fax}>

<{e-mail}>

8.

MARKETING AUTHORISATION NUMBER(S)

<[To be completed nationally]>

9.

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

<{DD/MM/YYYY}> <{DD month YYYY}>

<[To be completed nationally]>

10.

DATE OF REVISION OF THE TEXT

11/2020

<[To be completed nationally]>

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