Climara 25

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Estradiol hemihydrate 2.04 mg equivalent to estradiol 1.97 mg (25 µg/24h)
Available from:
Bayer New Zealand Limited
INN (International Name):
Estradiol hemihydrate 2.04 mg (equivalent to estradiol 1.97 mg (25 µg/24h))
Dosage:
25 mcg/24h
Pharmaceutical form:
Transdermal patch
Composition:
Active: Estradiol hemihydrate 2.04 mg equivalent to estradiol 1.97 mg (25 µg/24h) Excipient: Acrylates copolymer Ethyl oleate Glyceryl monolaurate Isopropyl myristate
Units in package:
Sachet, aluminium foil, laminated (not marketed), 4 patches
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Bayer AG
Therapeutic indications:
For short-term treatment of complaints associated with the menopause and post-menopause, including signs and symptoms of oestrogen deficiency, whether naturally or surgically induced.
Product summary:
Package - Contents - Shelf Life: Sachet, aluminium foil, laminated - 4 patches - 36 months from date of manufacture stored at or below 30°C
Authorization number:
TT50-5566/2
Authorization date:
1999-01-07

CLIMARA

CONSUMER MEDICINE INFORMATION

CLIMARA

®

oestradiol

Warning

The Women’s Health Initiative (WHI) trial examined the health benefits and risks of combined

oestrogen plus progestogen therapy (n=16,608) and oestrogen-alone therapy (n=10,739) in

postmenopausal women aged 50 to 79 years.

The oestrogen plus progestogen arm of the WHI trial indicated an increased risk of

myocardial infarction (MI), stroke, invasive breast cancer, pulmonary embolism and deep

vein thrombosis in postmenopausal women receiving treatment with combined conjugated

equine estrogens (CEE, 0.625 mg/day) and medroxyprogesterone acetate (MPA, 2.5

mg/day) for 5.2 years compared to those receiving placebo.

The oestrogen-alone arm of the WHI trial indicated an increased risk of stroke and deep vein

thrombosis in hysterectomised women treated with CEE-alone (0.625 mg/day) for 6.8 years

compared to those receiving placebo.

Other doses of oral conjugated oestrogens with medroxyprogesterone acetate, and other

combinations and dosage forms of oestrogens and progestogens were not studied in the

WHI clinical trials and, in the absence of comparable data, these risks should be assumed to

be similar.

Therefore, the following should be given serious consideration at the time of prescribing:

Oestrogens with or without progestogens should not be prescribed for primary or

secondary prevention of cardiovascular diseases.

Oestrogens with or without progestogens should be prescribed at the lowest effective

dose for the approved indication.

Oestrogens with or without progestogens should be prescribed for the shortest period

possible for the approved indication.

For the prevention of osteoporosis, oestrogen treatment should be considered in light

of other available therapies.

CLIMARA

1

CLIMARA

®

(Clim·AR·rah)

oestradiol

Consumer Medicine Information

WHAT IS IN THIS

LEAFLET

This leaflet answers some common

questions about Climara. It does

not contain all the available

information. It does not take the

place of talking to your doctor or

pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you using Climara

against the benefits they expect it

will have for you.

If you have any concerns about

using this medicine, ask your

doctor or pharmacist.

Keep this leaflet with the

medicine.

You may need to read it again.

WHAT CLIMARA IS

USED FOR

Climara is used for the treatment of

menopausal symptoms due to

oestrogen deficiency during

menopause or after a surgical

procedure, where oestrogen

production is decreased. Climara is

only intended for short term use.

Climara is an adhesive patch, which

delivers oestradiol through the skin

and into the blood stream. Climara

releases oestradiol in a continuous

and controlled way just as your

ovaries were doing before. Because

the medicine does not have to pass

through your stomach and liver, it

allows you to take a much lower

dose of oestrogen than would be

needed in a tablet. The oestradiol in

Climara can replace the oestrogen

in the body.

During menopause, the oestradiol

production of the ovaries declines.

Although menopause is natural, it

often causes distressing symptoms,

which are connected with the

gradual loss of the hormones

produced by the ovaries.

Climara provides oestrogen, which

the body is no longer making, to

prevent or relieve menopausal

symptoms such as hot flushes

(night sweats), sleep disturbances,

vaginal dryness, depression,

nervousness, irritability, headache,

dizziness.

Climara can also be used to

prevent bone mineral density loss

(where the bones become weaker,

more brittle and likely to break)

during menopause.

Calcium, vitamin D and regular

exercise are some other factors that

may help to prevent thinning of the

bones. You should include foods

that are good sources of calcium

and vitamin D in your daily diet and

exercise regularly. Your doctor can

advise you on which foods and

types of exercise are best for you.

Climara is not a contraceptive.

will not prevent you from falling

pregnant.

Ask your doctor if you have any

questions about why this

medicine has been prescribed

for you.

Your doctor may have prescribed

it for another reason.

BEFORE YOU USE

CLIMARA

When you must not use it

Do not use Climara if you have

an allergy to:

oestradiol, the active ingredient

in Climara

any of the ingredients listed at

the end of this leaflet.

Some of the symptoms of an

allergic reaction may include:

shortness of breath

wheezing or difficulty

breathing

swelling of the face, lips,

tongue or other parts of the

body

rash, itching or hives on the

skin.

Do not use Climara if you have:

severe uncontrolled high blood

pressure

severe liver disease such as

jaundice (signs of liver

problems such as yellowing of

skin and/or eyes) or persistent

itching during a previous

pregnancy

a history of or existing liver

tumours

suspected or existing tumours in

the uterus, ovaries or breast

known or suspected tumours

influenced by sex hormones

endometriosis (the presence of

tissue of the lining of the womb

in places in the body where it is

not usually found)

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2

a history of or existing blood clot

in the blood vessels (such as

blood clots in the legs)

if you recently had a heart attack

and/or stroke

if you have a high risk of venous

or arterial thrombosis (blood

clot)

severe diabetes

sickle-cell anaemia (inherited

disorder which causes the red

blood cells to change shape)

disturbances of fat metabolism

a history of herpes during

pregnancy

hearing loss (otosclerosis) that

worsens during pregnancy

undiagnosed abnormal vaginal

bleeding

If you have not had your uterus

(womb) removed (hysterectomy),

do not use Climara unless your

doctor has prescribed another

hormone progestogen to take with

Climara.

The use of oestrogens alone and

over a prolonged period can lead to

excessive development of the lining

of the womb and this can increase

the incidence of cancer of the

womb. This risk can be avoided by

the additional administration of a

progestogen. The general result of

this is regular shedding of the lining

of the womb and, therefore,

menstruation-like bleeding. If you

have not had a hysterectomy (your

uterus/womb removed) your doctor

should prescribe a progestogen for

you to take and you should discuss

this with your doctor before using

Climara.

If you have not told your doctor

about any of the above, tell them

before you start using Climara

Do not use this medicine if you

are pregnant.

It may affect your developing baby

if you use it during pregnancy.

Do not breast-feed if you are

using this medicine.

The active ingredient in Climara

passes into breast milk and there is

a possibility that your baby may be

affected.

Do not use this medicine after

the expiry date printed on the

pack and pouch.

The expiry date is printed on the

carton and on each pouch after

“EXP” (e.g. 11 18 refers to

November 2018). The expiry date

refers to the last day of that month.

If it has expired return it to your

pharmacist for disposal.

Do not use this medicine if the

packaging is torn or shows signs

of tampering.

If the packaging is damaged, return

it to your pharmacist for disposal.

If you are not sure whether you

should start using this medicine,

talk to your doctor.

Before you start to use it

Tell your doctor if you have

allergies to any other medicines,

foods, preservatives or dyes.

Tell your doctor if:

you are overweight

you smoke

you or anyone in your immediate

family has had blood clots

(thrombosis)

systemic lupus erythematosus

(SLE, a chronic inflammatory

disease)

you have any planned

hospitalisation, surgery or

prolonged immobilisation

Studies have suggested that HRT

may be associated with an

increased risk of developing blood

clots. You have an increased risk

of a blood clot if you have any of

the above risk factors. In addition

to these, there may be other risk

factors. In the case of a

combination of factors, the risk

may be higher than simply adding

two individual risks. Talk to your

doctor if you have any concerns.

Using Climara may also increase

your risk of coronary heart

disease. Tell your doctor if you

experience chest pain or

discomfort.

Using Climara may increase your

risk of gall bladder disease. This is

because oestrogen stimulates the

liver to remove more cholesterol

from blood and divert it to the gall

bladder.

Before being prescribed Climara,

your doctor should perform a

thorough medical and

gynaecological examination

(including the breasts and a pap

smear). Your doctor will also note

your family medical history and

exclude pregnancy.

Tell your doctor if you have or

have had any of the following

medical conditions:

diabetes

high blood pressure

varicose veins

otosclerosis (a type of hearing

loss)

endometriosis (the presence of

tissue of the lining of the

womb in places in the body

where it is not normally

found)

multiple sclerosis

epilepsy

porphyria (inherited or

acquired disorder of certain

enzymes)

tetany (mineral imbalance in

the body that results in severe

muscle spasms )

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3

chorea minor (disorder

characterised by irregular and

involuntary muscles )

kidney or heart disease

tumours in the pituitary gland

yellowing of the skin and/or

eyes (cholestatic jaundice) with

previous oestrogen use or

during pregnancy

migraine

a high level of triglycerides

(fats) in the blood

high or low calcium levels in

the blood

an underactive thyroid gland

(hypothyroidism)

an abnormal build-up of blood

vessels in the liver (hepatic

haemangioma)

chloasma (yellowish brown

pigmentation patches on the

skin, particularly of the face); if

so, avoid too much exposure to

the sun or ultraviolet radiation

asthma

systemic lupus erythematosus

(SLE; a disease affecting the

skin all over the body)

tumours in the womb or liver

hereditary angioedema, an

inherited disorder where

repeated episodes of severe

swelling occur

Tell your doctor if you are 65 years

or older when HRT is initiated. The

reason is that there is limited

evidence from clinical studies that

hormonal treatment may increase

the risk of significant loss of

intellectual abilities such as memory

capacity (dementia).

If Climara is used in the presence

of any of the conditions listed

above you will need to be kept

under close observation. Your

doctor can explain this to you.

Therefore, if any of these apply to

you, tell your doctor before starting

to use Climara.

HRT and cancer

Endometrial cancer

The risk of cancer of the lining of

the womb (endometrial cancer)

increases when oestrogens are

used alone for prolonged periods.

Taking a progestogen in addition

to the oestrogen lowers this risk.

Please inform your doctor if you

frequently have bleeding

irregularities or persistent bleeding

during the treatment with Climara.

Breast cancer

Tell your doctor if you have

suffered from fibrocystic disease of

the breasts (lumps in the breast) or

if you have first degree relatives

(mother, sisters, daughters) who

have had breast cancer.

Breast cancer has been diagnosed

slightly more often in women who

use hormone replacement therapy

(HRT) than in women of the same

age who do not use HRT. If you are

concerned about this information

you should discuss this with your

doctor. It is recommended that

yearly breast examinations are

conducted and regular breast self

examination (monthly) should be

carried out.

HRT has been reported to result in

an increased number of abnormal

mammograms requiring further

evaluation.

Ovarian cancer

Some observational studies show a

slightly increased overall risk of

developing ovarian cancer in

women who have used HRT

compared to women who have

never used HRT. In women

currently using HRT, this risk was

further increased. These

associations have not been shown

in all studies. There is no

consistent evidence that the risk of

developing ovarian cancer is

related to the duration of use of

HRT. However, the risk may be

more relevant with long-term use

(for several years).

Liver tumour

During or after the use of

hormones such as those that are

contained in Climara, benign liver

tumours have rarely occurred, and

malignant liver tumours even more

rarely. In isolated cases, bleeding

has occurred from such tumours

into the abdominal cavity.

Although such events are rare, you

should inform your doctor about

any pain in your upper abdomen

that does not disappear within a

short time

Taking other medicines

Tell your doctor or pharmacist

if you are taking any other

medicines, including any that

you get without a prescription

from your pharmacy,

supermarket or health food

shop.

Some medicines and Climara may

interfere with each other. These

include:

medicines to treat high blood

pressure, chest pain and/or

irregular heart beat such as

ACE inhibitors, verapamil,

diltiazem

macrolide antibiotics (e.g.

clarithromycin, erythromycin)

medication used to treat

epilepsy, such as hydantoins,

barbituates, primidone,

carbamazepine

rifampicin for the treatment of

tuberculosis

herbal medicines containing St

John’s Wort

medicines used to treat HIV

such as ritonavir or nevirapine

some medicines used to treat

Hepatitis C Virus (HCV) such

as boceprevir, telaprevir

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medicines used to treat fungal

infections such as

ketoconazole, itraconazole,

voriconazole, fluconazole

grapefruit juice

medicines used to treat

diabetes, such as insulin or anti-

diabetic medications

These medicines may be affected

by Climara or may affect how well

it works. You may need different

amounts of your medicines, or you

may need to take different

medicines.

Your doctor and pharmacist have

more information on medicines to

be careful with or avoid while

using this medicine.

HOW TO USE

CLIMARA

Follow all directions given to you

by your doctor or pharmacist

carefully.

They may differ from the

information contained in this

leaflet.

If you do not understand the

instructions printed on the

pharmacist label, ask your

doctor or pharmacist for help.

How much to use

The amount of oestrogen you need

will depend upon your body's

requirements. Your doctor may

adjust this amount by changing the

size of the patch you use.

How to use it

The best place to apply Climara

patches is on your lower abdomen

or buttocks.

NEVER put Climara

patches on your breasts

Do not put the patch on your

waistline where tight clothes may

rub it. Avoid putting the patch on

areas where the skin is hairy or

folded.

Before applying a Climara patch,

make sure your skin is clean and

dry. Do not apply the patch to oily,

broken or irritated skin.

1. Remove Climara from the

pouch

The Climara patch is packed in a

protective pouch. Tear open the

pouch at the notched corner and

remove the patch. Do not use

scissors as you may accidentally cut

the patch. Do not peel the square

silver sticker inside the pouch as

this contains the desiccant.

This is

not the Climara patch.

Dispose of

the pouch once the Climara patch

has been applied.

2. Take the backing off the patch

A clear plastic protective backing

which is slightly larger than the

patch itself covers the sticky side of

the patch. The backing must be

removed before you apply the patch

to your skin.

Remove the backing by holding the

edge of the patch in one hand and

peeling the backing off with the

other hand from the crease line.

Half of the backing will come off,

exposing part of the patch. As you

apply the patch to your skin, peel

off the rest of the backing. Do not

touch the sticky side of the patch.

Apply the patch immediately after

opening the pouch and removing

the backing. Throw away the

backing.

3. Apply the patch to your skin

Place the sticky side of the patch on

a clean, dry area of skin. Press the

patch firmly in place for about 10

seconds. Make sure the patch

sticks well, especially around the

edges.

4. Changing Climara patches

Change the patch once every week

(every 7 days). Remove the old

patch and discard it, out of the way

of children. Apply your new patch

to a

different

area of clean, dry

skin.

Do not put the patch on the

same area of skin each week.

5. What to do if your patch

comes off

Climara patches are unlikely to fall

off. But if the patch does fall off

put a new patch on for the rest of

the seven days.

When to use it

Climara patches are usually worn

continuously, and replaced every 7

days. You should only wear one

patch at a time, unless your doctor

tells you otherwise.

Your doctor will explain when to

start using the patch and if you

should use it any other way (for

example, for 3 weeks out of 4).

How long to use it

Your doctor will advise you on

how long to use Climara. Your

doctor should discuss with you

the risks and benefits with

extended use of this product and

your treatment with hormone

therapy should also be re-

evaluated at regular intervals.

Treatment with oestrogens such as

Climara, with or without

progestogens, should be used at

the lowest effective dose and for

the shortest period of time.

You may have an increased risk of

developing breast cancer, heart

disease, stroke, blood clots on the

lungs and dementia. On the other

hand, the risk of hip fractures and

bowel cancer may be reduced.

Your doctor can discuss these

risks and benefits with you, taking

into account your particular

circumstances.

CLIMARA

5

If you forget to use it

If you forget to change the Climara

patch, change it as soon as you

remember. One patch only works

for 7 days.

If you lose a patch or forget to

replace it for several days, irregular

bleeding may occur.

If you use too much

(overdose)

Oestrogen overdose is unlikely with

this type of application. In the event

of accidental overdose, remove the

patch.

If you are worried, telephone

your doctor or the Poisons

Information Centre (Australia:

13 11 26 or New Zealand: 0800

POISON or 0800 764 766) for

advice, or go to Accident and

Emergency at the nearest

hospital, if you think that you or

anyone else may have used too

much Climara.

Do this even if there are no signs

of discomfort or poisoning.

may need urgent medical attention.

Symptoms of an overdose may

include nausea, vomiting, breast

discomfort, breakthrough bleeding,

fluid retention and bloating.

WHILE YOU ARE

USING CLIMARA

Things you must do

If you are about to be started on

any new medicine, remind your

doctor and pharmacist that you

are using Climara.

Tell any other doctors, dentists,

and pharmacists who treat you

that you are using this medicine.

Tell your doctor immediately if

you become pregnant while using

Climara.

The use of Climara

should be stopped immediately.

If you are still able to fall pregnant,

barrier methods of contraception

should be practised (such as

condoms or a diaphragm). If there

is a chance that pregnancy has

occurred, stop using the patch until

it has been ruled out.

If you are going to have surgery,

tell the surgeon or anaesthetist

well in advance that you are

using this medicine.

Climara

should not be used at least four to

six weeks before surgery.

If irregular menstrual bleeding

occurs repeatedly during the use of

Climara or if the bleeding in the

treatment-free weeks is unusually

heavy, tell your doctor.

See your doctor at least once a

year for a check-up. Some

women will need to go more

often.

Your doctor will check your

breasts and order a mammogram at

regular intervals, check your uterus

and cervix and do a pap smear at

regular intervals, and monitor your

blood pressure

Check your breasts each month

and report any changes promptly

to your doctor.

Your doctor or nurse can show you

how to check your breasts properly.

Stop using it immediately

if

You should stop treatment at once

and consult your doctor if you

have any of the following

conditions:

your very first attack of

migraine (typically a throbbing

headache and nausea preceded

by visual disturbances)

worsening of pre-existing

migraine, any unusually

frequent or unusually severe

headaches

sudden disturbances of vision

or hearing

swollen veins

(thrombophlebitis),

itching of the whole body

unusual upper abdominal pains

that do not disappear within a

short period of time

planned operations/surgery or

immobilisation

seizures

increase in blood pressure

If you get a blood clot while you

are using Climara or there is a

suspicion of this you should stop

using it immediately and contact

your doctor. Warning signs to look

out for are:

coughing blood

unusual pains or swelling of

your arms or legs

sudden shortness of breath, pain

or tightness in the chest

fainting

Climara must also be stopped at

once if you develop jaundice

(yellowing of the skin and/or

eyes). Tell your doctor

immediately if either occurs.

Things you must not do

Do not use Climara to treat any

other complaints unless your

doctor tells you to.

Do not give your medicine to

anyone else, even if they have

the same condition as you.

Do not stop using your medicine

or lower the dosage without

checking with your doctor.

If you stop using it suddenly, your

condition may worsen or you may

have unwanted side effects.

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6

What to be careful of

Excess intake of alcohol during use

of HRT has an influence on the

treatment. Your doctor will advise

you.

Other things to know

You can bathe, shower or swim

when wearing a Climara patch.

The patch might, however,

become detached from the skin

in very hot water or in the

sauna.

You can still drive safely when

you are using Climara patches.

If there are, repeatedly,

persistent skin irritations (e.g.

persistent reddening or itching

at the application site) even if

the application site is changed

according to the directions

given, you should consider

stopping treatment.

SIDE EFFECTS

Tell your doctor or pharmacist

as soon as possible if you do not

feel well while you are using

Climara.

All medicines can have side

effects. Sometimes they are

serious, most of the time they are

not. You may need medical

attention if you get some of the

side effects.

Do not be alarmed by the

following list of side effects. You

may not experience any of them.

Ask your doctor or pharmacist

to answer any questions you may

have.

Tell your doctor or pharmacist if

you notice any of the following

and they worry you:

redness, rash, itching, stinging

and blisters on the skin after the

patch has been removed

tender or painful breasts, breast

enlargement

irregular menstrual bleeding

fluid retention (bloating or

swelling in the arms, ankles or

feet)

rash or itching

nausea

headache

nervousness or depressive

moods

dizziness

unusual tiredness

changes in body weight

pain (including back and pelvic

pain)

increased sweating

leg cramps

stomach pain, cramps or wind

acne

vaginal itching, burning or

discharge

Tell your doctor immediately or

go to Accident and Emergency at

your nearest hospital if you

notice any of the following:

signs of allergy such as rash,

itching or hives on the skin,

swelling of the face, lips,

tongue, or other parts of the

body, shortness of breath,

wheezing, or trouble breathing

yellowing of the skin and/or

eyes (cholestatic jaundice)

coughing blood, unusual pains

or swelling of your arms or

legs, sudden shortness of

breath, fainting

If you have these side effects, you

may need urgent medical attention.

Skin disorders have been reported

in women receiving HRT. Tell

your doctor if you notice itchy,

reddish, painful lumps (erythema

nodosum, erythema multiforme,

haemorrhagic dermatitis) or

yellowish brown pigmentation on

the skin (chloasma).

Tell your doctor or pharmacist

if you notice anything that is

making you feel unwell.

Other side effects not listed above

may also occur in some people.

Also tell your doctor if you have

any of the symptoms listed under

While you are taking Climara -

stop taking it immediately

”.

AFTER USING

CLIMARA

Storage

Keep your patches in the pack

until it is time to use them.

Do not remove the patch from

the protective pouch until you

are ready to apply it.

Keep your patches in a cool dry

place below 30

o

C.

Do not store it or any other

medicine in the bathroom, near

a sink, or on a window-sill.

Do not leave it in the car.

Heat and dampness can destroy

some medicines.

Keep it where children cannot

reach it.

A locked cupboard at least one-

and-a half metres above the

ground is a good place to store

medicines.

Disposal

If your doctor tells you to stop

using this medicine or the expiry

date has passed, ask your

pharmacist what to do with any

medicine that is left over.

When disposing of patches, make

sure children cannot reach them.

Return any unused medicine to

your pharmacist.

CLIMARA

7

PRODUCT

DESCRIPTION

What it looks like

A Climara patch is a clear oval thin

film with an adhesive side (sticky

side) attached to a clear plastic

protective backing. Each pack of

Climara contains 4 pouches each

containing a patch.

Climara is available in 4 strengths:

Climara 25

Climara 50

Climara 75

Climara 100

The suffixes ‘25”, “50”,”75” and

“100” refer to the daily amount of

oestradiol transferred via the skin to

your body from the respective

Climara patch.

Not all strengths may be marketed.

Ingredients

Active ingredient per patch:

Climara 25 – 2 mg of oestradiol

Climara 50 – 3.8 mg of

oestradiol

Climara 75 – 5.7 mg of

oestradiol

Climara 100 – 7.6 mg of

oestradiol

Inactive ingredients:

polymer 55236

ethyl oleate

polyethylene backing

acrylate copolymer adhesive

glycerol laurate

isopropyl myristate

Supplier

Made in USA for:

Bayer Australia Ltd

ABN 22 000 138 714

875 Pacific Highway

Pymble NSW 2073

Australia

Bayer New Zealand Limited

3 Argus Place

Hillcrest, North Shore

Auckland 0627

New Zealand

Australian Registration

Number

Climara 25 - AUST R 73962

Climara 50 - AUST R 56197

Climara 75 - AUST R 73963

Climara 100 - AUST R 56198

Date of preparation

March 2016

See TGA website

(www.ebs.tga.gov.au) for latest

Australian Consumer Medicine

Information.

See MEDSAFE website

(www.medsafe.govt.nz) for latest

New Zealand Consumer Medicine

Information.

® Registered trademark of the

Bayer group, Germany

© Bayer Australia Ltd

All rights reserved.

190523 CLIMARA

Page 1 of 21

NEW ZEALAND DATA SHEET

PRODUCT NAME

CLIMARA®

estradiol

QUALITATIVE AND QUANTITATIVE COMPOSITION

CLIMARA 25 patch contains 2.0 mg of estradiol (equivalent to 2.0 mg estradiol hemihydrate)

releasing a nominal 25 micrograms per 24 hours.

CLIMARA 50 patch contains 3.8 mg of estradiol (equivalent to 3.9 mg estradiol hemihydrate)

releasing a nominal 50 micrograms per 24 hours.

CLIMARA 75 patch contains 5.7 mg of estradiol (equivalent to 5.9 mg estradiol hemihydrate)

releasing a nominal 75 micrograms per 24 hours.

CLIMARA 100 patch contains 7.6 mg of estradiol (equivalent to 7.8 mg estradiol hemihydrate)

releasing a nominal 100 micrograms per 24 hours.

For a list of excipients see 6.1 List of excipients.

PHARMACEUTICAL FORM

The CLIMARA transdermal delivery system is a transparent oval patch containing estradiol in an

acrylate adhesive matrix.

CLINICAL PARTICULARS

Therapeutic indications

For short-term treatment of complaints associated with the menopause and post-menopause,

including signs and symptoms of estrogen deficiency, whether naturally or surgically induced.

Estrogen replacement therapy in women with an intact uterus should always be opposed by a

progestogen in an adequate dosage regimen to ensure secretory transformation of the

endometrium at regular intervals.

Prevention of postmenopausal osteoporosis.

For further information please refer to 5.1 Pharmacodynamic properties.

Dose and method of administration

Hormonal contraception should be stopped when hormone replacement therapy (HRT) is started

and the patient should be advised to take non-hormonal contraceptive precautions, if required.

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Dosage Regimen

Hormone replacement therapy should only be continued for as long as the benefit in alleviation of

severe symptoms outweighs the risk for the individual woman. The need for continuing treatment

should be reviewed periodically (e.g. at 6-monthly intervals). Treatment should be based on

individual considerations (see also 4.4 Special warnings and precautions for use).

Initiation of Therapy

Treatment to control postmenopausal symptoms is usually initiated with the CLIMARA 50 patch

applied to the skin once weekly. Treatment should begin with the lowest effective dose and be

adjusted as necessary until symptoms are controlled. Once treatment is established, the lowest dose

necessary for the relief of symptoms should be used. The treatment can be given without

interruption or it can be interrupted for one week after every 3 weeks.

For continuous use: A patch should be applied once a week, each used patch being removed after 7

days and a fresh patch applied to a different site.

For cyclical use: The patches should be applied weekly for 3 consecutive weeks followed by a seven-

day interval, without a patch being applied before the next course.

In women who are not currently taking oral estrogens, treatment with CLIMARA can be initiated at

once. In women who are currently taking oral estrogens, treatment with CLIMARA can be initiated

one week after withdrawal of oral therapy, or sooner if symptoms reappear before the end of the

week.

For prevention of osteoporosis: CLIMARA can prevent the accelerated loss of bone density due to

estrogen deficiency and may be used for prevention of postmenopausal bone mineral density loss in

the appropriate patient group (see 4.1 Therapeutic indications). The effect is seen only while

estrogen replacement therapy continues and discontinuation may re-establish the natural rate of

bone loss. In patients with established osteoporosis and evidence of fractures, therapy should be

initiated with CLIMARA 100, to prevent postmenopausal bone loss, as soon as possible after the

menopause.

Unopposed estrogen therapy should not be used unless the patient has had a hysterectomy. In

women with an intact uterus, the prolonged use of estrogens alone in the climacteric can induce

hyperplasia of the endometrium and, in this connection, increase the risk of endometrial cancer.

This risk can best be minimised by the additional administration of a progestogen, sequentially for at

least 10 - 14 days of each calendar month. This generally leads to secretory conversion and shedding

of the uterine lining and, as a result, to menstruation-like bleeding after the end of the period of

progestogen treatment (see 4.4 Special warnings and precautions for use). For patches releasing

more than 50 mcg/day, the endometrial protective effect of added progestogens has not been

demonstrated.

If a continuous treatment regimen has been chosen, the administration of a progestogen may be

initiated at an arbitrarily selected time (e.g. at the beginning or at the end of a month) and should be

repeated at regular intervals of about 4 weeks.

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If a cyclical (3-week) treatment regimen has been chosen, the progestogen should be administered

during the last 10 - 14 days of each 3-week period of estradiol administration, so that the 4th week

of each cycle remains without any treatment.

In either case a withdrawal bleed usually occurs 2 - 3 days after the end of the period of progestogen

administration.

Method of Application

Following removal of the protective liner, the adhesive side of the CLIMARA patch should be placed

on a clean, dry area of the skin of the trunk (lower abdomen) or buttocks. CLIMARA patches must

not be applied on or near 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 patches should not be applied

twice in succession to the same site. The area selected should not be oily, damaged or irritated. The

waistline should be avoided since tight clothing may rub the patch off. CLIMARA should be applied to

skin sites that will be covered by clothes. Application to areas where sitting would dislodge the patch

should be avoided. 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. If the patch lifts,

pressure should be applied to maintain adhesion.

The patch should be changed once weekly. Only one patch should be worn at any time during the 7-

day dosing interval. The sites of application should be rotated, with an interval of at least one week

between applications to a particular site.

If the patch is applied correctly, the patient can bath, shower or swim as usual. The patch might,

however, become detached from the skin in very hot water or in the sauna.

In the event that a patch falls off, before the 7 days are up, a new patch should be applied for the

remainder of the 7-day dosing interval.

If the patient forgets to replace the patch, this should be done as soon as possible after she notices

this. The next patch has to be used after the normal 7-day interval.

Contraindications

Hormone replacement therapy (HRT) should not be started in the presence of any of the conditions

listed below. If any of these conditions appear during use of CLIMARA, treatment should be stopped

immediately.

Known allergy to estradiol or any of the components of the transdermal delivery system

Severe uncontrolled hypertension

Pregnancy or lactation

Suspected or existing tumour of the uterus, breast or ovaries

Known or suspected premalignant conditions or malignancies, if sex steroid-influenced

Endometriosis

Severe disturbances of liver function

Previous or existing liver tumours, benign or malignant

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Active deep venous thrombosis, thromboembolic disorders, thrombophlebitis, or a recent

history of these conditions

Acute arterial thromboembolism (e.g. angina, myocardial infarction, stroke) or a recent

history of these conditions

A high risk of venous or arterial thrombosis

Severe diabetes with vascular changes

Sickle cell anaemia

Disturbances of lipometabolism

History of herpes of pregnancy

Otosclerosis with deterioration during pregnancy

Jaundice or persistent itching during a previous pregnancy

Undiagnosed abnormal vaginal bleeding

Non-hysterectomised women unless on concomitant progestogen therapy

Hereditary or acquired predisposition to venous thrombosis (e.g. antithrombin III deficiency)

Special warnings and precautions for use

The benefits and risks of hormone replacement therapy (HRT) must always be carefully weighed,

including consideration of the emergence of risks as therapy continues. HRT should only be used for

the short term relief of menopausal symptoms. Estrogens with or without progestogens should be

prescribed at the lowest effective doses and for the shortest duration consistent with the treatment

goals and risks for the individual woman. The risks of HRT should be assumed to be similar for all

doses of estrogens and estrogen/progestogen combinations.

All prospective and current users of HRT should be advised of the risks and benefits of estrogens and

progestogens and the need for treatment should be reviewed on a 6 monthly basis.

Medical Examination/Consultation

A complete medical history should be taken and a physical examination should be conducted prior

to the initiation or reinstitution of treatment with CLIMARA, guided by section 4.3 Contraindications

and section 4.4 Special warnings and precautions for use, and should be repeated periodically. The

frequency and nature of these examinations should be based on established practice guidelines, 6

monthly reviews are generally considered appropriate, and be adapted to the individual woman, but

should generally include pelvic organs, including routine cervical cytology, abdomen, breasts and

blood pressure. Pregnancy should also be excluded. The need for continued therapy should be

reconsidered at each review.

If any of the conditions/risk factors mentioned below are present or deteriorate, an individual risk-

benefit analysis should be done before CLIMARA is started or continued.

CLIMARA is not a Contraceptive

Where applicable, contraception should be practised with non-hormonal methods (with the

exception of the rhythm and temperature methods). If there is a chance that pregnancy has

occurred, tablet taking must be interrupted until it has been ruled out.

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Reasons for Immediate Discontinuation

Occurrence for the first time of migrainous headaches or more frequent occurrence of unusually

severe headaches, sudden perceptual disorders (e.g. disturbances of vision or hearing) or other

symptoms that are possible prodromata of vascular occlusion, first signs of thrombophlebitis or

thromboembolic symptoms (for example, unusual pains in or swelling of the legs, stabbing pains on

breathing or coughing for no apparent reason), acute arterial thromboembolism (e.g. myocardial

infarction, stroke), a feeling of pain and tightness in the chest, pending operations (six weeks

beforehand), immobilisation (for instance, following accidents), onset of jaundice, onset of hepatitis,

itching of the whole body, recurrence of cholestatic jaundice or cholestatic pruritus which occurred

first during pregnancy or previous use of sex steroids, increase in epileptic seizures, significant rise in

blood pressure, pregnancy.

Uterine myomas and pre-existing fibroids may increase in size under the influence of estrogens. If

this is observed, CLIMARA treatment should be discontinued.

Precautions before Use

Estrogens with or without progestogens should not be used for the long-term maintenance of

general health, including the primary prevention of cardiovascular disease as the risks of long-term

treatment with HRT in most circumstances, outweigh the benefits. The Women’s Health Initiative

(WHI) study reported increased risks of myocardial infarction, stroke, invasive breast cancer,

pulmonary emboli and deep vein thrombosis in postmenopausal women during five years of

treatment with conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone

acetate (2.5 mg) relative to the placebo (see Table 1).

The WHI study was designed to investigate the efficacy and safety of long-term HRT in preventing

coronary heart disease in healthy postmenopausal with an intact uterus. A total of 8506 women

received HRT and 8102 women received placebo for an average of 5.2 years.

Table 1. Summary of the incidence of adverse events described in the WHI study

Adverse Event

Relative Risk of HRT vs

placebo at 5.2 years (95% CI)

Change in number of

adverse events per 10,000

women in one year

Breast cancer

1.26 (1.00 - 1.59)

8 extra

Heart disease

1.29 (1.02 - 1.63)

7 extra

Stroke

1.41 (1.07 - 1.85)

8 extra

Pulmonary embolism

2.13 (1.39 - 3.25)

8 extra

Myocardial infarction

1.32 (1.02 - 1.72)

Deep vein thrombosis

2.07 (1.49 - 2.87)

Colorectal cancer

0.63 (0.43 - 0.92)

6 fewer

Hip fracture

0.66 (0.45 - 0.98)

5 fewer

* Information not available

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Other doses of conjugated estrogens and medroxyprogesterone acetate and other combinations of

estrogens and progestogens were not studied in the WHI and, in the absence of comparable data,

these risks should be assumed to be similar. Because of these risks, estrogens and progestogens

should be prescribed at the lowest effective doses and for the shortest duration (generally not

longer than 3 - 4 years), consistent with the treatment goals and risks for the individual woman, see

the WHI Studies and Million Women Study section below.

The prolonged use of estrogens alone in the climacteric can induce hyperplasia of the endometrium

and, in this connection, increase the risk of endometrial cancer. This risk can best be minimised by

the additional administration of a progestogen, normally for 10 - 14 days per month. This generally

leads to secretory conversion and shedding of the uterine lining and, as a result, to menstruation-like

bleeding after the end of the period of progestogen treatment (see 4.2 Dose and method of

administration).

If irregular bleeding occurs repeatedly during the use of CLIMARA, or if the bleeding in the

treatment-free weeks is unusually profuse, thorough differential-diagnostic clarification is essential.

If there are repeatedly persistent skin irritations (e.g. persistent erythema or pruritus at the

application site) even if the application has been regularly changed as instructed in the directions,

one should consider cessation of transdermal treatment.

Contact sensitisation is known to occur with all topical medicine applications. Although contact

sensitisation to any components of the patch is extremely rare, patients who develop it should be

warned that a severe hypersensitivity reaction may occur with subsequent exposure to the causative

agent.

Close medical supervision (including periodic measurement of prolactin levels) is necessary if the

patient suffers from prolactinoma.

The following conditions have been reported to occur or deteriorate with HRT use. Although the

evidence of an association with HRT use is inconclusive, close medical supervision is necessary in

patients with a history of, or risk factors for, thromboembolic disorders, diabetes, hypertension,

varicose veins, asthma, otosclerosis, systemic lupus erythematosus, multiple sclerosis, epilepsy,

porphyria, tetany, chorea minor, heart failure, disturbances of kidney or liver function, migraine,

endometriosis, chloasma, or a history of chloasma gravidarum. Patients with fibrocystic disease of

the breasts and patients with first degree relatives who have had breast cancer also require close

supervision and should be instructed in breast self-examination. The same applies to patients with

benign tumours of the uterine smooth muscles, since the size of such tumours can increase under

estrogen therapy. It is recommended in long term use that the benefits should be weighed against

the risks for each woman.

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms

of angioedema.

If any of the conditions/risk factors mentioned below is present or deteriorates, an individual risk-

benefit analysis should be done before CLIMARA is started or continued.

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Cardiovascular Risk

The WHI study reported increased risks of myocardial infarction and stroke, as well as pulmonary

emboli and deep vein thrombosis in postmenopausal women during five years of treatment with

oral conjugated equine estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg)

relative to placebo.

Venous Thromboembolism

Both randomised controlled and epidemiological studies have suggested that HRT may be associated

with an increased relative risk of developing venous thromboembolism (VTE), i.e. deep venous

thrombosis or pulmonary embolism. CLIMARA is contraindicated in women with a history of or

predisposition to thromboembolic disorders.

In a subset of WHI, women in the oral estrogen plus progestogen group had a two-fold greater rate

of VTE, including deep vein thrombosis and pulmonary embolism, compared to women receiving

placebo. The rates of VTE were 34 and 16 per 10,000 person years in the treatment and placebo

groups respectively. The increase in VTE risk was observed during the first year and persisted.

Risk benefit should therefore be carefully weighed, in consultation with the patient, when

prescribing HRT to women with a risk factor for VTE. Generally recognised risk factors for VTE

include a personal history, a family history (the occurrence of VTE in a direct relative at a relatively

early age may indicate genetic disposition), and obesity (body mass index > 30 kg/m2). The risk of

VTE also increases with age. Extensive varicose veins and superficial thrombophlebitis may have a

role in VTE. The risk of VTE may be temporarily increased with prolonged immobilisation, major

elective or post-traumatic surgery, or major trauma. Depending on the nature of the event and the

duration of the immobilisation, consideration should be given to a temporary discontinuation of

HRT. If feasible, estrogens should be discontinued at least 4 to 6 weeks before surgery of the type

associated with an increased risk of thromboembolism, or during periods of prolonged

immobilisation.

Treatment should be stopped at once if there are symptoms of a thrombotic event or suspicion

thereof. Symptoms of venous or arterial thrombosis can include: unilateral leg pain and/or swelling;

sudden severe pain in the chest, whether or not it radiates to the left arm; sudden breathlessness;

sudden onset of coughing; any unusual, severe, prolonged headache; sudden partial or complete

loss of vision; diplopia; slurred speech or aphasia; vertigo; collapse with or without focal seizure;

weakness or very marked numbness suddenly affecting one side or one part of the body; motor

disturbances; “acute” abdomen.

The potential for an increased synergistic risk of thrombosis should be considered in women who

possess a combination of risk factors or exhibit a greater severity of an individual risk factor. This

increased risk may be greater than a simple cumulative risk of the factors. HRT should not be

prescribed in case of a negative risk benefit assessment.

Arterial Thromboembolism

Two large clinical trials with continuous combined conjugated equine estrogens (CEE) and

medroxyprogesterone acetate (MPA) showed a possible risk of coronary heart disease (CHD) in the

first year of use and no benefit thereafter. One large clinical trial with CEE alone showed a potential

reduction of CHD rates in women aged 50 - 59 and no overall benefit in the total study population.

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As a secondary outcome, in two large clinical trials with CEE alone or combined with MPA a 30 - 40%

increased risk of stroke was found. It was uncertain whether these findings also extend to other HRT

products or non-hormonal routes of administration.

Breast Cancer

The use of estrogens alone as well as combined/sequential estrogen and progestogen use for several

years is associated with an increased risk of breast cancer. This emerges towards the end of the first

year of treatment.

A meta-analysis from 51 epidemiological studies reported that there is a modest increased risk of

having breast cancer diagnosed in women who have used HRT for more than 5 years. The findings

may be due to an earlier diagnosis, the biological effects of HRT, or a combination of both. The

relative risk increases with duration of treatment (by 2.3% per year of use) and may be lower or

possibly neutral with estrogen only products. This is comparable to the increased risk observed in

women with every year of delay of natural menopause (2.8% per year of delay). The increased risk

gradually disappears during the course of the first 5 years after cessation of HRT. Breast cancers

found in women using HRT are more likely to be localised to the breast than those found in non-

users (see WHI Studies and Million Women Study below). Data regarding spread outside the breast

are non-conclusive. The role of progestogens in the risk of breast cancer is unclear.

HRT increases the density of mammographic images which may adversely affect the radiological

detection of breast cancers in some cases. This may have implications for the sensitivity and

specificity of breast cancer screening. All women should undertake yearly breast examinations and

perform monthly breast self-examinations. In addition, mammography examinations should be

scheduled based on patient age, risk factors and prior mammogram results.

Endometrial Cancer

Prolonged exposure to unopposed estrogens in women with intact uteri increases the risk of

endometrial hyperplasia and carcinoma in postmenopausal women. Studies have suggested that the

addition of a progestogen to the regimen reduces the risk of endometrial hyperplasia and/or cancer.

Estrogen or estrogenic compounds must not be used alone as hormone replacement therapy in

women who have not had a hysterectomy. Close clinical surveillance of all women taking estrogens

is important. Adequate diagnostic measures, including endometrial sampling when indicated, should

be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal

vaginal bleeding. There is no evidence that the use of natural estrogens results in a different

endometrial risk profile than synthetic estrogens of equivalent estrogen dose.

Addition of a Progestogen when a Woman has not had a Hysterectomy

Studies of the addition of a progestogen for 10 or more days of a cycle of estrogen administration, or

daily with estrogen in a continuous regimen, have reported a lowered incidence of endometrial

hyperplasia than would be induced by estrogen treatment alone. Endometrial hyperplasia may be a

precursor to endometrial cancer.

There are, however, possible risks that may be associated with the use of progestogens with

estrogens compared to estrogen-alone regimens. These include: a possible increased risk of breast

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cancer, adverse effects on lipoprotein metabolism (e.g. lowering HDL, raising LDL) and impairment of

glucose tolerance.

Ovarian Cancer

Ovarian cancer is less prevalent than breast cancer. A meta-analysis from 52 epidemiological studies

reported that the overall risk of being diagnosed with ovarian cancer is slightly increased for users of

HRT compared to women who have never used HRT (prospective studies: RR 1.20, 95% CI 1.15-1.26;

all studies combined: RR 1.14, 95% CI 1.10-1.19). In women currently using HRT the risk of ovarian

cancer was further increased (RR 1.43, 95% CI 1.31-1.56).

These associations have not been shown in all studies including randomised controlled trials, e.g. the

WHI.

Furthermore, an effect of duration of exposure has not been consistently shown, but the risk may be

more relevant with long-term use (several years).

Liver Tumour

In rare cases benign, and in even rarer cases, malignant liver tumours leading in isolated cases led to

life-threatening intra-abdominal haemorrhage have been observed after use of hormonal

substances such as the one contained in CLIMARA. If severe upper abdominal complaints, liver

enlargement or signs of intra-abdominal haemorrhage occur, a liver tumour should be included in

the differential diagnostic considerations.

Gallbladder Disease

Estrogens are known to increase the lithogenicity of the bile. Some women are predisposed to

gallbladder disease during estrogen therapy. A two- to four-fold increase in the risk of gall bladder

disease in women receiving oral estrogens (including oral contraceptives) has been reported.

Dementia

The Women’s Health Initiative Memory Study (WHIMS), a sub-study of WHI, reported an increased

risk of developing probable dementia in post menopausal women 65 years of age or older during

four years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative

to placebo. The risk may be decreased if treatment is initiated in the early menopause as observed in

other studies. It is unknown whether these findings also extend to other HRT products.

WHI Studies and Million Women Study

In a prospective randomised US clinical trial involving 8506 postmenopausal women who received

oral hormone replacement therapy (HRT) using a continuous combined regimen of conjugated

equine estrogens (conjugated estrogens) 0.625 mg/day plus medroxyprogesterone acetate 2.5

mg/day and 8102 women who received placebo for an average of 5.2 years, adverse effects on the

cardiovascular system and the incidence of breast cancer were observed. The Women's Health

Initiative (WHI) study was designed to investigate the efficacy and safety of long-term HRT in

preventing coronary heart disease (CHD) in healthy postmenopausal women with an intact uterus. A

global index summarising the balance of risks and benefits included an analysis of the primary

outcome of CHD and the primary adverse outcome of invasive breast cancer, and the following

secondary outcomes: stroke, pulmonary embolism (PE), endometrial cancer, colorectal cancer, hip

fracture, and death due to other causes. The women enrolled in the study had a mean age at entry

of 63.3 years. On average they were overweight (mean body mass index [BMI] = 28.5) and one-third

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were obese (BMI

30), 50% were previous or current smokers, one-third had received treatment for

high blood pressure and over 10% had raised cholesterol levels requiring medication.

After a mean of 5.2 years of follow-up, the study was stopped prematurely because the preset

criterion for invasive breast cancer was fulfilled and the global index supported risks exceeding

benefits. Estimated hazard ratios (HRs) (nominal 95% confidence intervals [CIs]) were as follows:

CHD, 1.29 (1.02 - 1.63); breast cancer, 1.26 (1.00 - 1.59); stroke, 1.41 (1.07 - 1.85); PE, 2.13 (1.39 -

3.25); colorectal cancer, 0.63 (0.43 - 0.92); endometrial cancer, 0.83 (0.47 - 1.47); hip fracture, 0.66

(0.45 - 0.98), and death due to other causes, 0.92 (0.74 - 1.14). Corresponding HRs (nominal 95% CIs)

for composite outcomes were 1.22 (1.09 - 1.36) for total cardiovascular disease (arterial and venous

disease), 1.03 (0.90 - 1.17) for total cancer and 1.15 (1.03 - 1.28) for the global index. The HR for

total fractures was 0.76 (0.69 - 0.85) while total mortality was unchanged [0.98 (0.82 - 1.18)].

In this study, the absolute excess risks per 10,000 person-years attributable to estrogen plus

progestin were small, i.e. 7 more cases of CHD (37 vs 30), 8 more strokes (29 vs 21), 8 more

pulmonary emboli (15 vs 7) and 8 more invasive breast cancers (38 vs 30), while the absolute risk

reductions per 10,000 person-years were 6 fewer colorectal cancers (10 vs 16), 1 less endometrial

cancer (5 vs 6), 5 fewer hip fractures (10 vs 15), 44 fewer total fractures (147 vs 191) and one less

death (52 vs 53) than in women not using that form of HRT.

In the Million Women Study 1,084,110 women were followed up for cancer incidence and death.

The average age of the women at recruitment was 55.9 years, and the average period of follow-up

was 2.6 years for the analyses of cancer incidence and 4.1 years for the analyses of mortality. Overall

50% of the study population had used HRT at some point. There were 9,364 newly diagnosed cases

of invasive breast cancer and 637 breast cancer deaths. Current users of HRT at recruitment were

more likely to develop breast cancer and die from it than patients who had never used HRT. Patients

who had used HRT previously but were no longer using it were however not at an increased risk of

newly diagnosed or fatal disease. The incidence was significantly increased for current users of

preparations containing estrogen only, estrogen/progestogen and tibolone, but the magnitude of

the associated risk was greater for the combined treatment than for other types of HRT.

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Table 2. Relative risk of newly diagnosed invasive breast cancer in relation to recency and type of

HRT used

HRT use at baseline

Cases/population

Relative risk (95% FCI)*

All never users

2894/392,757

1.00 (0.96 - 1.04)

All past users

1044/150,170

1.01 (0.95 - 1.08)

Current users of:

Estrogen only

991/115,383

1.30 (1.22 - 1.38)

Estrogen –

progestogen

1934/142,870

184/18,186

2.00 (1.91 - 2.09)

1.45 (1.25 - 1.67)

Tibolone

93/9548

1.44 (1.17 - 1.76)

FCI = floated CI.

*Relative to never users, stratified by age, time since menopause, parity and age at first birth, family

history of breast cancer, body-mass index, region and deprivation index.

Results varied little between specific estrogens and progestogens or their doses, or between

continuous or sequential regimens. The relative risks were significantly increased separately for oral,

transdermal and implanted estrogen-only formulations. In terms of absolute risk, after ten years of

HRT use it is estimated that there would be 5 (95% CI 3 - 7) additional cases of breast cancer per

1000 users of estrogen-only preparations, and 19 (95% CI 15-23) additional cases of breast cancer

per 1000 users of estrogen-progestogen combinations. The elevated risk reduces after

discontinuation of HRT and is effectively lost after five years.

In the HRT subset of WHI a 26% increase in invasive breast cancer (38 vs 30 per person-years) after

an average of 5.2 years of treatment was observed in women receiving the estrogen/progestogen

combination compared to women receiving placebo. The increased risk of breast cancer became

apparent after four years on study medication. Women reporting prior postmenopausal hormone

use had a higher relative risk for breast cancer associated with HRT than those who had never used

postmenopausal hormones.

The Women's Health Initiative Memory Study (WHIMS), a substudy of WHI, reported a two-fold

increase in the risk of developing probable dementia in postmenopausal women 65 years of age or

older (n = 4,532, 54% older than 70) during four years of treatment with oral conjugated estrogens

plus medroxyprogesterone acetate relative to placebo. After an average follow-up of four years the

absolute risk of probable dementia was 45 per 10,000 person-years in the estrogen plus progestogen

group and 22 per 10,000 person-years in the placebo group. It is not known whether these findings

apply to younger postmenopausal women.

The risks and benefits in women receiving treatment for the short-term management of menopausal

symptoms of estrogen deficiency or for the management of premature menopause were not

examined in the WHI and WHIMS studies. As well, the studies did not include other formulations,

dosage regimens or routes of administration of HRT; such as transdermal patches containing

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estradiol. However, in the absence of comparable data, these risks should be assumed to be similar.

If prescribing any form of hormone replacement therapy, the potential for increased cardiovascular,

thrombotic and neoplastic adverse events must be considered.

Other Conditions

Since prolonged use of estrogens influences the metabolism of calcium and phosphorous CLIMARA

should be used with caution in women with metabolic bone disease associated with hypercalcaemia.

Also, patients with pre-existing hypercalcaemia, serum calcium levels should be carefully monitored.

Treatment should be stopped at once if migrainous or frequent and unusually severe headaches

occur for the first time, or if there are other symptoms that are possible premonitory signs of

cerebrovascular occlusion.

In patients with pre-existing hypertriglyceridaemia, estrogen therapy may be associated with

elevations of plasma triglycerides leading to pancreatitis and other complications.

A general association between HRT use and development of clinical hypertension has not been

established. There have been occasional reports of elevated blood pressure with the use of

transdermal estradiol patches in the menopause; therefore blood pressure should be monitored.

Estrogens may be poorly metabolised in patients with impaired liver function. Caution is advised in

patients with a long history of estrogen related jaundice. If cholestatic jaundice develops in a patient

receiving estrogen, treatment should be discontinued while the cause is investigated.

Non-severe disturbances of liver function, including hyperbilirubinaemias such as Dubin-Johnson

syndrome or Rotor syndrome, need close supervision and liver function should be checked

periodically. In case of deterioration of markers of liver function, use of HRT should be stopped.

Although HRT may have an effect on peripheral insulin resistance and glucose tolerance, there is

generally no need to alter the therapeutic regimen in diabetics using CLIMARA. However, it is

recommended that diabetic patients requiring combined treatment should be kept under special

surveillance.

Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum.

Women with a tendency to chloasma should avoid exposure to the sun or ultraviolet radiation whist

taking HRT.

Certain patients may develop undesirable manifestations of estrogenic stimulation under HRT such

as abnormal uterine bleeding. Frequent or persistent abnormal uterine bleeding during treatment is

an indication for endometrial assessment.

Pre-existing fibroids may increase in size under the influence of estrogens. If this is observed,

CLIMARA treatment should be discontinued.

Should endometriosis be reactivated during treatment with CLIMARA, discontinuation of therapy is

recommended.

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Use in Elderly

Of the total number of subjects in the conjugated equine estrogens in combination with

medroxyprogesterone acetate sub-study of the WHI study, 44% (7320) were 65 years and over,

while 6.6% (1095) were 75 years and over. No significant differences were observed between

subjects 65 years and over compared to younger subjects. There was a higher incidence of stroke

and invasive breast cancer in women 75 years and over compared to younger subjects.

In the Women’s Health Initiative Memory Study, including 4532 women 65 years of age and older

followed up for an average of four years, 71% (3762) were 65 - 74 while 18% were 75 and over. Most

women (80%) had no prior HRT use. Women treated with 0.625 mg conjugated estrogens plus 2.5

mg medroxyprogesteron acetate were reported to have a two-fold increase in the risk of developing

probable dementia. Ninety percent of cases of probable dementia occurred in the 54% of women

that were older than 70.

Interaction with other medicines and other forms of interaction

Interaction studies have not been performed with CLIMARA patches or with other estradiol

transdermal systems. The Data Sheet of concomitant medications should be consulted to identify

potential interactions.

The requirement for oral antidiabetics or insulin can change.

Effect of other medicines on CLIMARA

As for other steroid hormones it may be anticipated that medicines which induce microsomal liver

enzymes could affect the systemic bioavailability of transdermal estradiol. However, it is probable

that the systemic bioavailability of transdermally applied estradiol is less affected by such an

interaction than that of orally administered estrogens.

Interactions can occur with drugs that induce microsomal enzymes which can result in increased

clearance of sex hormones and which may lead to changes in the uterine bleeding profile and/or

reduction of the therapeutic effect.

Substances increasing the clearance of sex hormones (diminished efficacy by enzyme-induction),

e.g.:

Phenytoin, barbiturates, primidone, carbamazepine, and rifampicin and are possibly also suspected

for oxcarbazepine, topiramate, felbamate, and griseofulvin and products containing St. John’s wort.

Enzyme induction can already be observed after a few days of treatment. Maximal enzyme induction

is generally seen within a few weeks. After the cessation of drug therapy, enzyme induction may be

sustained for about 4 weeks.

Substances with variable effects on the clearance of sex hormones, e.g.:

When co-administered with sex hormones, many HIV/HCV protease inhibitors and non-nucleoside

reverse transcriptase inhibitors can increase or decrease plasma concentrations of the estrogen.

These changes may be clinically relevant in some cases.

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Substances decreasing the clearance of sex hormones (enzyme inhibitors)

Strong and moderate CYP3A4 inhibitors such as azole antifungals (e.g. fluconazole, itraconazole,

ketoconazole, voriconazole), verapamil, macrolides (e.g. clarithromycin, erythromycin), diltiazem

and grapefruit juice can increase plasma concentrations of the estrogen.

Interaction with alcohol

Acute alcohol ingestion during use of HRT may lead to elevations in circulating estradiol levels.

Interaction with laboratory tests

The use of sex steroids may influence the results of certain laboratory tests, including biochemical

parameters of liver, thyroid, adrenal and renal function, plasma levels of (carrier) proteins, e.g.

corticosteroid binding globulin and lipid/lipoprotein fractions, parameters of carbohydrate

metabolism, and parameters of coagulation and fibrinolysis. Changes generally remain within the

normal laboratory range.

Fertility, pregnancy and lactation

Pregnancy

Category B1. Estrogens must not be used during pregnancy (see 4.3 Contraindications). If pregnancy

occurs during medication with CLIMARA, treatment should be withdrawn immediately.

Lactation

Estrogens must not be used during lactation (see 4.3 Contraindications). Small amounts of sex

hormones may be excreted in human milk.

Effects on ability to drive and use machines

CLIMARA is unlikely to produce any effect on the ability to drive or use machinery.

Undesirable effects

Serious undesirable effects associated with the use of hormone replacement therapy have been

referred to in section 4.4 Special warnings and precautions for use.

In clinical trials adverse reactions were reported at the frequencies reported below:

very common

1/10

common

1/100 and < 1/10

uncommon

1/1000 and < 1/100

The most commonly reported adverse reactions with CLIMARA during clinical trials were application

site irritation and breast pain (> 10%). Symptoms at the application site are typically mild and may

include erythema, itching, a stinging sensation or vesicle formation. A summary of the most common

adverse reactions with CLIMARA is listed in the table below:

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System Organ

Class

Very Common

1/10

Common

1/100 and < 1/10

Uncommon

1/1000 and < 1/100

Application site

Application site

reaction, tape site

reaction

Autonomic

nervous system

Increased sweating

Body as a whole

Headache, oedema,

back pain, fatigue, pain

Migraine

Cardiovascular

Tachycardia

Central and

peripheral nervous

system

Dizziness

Muscle cramps

Gastrointestinal

system

Abdominal pain,

flatulence, nausea,

bloating

Metabolic and

nutritional

Alteration in body

weight

Psychiatric

Depressive moods,

nervousness

Reproductive

Breast pain

Breast tenderness,

changes in uterine

bleeding pattern

(including breakthrough

bleeding and spotting),

endometrial

hyperplasia,

leucorrhoea, pelvic

pain, uterine disorder,

uterine spasm, vaginal

disorder, vaginal

moniliasis,

Breast enlargement

Skin and

appendages

Acne, pruritus, rash

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In addition to the above adverse reactions, the following adverse reactions are also known to be

estrogen related and therefore may be associated with CLIMARA therapy:

System Organ Class

Adverse Event

Gastrointestinal system

Vomiting, cholestatic jaundice, increased

incidence of gallbladder disease, abdominal

cramps, bloating

Cardiovascular system

Rise in blood pressure in susceptible individuals

Haematological

Thromboembolism and thrombotic disorders

(see 4.4 Special warnings and precautions for

use)

Genitourinary system

Increase in size of uterine leiomyomata,

alterations in the amount of cervical secretion,

change in cervical erosion, reactivation of

endometriosis, cystitis-like syndrome

Skin

Chloasma or melasma which may persist after

the medicine is discontinued, allergic contact

dermatitis, post-inflammatory pruritus,

haemorrhagic eruptions, erythema nodosum,

erythema multiforme, rash, generalised

exanthema

Miscellaneous

Worsening of porphyria, changes in libido,

premenstrual-like syndrome

Ocular

Steepening of corneal curvature, intolerance of

contact lenses

In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms

of angioedema (see 4.4 Special warnings and precautions for use).

Estrogen-only and combined estrogen-progestogen HRT has been associated with a slightly

increased risk of ovarian cancer in epidemiological studies. The risk may be more relevant with long-

term use (several years) (see 4.4 Special warnings and precautions for use).

Overdose

Estrogen overdosage is unlikely with this type of application.

Symptoms

Overdosage may cause nausea and vomiting and withdrawal bleeding may occur in some women.

There is no specific antidote. Signs of overdosage may be one or more of the following: breast

discomfort, breakthrough bleeding, fluid retention and bloating (see 4.2 Dose and method of

administration). Toxicity is unlikely following acute single exposure; ingestion may cause nausea and

vomiting.

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Treatment

Treatment should be symptomatic and the patch(es) should be removed.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

CLIMARA provides systemic estrogen replacement therapy by releasing estradiol. Estradiol is the

major estrogenic hormone secreted by the human ovary from the menarche to the menopause and

is the most potent of the endogenous estrogens.

Estrogens are important in the development and maintenance of the female reproductive system

and secondary sexual characteristics. They also contribute to the shaping of the skeleton,

maintenance of tone and elasticity of urogenital structures and changes in the epiphyses of the long

bones that allow for the pubertal growth spurt and its termination. Estrogens play an important role

in various metabolic processes, including the modulation of bone resorption.

Estrogens exert their metabolic effects by binding to specific receptors in target cells. Estrogen

receptors have been identified in all known estrogen target organs including the uterus,

hypothalamus, pituitary, vagina, urethra, breast, liver and osteoblasts.

There are several forms of naturally occurring estrogen. Estradiol is the principal intracellular human

estrogen and is substantially more potent than the others, estrone or estriol. The ovarian follicle

secretes 70 to 500 micrograms of estradiol daily, varying with the phase of the menstrual cycle. This

is converted primarily to estrone, and to small amounts of estriol in the liver. The estradiol/estrone

ratio during fertile life is greater than 1. However, in postmenopausal women, estrone is the most

abundant circulating estrogen.

After menopause, when the ovaries have ceased to function, estrone is produced from the

aromatisation of androstenedione and only small amounts of estradiol are produced from metabolic

conversion of testosterone and estrone.

The estrogen deficiency around and after the menopause produces symptoms such as severe hot

flushes, night sweats, insomnia, dyspareunia and progressive atrophy of the urogenital system in

many women. These disorders can be largely eliminated by means of estrogen replacement therapy.

There is also an increased risk of bone fractures and osteoporosis, particularly of the vertebral

column, hip, and wrist due to the increased loss of bone substance caused by low levels of estrogen,

and cardiovascular disease.

Short-term treatment with estrogen replacement therapy perimenopausally has been shown to

prevent loss of bone density. There is currently no evidence of the minimum duration of estrogen

replacement therapy, which will be effective for younger postmenopausal women in reducing

fracture when they reach 75 years of age (the age of greatest fracture risk).

Known risk factors for post-menopausal osteoporosis include early menopause or surgical

oophorectomy, prolonged secondary amenorrhoea, prolonged systemic steroid use and a family

history of osteoporosis. Women especially at risk are those who are Caucasian, small boned,

smokers and live a sedentary lifestyle. The mainstays for decreasing the risk of postmenopausal

osteoporosis are weight-bearing exercise, adequate calcium and Vitamin D intake, and when

190523 CLIMARA

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indicated, pharmacologic therapy. When CLIMARA is used for the short term relief of menopausal

symptoms, it will provide a concomitant effect in reducing bone mineral density loss.

Transdermal administration of estrogen offers many advantages over conventional oral delivery. It

avoids the hepatic first-pass effects resulting in a constant serum level which reflects the pre-

menopausal physiological serum profile and ratio of estradiol to estrone. In plasma, the

concentration ratio of estradiol (E2) to estrone (E1) undergoes a shift from between 1:5 and 1:2 to

approximately 1:1, i.e. to values which are recorded before the menopause in women with normally

functioning ovaries. Gastrointestinal side effects are avoided also. The skin metabolises estradiol to a

small extent only, thus transdermal administration provides therapeutic serum levels of estradiol

using smaller total doses than oral therapy. Constant delivery of the therapeutic dose is maintained

with CLIMARA patches over the 7 day application period. However, therapy is easily discontinued by

removal of the patch.

Following the application of transdermal estradiol for 28 days, no effect has been observed on the

concentrations or activity of the blood coagulation factors fibrinopeptide A, high molecular weight

fibrinogen and antithrombin III. After this period of 28 days, transdermally administered estradiol

did not induce any change in the concentrations either of circulating renin substrate or of the sex

hormone binding, thyroxine binding or cortisol binding globulins. It has been found, however, that

after only three weeks administration, transdermally administered estradiol elicits a dose dependent

reduction in urinary excretion of calcium and hydroxyproline.

Independent of the route of administration, estrogen doses, which are necessary for improvement

of menopausal complaints, exert a dose dependent stimulating effect on mitosis and proliferation of

the endometrium. Estrogen monotherapy increases the frequency of endometrial hyperplasia and

thus the risk of endometrial cancer. In order to avoid endometrial hyperplasia the sequential

administration of a progestogen for 10 - 14 days every 4 weeks is recommended in non-

hysterectomised postmenopausal women (see 4.4 Special warnings and precautions for use, WHI

Studies and Million Women Study).

Hormone replacement therapy (HRT) with an adequate estrogen dosage reduces bone resorption

and retards or halts postmenopausal bone loss. When HRT is discontinued, bone mass declines at a

rate comparable to that in the immediate postmenopausal period. There is no evidence that HRT

restores bone mass to premenopausal levels.

Pharmacokinetic properties

Transdermal estradiol administration aims at achieving smooth, stable, plateau-like estradiol serum

levels similar to those during the early/mid follicular phase of the reproductive life span. Estradiol

serum levels in the range between 30 - 100 pg/mL are necessary for an efficacious transdermal

estrogen replacement therapy. Nominal average in vivo absorption rates for CLIMARA 25, CLIMARA

50, CLIMARA 75 and CLIMARA 100 are 25

g/day, 50

g/day, 75

g/day and 100

g/day

respectively. In pharmacokinetic studies, mean steady state estradiol levels of 18 pg/mL, 35 pg/mL,

53 pg/mL and 70 pg/mL were obtained after application of the CLIMARA 25, CLIMARA 50, CLIMARA

75 and CLIMARA 100 patch, respectively. No accumulation of either estradiol or estrone occurred

after multiple one-week applications, with serum levels returning to baseline within 6 hours of patch

removal.

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Linear dose proportionality has been demonstrated for the CLIMARA transdermal delivery system. In

a 1-week application study in 54 post-menopausal women CLIMARA 100 produced estradiol serum

level profiles and pharmacokinetic parameters that were twice as high as CLIMARA 50. Statistical

analyses confirmed the 2:1 dose proportionality.

Two transdermal absorption studies were conducted comparing serum estradiol level profiles and

pharmacokinetic parameters following once-a-week application of CLIMARA patches and twice-a-

week applications of another brand of patches (Estraderm). Both patch sizes were examined: In the

first study CLIMARA 50 (12.5 cm2) was compared with Estraderm 50 (10 cm2) and in the second

study CLIMARA 100 (25 cm2) was compared with Estraderm 100 (20 cm2). With both patch sizes,

CLIMARA once-a-week treatments maintained smoother and more stable estradiol serum level

profiles than did the Estraderm twice-a-week patches. Cmax, AUC and MSS were all significantly

higher for the Estraderm patch application, but towards the end of the one-week application

interval, both CLIMARA patches maintained similar (144 hours) or higher (168 hours) mean trough

serum levels than did the Estraderm patches. The mean peak to end of application interval trough

level fluctuations were smaller with CLIMARA than with Estraderm.

The biotransformation and excretion of transdermally administered estradiol is the same as that of

the endogenous hormone. The plasma elimination half-life of estradiol is approximately one hour.

Estradiol is eliminated from the body with a total serum clearance of approximately 15 - 30

mL/min/kg by biotransformation mainly in the liver but also extrahepatically. Its most important

metabolites are estriol and estrone and their conjugates (glucuronides and sulphates); these are far

less pharmacologically active than estradiol. The bulk of the conjugates are excreted in the urine.

Estrogen metabolites are also subject to enterohepatic circulation.

Preclinical safety data

In primary dermal irritation studies in rabbits, application of CLIMARA resulted in mild irritation

related to mechanical trauma at removal. In sensitisation studies in guinea pigs, CLIMARA patches

had no dermal sensitising potential.

The components of the adhesive matrix of CLIMARA (monomer and polymer) have been studied

extensively and, at many times the projected human exposure, present a low risk. Additional

excipients used in the adhesive matrix are either generally regarded as safe for use in food

components or considered acceptable as an inactive ingredient for prescription and topical

transdermal products.

The adhesive backing and release liner of CLIMARA patches were tested using biological test

methods and were considered to be compatible with biological systems.

Animal toxicity studies with repeated administration, including tumourigenicity studies, did not

suggest a particular risk related to use in humans. However, it should be borne in mind that sex

steroids might stimulate the growth of certain hormone-dependent tissues and tumours.

In vitro and in vivo studies with 17ß-estradiol gave no indications of a mutagenic potential.

190523 CLIMARA

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Reproductive toxicity studies with estradiol valerate did not indicate a teratogenic potential. As no

non-physiological plasma concentrations of estradiol are produced by administration of estradiol

valerate, this preparation does not present a risk to the fetus.

Preclinical data reveal no special hazard for humans based on conventional studies of safety

pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential or toxicity to

reproduction.

Chemical Structure

CLIMARA is a transdermal delivery system containing estradiol as the active ingredient. Estradiol is

estra-1,3,5(10)-triene-3,17ß-diol, the major estrogenic hormone produced by the human ovary. The

remaining components of the system are pharmacologically inactive.

The CAS Registry number for estradiol is 50-28-2.

Structural Formula

PHARMACEUTICAL PARTICULARS

List of excipients

Ethyl oleate, isopropyl myristate, glycerol monolaurate, acrylate copolymer

Incompatibilities

No known incompatibility.

Shelf life

See pack for expiry date. Store below 30°C.

Special precautions for storage

Do not store unpouched. Apply immediately upon removal from the protective pouch.

Packs containing 4 patches individually wrapped in a protective pouch. The pouch contains

desiccant.

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Nature and contents of container

A protective pouch containing a CLIMARA 25 patch with a surface area of 6.5 cm2, CLIMARA 50

patch with a surface area of 12.5 cm², CLIMARA 75 patch with a surface area of 18.75 cm2, or a

CLIMARA 100 patch with a surface area of 25 cm². Not all pack sizes may be marketed.

The patches comprise two layers. From the visible surface to the surface attached to the skin these

are: a translucent polyethylene film; a medicine reservoir of estradiol in an acrylate adhesive matrix;

a protective liner of release-coated polyester film which is attached to the adhesive surface and

must be removed prior to use. The protective pouch contains a desiccant.

Special precautions for disposal

Store all medicines properly and keep them out of reach of children.

MEDICINE SCHEDULE

Prescription Medicine

SPONSOR

Bayer New Zealand Limited

3 Argus Place

Hillcrest

North Shore

Auckland 0627

Free Phone 0800 233 988

www.bayer.co.nz

DATE OF FIRST APPROVAL

17 November 1994

DATE OF REVISION OF THE TEXT

06 June 2019

SUMMARY TABLE OF CHANGES

Section Changed

Summary of New Information

Whole document

Data sheet reformatted with minor editorial

changes. No addition of new information.

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