New Zealand - English - Medsafe (Medicines Safety Authority)
CONSUMER MEDICINE INFORMATION
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
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.
Consumer Medicine Information
WHAT IS IN THIS
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
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
You may need to read it again.
WHAT CLIMARA IS
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,
Climara can also be used to
prevent bone mineral density loss
(where the bones become weaker,
more brittle and likely to break)
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
Ask your doctor if you have any
questions about why this
medicine has been prescribed
Your doctor may have prescribed
it for another reason.
BEFORE YOU USE
When you must not use it
Do not use Climara if you have
an allergy to:
oestradiol, the active ingredient
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
swelling of the face, lips,
tongue or other parts of the
rash, itching or hives on the
Do not use Climara if you have:
severe uncontrolled high blood
severe liver disease such as
jaundice (signs of liver
problems such as yellowing of
skin and/or eyes) or persistent
itching during a previous
a history of or existing liver
suspected or existing tumours in
the uterus, ovaries or breast
known or suspected tumours
influenced by sex hormones
endometriosis (the presence of
tissue of the lining of the womb
in places in the body where it is
not usually found)
a history of or existing blood clot
in the blood vessels (such as
blood clots in the legs)
if you recently had a heart attack
if you have a high risk of venous
or arterial thrombosis (blood
sickle-cell anaemia (inherited
disorder which causes the red
blood cells to change shape)
disturbances of fat metabolism
a history of herpes during
hearing loss (otosclerosis) that
worsens during pregnancy
undiagnosed abnormal vaginal
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
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
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
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
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
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 or anyone in your immediate
family has had blood clots
systemic lupus erythematosus
(SLE, a chronic inflammatory
you have any planned
hospitalisation, surgery or
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
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
Before being prescribed Climara,
your doctor should perform a
thorough medical and
(including the breasts and a pap
smear). Your doctor will also note
your family medical history and
Tell your doctor if you have or
have had any of the following
high blood pressure
otosclerosis (a type of hearing
endometriosis (the presence of
tissue of the lining of the
womb in places in the body
where it is not normally
porphyria (inherited or
acquired disorder of certain
tetany (mineral imbalance in
the body that results in severe
muscle spasms )
chorea minor (disorder
characterised by irregular and
involuntary muscles )
kidney or heart disease
tumours in the pituitary gland
yellowing of the skin and/or
eyes (cholestatic jaundice) with
previous oestrogen use or
a high level of triglycerides
(fats) in the blood
high or low calcium levels in
an underactive thyroid gland
an abnormal build-up of blood
vessels in the liver (hepatic
chloasma (yellowish brown
pigmentation patches on the
skin, particularly of the face); if
so, avoid too much exposure to
the sun or ultraviolet radiation
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
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
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
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.
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
HRT has been reported to result in
an increased number of abnormal
mammograms requiring further
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).
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
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
Some medicines and Climara may
interfere with each other. These
medicines to treat high blood
pressure, chest pain and/or
irregular heart beat such as
ACE inhibitors, verapamil,
macrolide antibiotics (e.g.
medication used to treat
epilepsy, such as hydantoins,
rifampicin for the treatment of
herbal medicines containing St
medicines used to treat HIV
such as ritonavir or nevirapine
some medicines used to treat
Hepatitis C Virus (HCV) such
as boceprevir, telaprevir
medicines used to treat fungal
infections such as
medicines used to treat
diabetes, such as insulin or anti-
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
Your doctor and pharmacist have
more information on medicines to
be careful with or avoid while
using this medicine.
HOW TO USE
Follow all directions given to you
by your doctor or pharmacist
They may differ from the
information contained in this
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
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
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
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.
not the Climara patch.
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
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
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
area of clean, dry
Do not put the patch on the
same area of skin each week.
5. What to do if your patch
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
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
Oestrogen overdose is unlikely with
this type of application. In the event
of accidental overdose, remove the
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
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
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
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.
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
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
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
You should stop treatment at once
and consult your doctor if you
have any of the following
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
sudden disturbances of vision
itching of the whole body
unusual upper abdominal pains
that do not disappear within a
short period of time
planned operations/surgery or
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:
unusual pains or swelling of
your arms or legs
sudden shortness of breath, pain
or tightness in the chest
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.
What to be careful of
Excess intake of alcohol during use
of HRT has an influence on the
treatment. Your doctor will advise
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
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
Tell your doctor or pharmacist
as soon as possible if you do not
feel well while you are using
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
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
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
irregular menstrual bleeding
fluid retention (bloating or
swelling in the arms, ankles or
rash or itching
nervousness or depressive
changes in body weight
pain (including back and pelvic
stomach pain, cramps or wind
vaginal itching, burning or
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
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
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
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
Keep it where children cannot
A locked cupboard at least one-
and-a half metres above the
ground is a good place to store
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
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:
The suffixes ‘25”, “50”,”75” and
“100” refer to the daily amount of
oestradiol transferred via the skin to
your body from the respective
Not all strengths may be marketed.
Active ingredient per patch:
Climara 25 – 2 mg of oestradiol
Climara 50 – 3.8 mg of
Climara 75 – 5.7 mg of
Climara 100 – 7.6 mg of
acrylate copolymer adhesive
Made in USA for:
Bayer Australia Ltd
ABN 22 000 138 714
875 Pacific Highway
Pymble NSW 2073
Bayer New Zealand Limited
3 Argus Place
Hillcrest, North Shore
Climara 25 - AUST R 73962
Climara 50 - AUST R 56197
Climara 75 - AUST R 73963
Climara 100 - AUST R 56198
Date of preparation
See TGA website
(www.ebs.tga.gov.au) for latest
Australian Consumer Medicine
See MEDSAFE website
(www.medsafe.govt.nz) for latest
New Zealand Consumer Medicine
® Registered trademark of the
Bayer group, Germany
© Bayer Australia Ltd
All rights reserved.
Page 1 of 21
NEW ZEALAND DATA SHEET
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.
The CLIMARA transdermal delivery system is a transparent oval patch containing estradiol in an
acrylate adhesive matrix.
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.
Page 2 of 21
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
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
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
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.
Page 3 of 21
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
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.
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
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
Severe disturbances of liver function
Previous or existing liver tumours, benign or malignant
Page 4 of 21
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.
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.
Page 5 of 21
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
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
1.26 (1.00 - 1.59)
1.29 (1.02 - 1.63)
1.41 (1.07 - 1.85)
2.13 (1.39 - 3.25)
1.32 (1.02 - 1.72)
Deep vein thrombosis
2.07 (1.49 - 2.87)
0.63 (0.43 - 0.92)
0.66 (0.45 - 0.98)
* Information not available
Page 6 of 21
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
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
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
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.
Page 7 of 21
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.
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
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.
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.
Page 8 of 21
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.
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.
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
Page 9 of 21
cancer, adverse effects on lipoprotein metabolism (e.g. lowering HDL, raising LDL) and impairment of
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
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).
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.
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.
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
Page 10 of 21
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.
Page 11 of 21
Table 2. Relative risk of newly diagnosed invasive breast cancer in relation to recency and type of
HRT use at baseline
Relative risk (95% FCI)*
All never users
1.00 (0.96 - 1.04)
All past users
1.01 (0.95 - 1.08)
Current users of:
1.30 (1.22 - 1.38)
2.00 (1.91 - 2.09)
1.45 (1.25 - 1.67)
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
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
Page 12 of 21
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.
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
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
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
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
Page 13 of 21
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
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),
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.
Page 14 of 21
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
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.
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.
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:
1/100 and < 1/10
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:
Page 15 of 21
1/100 and < 1/10
1/1000 and < 1/100
reaction, tape site
Body as a whole
back pain, fatigue, pain
Alteration in body
changes in uterine
bleeding and spotting),
pain, uterine disorder,
uterine spasm, vaginal
Acne, pruritus, rash
Page 16 of 21
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
Vomiting, cholestatic jaundice, increased
incidence of gallbladder disease, abdominal
Rise in blood pressure in susceptible individuals
Thromboembolism and thrombotic disorders
(see 4.4 Special warnings and precautions for
Increase in size of uterine leiomyomata,
alterations in the amount of cervical secretion,
change in cervical erosion, reactivation of
endometriosis, cystitis-like syndrome
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
Worsening of porphyria, changes in libido,
Steepening of corneal curvature, intolerance of
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).
Estrogen overdosage is unlikely with this type of application.
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
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Treatment should be symptomatic and the patch(es) should be removed.
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
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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.
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 and 100
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
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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
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.
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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
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.
List of excipients
Ethyl oleate, isopropyl myristate, glycerol monolaurate, acrylate copolymer
No known incompatibility.
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
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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.
Bayer New Zealand Limited
3 Argus Place
Free Phone 0800 233 988
DATE OF FIRST APPROVAL
17 November 1994
DATE OF REVISION OF THE TEXT
06 June 2019
SUMMARY TABLE OF CHANGES
Summary of New Information
Data sheet reformatted with minor editorial
changes. No addition of new information.