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KLIOFEM FILM-COATED TABLETS

Active substance(s): ESTRADIOL HEMIHYDRATE / NORETHISTERONE ACETATE

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8-2850-01-001-4_v1-11:Layout 1

Package leaflet:
Information for the user

Kliofem® 2 mg/1 mg
film-coated tablets
Estradiol/norethisterone acetate
Read this entire leaflet carefully
before you start taking this
medicine because it contains
important information for you.
- Keep this leaflet. You may need
to read it again.
- If you have any further
questions, ask your doctor or
pharmacist.
- This medicine has been
prescribed for you only. Do not
pass it on to others. It may harm
them, even if their signs of illness
are the same as yours.

2015-11-26

4:17 PM

- If you get any side effects, talk to
your doctor or pharmacist. This
includes any possible side effects
not listed in this leaflet. See
section 4.
What is in this leaflet
1. What Kliofem® is and what it is
used for
2. What you need to know before
you take Kliofem®
3. How to take Kliofem®
4. Possible side effects
5. How to store Kliofem®
6. Contents of the pack and other
information
1. What Kliofem® is and what it
is used for
Kliofem® is a continuous combined
Hormone Replacement Therapy
(HRT) which is taken every day
without interruption. Kliofem® is
used in postmenopausal women
with at least 1 year since their last
natural period.
The tablets contain 2 hormones:
estradiol 2 mg (an oestrogen

8-2850-01-001-4

RA Labelling & IT
Insert size: 999x100-006
Current: 2.0

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Improved DI28MKII
Colour: PMS 280C

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Code: 100% Direction
Length: Max. 29 mm (100%)

identical to the one made in the
ovaries) and norethisterone acetate
1 mg (a progestagen that acts in
a similar way to the body’s own
hormone progesterone).
Kliofem® is used for:
Relief of symptoms occurring
after menopause
During the menopause, the
amount of the oestrogen produced
by a woman’s body drops. This can
cause symptoms such as hot face,
neck and chest (‘hot flushes’).
Kliofem® alleviates these symptoms
after menopause. You will only be
prescribed Kliofem® if your symptoms seriously hinder your daily life.
Prevention of osteoporosis
After the menopause some women
may develop fragile bones
(osteoporosis). You should discuss
all available options with your
doctor.
If you are at an increased risk of
fractures due to osteoporosis and
other medicines are not suitable for

you, you can use Kliofem® to prevent osteoporosis after menopause.
Kliofem® is prescribed for women
who have not had their womb
removed, and whose periods
stopped more than a year ago.
The experience of treating women
older than 65 years is limited.
2. What you need to know
before you take Kliofem®
Medical history and regular
check-ups
The use of HRT carries risks which
need to be considered when
deciding whether to start taking it
or whether to carry on taking it.
The experience in treating women
with a premature menopause (due
to ovarian failure or surgery) is
limited. If you have a premature
menopause, the risks of using HRT
may be different. Please talk to
your doctor.
Before you start (or restart) HRT,
your doctor will ask about your
own and your family’s medical

history. Your doctor may decide to
perform a physical examination.
This may include an examination of
your breasts and/or an internal
examination, if necessary.
Once you have started on Kliofem®
you should see your doctor for
regular check-ups (at least once
a year). At these check-ups, discuss
with your doctor the benefits and
risks of continuing with Kliofem®.
Go for regular breast screening, as
recommended by your doctor.
Do not take Kliofem®
If any of the following applies to
you. If you are not sure about any
of the points below, talk to your
doctor before taking Kliofem®.
Do not take Kliofem®:
• if you have, have had or suspect
having breast cancer
• if you have, have had or suspect
having cancer of the womb
lining (endometrial cancer), or
any other oestrogen dependent
cancer

• if you have any unexplained
vaginal bleeding
• if you have excessive
thickening of the womb
lining (endometrial hyperplasia)
that is not being treated
• if you have or have ever had
a blood clot in a vein (venous
thromboembolism), such as in
the legs (deep venous
thrombosis) or the lungs
(pulmonary embolism)
• if you have a blood clotting
disorder (such as protein C,
protein S or antithrombin
deficiency)
• if you have or previously have
had a disease caused by blood
clots in the arteries, such as
a heart attack, stroke or angina
• if you have or have ever had
a liver disease and your liver
function tests have not returned
to normal
• if you have a rare blood problem
called ‘porphyria’ which is
passed down in families (inherited)

• if you are allergic
(hypersensitive) to estradiol,
norethisterone acetate or any
of the other ingredients of
Kliofem® (listed in section 6
Contents of the pack and other
information).
Warnings and precautions
Tell your doctor if you have ever
had any of the following problems,
before you start the treatment, as
these may return or become worse
during treatment with Kliofem®.
If so, you should see your doctor
more often for check-ups:
• fibroids inside your womb
• growth of the womb lining
outside your womb
(endometriosis) or a history of
excessive growth of the womb
lining (endometrial hyperplasia)
• increased risk of developing
blood clots (see Blood clots in
a vein (venous thromboembolism))
• increased risk of getting an
oestrogen-sensitive cancer (such
as having a mother, sister or















grandmother who has had
breast cancer)
high blood pressure
a liver disorder, such as a benign
liver tumour
diabetes
gallstones
migraine or severe headaches
a disease of the immune system
that affects many organs of the
body (systemic lupus
erythematosus, SLE)
epilepsy
asthma
a disease affecting the eardrum
and hearing (otosclerosis)
a very high level of fat in your
blood (triglycerides)
fluid retention due to cardiac or
kidney problems
if you are taking medicine for an
underactive thyroid gland your
doctor will perform tests while
you are taking HRT to ensure

that your thyroid hormone level
remains acceptable
• a hereditary condition causing
recurrent episodes of severe
swelling (hereditary angioedema)
or if you have had episodes of
rapid swelling of the hands, face,
feet, lips, eyes, tongue, throat
(airway blockage) or digestive
tract
• lactose intolerance.
Stop taking Kliofem® and see
a doctor immediately
If you notice any of the following
when taking HRT:
• any of the conditions mentioned
in the Do not take Kliofem®
section
• yellowing of your skin or the
whites of your eyes (jaundice).
These may be signs of a liver
disease
• a large rise in your blood
pressure (symptoms may be
headache, tiredness, dizziness)

• migraine-like headaches which
happen for the first time
• if you become pregnant
• if you notice signs of a blood
clot, such as:
- painful swelling and redness of
the legs
- sudden chest pain
- difficulty in breathing.
For more information, see Blood
clots in a vein (venous
thromboembolism)
Note: Kliofem® is not a contraceptive. If it is less than 12 months
since your last menstrual period or
you are under 50 years old, you
may still need to use additional
contraception to prevent pregnancy. Speak to your doctor for
advice.
HRT and cancer
Excessive thickening of the
lining of the womb
(endometrial hyperplasia) and

cancer of the lining of the
womb (endometrial cancer)
Taking oestrogen-only HRT will
increase the risk of excessive
thickening of the lining of the
womb (endometrial hyperplasia)
and cancer of the womb lining
(endometrial cancer).
The progestagen in Kliofem®
protects you from this extra risk.
Compare
In women who still have a womb
and who are not taking HRT, on
average, 5 in 1,000 will be
diagnosed with endometrial
cancer between the ages of 50
and 65.
For women aged 50 to 65 who
still have a womb and who take
oestrogen-only HRT, between 10
and 60 women in 1,000 will be
diagnosed with endometrial cancer
(i.e. between 5 and 55 extra
cases), depending on the dose
and for how long it is taken.

Irregular bleeding
You may have irregular bleeding or
drops of blood (spotting) during
the first 3-6 months of taking
Kliofem®. However, if the irregular
bleeding:
• carries on for more than the first
6 months
• starts after you have been taking
Kliofem® for more than 6 months
• carries on after you have stopped
taking Kliofem®
see your doctor as soon as possible.
Breast cancer
Evidence suggests that taking combined oestrogen-progestagen and
possibly also oestrogen-only HRT
increases the risk of breast cancer.
The extra risk depends on how
long you take HRT. The additional
risk becomes clear within a few
years. However, it returns to normal
within a few years (at most 5) after
stopping treatment.

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Compare
Women aged 50 to 79 who are
not taking HRT, on average, 9 to
17 in 1,000 will be diagnosed
with breast cancer over a 5-year
period. For women aged 50 to 79
who are taking oestrogenprogestagen HRT over 5 years,
there will be 13 to 23 cases in
1,000 users (i.e. an extra 4 to
6 cases).

medication may increase the
density of your breasts which may
affect the outcome of the mammogram. Where the density of the
breast is increased, mammography
may not detect all lumps.
Ovarian cancer
Ovarian cancer is rare. A slightly
increased risk of ovarian cancer has
been reported in women taking
HRT for at least 5 to 10 years.

Regularly check your breasts.
See your doctor if you notice
any changes such as:
• dimpling of the skin
• changes in the nipple
• any lumps you can see or feel.
Additionally, you are advised to join
mammography screening programs
when offered to you. For mammogram screening, it is important that
you inform the nurse/healthcare
professional who is actually taking
the x-ray that you use HRT, as this

Compare
Women aged 50 to 69 who are
not taking HRT, on average, about
2 women in 1,000 will be
diagnosed with ovarian cancer
over a 5-year period. For women
who have been taking HRT for
5 years, there will be between 2
and 3 cases per 1,000 users
(i.e. up to 1 extra case).

Effect of HRT on heart and
circulation
Blood clots in a vein (venous
thromboembolism)
The risk of blood clots in the
veins is about 1.3 to 3 times
higher in HRT users than in nonusers, especially during the first
year of taking it.
Blood clots can be serious, and if
one travels to the lungs, it can
cause chest pain, breathlessness,
fainting or even death.
You are more likely to get a blood
clot in your veins as you get older
and if any of the following applies
to you. Inform your doctor if any of
these situations applies to you:
• you are unable to walk for a long
time because of major surgery,
injury or illness (see section 3,
If you need to have surgery)
• you are seriously overweight
(BMI > 30 kg/m2)
• you have any blood clotting
problem that needs long-term

treatment with a medicine used
to prevent blood clots
• if any of your close relatives has
ever had a blood clot in the leg,
lung or another organ
• you have systemic lupus
erythematosus (SLE)
• you have cancer.
For signs of a blood clot, see Stop
taking Kliofem® and see a doctor
immediately.
Compare
Looking at women in their 50s
who are not taking HRT, on
average, over a 5-year period, 4 to
7 in 1,000 would be expected to
get a blood clot in a vein.
For women in their 50s who have
been taking oestrogenprogestagen HRT for over 5 years,
there will be 9 to 12 cases in
1,000 users (i.e. an extra 5 cases).
Heart disease (heart attack)
There is no evidence that HRT will
prevent a heart attack. Women
over the age of 60 years who use

oestrogen-progestagen HRT are
slightly more likely to develop heart
disease than those not taking any
HRT.
Stroke
The risk of getting stroke is about
1.5 times higher in HRT users than
in non-users. The number of extra
cases of stroke due to use of HRT
will increase with age.
Compare
Looking at women in their 50s
who are not taking HRT, on
average, 8 in 1,000 would be
expected to have a stroke over
a 5-year period. For women in
their 50s who are taking HRT,
there will be 11 cases in
1,000 users over 5 years (i.e. an
extra 3 cases).
Other conditions
HRT will not prevent memory loss.
There is some evidence of a higher
risk of memory loss in women who
start using HRT after the age of 65.
Speak to your doctor for advice.

Using other medicines
Some medicines may interfere with
the effect of Kliofem®. This might
lead to irregular bleeding. This
applies to the following medicines:
• Medicines for epilepsy (such as
phenobarbital, phenytoin and
carbamazepine)
• Medicines for tuberculosis (such
as rifampicin and rifabutin)
• Medicines for HIV infection
(such as nevirapine, efavirenz,
ritonavir and nelfinavir)
• Medicines for hepatitis C
infections (such as telaprevir)
• Herbal remedies containing
St John’s Wort (Hypericum
perforatum).
Other medicines may increase the
effects of Kliofem®:
• Medicines containing
ketoconazole (a fungicide).
Kliofem® may have an impact on
a concomitant treatment with
cyclosporine.

Please tell your doctor or
pharmacist if you are taking or
have recently taken any other
medicines, including medicines
obtained without a prescription,
herbal medicines or other natural
products.
Taking Kliofem® with food and
drink
The tablets can be taken with or
without food and drink.
Laboratory tests
If you need a blood test, tell your
doctor or the laboratory staff that
you are taking Kliofem®, because
this medicine can affect the results
of some tests.
Pregnancy and breast-feeding
Pregnancy: Kliofem® is for use in
postmenopausal women only. If
you become pregnant, stop taking
Kliofem® and contact your doctor.
Breast-feeding: You should not
take Kliofem® if you are
breast-feeding.

Driving and using machines
Kliofem® has no known effect on
the ability to drive or use machines.
Important information about
some of the ingredients in
Kliofem®
Kliofem® contains lactose monohydrate. If you have an intolerance to
some sugars, contact your doctor
before taking Kliofem®.
3. How to take Kliofem®
Always take this medicine exactly
as your doctor has told you. Check
with your doctor or pharmacist if
you are unsure.
Take one tablet once a day, at
about the same time each day.
Take the tablet with a glass of water.
Take a tablet every day without
stopping. After you have used all
28 tablets in a calendar pack, go
straight to using the next pack.
For further information on the use
of the calendar pack, see USER
INSTRUCTIONS at the end of the
package leaflet.

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You may start treatment with
Kliofem® on any convenient day.
However, if you are switching from
an HRT product when you have
monthly bleeding, start your
treatment straight after the
bleeding has ended.
Your doctor should aim to prescribe
the lowest dose to treat your
symptom for as short as necessary.
Speak to your doctor if you think
this dose is too strong or not strong
enough.
If you take more Kliofem® than
you should
If you have taken more Kliofem®
than you should, talk to a doctor or
pharmacist as soon as possible.
Taking more oestrogens than prescribed by your doctor may cause
breast tenderness, nausea, vomiting
and/or irregular vaginal bleeding
(metrorrhagia). Taking more
progestagens than prescribed by
your doctor may lead to depressive
mood, fatigue, acne and growth of
body or facial hair (hirsutism).

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If you forget to take Kliofem®
If you forget to take your tablet at
the usual time, take it within the
next 12 hours. If more than 12 hours
have gone by, start again as normal
the next day. Do not take a double
dose to make up for a forgotten
tablet.
Forgetting a dose may increase the
likelihood of breakthrough
bleeding and spotting if you still
have your womb.
If you stop taking Kliofem®
If you would like to stop taking
Kliofem®, talk to your doctor first.
Your doctor will explain the effects
of stopping treatment and discuss
other possibilities with you.
If you have any further questions
on the use of this medicine, ask
your doctor or pharmacist.
If you need to have surgery
If you are going to have surgery,
tell the surgeon that you are taking
Kliofem®. You may need to stop
taking Kliofem® about 4 to

6 weeks before the operation to
reduce the risk of a blood clot
(see section 2, Blood clots in a vein
(venous thromboembolism)). Ask
your doctor when you can start
taking Kliofem® again.
4. Possible side effects
Like all medicines, this medicine
can have side effects, although not
everybody gets them.
The following diseases are reported
more often in women using HRT
compared to women not using HRT:
• breast cancer
• abnormal growth or cancer of
the lining of the womb
(endometrial hyperplasia or
cancer)
• ovarian cancer
• blood clots in the veins of the
legs or lungs (venous
thromboembolism)
• heart disease
• stroke
• probable memory loss if HRT is
started over the age of 65.

For more information about these
side effects, see section 2 What
you need to know before you take
Kliofem®.
Hypersensitivity/allergy
(uncommon side effect – may
affect up to 1 in 100 people)
Though it is an uncommon event,
hypersensitivity/allergy may occur.
Signs of hypersensitivity/allergy may
include one or more of the
following symptoms: hives, itching,
swelling, difficulty in breathing, low
blood pressure (paleness and
coldness of skin, rapid heartbeat),
feeling dizzy, sweating, which
could be signs of anaphylactic
reaction/shock. If one of the
mentioned symptoms appears,
stop taking Kliofem® and seek
immediate medical help.
Very common side effects (may
affect more than 1 in 10 people)
• Breast pain or breast tenderness
• Vaginal bleeding.

Common side effects (may affect
up to 1 in 10 people)
• Headache
• Weight gain caused by fluid
retention
• Vaginal inflammation
• Migraine, new or worse than
before
• Vaginal infection with a fungus
• Depression, new or worse than
before
• Nausea
• Abdominal pain, swelling or
discomfort
• Enlargement or swelling of the
breasts (breast oedema)
• Back pain
• Leg cramps
• Uterine fibroid (benign tumour),
aggravation, occurrence or
recurrence
• Swelling of arms and legs
(peripheral oedema)
• Weight increase.
Uncommon side effects (may
affect up to 1 in 100 people)
• Bloating or flatulence

• Acne
• Hair loss (alopecia)
• Abnormal (male pattern) hair
growth
• Itching or hives (urticaria)
• Inflammation of a vein
(superficial thrombophlebitis)
• Drug ineffective
• Allergic reaction
• Nervousness.
Rare side effects (may affect up
to 1 in 1,000 people)
• Blood clots in the blood vessels
of the legs or the lungs (deep
vein thrombosis, lung embolism).
Very rare side effects (may affect
up to 1 in 10,000 people)
• Cancer of the lining of the
womb (endometrial cancer)
• Excessive growth of the lining of
the womb (endometrial
hyperplasia)
• Increase in blood pressure or
worsening of high blood pressure
• Gall bladder disease, gallstones
occurrence/recurrence or
aggravated

• Excessive secretion of sebum,
skin eruption
• Acute or recurring attack of
oedema (angioneurotic oedema)
• Insomnia, dizziness, anxiety
• Change in sexual desire
• Visual disturbances
• Weight decreased
• Vomiting
• Heartburn
• Vaginal and genital itching
• Heart attack and stroke.
Other side effects of
combined HRT
The following side effects have
been reported with other HRTs:
• Various skin disorders:
- discolouration of the skin,
especially of the face or neck,
known as ‘pregnancy patches’
(chloasma)
- painful reddish skin nodules
(erythema nodosum)
- rash with target-shaped
reddening or sores (erythema
multiforme)

- red or purple discolourations of
the skin and/or mucous
membranes (vascular purpura)
• Dry eyes
• Tear film composition changes.
Reporting of side effects
If you get any side effects, talk to
your doctor or pharmacist. This
includes any possible side effects
not listed in this leaflet. You can
also report side effects directly via
the Yellow Card Scheme Website:
www.mhra.gov.uk/yellowcard. By
reporting side effects you can help
provide more information on the
safety of this medicine.
5. How to store Kliofem®
Keep this medicine out of the sight
and reach of children.
Do not use this medicine after the
expiry date, which is stated on the
label and carton after ‘EXP’. The
expiry date refers to the last day of
that month.

Do not refrigerate.
Keep the container in the outer
carton in order to protect it from
light.
Do not throw away any medicines
via wastewater or household
waste. Ask your pharmacist how to
throw away medicines you no
longer use. These measures will
help protect the environment.
6. Contents of the pack and
other information
What Kliofem® contains
• The active substances are
estradiol 2 mg (as estradiol
hemihydrate) and norethisterone
acetate 1 mg.
• The other ingredients are: lactose
monohydrate, maize starch,
hydroxypropylcellulose, talc and
magnesium stearate.
• The film-coating contains:
hypromellose, triacetin and talc.

What Kliofem® looks like and
contents of the pack
The film-coated tablets are white,
round with a diameter of 6 mm.
The tablets are engraved
NOVO 281.
Pack sizes available:
• 1×28 film-coated tablets
• 3×28 film-coated tablets
Not all pack sizes may be
marketed.
Marketing authorisation holder
Novo Nordisk Limited
3 City Place, Beehive Ring Road,
Gatwick, West Sussex RH6 0PA
Manufacturer
Novo Nordisk A/S
Novo Allé
DK-2880 Bagsværd, Denmark
This leaflet was last approved:
11/2015

USER INSTRUCTIONS
How to use the calendar pack
1. Set the day reminder
Turn the inner disc to set the day of
the week opposite the little plastic
tab.

2. Take the first day’s tablet
Break the plastic tab and tip out
the first tablet.

3. Move the dial every day
On the next day simply move the
transparent dial clockwise 1 space
as indicated by the arrow. Tip out
the next tablet. Remember to take
only 1 tablet once a day.
You can only turn the
transparent dial after the tablet
in the opening has been
removed.

Kliofem® is a trademark owned by
Novo Nordisk Health Care AG,
Switzerland
© 2015
Novo Nordisk A/S

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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