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Novofem film-coated tablets



One red film-coated tablet contains:
Estradiol 1 mg (as estradiol hemihydrate).
One white film-coated tablet contains:
Estradiol 1 mg (as estradiol hemihydrate) and norethisterone acetate 1 mg.
Excipient with known effect: lactose monohydrate:
Each red film-coated tablet contains lactose monohydrate 37.3 mg
Each white film-coated tablet contains lactose monohydrate 37.9 mg
For the full list of excipients, see section 6.1.


Film-coated tablets
Red film-coated, biconvex tablets engraved with NOVO 282. Diameter: 6 mm.
White film-coated, biconvex tablets engraved with NOVO 283. Diameter: 6 mm.




Therapeutic indications

Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in
postmenopausal women with at least 6 months since last menses.
Prevention of osteoporosis in postmenopausal women at high risk of future fractures
who are intolerant of or contraindicated for other medicinal products approved for the
prevention of osteoporosis (see also section 4.4).
The experience treating women older than 65 years is limited.


Posology and method of administration

Novofem is a continuous sequential HRT product for oral use. The oestrogen is dosed
continuously. The progestagen is added for 12 days of every 28 day cycle, in a
sequential manner.
One tablet is taken daily in the following order: oestrogen therapy (red film-coated
tablet) over 16 days, followed by 12 days of oestrogen/progestagen therapy (white
film-coated tablet).
After intake of the last white tablet, treatment is continued with the first red tablet of a
new pack on the next day. A menstruation-like bleeding usually occurs at the
beginning of a new treatment cycle.
In women who are not taking HRT or women in transition from a continuous
combined HRT product, treatment with Novofem may be started on any convenient
day. In women in transition from another sequential HRT regimen, treatment should
begin the day following completion of the preceding regimen.
For initiation and continuation of treatment of postmenopausal symptoms, the lowest
effective dose for the shortest duration (see also section 4.4) should be used.
A switch to a higher dose combination product could be indicated if the response after
3 months is insufficient for symptom relief.
If the patient has forgotten to take a tablet, the tablet should be taken as soon as
possible within the next 12 hours. If more than 12 hours have passed, the tablet should
be discarded. Forgetting a dose may increase the likelihood of breakthrough bleeding
and spotting.


Known, past or suspected breast cancer
Known, past or suspected oestrogen-dependent malignant tumours (e.g. endometrial
Undiagnosed genital bleeding
Untreated endometrial hyperplasia
Previous or current venous thromboembolism (deep venous thrombosis, pulmonary
Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency
(see section 4.4))
Active or previous arterial thromboembolic disease (e.g. angina, myocardial infarction)
Acute liver disease or a history of liver disease as long as liver function tests have
failed to return to normal
Known hypersensitivity to the active substances or to any of the excipients

Special warnings and precautions for use

For the treatment of postmenopausal symptoms, HRT should only be initiated for
symptoms that adversely affect quality of life. In all cases, a careful appraisal of the
risks and benefits should be undertaken at least annually and HRT should only be
continued as long as the benefit outweighs the risk.
Evidence regarding the risks associated with HRT in the treatment of premature
menopause is limited. Due to the low level of absolute risk in younger women,
however, the balance of benefits and risks for these women may be more favourable
than in older women.
Medical examination/follow-up
Before initiating or reinstituting HRT, a complete personal and family medical history
should be taken. Physical (including pelvic and breast) examination should be guided
by this and by the contraindications and warnings for use. During treatment, periodic
check-ups are recommended of a frequency and nature adapted to the individual
woman. Women should be advised what changes in their breasts should be reported to
their doctor or nurse (see ‘Breast cancer’ below). Investigations, including appropriate
imaging tools, e.g. mammography, should be carried out in accordance with currently
accepted screening practices and modified to the clinical needs of the individual.
Conditions which need supervision
If any of the following conditions are present, have occurred previously and/or have
been aggravated during pregnancy or previous hormone treatment, the patient should
be closely supervised. It should be taken into account that these conditions may recur
or be aggravated during treatment with Novofem in particular:

Leiomyoma (uterine fibroids) or endometriosis
Risk factors for thromboembolic disorders (see below)
Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast
Liver disorders (e.g. liver adenoma)
Diabetes mellitus with or without vascular involvement
Migraine or (severe) headache
Systemic lupus erythematosus
A history of endometrial hyperplasia (see below)

Reasons for immediate withdrawal of therapy
Therapy should be discontinued in case a contraindication is discovered and in the
following situations:

Jaundice or deterioration in liver function
Significant increase in blood pressure

New onset of migraine-type headache

Endometrial hyperplasia and carcinoma
In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is
increased when oestrogens are administered alone for prolonged periods. The reported
increase in endometrial cancer risk among oestrogen-only users varies from 2- to 12fold greater compared with non-users, depending on the duration of treatment and
oestrogen dose (see section 4.8). After stopping treatment the risk may remain
elevated for at least 10 years.
The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or
continuous combined oestrogen-progestagen therapy in non-hysterectomised women
prevents the excess risk associated with oestrogen-only HRT.
Breakthrough bleeding and spotting may occur during the first months of treatment. If
breakthrough bleeding or spotting continues after the first months of treatment,
appears after some time during therapy, or continues after treatment has been
discontinued, the reason should be investigated, which may include endometrial
biopsy to exclude endometrial malignancy.
Breast cancer
The overall evidence suggests an increased risk of breast cancer in women taking
combined oestrogen-progestagen and possibly also oestrogen-only HRT that is
dependent on the duration of taking HRT.
The randomised placebo-controlled trial, the Women’s Health Initiative study (WHI),
and epidemiological studies are consistent in finding an increased risk of breast cancer
in women taking combined oestrogen-progestagen HRT that becomes apparent after
about 3 years (see section 4.8).
The excess risk becomes apparent within a few years of use, but returns to baseline
within a few (at most 5) years after stopping treatment.
HRT, especially oestrogen-progestagen combined treatment, increases the density of
mammographic images which may adversely affect the radiological detection of
breast cancer.
Ovarian cancer
Ovarian cancer is much rarer than breast cancer. Long-term (at least 5-10 years) use
of oestrogen-only HRT products has been associated with a slightly increased risk of
ovarian cancer (see section 4.8). Some studies, including the WHI trial, suggest that
the long-term use of combined HRT may confer a similar or slightly smaller risk (see
section 4.8).
Venous thromboembolism

HRT is associated with a 1.3- to 3-fold risk of developing venous thromboembolism
(VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an
event is more likely in the first year of HRT than later (see section 4.8).
Patients with known thrombophilic states have an increased risk of VTE and HRT
may add to this risk. HRT is therefore contraindicated in these patients (see section
Generally recognised risk factors for VTE include use of oestrogens, older age, major
surgery, prolonged immobilisation, obesity (BMI > 30 kg/m²), pregnancy/postpartum
period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about
the possible role of varicose veins in VTE.
As in all postoperative patients, prophylactic measures need to be considered to
prevent VTE following surgery. If prolonged immobilisation is to follow elective
surgery, temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment
should not be restarted until the woman is completely mobilised.
In women with no personal history of VTE but with a first degree relative with a
history of venous thromboembolism at a young age, screening may be offered after
careful counselling regarding its limitations (only a proportion of thrombophilic
defects are identified by screening).
If a thrombophilic defect is identified which segregates with venous
thromboembolism in family members or if the defect is ‘severe’ (e.g. antithrombin,
protein S, or protein C deficiencies or a combination of defects), HRT is
Women already on chronic anticoagulant treatment require careful consideration of
the benefit-risk of use of HRT.
If VTE develops after initiating therapy, the drug should be discontinued. Patients
should be told to contact their doctors immediately when they are aware of a potential
thromboembolic symptom (e.g. painful swelling of a leg, sudden pain in the chest,
Coronary artery disease (CAD)
There is no evidence from randomised controlled trials of protection against
myocardial infarction in women with or without existing CAD who received
combined oestrogen-progestagen or oestrogen-only HRT.
The relative risk of CAD during use of combined oestrogen-progestagen HRT is
slightly increased. As the baseline absolute risk of CAD is strongly dependent on age,
the number of extra cases of CAD due to oestrogen-progestagen use is very low in
healthy women close to menopause, but will rise with more advanced age.
Ischaemic stroke

Combined oestrogen-progestagen and oestrogen-only therapy are associated with an
up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change
with age or time since menopause. However, as the baseline risk of stroke is strongly
age-dependent, the overall risk of stroke in women who use HRT will increase with
age (see section 4.8).
Patients who require thyroid hormone replacement therapy should have their thyroid
function monitored regularly while on HRT to ensure that thyroid hormone levels
remain in an acceptable range.
Oestrogens may induce or exacerbate symptoms of angioedema, in particular in
women with hereditary angioedema.
Other conditions
Oestrogens may cause fluid retention, and therefore patients with cardiac or renal
dysfunction should be carefully observed.
Women with pre-existing hypertriglyceridaemia should be followed closely during
oestrogen replacement or hormone replacement therapy, since rare cases of large
increases of plasma triglycerides leading to pancreatitis have been reported with
oestrogen therapy in this condition.
Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating
total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by
column or by radioimmunoassay) or T3 levels (by radioimmunoassay). T3 resin
uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations
are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding
globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased
circulating corticosteroids and sex steroids, respectively. Free or biological active
hormone concentrations are unchanged. Other plasma proteins may be increased
(angiotensinogen/renin substrate, alpha-I-antitrypsin and ceruloplasmin).
HRT use does not improve cognitive function. There is some evidence of increased
risk of probable dementia in women who start using continuous combined or
oestrogen-only HRT after the age of 65.
Novofem tablets contain lactose monohydrate. Patients with rare hereditary problems
of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose
malabsorption should not take this medicine.

Interaction with other medicinal products and other forms of interaction

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

Ritonavir, telaprevir and nelfinavir, although known as strong inhibitors, by contrast
exhibit inducing properties when used concomitantly with steroid hormones. Herbal
preparations containing St John’s Wort (Hypericum perforatum) may induce the
metabolism of oestrogens and progestagens.
Clinically, an increased metabolism of oestrogens and progestagens may lead to
decreased effect and changes in the uterine bleeding profile.
Some laboratory tests may be influenced by oestrogen therapy, such as tests for
glucose tolerance or thyroid function.
Drugs that inhibit the activity of hepatic microsomal drug metabolising enzymes, e.g.
ketoconazole, may increase circulating levels of the active substances in Novofem.
Concomitant administration of cyclosporine may cause increased blood levels of
cyclosporine, creatinine and transaminases due to decreased metabolism of
cyclosporine in the liver.

Fertility, pregnancy and lactation

Novofem is not indicated during pregnancy.
If pregnancy occurs during medication with Novofem, treatment should be withdrawn
Clinically, data on a limited number of exposed pregnancies indicate adverse effects
of norethisterone on the foetus. At doses higher than those normally used in OC and
HRT formulations, masculinisation of female foetuses was observed.
The results of most epidemiological studies to date, relevant to inadvertent foetal
exposure to combinations of oestrogens and progestagens, indicate no teratogenic or
foetotoxic effect.
Novofem is not indicated during lactation.


Effects on ability to drive and use machines

Novofem has no known effect on the ability to drive or use machines.

Undesirable effects

Clinical experience
The most frequently reported adverse events during treatment in clinical trials conducted with
an HRT product similar to Novofem were breast tenderness and headache (reported in ≥ 10%
of patients).
The adverse events listed below may occur during oestrogen-progestagen treatment.
The frequencies are derived from clinical trials conducted with an HRT product similar to
Novofem and from a Post-marketing Surveillance study on Novofem.

System organ class
Infections and
Immune system
Psychiatric disorders
Nervous system

Very common
≥ 1/10


≥ 1/100; < 1/10

≥ 1/10,000;
< 1/1,000

Vaginal candidiasis



Increased blood
Abdominal pain

Vascular disorders


Skin and
subcutaneous tissue
Musculoskeletal and
connective tissue
Reproductive system
and breast disorders

≥ 1/1,000; < 1/100


Libido disorder
NOS (not otherwise


embolism and

Gall bladder



Muscle cramps


General disorders
and administration
site conditions

Vaginal haemorrhage


Uterine fibroids

Weight increased

Post-marketing experience
In addition to the above mentioned adverse drug reactions, those presented below have been
spontaneously reported, and are by an overall judgement considered possibly related to

Novofem treatment. Frequences of these adverse events cannot be estimated from the
available data:

Neoplasms benign and malignant (including cysts and polyps): Endometrial cancer
Immune system disorders: Generalised hypersensitivity reactions (e.g. anaphylactic
Psychiatric disorders: Anxiety
Nervous system disorders: Stroke
Eye disorders: Visual disturbances
Cardiac disorders: Myocardial infarction
Vascular disorders: Hypertension aggravated
Hepatobiliary disorders: Cholelithiasis aggravated, cholelithiasis recurrence
Skin and subcutaneous tissue disorders: Seborrhoea, angioneurotic oedema, hirsutism
Reproductive system and breast disorders: Endometrial hyperplasia, vulvovaginal
Investigations: Weight decreased.

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

Skin and subcutaneous disorders: Chloasma, erythema multiforme, erythema nodosum,
haemorrhagic eruption, vascular purpura

Probable dementia over the age of 65 (see section 4.4)

Dry eyes

Tear film composition changes.
Breast cancer risk
An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking
combined oestrogen-progestagen therapy for more than 5 years.
Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in
users of oestrogen-progestagen combinations.
The level of risk is dependent on the duration of use (see section 4.4).
Results of the largest randomised placebo-controlled trial (WHI-study) and largest
epidemiological study (MWS) are presented below:
Million Women Study – Estimated additional risk of breast cancer after 5 years’ use
Age range (years)


Incidence per 1,000
never-users of
HRTover 5 years

Risk ratio**

Oestrogen-only HRT
Combined oestrogen-progestagen

Additional cases per
1,000 HRT users
over 5 years’ use
(95% CI)
1-2 (0-3)
6 (5-7)

* Taken from baseline incidence rates in developed countries.
** Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use.
Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of
breast cancer will also change proportionately.

US WHI Studies – Additional risk of breast cancer after 5 years’ use

Age range (years)

Incidence per 1,000
women in placebo
arm over 5 years




Risk ratio and
95% CI

CEE oestrogen-only
0.8 (0.7-1.0)
CEE+MPA oestrogen-progestagen**
1.2 (1.0-1.5)

Additional cases per
1,000 HRT users
over 5 years’ use
(95% CI)
-4 (-6-0)*
4 (0-9)

* WHI study in women with no uterus, which did not show an increase in risk of breast cancer.
** When the analysis was restricted to women who had not used HRT prior to the study there was no increased
risk apparent during the first 5 years of treatment. After 5 years the risk was higher than in non-users.

Endometrial cancer risk
The endometrial cancer risk is about 5 in every 1,000 women with a uterus not using HRT.
In women with a uterus, use of oestrogen-only HRT is not recommended because it increases
the risk of endometrial cancer (see section 4.4).
Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of
endometrial cancer in epidemiological studies varied from between 5 and 55 extra cases
diagnosed in every 1,000 women between the ages of 50 and 65.
Adding a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this
increased risk. In the Million Women Study the use of 5 years of combined (sequential or
continuous) HRT did not increase the risk of endometrial cancer (RR of 1.0 (0.8-1.2)).
Ovarian cancer risk
Long-term use of oestrogen-only and combined oestrogen-progestagen HRT has been
associated with a slightly increased risk of ovarian cancer. In the Million Women Study,
5 years of HRT resulted in 1 extra case per 2,500 users.
Risk of venous thromboembolism
HRT is associated with a 1.3- to 3-fold increased relative risk of developing venous
thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence
of such an event is more likely in the first year of using HRT (see section 4.4). Results of the
WHI studies are presented below:
WHI Studies – Additional risk of VTE over 5 years’ use
Age range (years)


Incidence per 1,000
women in placebo
arm over 5 years

Risk ratio and
95% CI

Oral oestrogen-only*
1.2 (0.6-2.4)
Oral combined oestrogen-progestagen
2.3 (1.2-4.3)

* Study in women with no uterus.

Risk of coronary artery disease

Additional cases per
1,000 HRT users
over 5 years’ use
(95% CI)
1 (-3-10)
5 (1-13)

The risk of coronary artery disease is slightly increased in users of combined oestrogenprogestagen HRT over the age of 60 (see section 4.4).
Risk of ischaemic stroke
The use of oestrogen-only and oestrogen-progestagen therapy is associated with an up to 1.5fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not
increased during use of HRT.
This relative risk is not dependent on age or on duration of use, but the baseline risk is
strongly age-dependent. The overall risk of stroke in women who use HRT will increase with
age (see section 4.4).
WHI Studies Combined – Additional risk of ischaemic stroke* over 5 years’ use
Age range (years)

Incidence per 1,000
women in placebo
arm over 5 years

Risk ratio and
95% CI



1.3 (1.1-1.6)

Additional cases per
1,000 HRT users
over 5 years’ use
(95% CI)
3 (1-5)

* No differentiation was made between ischaemic and haemorrhagic stroke.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is
important. It allows continued monitoring of the benefit/risk balance of the medicinal product.
Healthcare professionals are asked to report any suspected adverse reactions via the Yellow
Card Scheme



Symptoms of over dosage with oral oestrogens are breast tenderness, nausea,
vomiting and/or metrorrhagia. Overdosage of progestagens may lead to a depressive
mood, fatigue, acne and hirsutism. Treatment should be symptomatic.




Pharmacodynamic properties

Pharmacotherapeutic group: Progestagens and oestrogens, sequential preparations,
ATC code: G03FB05.
Estradiol: The active ingredient, synthetic 17β-estradiol, is chemically and
biologically identical to endogenous human estradiol. It substitutes for the loss of
oestrogen production in postmenopausal women and alleviates menopausal
Oestrogens prevent bone loss following menopause or ovariectomy.

Norethisterone acetate: Synthetic progestagen. As oestrogens promote the growth of
the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia
and cancer. The addition of a progestagen reduces the oestrogen-induced risk of
endometrial hyperplasia in non-hysterectomised women.
Relief of postmenopausal symptoms is achieved during the first few weeks of
In a post-marketing study regular withdrawal bleeding with a mean duration of 34 days occurred in 91% of women who took Novofem over 6 months. Withdrawal
bleeding usually started a few days after the last tablet of the progestagen phase.
Oestrogen deficiency at menopause is associated with an increased bone turnover and
decline in bone mass. The effect of oestrogens on the bone mineral density is dosedependent. Protection appears to be effective for as long as treatment is continued.
After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated
Evidence from the WHI trial and meta-analysis of trials show that current use of HRT,
oestrogen alone or in combination with a progestagen – given to predominantly
healthy women – reduces the risk of hip, vertebral, and other osteoporotic fractures.
HRT may also prevent fractures in women with low bone density and/or established
osteoporosis, but the evidence for that is limited.
Randomised, double-blind, placebo-controlled studies showed that 1 mg estradiol
prevents the postmenopausal loss of bone minerals and increases the bone mineral
density. The responses in the spine, femoral neck and trochanter were 2.8%, 1.6% and
2.5%, respectively, over 2 years with 1 mg 17ß-estradiol unopposed.

Pharmacokinetic properties

Following oral administration of 17β-estradiol in micronised form, rapid absorption
from the gastrointestinal tract occurs. It undergoes extensive first-pass metabolism in
the liver and other enteric organs, and a peak plasma concentration of approximately
27 pg/ml (range 13-40 pg/ml) occurs within 6 hours after intake of 1 mg. The area
under the curve (AUC(0-tz))= 629 h x pg/ml. The half-life of 17β-estradiol is about
25 hours. It circulates bound to SHBG (37%) and to albumin (61%), while only
approximately 1-2% is unbound. Metabolism of 17β-estradiol occurs mainly in the
liver and the gut but also in target organs, and involves the formation of less active or
inactive metabolites, including oestrone, catecholoestrogens and several oestrogen
sulfates and glucuronides. Oestrogens are excreted with the bile, hydrolysed and
reabsorbed (enterohepatic circulation), and mainly eliminated in urine in biologically
inactive form.
After oral administration, norethisterone acetate is rapidly absorbed and transformed
to norethisterone (NET). It undergoes first-pass metabolism in the liver and other
enteric organs, and reaches a peak plasma concentration of approximately 9 ng/ml
(range 6-11 ng/ml) within 1 hour after intake of 1 mg. The area under the curve

(AUC(0-tz)) = 29 h x pg/ml. The terminal half-life of NET is about 10 hours. NET
binds to SHBG (36%) and to albumin (61%). The most important metabolites are
isomers of 5α-dihydro-NET and of tetrahydro-NET, which are excreted mainly in the
urine as sulfate or glucuronide conjugates.
The pharmacokinetics of estradiol is not influenced by norethisterone acetate.
The pharmacokinetic properties in the elderly have not been studied.

Preclinical safety data

Animal studies with estradiol and norethisterone acetate have shown oestrogenic and
progestagenic effects as expected. Both compounds induced adverse effects in
preclinical reproductive toxicity studies, in particular embryotoxic effects and
anomalies in urogenital tract development. Concerning other preclinic effects, the
toxicity profiles of estradiol and norethisterone acetate are well-known and reveal no
particular human risks beyond those discussed in other sections of the Summary of
Product Characteristics and which generally apply to hormone substitution therapy.




List of excipients
Both the white and the red tablets contain:
Lactose monohydrate
Maize starch
Magnesium stearate

White film-coated tablet:
Hypromellose, triacetin and talc.
Red film-coated tablet:
Hypromellose, red iron oxide (E 172), titanium dioxide (E 171), propylene glycol and

Not applicable.


Shelf life

3 years.

Special precautions for storage

Do not store above 25°C. Do not refrigerate. Keep the container in the outer carton in
order to protect it from light.

Nature and contents of container

1 x 28 tablets or 3 x 28 tablets in calendar dial packs.
The calendar dial pack with 28 tablets consists of the following 3 parts:

The base made of coloured non-transparent polypropylene.

The ring-shaped lid made of transparent polystyrene.

The centre-dial made of coloured non-transparent polystyrene.
Not all pack sizes may be marketed.

Special precautions for disposal

Any unused medicinal product or waste material should be disposed of in accordance
with local requirements.



Marketing Authorisation Holder:
Novo Nordisk Limited
3 City Place
Beehive Ring Road
West Sussex
PL 03132/0141





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