ESTROFEM 2 MG

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 one space as indicated by the arrow. Tip

out the next tablet. Remember to take only one

tablet once a day.

You can only turn the transparent dial after the

tablet in the opening has been removed.

1

2

3

י"ע עבקנ הז ןולע טמרופ ב רשואו קדבנ ונכותו תואירבה דרשמ טסוגוא

2016

1

NAME OF THE MEDICINAL PRODUCT

Estrofem® 1 mg film-coated tablets

Estrofem® 2 mg film-coated tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains estradiol 1 mg or 2 mg (as estradiol hemihydrate).

Excipient with known effect: lactose monohydrate.

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Film-coated tablets.

Estrofem 1 mg: Red, film-coated, round, biconvex tablets, engraved with NOVO 282.

Diameter 6 mm.

Estrofem 2 mg: Blue, film-coated, round, biconvex tablets, engraved with NOVO 280.

Diameter 6 mm.

4

CLINICAL PARTICULARS

4.1

Therapeutic indications

Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in postmenopausal

women.

Prevention of osteoporosis in postmenopausal women at high risk of future fractures, who are tolerant

of, or contraindicated for other medicinal products approved for the prevention of osteoporosis.

Estrofem is particularly for women who have been hysterectomised and therefore do not require

combined oestrogen/progestagen therapy.

The experience treating women older than 65 years is limited.

4.2

Posology and method of administration

Estrofem is an oestrogen-only product for hormonal replacement. Estrofem is administered orally, one

tablet daily without interruption. For initiation and continuation of treatment of menopausal

symptoms, the lowest effective dose for the shortest duration (see also section 4.4) should be used.

A switch to a higher dose or a lower dose of Estrofem could be indicated if the response after three

months is insufficient for satisfactory symptom relief or if the tolerability is not satisfactory.

In women without a uterus, Estrofem may be started on any convenient day. In women with a uterus

who present amenorrhoea and are being transferred from a sequential HRT, Estrofem may be initiated

on day 5 of bleeding and only in combination with a progestagen for at least 12–14 days; if transferred

from a continuous-combined HRT, Estrofem along with a progestin, may be started on any convenient

day. The progestagen type and dose should provide sufficient inhibition of the oestrogen induced

endometrial proliferation (see also section 4.4).

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 for

women with a uterus may increase the likelihood of breakthrough bleeding and spotting.

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

hysterectomised women.

4.3

Contraindications

Known, past or suspected breast cancer

Known, past or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)

Undiagnosed genital bleeding

Untreated endometrial hyperplasia

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

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

(see section 4.4))

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

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

return to normal

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1

Porphyria.

4.4

Special warnings and precautions for use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that

adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be

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

risk.

As the experience in treating women with a premature menopause (due to ovarian failure or surgery) is

limited, the evidence regarding the risks associated with HRT in the treatment of premature

menopause is also 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

Estrofem, in particular:

Leiomyoma (uterine fibroids) or endometriosis

Risk factors for thromboembolic disorders (see below)

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

degree heredity for breast cancer

Hypertension

Liver disorders (e.g. liver adenoma)

Diabetes mellitus with or without vascular involvement

Cholelithiasis

Migraine or (severe) headache

Systemic lupus erythematosus

A history of endometrial hyperplasia (see below)

Epilepsy

Asthma

Otosclerosis.

Reasons for immediate withdrawal of therapy:

Therapy should be discontinued in case a contra-indication is discovered and in the following

situations:

Jaundice or deterioration in liver function

Significant increase in blood pressure

New onset of migraine-type headache

Pregnancy.

Endometrial hyperplasia and carcinoma

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

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

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

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

remain elevated for at least 10 years.

The addition of a progestagen for at least 12 days per cycle 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 in women with

intact uterus. If breakthrough bleeding or spotting 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.

Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the

residual foci of endometriosis. Therefore, the addition of progestagens to oestrogen replacement

therapy should be considered in women who have undergone hysterectomy because of endometriosis,

if they are known to have residual endometriosis.

Breast cancer

The overall evidence 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 Women’s Health Initiative study (WHI) found no increase in the risk of breast cancer in

hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a

small increase in the risk of having breast cancer diagnosed that is substantially lower than that found

in users of oestrogen-progestagen combinations (see section 4.8).

The excess risk becomes apparent after about 3 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.

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

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

5 years of use and diminishes over time after stopping.

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

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

Venous thromboembolism

HRT is associated with a 1.3 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 4.3).

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 thrombosis

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 thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin,

protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated.

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, dyspnoea).

Smoking

This product should not be prescribed to a woman who is a smoker, espcially if she is older than 35,

without careful medical evaluation

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

using oestrogen-only therapy.

Ischaemic stroke

Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold

increase in risk of ischaemic stroke. The relative risk does not change with age or time since

menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of

stroke in women who use HRT will increase with age (see section 4.8).

Other conditions

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

be carefully observed.

Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen

replacement or hormone replacement therapy, since rare cases of large increases of plasma

triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.

Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid

hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay)

or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free

T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e.

corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased

circulating corticosteroids and sex steroids, respectively. Free or biological active hormone

concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin

substrate, alpha-I-antitrypsin, ceruloplasmin).

HRT use does not improve cognitive function. There is some evidence of increased risk of probable

dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.

Estrofem

tablets contain lactose. Patients with rare hereditary galactose intolerance, the Lapp lactase

deficiency or glucose-galactose malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interaction

The metabolism of oestrogens may be increased by concomitant use of substances known to induce

drug-metabolising enzymes, specifically cytochrome P450 enzymes such as anticonvulsants (e.g.

phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine,

efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties

when used concomitantly with steroid hormones. Herbal preparations containing St John’s wort

(Hypericum Perforatum) may induce the metabolism of oestrogens.

Clinically, an increased metabolism of oestrogens may lead to decreased effect and changes in the

uterine bleeding profile.

4.6

Fertility, pregnancy and lactation

Pregnancy

Estrofem is not indicated during pregnancy.

If pregnancy occurs during medication with Estrofem, treatment should be withdrawn immediately.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to

oestrogens indicate no teratogenic or foetotoxic effects.

Breast-feeding

Estrofem is not indicated during breast-feeding.

4.7

Effects on ability to drive and use machines

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

4.8

Undesirable effects

Clinical experience

In clinical trials less than 10% of the patients experienced adverse drug reactions. The most frequently

reported adverse reactions are breast tenderness/breast pain, abdominal pain, oedema, and headache.

The adverse reactions listed below occurred in the clinical trials during Estrofem treatment.

System organ

class

Very common

> 1/10

Common

> 1/100;

< 1/10

Uncommon

> 1/1,000;

< 1/100

Rare

> 1/10,000;

< 1/1,000

Psychiatric

disorders

Depression

Nervous system

disorders

Headache

Eye disorders

Vision abnormal

Vascular

disorders

Venous

embolism

Gastrointestinal

disorders

Abdominal pain

or nausea

Dyspepsia,

vomiting,

flatulence or

bloating

Hepatobiliary

disorders

Cholelithiasis

Skin and

subcutaneous

tissue disorders

Rash or urticaria

Musculoskeletal

and connective

tissue disorders

Leg cramps

System organ

class

Very common

> 1/10

Common

> 1/100;

< 1/10

Uncommon

> 1/1,000;

< 1/100

Rare

> 1/10,000;

< 1/1,000

Reproductive

system and breast

disorders

Breast

tenderness,

breast

enlargement or

breast pain

General

disorders and

administration

site conditions

Oedema

Investigations

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 judgment considered possibly related to Estrofem

treatment. The reporting rate of these spontaneous adverse drug reactions is very rare (< 1/10,000, not

known (cannot be estimated from the available data)). Post-marketing experience is subject to

underreporting especially with regard to trivial and well-known adverse drug reactions. The presented

frequencies should be interpreted in that light:

Immune system disorder: Generalised hypersensitivity reactions (e.g. anaphylactic

reaction/shock)

Nervous system disorder: Deterioration of migraine, stroke, dizziness, depression

Gastrointestinal disorder: Diarrhoea

Skin and subcutaneous tissue disorders: Alopecia

Reproductive system and breast disorders: Irregular vaginal bleeding*

Investigations: Increased blood pressure.

The following adverse reactions have been reported in association with other oestrogen treatment:

Myocardial infarction, congestive heart disease

Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism

Gall bladder disease

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

purpura, pruritus

Vaginal candidiasis

Oestrogen-dependent neoplasms benign and malignant. e.g. endometrial cancer (see section

4.4), endometrial hyperplasia or increase in size of uterine fibroids*

Insomnia

Epilepsy

Libido disorder NOS (not otherwise specified)

Deterioration of asthma

Probable dementia (see section 4.4).

* In non-hysterectomised women

Breast cancer risk

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)

Cases per 1,000 never-

users of HRT over a 5-

year period*

Risk ratio and

95% CI**

Additional cases per

1,000 HRT users

over 5 years’ use

(95% CI)

Oestrogen-only HRT

50-65

9-12

1-2 (0-3)

Combined oestrogen-progestagen

50-65

9-12

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 proportionally.

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

Additional cases per

1,000 HRT users

over 5 years

(95% CI)

CEE oestrogen-only

50-79

0.8 (0.7-1.0)

-4 (-6-0)*

CEE+MPA oestrogen-progestagen**

50-79

1.2 (1.0-1.5)

4 (0-9)

* 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

Postmenopausal women with a uterus

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

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

of endometrial cancer (see section 4.4).

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

endometrial cancer in 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

Use of oestrogen-only or combined oestrogen-progestagen HRT has been associated with a slightly

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

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

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

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

2,000 users. In women aged 50 to 54 who are not taking HRT, about 2 women in 2,000 will be

diagnosed with ovarian cancer over a 5-year period.

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

Additional cases

per 1,000 HRT

users over

5 years (95% CI)

Oral oestrogen-only*

50-59

1.2 (0.6-2.4)

1 (-3-10)

Oral combined oestrogen-progestagen

50-59

2.3 (1.2-4.3)

5 (1-13)

* Study in women with no uterus

Risk of coronary artery disease

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

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

Risk of ischaemic stroke

The use of oestrogen-only and oestrogen-progestagen therapy is associated with an up to 1.5-fold

increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use

of HRT.

This relative risk is not dependent on age or on duration of use, but the baseline risk is strongly age-

dependent. The overall risk of stroke in women who use HRT will increase with age (see section 4.4).

WHI Studies Combined – Additional risk of ischaemic stroke* over 5 years’ use

Age range

(years)

Incidence per 1,000

women in placebo arm

over 5 years

Risk ratio and

95% CI

Additional cases per

1,000 HRT users

over 5 years

(95% CI)

50-59

1.3 (1.1-1.6)

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.

Any suspected adverse events should be reported to the Ministry of Health according to the National

Regulation by using an online form

(http://forms.gov.il/globaldata/getsequence/getsequence.aspx?formType=AdversEffectMedic@moh.g

ov.il).

4.9

Overdose

Overdosage may be manifested by nausea and vomiting. There is no specific antidote and treatment

should be symptomatic.

5

PHARMACOLOGICAL PROPERTIES

5.1

Pharmacodynamic properties

Pharmacotherapeutic group: Natural and semisynthetic estrogens, plain, ATC code: G03CA03.

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

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

alleviates menopausal symptoms.

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

5.2

Pharmacokinetic properties

Novo Nordisk’s orally administered micronised 17β-estradiol as contained in Estrofem is rapidly and

efficiently absorbed from the gastrointestinal tract, reaching a peak plasma concentration of

approximately 44 pg/ml (range 30-53 pg/ml) within 4-6 hours after intake of 2 mg. 17β-estradiol has a

half life of approximately 14-16 hours. More than 90% of 17β-estradiol is bound to plasma proteins.

17β-estradiol is oxidised to estrone, which in turn is converted to estrone sulphate. Both

transformations take place mainly in the liver. Oestrogens are excreted into the bile and then undergo

reabsorption from the intestine. During this enterohepatic circulation, degradation occurs. 17β-

estradiol and its metabolites are excreted in the urine (90-95%) as biologically inactive glucuronide

and sulphate conjugates or in the faeces (5-10%) mostly unconjugated.

5.3

Preclinical safety data

Acute toxicity of oestrogens is low. Because of marked differences between animal species and

between animals and humans preclinical results possess a limited predictive value for the application

of oestrogens in humans.

In experimental animals estradiol or estradiol valerate displayed an embryolethal effect already at

relatively low doses; malformations of the urogenital tract and feminisation of male fetuses were

observed.

Preclinical data based on conventional studies of repeated dose toxicity, genotoxicity and carcinogenic

potential revealed no particular human risks beyond those discussed in other sections of the SmPC.

6

PHARMACEUTICAL PARTICULARS

6.1

List of excipients

The tablet cores of both strengths contain:

Lactose monohydrate

Maize starch

Hydroxypropylcellulose

Talc

Magnesium stearate

Film-coating:

Estrofem 1 mg: Hypromellose, red iron oxide (E172), titanium dioxide (E171), propylene glycol and

talc.

Estrofem 2 mg: Hypromellose, indigo carmine (E132), talc, titanium dioxide (E171) and macrogol

400.

6.2

Incompatibilities

Not applicable.

6.3

Shelf life

4 years.

6.4

Special precautions for storage

Store below 25 °C. Do not refrigerate.

6.5

Nature and contents of container

1 x 28 tablets or 3 x 28 tablets in calendar dial packs.

Calendar pack with 28 tablets consists of the following three 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.

6.6

Special precautions for disposal and other handling

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

requirements.

7. Registration number:

Estrofem® 1mg:

54-29845

Estrofem® 2mg:

060-75

27769-10

8. Manufacturer:

Novo Nordisk A/S

Novo Allé

DK-2880 Bagsværd

Denmark

9. Marketing Authorisation Holder:

Novo Nordisk Ltd.

20 HaTa’as St. Indust. Area,

Kfar Saba, 4442520

The content of this leaflet was checked and approved by the Ministry of Health in August 2016.