Estrofem 2mg

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

Anxiety, Libido decreased or Libido increased

Nervous system disorders

Headache

Dizziness

Migraine

Eye disorders

Vision abnormal

Contact lens intolerance

Cardiac disorders

Palpitations

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, Erythema nodosum

Hirsutism, Acne

Musculoskeletal and connective tissue disorders

Leg cramps

Reproductive system and breast disorders

Breast tenderness, breast enlargement or breast pain, Uterine/Vaginal bleeding including spotting

Dysmenorrhea, Vaginal discharge, Premenstrual-like syndrome

General disorders and administration site conditions

Oedema

Fatigue

InvestigationsMetabolism and nutrition disorders

Weight increase or weight decreased

Immune system disorders

Hypersensitivity reaction

2.      QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2 mg estradiol as hemihydrate

Each film-coated tablet contains 36.8 mg lactose monohydrate

For full list of excipients, see section 6.1.

2.         QUALITATIVE AND QUANTITATIVE COMPOSITION

Each film-coated tablet contains 2 mg estradiol as hemihydrate

Each film-coated tablet contains 36.8 mg lactose monohydrate

For a full list of excipients, see section 6.1.

4.1      Therapeutic Iindications

Hormone replacement therapy (HRT) for oestrogen deficiency as a result of natural menopause or oophorectomy.

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.

In women with intact uterus, progestogen therapy should be added.

The experience of treating women older than 65 years is limited.

4.1      Therapeutic Iindications

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 intolerant 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 of treating women older than 65 years is limited.

4.2    Posology and method of administration

Estrofem is an oestrogen-only product for hormonal replacement. 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 lower dose of Estrofem could be indicated if the tolerability is not satisfactory.

One tablet should be taken daily without interruption. If clinical response is inadequate, dosage may be increased to two tablets daily, but should be reduced to one tablet daily as soon as practicable.

Estrofem is administered orally, one tablet daily without interruption. Treatment of hysterectomised women and postmenopausal women may be started on any convenient day. If the woman is menstruating, treatment is started on day 5 of bleeding.

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.

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 progestogen type and dose should provide a 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 progestogen in hysterectomised women.

4.3    Contraindications

- Known, past or suspected breast cancer;

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

- Undiagnosed genital bleeding;

- Untreated endometrial hyperplasia;

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

- Active or recent arterial thromb

oembolic 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 substance or to any of the excipients;

- Porphyria

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

- Known hypersensitivity to the active substance or to any of the excipients

  - Porphyria

4.4    Special warnings and precautions for use

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.

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 mammography, should be carried out in accordance with currently accepted screening practices, 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

- A history of, or risk factors for, thromboembolic disorders (see below)

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

Women with an intact uterus with abnormal bleeding of unknown aetiology or women with an intact uterus who have previously been treated with unopposed oestrogens should be examined with special care in order to disclose a possible hyperstimulation/malignancy of the endometrium before initiation of treatment with Estrofem.

The risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods (see section 4.8).

The addition of a progestogen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.

For oral doses of estradiol >2mg the endometrial safety of added progestogens has not been studied.

Break-through bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time on 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 progestogens to oestrogen replacement therapy is recommended in women who have undergone hysterectomy because of endometriosis, especially if they are known to have residual endometriosis.

Breast Cancer

A randomised placebo-controlled trial, the Women's Health Initiative (WHI), and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking oestrogens, oestrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8). For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

In the MWS, the relative risk of breast cancer with conjugated equine oestrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. There was no evidence of a difference in the risk between the different routes of administration.

In the WHI study, the continuous combined conjugated equine oestrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.

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^st 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 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 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 progestogen for at least 12 days per cycle in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.

Break-through 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 progestogens 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 (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-progestogen 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 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).

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 (TGB), 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 biologically active hormone concentrations are unchanged.  Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

HRT 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 monohydrate. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine.

4.6    Pregnancy and lactation

Estrofem is not indicated during pregnancy. If pregnancy occurs during medication with Estrofem, treatment should be withdrawn immediately.

Clinically, the results of epidemiological studies to-date have not indicated teratogenic or foetotoxic effects when oestrogens in dose levels relevant for Estrofem were taken inadvertently during pregnancy.

Estrofem is not indicated during lactation.

4.6      Fertility, pregnancy and lactation

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.

Lactation.

Estrofem is not indicated during lactation.

4.7    Effects on ability to drive and use machines

No effects known.

4.7      Effects on ability to drive and use machines

Estrofem has no known effects on the ability to drive or use machines.

4.8    Undesirable effects

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 Estrofem treatment. The reporting rate of these spontaneous adverse drug reactions is very rare (<1/10,000). Post-marketing experience is subject to under-reporting especially with regard to trivial and well-known adverse drug reactions. The presented frequencies should be interpreted in that light:

- 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

- Gall bladder disease

- Skin and subcutaneous disorders: chloasma, erythema multiforme, erythema nodosum, vascular purpura, pruritus

- Vaginal candidiasis

- 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:

[Section completely re-written]

Endometrial cancer:

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed oestrogens. According to data from epidemiological studies, the best estimate of the risk is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and oestrogen dose, the reported increase in endometrial cancer risk among unopposed oestrogen users varies from 2- to 12-fold greater compared with non-users. Adding a progestogen to oestrogen-only therapy greatly reduces this increased risk.

4.8      Undesirable effects

Amends to the table:

System organ class

Very common ≥ 1/10

Common ≥ 1/100; <1/10   

Uncommon ≥ 1/1000; <1/100       

Rare ≥ 1/10,000; <1/1000

[Removal of NOS from Eye disorders and Vascular disorders under Uncommon.]

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 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 under-reporting especially with regard to trivial and well-known adverse drug reactions. The presented frequencies should be interpreted in that light:

- Immune system disorder: Generalized 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 [new table]

US WHI Studies – Additional risk of breast cancer after 5 years’ use [new table]

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 [new table]

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 [new table]

4.9 Overdose

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

4.9      Overdose

Overdose may be manifested by nausea and vomiting.  Treatment should be symptomatic.

5.1    Pharmacodynamic properties

5.1    Pharmacodynamic properties

ATC code G03C A03

Oestrogen-only product for continuous hormone replacement therapy (HRT).

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.

Endogenous 17β-estradiol induces and maintains the primary and secondary sexual characteristics. The biological effect of 17β-estradiol is carried out through a number of specific oestrogen receptors. The steroid receptor complex is bound to the cell’s DNA and induces specific proteins.

17β-estradiol increases SHBG-BC (sex-hormone-binding-globulin binding capacity) and CBG-BC (corticosteroid-binding-globulin binding capacity). The gonadotrophins FSH (follicle stimulating hormone) and LH (luteinizing hormone) are suppressed.

Pharmacotherapeutic group: Natural and semisynthetic estrogens, plain, ATC code: G03C A03

The active ingredient, synthetic 17b-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.

Oestrogens prevent bone loss following menopause or ovariectomy.

Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of oestrogens on the bone mineral density is dose-dependent. 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 women.

Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, 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.

The effects of Estrofem^® on bone mineral density were examined in a 2-year randomized, double-blind, placebo-controlled trial in early postmenopausal women (n=166, including 41 on Estrofem^® 1 mg and 42 on Estrofem^® 2 mg). Estrofem^® 1 mg and 2 mg significantly prevented bone loss at the lumbar spine and total hip in comparison with the placebo-treated women. The overall difference in mean percentage change in bone mineral density versus placebo was for 1 mg and 2 mg respectively 4.3% and 5.3% at the lumbar spine, 4.0% and 3.9% at the femoral neck. The corresponding numbers for the trochanter were 3.3% and 3.2% after 2 years of treatment.

The percentage of women who maintained or gained BMD in lumbar zone during treatment was 61% and 68% in women treated with 1 mg and 2 mg Estrofem^® respectively.

5.2 Pharmacokinetic properties

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 44pg/ml (range 30-53pg/ml) within 6 hours after intake of 2mg. 17β-estradiol has a half life of approximately 18 hours. More than 90% of 17β-estradiol is bound to plasma proteins.

17β-estradiol is oxidised to oestrone, which in turn is converted to oestriol 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-oestradiol 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.

Following oral administration of 17b-estradiol in micronized form, rapid absorption from the gastrointestinal tract occurs. It undergoes extensive first-pass metabolism in the liver and other enteric organs, and reaches a peak plasma concentration of approximately 44 pg/ml (range 30-53 pg/ml) within 6 hours after intake of 2 mg. The half-life of 17b-estradiol is about 18 hours. It circulates bound to SHBG (37%) and to albumin (61%), while only approximately 1-2% is unbound. Metabolism of 17b-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 estrone, catecholoestrogens and several oestrogen sulphates and glucuronides. Oestrogens are excreted by the bile, where they are hydrolysed and reabsorbed (enterohepatic circulation), and mainly in urine in biologically inactive form.

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 to humans.

In experimental animals estradiol or estradiol valerate displayed an embryolethal effect already at relatively low doses; malformation of the urogenital tract and feminisation of male foetuses were observed.

5.3      Preclinical safety data

The toxicity profile of estradiol is well-known. There are no preclinical data of relevance to the prescriber which are additional to that already included in other sections of the SmPC.

6.1    List of excipients

Lactose monohydrate

Maize starch

Hydroxypropylcellulose

Talc

Magnesium stearate

Titanium dioxide (E171)

Hypromellose (E464)

Macrogol 400

Indigo carmine (E132)

E464

6.1      List of excipients

The tablet core contains:

Lactose monohydrate

Maize starch

Hydroxypropylcellulose

Talc

Magnesium stearate

Film coating:

Hypromellose

Talc

Ttitanium dioxide (E171)

Macrogol 400

Indigo carmine (E132)

6.4    Special precautions for storage

Do not store above 25°C. Do not refrigerate or freeze. Store in the original package in order to protect from light.

6.4      Special precautions for storage

Store below 25°C.  Do not refrigerate.

6.5    Nature and contents of container

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.

6.5      Nature and contents of container

1 x 28 tablets in a calendar dial pack.

The calendar 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 white non-transparent polystyrene.

10.    DATE OF REVISION OF THE TEXT

July 2010

10.      DATE OF REVISION OF THE TEXT

July 2012

2.    QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipients: Each tablet contains approximately 38mg lactose monohydrate.

2.      QUALITATIVE AND QUANTITATIVE COMPOSITION

Excipients: Each tablet contains approximately 37mg lactose monohydrate.

4.4  Special warnings and precautions for use

4.4  Special warnings and precautions for use

Ovarian cancer

Use of estrogen alone and estrogen plus progestogen therapies for at least 5 or 10 years has been associated with an increased risk of ovarian cancer in some epidemiological studies.

Ovarian cancer

Use of oestrogen alone and oestrogen plus progestogen therapies for at least 5 or 10 years has been associated with an increased risk of ovarian cancer in some epidemiological studies.

4.5    Interaction with other medicinal products and other forms of interaction

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 and progestogens.

4.5    Interaction with other medicinal products and other forms of interaction

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 and progestogens.

4.8    Undesirable effects

Breast cancer

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to oestrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years. According to calculations from the trial data, it is estimated that:

• For 1000 women in the placebo group,

- about 16 cases of invasive breast cancer would be diagnosed in 5 years.

• For 1000 women who used oestrogen + progestogen combined HRT (CEE + MPA), the number of additional cases would be

- between 0 and 9 (best estimate = 4) for 5 years’ use.

4.8    Undesirable effects

Breast cancer

The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to oestrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years. According to calculations from the trial data, it is estimated that:

• For 1000 women in the placebo group: About 16 cases of invasive breast cancer would be diagnosed in 5 years.

• For 1000 women who used oestrogen + progestogen combined HRT (CEE + MPA), the number of additional cases would be between 0 and 9 (best estimate = 4) for 5 years’ use.

6.1  List of Excipients

Gelatin

Blue tablets:          Indigotin E132

6.1  List of Excipients

Hydroxypropylcellulose

Blue tablets:          Indigo carmine E132       

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

Date of first authorisation: 21st May 1977

Date of last renewal: 21^st May 2007

9.      DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 21 May 1977

        Date of last renewal: 21 May 2007

10.  DATE OF REVISION OF THE TEXT

October 2009

10.    DATE OF REVISION OF THE TEXT

July 2010