Fematab 2mg Film-coated tablets

- section 4.2: addition of text "One tablet daily to be taken orally" 

- section 4.3: deletion of contraindication "non hysterectomised women without opposing progestagen"

- section 4.8: Addition of new undesirable effects: vaginal candidiasis, gall bladder disorder, metrorrhagia. Deletion of other adverse reactions that have been reported in association with estradiol treatment (frequency unknown).

- section 4.9: Deletion of text "Acute toxicity studies did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose"

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate
Hypromellose
Maize starch
Colloidal anhydrous silica
Magnesium stearate
Opadry OY 6957 Pink coatingFilm coating mix Pink I containing:
Macrogol 400
Titanium dioxide (E171)
Hypromellose
Black, red and yellow iron oxides (E172).
Talc

10. DATE OF REVISION OF THE TEXT

June 2017November 2017

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate
Hypromellose
Maize starch
Colloidal anhydrous silica
Magnesium stearate
Opadry OY 6957 Pink coatingFilm coating mix Pink I containing:
Macrogol 400
Titanium dioxide (E171)
Hypromellose
Black, red and yellow iron oxides (E172).
Talc

10. DATE OF REVISION OF THE TEXT

June 2017November 2017

7.  MARKETING AUTHORISATION HOLDER

Mylan IRE Healthcare Limited

Unit 35/36

Grange Parade

Baldoyle Industrial Estate

Dublin 13

Ireland

BGP Products Ireland Limited

4051 Kingswood Drive,

Citywest Business Campus,

Dublin 24

8. MARKETING AUTHORISATION NUMBER

 

PA 2010/11/2 2007/7/2

10. DATE OF REVISION OF THE TEXT

 

June 2017

7.  MARKETING AUTHORISATION HOLDER

Mylan IRE Healthcare Limited

Unit 35/36

Grange Parade

Baldoyle Industrial Estate

Dublin 13

Ireland

BGP Products Ireland Limited

4051 Kingswood Drive,

Citywest Business Campus,

Dublin 24

8. MARKETING AUTHORISATION NUMBER

 

PA 2010/11/2 2007/7/2

10. DATE OF REVISION OF THE TEXT

 

June 2017

Section 5.2: correction of absorption data for estradiol 2mg

Section 5.2: correction of absorption data for estradiol 2mg

- In section 4.4 - update to text for ovarian cancer risk
- In section 4.8 - update to text for ovarian cancer risk

- In section 4.4 - update to text for ovarian cancer risk
- In section 4.8 - update to text for ovarian cancer risk

Section 7:
MA Holder changed from Abbott Healthcare Products Limited to BGP Products Ltd

Section 8:
PA number changed from PA 108/18/1 to PA 2007/7/2

Section 7:
MA Holder changed from Abbott Healthcare Products Limited to BGP Products Ltd

Section 8:
PA number changed from PA 108/18/1 to PA 2007/7/2

In Section 7:
The address of the MA holder has changed:-

from Mansbridge Road
West End
Southampton
SO18 3JD, UK

to Abbott House
Vanwall Business Park
Vanwall Road
Maidenhead
SL6 4XE, UK

In Section 7:
The address of the MA holder has changed:-

from Mansbridge Road
West End
Southampton
SO18 3JD, UK

to Abbott House
Vanwall Business Park
Vanwall Road
Maidenhead
SL6 4XE, UK

Section 4.2 Posology and method of administration:
Removal of "Prevention of osteoporosis" paragraph.
Addition of "Paediatric Population" paragraph.

Section 4.8 Undesirable effects:
Update to the MedDRA table
Further adverse reactions added
Addition of data in relation to the "Million Women Study"

Section 5.1 Pharmacodynamic properties:
Addition of "Clinical Trial" data

Section 5.2 Pharmacokinetic properties:
Further information added in relation to absorbtion, distribution, biotransformation, elimination and linearity/non-linearity.
 
Section 5.3 Preclinical safety data:
Removal of "Supraphysiologically high doses (prolonged overdoses) of estradiol have been associated with the induction of tumours in oestrogen-dependent target organs for all animal species tested".
Addition of "There are no preclinical safety data of relevance to the prescriber in the target population that are additional to those already included in other sections of the Summary of Product Characteristics".

Section 6.6 Instructions for use, handling or storage:
Addition of "Medicines no longer required should not be disposed of via wastewater or household waste".

Section 4.2 Posology and method of administration:
Removal of "Prevention of osteoporosis" paragraph.
Addition of "Paediatric Population" paragraph.

Section 4.8 Undesirable effects:
Update to the MedDRA table
Further adverse reactions added
Addition of data in relation to the "Million Women Study"

Section 5.1 Pharmacodynamic properties:
Addition of "Clinical Trial" data

Section 5.2 Pharmacokinetic properties:
Further information added in relation to absorbtion, distribution, biotransformation, elimination and linearity/non-linearity.
 
Section 5.3 Preclinical safety data:
Removal of "Supraphysiologically high doses (prolonged overdoses) of estradiol have been associated with the induction of tumours in oestrogen-dependent target organs for all animal species tested".
Addition of "There are no preclinical safety data of relevance to the prescriber in the target population that are additional to those already included in other sections of the Summary of Product Characteristics".

Section 6.6 Instructions for use, handling or storage:
Addition of "Medicines no longer required should not be disposed of via wastewater or household waste".

Estrogen changed to Oestrogen
Progestogen changes to Progestagen

Section 4.1 Therapeutic Indication:-
Indication amended to read "Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women at least 6 months since last menses"

Section 4.4 Special warnings and special precautions for use:-
Addition of "See 'Breast cancer' below
Addition of "appropriate imaging tools, e.g. mamography

Section 4.8 Undesirable Effects:-
Addition of "Reporting of suspected adverse reactions" paragraph

Section 4.9 Overdose:-
Addition of "Acute toxicity studies did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose.
Nausea, vomiting, sleepiness, dizziness and withdrawal bleeding may occur in some women.  There is no specific antidote and treatment should be symptomatic.
Aforementioned information is applicable for overdosing in children.

Estrogen changed to Oestrogen
Progestogen changes to Progestagen

Section 4.1 Therapeutic Indication:-
Indication amended to read "Hormone replacement therapy (HRT) for oestrogen deficiency symptoms in postmenopausal women at least 6 months since last menses"

Section 4.4 Special warnings and special precautions for use:-
Addition of "See 'Breast cancer' below
Addition of "appropriate imaging tools, e.g. mamography

Section 4.8 Undesirable Effects:-
Addition of "Reporting of suspected adverse reactions" paragraph

Section 4.9 Overdose:-
Addition of "Acute toxicity studies did not indicate a risk of acute adverse effects in case of inadvertent intake of a multiple of the daily therapeutic dose.
Nausea, vomiting, sleepiness, dizziness and withdrawal bleeding may occur in some women.  There is no specific antidote and treatment should be symptomatic.
Aforementioned information is applicable for overdosing in children.

4.1       Therapeutic indications

 

Hormone replacement therapy (HRT) for estrogen deficiency symptoms in menopausal women 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)

 

Elderly population

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

                       

4.2       Posology and method of administration

 

Fematab is an estrogen only continuous HRT for women with or without a uterus.

In women with a uterus, a progestagen such as Dydrogesterone 10mg, should be added to Fematab for 12-14 days each month to reduce the risk to the endometrium. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.

 

In general, treatment should start with Fematab 1mg. Depending on the clinical response, the dosage can afterwards be adjusted to individual need. If the complaints linked to estrogen deficiency are not ameliorated the dosage can be increased by using Fematab 2mg.

 

The dosage is one tablet per day. Fematab should be taken continuously without a break between packs.

 

Hormone replacement therapy

The initial daily dosage is 1 mg. The dosage may be increased to 2 mg if required. 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.

 

 

 

Starting Fematab

In women who are not taking hormone replacement therapy, have established amenorrhoea, are hysterectomised, or women who switch from a continuous combined hormone replacement therapy, treatment may be started on any convenient day. In women transferring from a cyclic or continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen. If the patient is menstruating, treatment is started within five days of the start of bleeding

 

Prevention of osteoporosis

One or two mg once daily without interruption. Treatment should start as soon as possible after the onset of menopause and latest within 2 to 3 years after the onset of menopause. Protection appears to be effective for as long as treatment continues, however data beyond 10 years are limited. A careful reappraisal of the risk benefit ratio should be undertaken before treating a patient for more than 5-10 years.

 

Treatment of hysterectomized women and postmenopausal women may be started on any convenient day.

 

If the patient is menstruating, treatment is started on day 5 of bleeding.

 

In women with a uterus, a progestogen should be added to Fematab for 10-14 days each month/28 day cycle.

 

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomized women.

 

Fematab can be taken with or without food.

 

If a dose has been forgotten, it should be taken as soon as possible. When If more than 12 hours have elapsed, it is recommended to continue with the next dose treatment should be continued with the next tablet without taking the forgotten tablet. The likelihood of breakthrough bleeding or spotting may be increased. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

 

 

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.

 

4.3       Contraindications

           

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

Non hysterectomized women without opposing progestogen

Known, past or suspected breast cancer

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

Undiagnosed genital bleeding

Untreated endometrial hyperplasia

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

Known thrombophilic 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, cerebral vascular accident)

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

Porphyria

 

4.4       Special warnings and special 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 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 Fematab, in particular:

 

-          Leiomyoma (uterine fibroids) or endometriosis

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

-          Risk factors for estrogen-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 cases where 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

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

In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2- to 12- fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.

 

 

 

The addition of a progestoagen for at least 12 days of the cycle in non-hysterectomised women greatly reduces this risk. cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women can prevent the excess risk associated with estrogen-only HRT.

 

For oral doses of estradiol >2mg, and patches >50μg/day the endometrial safety of added progesterones has not been demontratedstudied.

 

Breakthrough bleeding and spotting may occasionally occur during the first few months of treatment. If break-through 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 estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestoagens to estrogen 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 estrogen-progestogen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.

 

Combined estrogen-progestogen therapy

A randomised placebo-controlled trial, the Womens Health Initiative study (WHI) and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8). are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestogen for HRT that becomes apparent after about 3 years (see section 4.8).

 

Estrogen-only therapy

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of estrogen-progestogen combinations (see section 4.8).

 

For all HRT, an The 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 estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen.  There was no evidence of a difference in risk between the different routes of administration.

 

In the WHI study, the continuous combined conjugated equine estrogen 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.

 

HRT, especially estrogen-progestoagen 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 to 10 years) use of estrogen-only HRT products in hysterectomised women has been associated with a slightlyan increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long term use of combined HRT confers a different risk than estrogen-only products (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 1.3-3 fold risk higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism.

One randomised controlled trial and epidemiological studies found a two-to threefold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate=4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later (see section 4.8).

 

Patients with a history of VTE or 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).Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

 

Generally recognised risk factors for VTE include a personal or family history and severe obesity (BMI >30 kg/m²) and systemic lupus erythematosus (SLE).  use of estrogens, 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.

 

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures need to be considered to prevent VTE following surgery.  IfWhere prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible 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 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, dyspnea).

 

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products. protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestogen or estrogen-only HRT.

 

Combined estrogen-progestogen therapy

The relative risk of CAD during use of combined estrogen+progestogen 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 estrogen+progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.

 

Estrogen-only

Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.

 

Ischaemic Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Combined estrogen-progestogen and estrogen-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

Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Fematab is increased.

 

Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

 

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

 

There is no conclusive evidence for improvement of HRT use does not improve cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65.  It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

 

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

 

 

 

4.5       Interactions with other medicines and other forms of interactions

 

No interaction studies have been performed.

 

            The efficacy of estrogens might be impaired:

-     The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes 2B6, 3A4, 3A5, 3A7, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamezapine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

-     Ritonavir and nelfinavir, although known as strong inhibitors of CYP450 3A4, A5, A7, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

-     Herbal preparations containing St John’s wWort (Hypericum perforatum) may induce the metabolism of estrogens and progestagens via the CYP450 3A4 pathway.

-     Clinically an increased metabolism of estrogens and progestagens may lead to decreased effect

      and changes in the uterine bleeding profile.

 

Estrogens might interfere with the metabolism of other drugs:

Estrogens per se may inhibit CYP450 drug-metabolising enzymes via competitive inhibition.

This is in particular to be considered for substrates with a narrow therapeutic index, such as

• tacrolimus and cyclosporine A (CYP450 3A4, 3A3)

• fentanyl (CYP450 3A4)

• theophylline (CYP450 1A2).

Clinically this may lead to an increased plasma level of the affected substances up to toxic concentrations. Thus, careful drug monitoring for an extended period of time might be indicated and a dosage decrease of tacrolimus, fentanyl, cyclosporin A, and theophylline may be necessary.

 

 

4.7       Effects on ability to drive and use machines

 

            Fematab has no or negligible influence on the does not affect the ability to drive or use machines

 

4.8       Undesirable effects

 

Undesirable effects reported in clinical trials and in postmarketing experience are the following:

 

MedDRA system organ class	Common >1/100, <1/10	Uncommon >1/1,000, <1/100	Rare >1/10,000, <1/1,000	Very rare <1/10,000 incl. isolated reports
Infections and infestations		Cystitis-like syndrome, Vaginal candidiasis
Neoplasms benign, malignant and unspecified		Increase in size of leiomyoma
Immune system disorders				Hypersensitivity reactions
Blood and the lymphatic system disorders				Haemolytic anaemia
Psychiatric disorders		Depression, Change in libido, Nervousness
Nervous system disorders	Headache, Migraine	Dizziness		Chorea
Eye disorders			Intolerance to contact lenses, Steepening of corneal curvature
Cardiac disorders				Myocardial infarction a
Vascular disorders		Hypertension, Peripheral vascular disease, Varicose vein, Venous thromboembolismc		Stroke b
Gastrointestinal disorders	Nausea, Abdominal pain, Flatulence	Dyspepsia		Vomiting
Hepatobiliary disorders		Gall bladder disease	Alterations in liver function, sometimes with Asthenia or Malaise, Jaundice and Abdominal pain
Skin and subcutaneous tissue disorders		Allergic skin reactions, Rash, Urticaria, Pruritus		Chloasma or melasma, which may persist when drug is discontinued, Erythema multiforme, Erythema nodosum, Vascular purpura, Angioedema
Renal and urinary disorders		Cystitic like complaints
Musculoskeletal and connective tissue disorders	Leg cramps	Back pain
Reproductive system and breast disorders	Breast pain/tenderness, Breakthrough bleeding and spotting, Pelvic pain	Change in cervical erosion, Change in cervical secretion, Dysmenorrhoea, Menorrhagia, Metrorrhagia	Breast enlargement, Premenstrual-like symptoms
Congenital and familial/genetic disorders				Aggravation of porphyria
General disorders and administration site reactions	Asthenia	Peripheral oedema
Investigations	Increase/decrease in weight

 

Changes in carbohydrate metabolism have been reported.

 

Other adverse reactions have been reported in association with estrogen/progestoagen treatment:

      Neoplasms benign, and malignant, and unspecified

Breast cancer ^d.

^-Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer ^e, ovarian cancer^f

 

Immune system disorders:

Hypersensitivity reactions

Systemic lupus erythematosus

 

Metabolism and nutrition disorders:

Change in carbohydrate metabolism

Hypertriglyceridemia

 

Nervous system disorders:

Exacerbation of epilepsy

Probable dementia (see section 4.4)

 

Vascular disorders:

Arterial thromboembolism. For further information see sections 4.3 and 4.4

Venous thromboembolism ^c, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.

 

Reproductive system and breast disorders:

Fibrocystic breast changes

 

Gastrointestinal disorders:

Pancreatitis (in women with pre-existing hypertriglyceridemia)

Gastrooesophageal reflux disease,

 

Renal and urinary disorders:

Urinary incontinence

 

Investigation:

Total thyroid hormones increased

 

 

^a Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined estrogen

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

 

 

^b Risk of ischaemic stroke

The use of estrogen-only and estrogen + progestogen 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 as 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 stroke³ over 5 years’ use

 

³ No differentiation was made between ischaemic and haemorrhagic stroke

 

 

^c Risk of venous thromboembolism

HRT is associated with a 1.3-3-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 HT (see section 4.4). Results of the WHI studies are presented:

 

WHI Studies - Additional risk of VTE over 5 years’ use

 

4 Study in women with no uterus

 

^d Breast Cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women’s Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

 

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

 

For estrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

 

The MWS reported that, compared to never users, the use of various types of estrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68). 

 

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.

 

The absolute risks calculated from the MWS and the WHI trials are presented below:

 

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

-     For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

-     For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be

-     For users of estrogen-only replacement therapy

·between 0 and 3 (best estimate = 1.5) for 5 years’ use

·between 3 and 7 (best estimate = 5) for 10 years’ use. 

     -      For users of estrogen plus progestagen combined HRT,

·between 5 and 7 (best estimate = 6) for 5 years’ use

·between 18 and 20 (best estimate = 19) for 10 years’ use.

 

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 estrogen-progestagen 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 estrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be

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

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestogen therapy for more than 5 years.

Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestogen 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.

 

Million Women study– Estimated additional risk of breast cancer after 5 years’ use

[1] Taken from baseline incidence rates in developed countries

 

US WHI studies - additional risk of breast cancer after 5 years’ use

 

2 WHI study in women with no uterus, which did not show an increase in risk of breast cancer

 

^e Endometrial cancer risk

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. 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 estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2-to 12-fold greater compared with non-users.  Adding a progestagen to estrogen-only therapy greatly reduces this increased risk.

 

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.

In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).

Depending on the duration of estrogen-only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding a progestogen to estrogen-only therapy for at least 12 days per cycle can prevent this

increased risk. In the Million Women Study the use of five years of combined (sequential or

continuous) HRT did not increase the risk of endometrial cancer (RR of 1.0 (0.8-1.2).

 

 

^f Ovarian cancer

Long-term use of estrogen-only and combined estrogen-progestogen 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 2500 users.

 

 

5.1       Pharmacodynamic properties

           

            Pharmacotherapeutic group: Natural and semisynthetic estrogens, plain.  ATC code: G03 CA03

 

Estradiol

The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.

 

Combined therapy with progestagens is also recommended in hysterectomised women with a history of endometriosis as cancer development in extra-uterine endometriotic implants in women on estrogen-only therapy has been reported (see section 4.4 Special warnings and precautions).

 

Clinical trial information

·Relief of estrogen-deficiency symptoms and bleeding patterns

-     Relief of menopausal symptoms was achieved during the first few weeks of

      treatment.

-     Regular withdrawal bleeding in women treated with Fematab 1mg daily for 28 days and Dydrogesterone 10mg daily for the last 12-14 days of a 28 day cycle, occurred in approximately 75-80% of women with a mean duration of 5 days. Withdrawal bleeding usually started on the day of the last pill of the progestagen phase. Break-through bleeding and/or spotting occurred in approximately 10% of the women; amenorrhoea occurred in 10 - 25% of the women per cycle during the first year of treatment.

-     In women treated with Fematab 2mg daily for 28 days and Dydrogesterone 10mg daily for the last 12-14 days of a 28 day cycle, approximately 90% of women had regular withdrawal bleeding. The start day and duration of bleeding, and the number of women with intermittent bleeding was the same as with Fematab 1mg, amenorrhoea (no bleeding or spotting) occurred in 5 - 15% of the women per cycle during the first year of treatment.

 

·          Prevention of osteoporosis

            -   Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens 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.

-         After two years of treatment with Fematab 1mg, the increase in lumbar spine bone mineral density (BMD) was 5.2% ± 3.7% (mean ± SD). The percentage of women who maintained or gained BMD in lumbar zone during treatment was 95%. For Fematab 2mg the increase in lumbar spine BMD was 6.6% ± 3.8% (mean ± SD), and the percentage of women with no change or an increase in lumbar spine BMD was 95%.

-   Fematab also had an effect on hip BMD. The increase after two years of treatment with 1mg estradiol was 2.7% ± 4.2% (mean ± SD) at femoral neck, 3.5% +/- 5.0% (mean ± SD) at trochanter and 2.7%± 6.7% (mean ± SD) at Wards triangle, after two years of treatment with 2mg estradiol these figures were respectively, 2.6% ± 5.0%; 4.6% ± 5.0% and 4.1% ± 7.4%. The percentage of women who maintained or gained BMD in the 3 hip areas after treatment with 1mg estradiol was 67-78% and 71-88% after treatment with 2mg estradiol.

 

5.2       Pharmacokinetic properties

                       

Orally administered estradiol, comprising particles whose size has been reduced to less than 5 micrometres, is quickly and efficiently absorbed from the gastrointestinal tract. The primary unconjugated and conjugated metabolites are estrone and estrone sulphate. These metabolites can contribute to the estrogen effect, both directly and after conversion to estradiol. Estrogens are excreted in the bile and reabsorbed from the intestine. During this enterohepatic cycle the estrogens are broken down. Estrogens are excreted in the urine as biologically inactive glucuronide and sulphate compounds (90 to 95%), or in the faeces (5 to 10%), mostly unconjugated. Estrogens are secreted in the milk of nursing mothers.

 

            The C_average is 28 pg/ml, the C_min is 20 pg/ml and the C_max is 54 pg/ml. The E1/E2 (Estrone/Estradiol) ratio is 7.0.

Absorption

Absorption of estradiol is dependent on the particle size: in contrast to orally administered crystalline estradiol, which is poorly absorbed, micronized estradiol is readily absorbed from the gastrointestinal tract.

 

The following table provides the mean single dose pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized estradiol:

 

Distribution

Estrogens are found either unbound or weakly associated to serum albumin by nonspecific binding or specifically bound with high affinity to sex hormone-binding globulin (SHBG).

The percentage of SHBG binding varies between 9 and 37% in premenopausal and 23-53% in postmenopausal women receiving conjugated estrogens.

 

Metabolism

Following oral administration, estradiol is extensively metabolised. The major unconjugated and conjugated metabolites are estrone and estrone sulphate. These metabolites can contribute to the estrogen activity, either directly or after conversion to estradiol. Estrone sulphate may undergo enterohepatic circulation.

 

Elimination:

Estrogens are excreted in the urine as biologically inactive glucuronides of estrone and estradiol and sulphate compounds (90 to 95%), or in the faeces (5 to 10%), mostly unconjugated.

The elimination half-life is between 10-16 h.

 

Estrogens are secreted in the milk of nursing mothers.

 

Dose and time dependencies

Following daily oral administration, estradiol concentrations reached a steady-state after about five days. 

Generally, steady state concentrations appeared to be reached within 8 to 11 days of dosing.

 

 

5.3       Preclinical safety data

 

Supraphysiologically high doses (prolonged overdoses) of estradiol have been associated with the induction of tumours in estrogen-dependent target organs for all animal rodent species tested. The changes observed with dydrogesterone in animal toxicity studies are characteristic for progesterone-like compounds. In-vitro and in-vivo data gave no indications of mutagenic effects of dydrogesterone. In long-term studies, doses administered to rats and mice were sufficient to produce hormone-mediated changes, but did not provide tumorogenic potential.

 

 

 

6.1       List of excipients

 

            Lactose monohydrate

            Hypromellose

            Maize starch

            Colloidal anhydrous silica

            Purified water

            Magnesium stearate

            Opadry coating containing:

            Macrogol 400

            Titanium dioxide (E171)

            Hypromellose

           

 

6.6       Instructions for use, handling or storage

 

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

No special requirements

 

 

10.       DATE OF REVISION OF THE TEXT

September 2011 Month YYYY

4.1       Therapeutic indications

 

Hormone replacement therapy (HRT) for estrogen deficiency symptoms in menopausal women 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)

 

Elderly population

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

                       

4.2       Posology and method of administration

 

Fematab is an estrogen only continuous HRT for women with or without a uterus.

In women with a uterus, a progestagen such as Dydrogesterone 10mg, should be added to Fematab for 12-14 days each month to reduce the risk to the endometrium. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.

 

In general, treatment should start with Fematab 1mg. Depending on the clinical response, the dosage can afterwards be adjusted to individual need. If the complaints linked to estrogen deficiency are not ameliorated the dosage can be increased by using Fematab 2mg.

 

The dosage is one tablet per day. Fematab should be taken continuously without a break between packs.

 

Hormone replacement therapy

The initial daily dosage is 1 mg. The dosage may be increased to 2 mg if required. 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.

 

 

 

Starting Fematab

In women who are not taking hormone replacement therapy, have established amenorrhoea, are hysterectomised, or women who switch from a continuous combined hormone replacement therapy, treatment may be started on any convenient day. In women transferring from a cyclic or continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen. If the patient is menstruating, treatment is started within five days of the start of bleeding

 

Prevention of osteoporosis

One or two mg once daily without interruption. Treatment should start as soon as possible after the onset of menopause and latest within 2 to 3 years after the onset of menopause. Protection appears to be effective for as long as treatment continues, however data beyond 10 years are limited. A careful reappraisal of the risk benefit ratio should be undertaken before treating a patient for more than 5-10 years.

 

Treatment of hysterectomized women and postmenopausal women may be started on any convenient day.

 

If the patient is menstruating, treatment is started on day 5 of bleeding.

 

In women with a uterus, a progestogen should be added to Fematab for 10-14 days each month/28 day cycle.

 

Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomized women.

 

Fematab can be taken with or without food.

 

If a dose has been forgotten, it should be taken as soon as possible. When If more than 12 hours have elapsed, it is recommended to continue with the next dose treatment should be continued with the next tablet without taking the forgotten tablet. The likelihood of breakthrough bleeding or spotting may be increased. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

 

 

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.

 

4.3       Contraindications

           

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

Non hysterectomized women without opposing progestogen

Known, past or suspected breast cancer

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

Undiagnosed genital bleeding

Untreated endometrial hyperplasia

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

Known thrombophilic 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, cerebral vascular accident)

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

Porphyria

 

4.4       Special warnings and special 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 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 Fematab, in particular:

 

-          Leiomyoma (uterine fibroids) or endometriosis

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

-          Risk factors for estrogen-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 cases where 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

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

In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen-only users varies from 2- to 12- fold greater compared with non-users, depending on the duration of treatment and estrogen dose (see section 4.8). After stopping treatment risk may remain elevated for at least 10 years.

 

 

 

The addition of a progestoagen for at least 12 days of the cycle in non-hysterectomised women greatly reduces this risk. cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women can prevent the excess risk associated with estrogen-only HRT.

 

For oral doses of estradiol >2mg, and patches >50μg/day the endometrial safety of added progesterones has not been demontratedstudied.

 

Breakthrough bleeding and spotting may occasionally occur during the first few months of treatment. If break-through 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 estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestoagens to estrogen 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 estrogen-progestogen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.

 

Combined estrogen-progestogen therapy

A randomised placebo-controlled trial, the Womens Health Initiative study (WHI) and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking estrogens, estrogen-progestagen combinations or tibolone for HRT for several years (see Section 4.8). are consistent in finding an increased risk of breast cancer in women taking combined estrogen-progestogen for HRT that becomes apparent after about 3 years (see section 4.8).

 

Estrogen-only therapy

The WHI trial found no increase in the risk of breast cancer in hysterectomised women using estrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of estrogen-progestogen combinations (see section 4.8).

 

For all HRT, an The 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 estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen.  There was no evidence of a difference in risk between the different routes of administration.

 

In the WHI study, the continuous combined conjugated equine estrogen 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.

 

HRT, especially estrogen-progestoagen 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 to 10 years) use of estrogen-only HRT products in hysterectomised women has been associated with a slightlyan increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long term use of combined HRT confers a different risk than estrogen-only products (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 1.3-3 fold risk higher relative risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism.

One randomised controlled trial and epidemiological studies found a two-to threefold higher risk for users compared with non-users. For non-users, it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate=4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. The occurrence of such an event is more likely in the first year of HRT than later (see section 4.8).

 

Patients with a history of VTE or 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).Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

 

Generally recognised risk factors for VTE include a personal or family history and severe obesity (BMI >30 kg/m²) and systemic lupus erythematosus (SLE).  use of estrogens, 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.

 

The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures need to be considered to prevent VTE following surgery.  IfWhere prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible 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 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, dyspnea).

 

Coronary artery disease (CAD)

There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and medroxyprogesterone acetate (MPA). Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products. protection against myocardial infarction in women with or without existing CAD who received combined estrogen-progestogen or estrogen-only HRT.

 

Combined estrogen-progestogen therapy

The relative risk of CAD during use of combined estrogen+progestogen 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 estrogen+progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.

 

Estrogen-only

Randomised controlled data found no increased risk of CAD in hysterectomised women using estrogen-only therapy.

 

Ischaemic Stroke

One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.

Combined estrogen-progestogen and estrogen-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

Estrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients in Fematab is increased.

 

Women with pre-existing hypertriglyceridemia should be followed closely during estrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this condition.

 

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

 

There is no conclusive evidence for improvement of HRT use does not improve cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65.  It is unknown whether the findings apply to younger post-menopausal women or other HRT products.

 

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

 

 

 

4.5       Interactions with other medicines and other forms of interactions

 

No interaction studies have been performed.

 

            The efficacy of estrogens might be impaired:

-     The metabolism of estrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes 2B6, 3A4, 3A5, 3A7, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamezapine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

-     Ritonavir and nelfinavir, although known as strong inhibitors of CYP450 3A4, A5, A7, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

-     Herbal preparations containing St John’s wWort (Hypericum perforatum) may induce the metabolism of estrogens and progestagens via the CYP450 3A4 pathway.

-     Clinically an increased metabolism of estrogens and progestagens may lead to decreased effect

      and changes in the uterine bleeding profile.

 

Estrogens might interfere with the metabolism of other drugs:

Estrogens per se may inhibit CYP450 drug-metabolising enzymes via competitive inhibition.

This is in particular to be considered for substrates with a narrow therapeutic index, such as

• tacrolimus and cyclosporine A (CYP450 3A4, 3A3)

• fentanyl (CYP450 3A4)

• theophylline (CYP450 1A2).

Clinically this may lead to an increased plasma level of the affected substances up to toxic concentrations. Thus, careful drug monitoring for an extended period of time might be indicated and a dosage decrease of tacrolimus, fentanyl, cyclosporin A, and theophylline may be necessary.

 

 

4.7       Effects on ability to drive and use machines

 

            Fematab has no or negligible influence on the does not affect the ability to drive or use machines

 

4.8       Undesirable effects

 

Undesirable effects reported in clinical trials and in postmarketing experience are the following:

 

MedDRA system organ class	Common >1/100, <1/10	Uncommon >1/1,000, <1/100	Rare >1/10,000, <1/1,000	Very rare <1/10,000 incl. isolated reports
Infections and infestations		Cystitis-like syndrome, Vaginal candidiasis
Neoplasms benign, malignant and unspecified		Increase in size of leiomyoma
Immune system disorders				Hypersensitivity reactions
Blood and the lymphatic system disorders				Haemolytic anaemia
Psychiatric disorders		Depression, Change in libido, Nervousness
Nervous system disorders	Headache, Migraine	Dizziness		Chorea
Eye disorders			Intolerance to contact lenses, Steepening of corneal curvature
Cardiac disorders				Myocardial infarction a
Vascular disorders		Hypertension, Peripheral vascular disease, Varicose vein, Venous thromboembolismc		Stroke b
Gastrointestinal disorders	Nausea, Abdominal pain, Flatulence	Dyspepsia		Vomiting
Hepatobiliary disorders		Gall bladder disease	Alterations in liver function, sometimes with Asthenia or Malaise, Jaundice and Abdominal pain
Skin and subcutaneous tissue disorders		Allergic skin reactions, Rash, Urticaria, Pruritus		Chloasma or melasma, which may persist when drug is discontinued, Erythema multiforme, Erythema nodosum, Vascular purpura, Angioedema
Renal and urinary disorders		Cystitic like complaints
Musculoskeletal and connective tissue disorders	Leg cramps	Back pain
Reproductive system and breast disorders	Breast pain/tenderness, Breakthrough bleeding and spotting, Pelvic pain	Change in cervical erosion, Change in cervical secretion, Dysmenorrhoea, Menorrhagia, Metrorrhagia	Breast enlargement, Premenstrual-like symptoms
Congenital and familial/genetic disorders				Aggravation of porphyria
General disorders and administration site reactions	Asthenia	Peripheral oedema
Investigations	Increase/decrease in weight

 

Changes in carbohydrate metabolism have been reported.

 

Other adverse reactions have been reported in association with estrogen/progestoagen treatment:

      Neoplasms benign, and malignant, and unspecified

Breast cancer ^d.

^-Estrogen-dependent neoplasms benign and malignant, e.g. endometrial cancer ^e, ovarian cancer^f

 

Immune system disorders:

Hypersensitivity reactions

Systemic lupus erythematosus

 

Metabolism and nutrition disorders:

Change in carbohydrate metabolism

Hypertriglyceridemia

 

Nervous system disorders:

Exacerbation of epilepsy

Probable dementia (see section 4.4)

 

Vascular disorders:

Arterial thromboembolism. For further information see sections 4.3 and 4.4

Venous thromboembolism ^c, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.

 

Reproductive system and breast disorders:

Fibrocystic breast changes

 

Gastrointestinal disorders:

Pancreatitis (in women with pre-existing hypertriglyceridemia)

Gastrooesophageal reflux disease,

 

Renal and urinary disorders:

Urinary incontinence

 

Investigation:

Total thyroid hormones increased

 

 

^a Risk of coronary artery disease

The risk of coronary artery disease is slightly increased in users of combined estrogen

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

 

 

^b Risk of ischaemic stroke

The use of estrogen-only and estrogen + progestogen 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 as 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 stroke³ over 5 years’ use

 

³ No differentiation was made between ischaemic and haemorrhagic stroke

 

 

^c Risk of venous thromboembolism

HRT is associated with a 1.3-3-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 HT (see section 4.4). Results of the WHI studies are presented:

 

WHI Studies - Additional risk of VTE over 5 years’ use

 

4 Study in women with no uterus

 

^d Breast Cancer

According to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women’s Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.

 

For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 – 1.49) and 1.30 (95%CI 1.21 – 1.40), respectively.

 

For estrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.

 

The MWS reported that, compared to never users, the use of various types of estrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 – 1.40) or use of tibolone (RR=1.45; 95%CI 1.25-1.68). 

 

The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 – 1.54) after 5.6 years of use of estrogen-progestagen combined HRT (CEE + MPA) in all users compared with placebo.

 

The absolute risks calculated from the MWS and the WHI trials are presented below:

 

The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:

-     For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.

-     For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be

-     For users of estrogen-only replacement therapy

·between 0 and 3 (best estimate = 1.5) for 5 years’ use

·between 3 and 7 (best estimate = 5) for 10 years’ use. 

     -      For users of estrogen plus progestagen combined HRT,

·between 5 and 7 (best estimate = 6) for 5 years’ use

·between 18 and 20 (best estimate = 19) for 10 years’ use.

 

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 estrogen-progestagen 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 estrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be

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

The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestogen therapy for more than 5 years.

Any increased risk in users of estrogen-only therapy is substantially lower than that seen in users of estrogen-progestogen 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.

 

Million Women study– Estimated additional risk of breast cancer after 5 years’ use

[1] Taken from baseline incidence rates in developed countries

 

US WHI studies - additional risk of breast cancer after 5 years’ use

 

2 WHI study in women with no uterus, which did not show an increase in risk of breast cancer

 

^e Endometrial cancer risk

In women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. 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 estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2-to 12-fold greater compared with non-users.  Adding a progestagen to estrogen-only therapy greatly reduces this increased risk.

 

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT.

In women with a uterus, use of estrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4).

Depending on the duration of estrogen-only use and estrogen dose, the increase in risk of endometrial cancer in epidemiology studies varied from between 5 and 55 extra cases diagnosed in every 1000 women between the ages of 50 and 65.

Adding a progestogen to estrogen-only therapy for at least 12 days per cycle can prevent this

increased risk. In the Million Women Study the use of five years of combined (sequential or

continuous) HRT did not increase the risk of endometrial cancer (RR of 1.0 (0.8-1.2).

 

 

^f Ovarian cancer

Long-term use of estrogen-only and combined estrogen-progestogen 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 2500 users.

 

 

5.1       Pharmacodynamic properties

           

            Pharmacotherapeutic group: Natural and semisynthetic estrogens, plain.  ATC code: G03 CA03

 

Estradiol

The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms. Estrogens prevent bone loss following menopause or ovariectomy.

 

Combined therapy with progestagens is also recommended in hysterectomised women with a history of endometriosis as cancer development in extra-uterine endometriotic implants in women on estrogen-only therapy has been reported (see section 4.4 Special warnings and precautions).

 

Clinical trial information

·Relief of estrogen-deficiency symptoms and bleeding patterns

-     Relief of menopausal symptoms was achieved during the first few weeks of

      treatment.

-     Regular withdrawal bleeding in women treated with Fematab 1mg daily for 28 days and Dydrogesterone 10mg daily for the last 12-14 days of a 28 day cycle, occurred in approximately 75-80% of women with a mean duration of 5 days. Withdrawal bleeding usually started on the day of the last pill of the progestagen phase. Break-through bleeding and/or spotting occurred in approximately 10% of the women; amenorrhoea occurred in 10 - 25% of the women per cycle during the first year of treatment.

-     In women treated with Fematab 2mg daily for 28 days and Dydrogesterone 10mg daily for the last 12-14 days of a 28 day cycle, approximately 90% of women had regular withdrawal bleeding. The start day and duration of bleeding, and the number of women with intermittent bleeding was the same as with Fematab 1mg, amenorrhoea (no bleeding or spotting) occurred in 5 - 15% of the women per cycle during the first year of treatment.

 

·          Prevention of osteoporosis

            -   Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens 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.

-         After two years of treatment with Fematab 1mg, the increase in lumbar spine bone mineral density (BMD) was 5.2% ± 3.7% (mean ± SD). The percentage of women who maintained or gained BMD in lumbar zone during treatment was 95%. For Fematab 2mg the increase in lumbar spine BMD was 6.6% ± 3.8% (mean ± SD), and the percentage of women with no change or an increase in lumbar spine BMD was 95%.

-   Fematab also had an effect on hip BMD. The increase after two years of treatment with 1mg estradiol was 2.7% ± 4.2% (mean ± SD) at femoral neck, 3.5% +/- 5.0% (mean ± SD) at trochanter and 2.7%± 6.7% (mean ± SD) at Wards triangle, after two years of treatment with 2mg estradiol these figures were respectively, 2.6% ± 5.0%; 4.6% ± 5.0% and 4.1% ± 7.4%. The percentage of women who maintained or gained BMD in the 3 hip areas after treatment with 1mg estradiol was 67-78% and 71-88% after treatment with 2mg estradiol.

 

5.2       Pharmacokinetic properties

                       

Orally administered estradiol, comprising particles whose size has been reduced to less than 5 micrometres, is quickly and efficiently absorbed from the gastrointestinal tract. The primary unconjugated and conjugated metabolites are estrone and estrone sulphate. These metabolites can contribute to the estrogen effect, both directly and after conversion to estradiol. Estrogens are excreted in the bile and reabsorbed from the intestine. During this enterohepatic cycle the estrogens are broken down. Estrogens are excreted in the urine as biologically inactive glucuronide and sulphate compounds (90 to 95%), or in the faeces (5 to 10%), mostly unconjugated. Estrogens are secreted in the milk of nursing mothers.

 

            The C_average is 28 pg/ml, the C_min is 20 pg/ml and the C_max is 54 pg/ml. The E1/E2 (Estrone/Estradiol) ratio is 7.0.

Absorption

Absorption of estradiol is dependent on the particle size: in contrast to orally administered crystalline estradiol, which is poorly absorbed, micronized estradiol is readily absorbed from the gastrointestinal tract.

 

The following table provides the mean single dose pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized estradiol:

 

Distribution

Estrogens are found either unbound or weakly associated to serum albumin by nonspecific binding or specifically bound with high affinity to sex hormone-binding globulin (SHBG).

The percentage of SHBG binding varies between 9 and 37% in premenopausal and 23-53% in postmenopausal women receiving conjugated estrogens.

 

Metabolism

Following oral administration, estradiol is extensively metabolised. The major unconjugated and conjugated metabolites are estrone and estrone sulphate. These metabolites can contribute to the estrogen activity, either directly or after conversion to estradiol. Estrone sulphate may undergo enterohepatic circulation.

 

Elimination:

Estrogens are excreted in the urine as biologically inactive glucuronides of estrone and estradiol and sulphate compounds (90 to 95%), or in the faeces (5 to 10%), mostly unconjugated.

The elimination half-life is between 10-16 h.

 

Estrogens are secreted in the milk of nursing mothers.

 

Dose and time dependencies

Following daily oral administration, estradiol concentrations reached a steady-state after about five days. 

Generally, steady state concentrations appeared to be reached within 8 to 11 days of dosing.

 

 

5.3       Preclinical safety data

 

Supraphysiologically high doses (prolonged overdoses) of estradiol have been associated with the induction of tumours in estrogen-dependent target organs for all animal rodent species tested. The changes observed with dydrogesterone in animal toxicity studies are characteristic for progesterone-like compounds. In-vitro and in-vivo data gave no indications of mutagenic effects of dydrogesterone. In long-term studies, doses administered to rats and mice were sufficient to produce hormone-mediated changes, but did not provide tumorogenic potential.

 

 

 

6.1       List of excipients

 

            Lactose monohydrate

            Hypromellose

            Maize starch

            Colloidal anhydrous silica

            Purified water

            Magnesium stearate

            Opadry coating containing:

            Macrogol 400

            Titanium dioxide (E171)

            Hypromellose

           

 

6.6       Instructions for use, handling or storage

 

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

No special requirements

 

 

10.       DATE OF REVISION OF THE TEXT

September 2011 Month YYYY