ESTRADIOL 1 MG FILM-COATED TABLETS - summary of medicine characteristics

Estradiol 1mg Film-coated Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 1 mg estradiol (as hemihydrate)

Excipient with known effect: each tablet contains 119.1 mg lactose

monohydrate. For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Film-coated tablets.

Round, biconvex, white tablets with inscription ‘379’ on one side

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Hormone replacement therapy (HRT) for estrogen deficiency symptoms in postmenopausal women at least 6 months since last menses.

Older people

The experience treating women older than 65 years is limited.

4.2 Posology and method of administration

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

In women with a uterus, a progestagen should be added to Estradiol 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.

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.

In general, treatment should start with Estradiol 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 Estradiol 2mg.

Starting Estradiol

In women who are not taking hormone replacement therapy and who are amenorrhoeic, 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 has regular menstruation periods, treatment is started on day one of bleeding.

Administration

The dosage is one tablet per day. Estradiol should be taken continuously without a break between packs. Estradiol can be taken with or without food.

If a dose has been forgotten, it should be taken as soon as possible. When more than 12 hours have elapsed, it is recommended to continue with the next dose without taking the forgotten tablet. In the

case of a missed or delayed dose the likelihood of breakthrough bleeding or spotting may be increased.

Paediatric population:

There is no relevant indication for the use of Estradiol in the paediatric population.

4.3 Contraindications

Known, past or suspected breast cancer;

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

Untreated endometrial hyperplasia;

Previous 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);

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

Porphyria

Non-hysterectomized women without opposing progestogen

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

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.

Evidence regarding the risks associated with HRT in the treatment of premature menopause is limited. Due to the low level of absolute risk in younger women, however, the balance of benefits and risks for these women may be more favourable than in older women.

Medical examination/follow up

Before initiating or reinstituting HRT, a complete personal and family medical history should be taken. Physical (including pelvic and breast) examination should be guided by this and by the contraindications

and warnings for use. During treatment, periodic check-ups are recommended of a frequency and nature adapted to the individual woman. Women should be advised what changes in their breasts should be reported to their doctor or nurse (See “breast cancer” below).

Investigations, including appropriate imaging tools, e.g. mammography, should be carried out in

accordance with currently accepted screening practices, 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

Estradiol, in particular:

– Leiomyoma (uterine fibroids) or endometriosis

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

– Risk factors for estrogen 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 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

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 progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT.

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

Break-through bleeding and spotting may occur during the first few 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 estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestagens 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-progestagen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT.

Combined estrogen-progestagen therapy

The randomised placebo-controlled trial the (Women’s Health Initiative study (WHI), and epidemiological studies are consistent in finding an increased risk of breast cancer in women taking

combined estrogen-progestagen 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-progestagen combinations (see section 4.8).

The excess risk becomes apparent within a few years of use but returns to baseline within a few (at most five)

years after stopping treatment.

HRT, especially estrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.

Ovarian cancer

Ovarian cancer is much rarer than breast cancer. Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking estrogen-only or combined estrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other

studies including the WHI trial, suggest that the use of combined HRTs may be associated with a similar, or slightly smaller risk (see section 4.8).

Venous thromboembolism

HRT is associated with a 1.3–3 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 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.

As in all postoperative patients, prophylactic measures need 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 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 estrogen-progestagen or estrogen-only HRT.

Combined estrogen-progestagen therapy

The relative risk of CAD during use of combined estrogen+proges­tagen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to estrogen+proges­tagen 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

Combined estrogen-progestagen 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.

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 biological active hormone concentrations are unchanged. Other plasma proteins may be increased

(angiotensino­gen/renin substrate, alpha-1-antitrypsin, ceruloplasmin).

HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or estrogen-only HRT after the age of 65.

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

Women who may be at risk of pregnancy should be advised to adhere to non-hormonal contraceptive methods.

4.5 Interaction with other medicinal products and other forms of interaction

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,

3 A7, such as anticonvulsants (eg. phenobarbital, phenytoin, carbamezepine) 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 wort (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 a plasma increase of the affected substances up to toxic levels. 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.

4.6 Fertility, pregnancy and lactation

Pregnancy

Estradiol is not indicated during pregnancy. If pregnancy occurs during medication with

Estradiol, treatment should be withdrawn immediately.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to estrogens indicate no teratogenic or foetotoxic effects.

Lactation:

Estradiol is not indicated during lactation.

4.7 Effects on ability to drive and use machines

Estradiol does not affect the ability to drive or use machines.

4.8 Undesirable effects

Serious undesirable effects associated with the use of hormone replacement therapy are also mentioned in section 4.4 ‘Special warnings and precautions for use’.

The table below reports undesirable effects that have been reported in users of hormone replacement therapy (HRT) by MedDRA system organ classes (MedDRA SOCs).

Other adverse reactions have been reported in association with estradiol treatment:

Neoplasms benign, malignant and unspecified (incl. cysts and

polyps) Breast cancera

Estrogen dependent neoplasms benign and malignant, e.g. endometrial cancerb, ovarian cancerc

Immune system disorders

Systemic lupus erythematosus

Metabolism and nutrition

disorders Change in carbohydrate

metabolism

Hypertriglyce­ridaemia

Nervous system disorders

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

Vascular disorders

Arterial thromboembolism. For further information see sections 4.3 and 4.4.

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

For further information see sections 4.3 and 4.4.

Gastrointestinal disorders

Pancreatitis (in women with pre-existing

hypertriglyce­ridaemia) Gastrooesophageal reflux disease

Hepatobiliary disorders

Gall bladder disease

Skin and subcutaneous tissue disorders

Chloasma, erythema multiforme, erythema nodosum, vascular purpura.

Renal and urinary disorders

Urinary incontinence

Reproductive system and breast disorders

Fibrocystic breast disease

Investigations

Total thyroid hormones increased

An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestagen 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-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.

risk of breast cancer after 5 years’ use

Million Women study- Estimated

US WHI studies – additional risk of

breast cancer after 5

use

b.Endometrialcancerrisk

Postmenopausal women with a uterus

The endometrial cancer risk is about 5 in every 1000 women with an 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 progestagen 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 risk of endometrial cancer (RR of 1.0 (0.8–1.2)).

c.Ovariancancerrisk

Use of estrogen-only or combined estrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see section 4.4). A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.311.56). For women aged 50 to 54 years taking 5 years of HRT this results in about 1 extra case per 2000 users. In women aged 50 to 54 who are not taking HRT about 2 women in 2000 will be diagnosed with ovarian cancer over a 5-year period.

d.Riskofvenousthromboembolism

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

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

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

The use of estrogen-only and estrogen + 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 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 stroke*4 over 5 years’ use

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions directly via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

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 also applicable for overdosing in children.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

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

Estradiol

The active ingredient, synthetic 17p-estradioi, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of estrogen production in menopausal women, and alleviates menopausal symptoms.

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.

– Hot flushes have been shown to be significantly reduced with 1 mg and 2 mg 17 beta estradiol

at 4 weeks.

– Regular withdrawal bleeding in women treated with Estradiol 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 21

25% of the women for months 10 to 12 of treatment.

– In women treated with Estradiol 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 Estradiol 1mg, amenorrhoea (no bleeding or spotting) occurred in 7–11% of the women for months 10 to 12 of treatment.

5.2 Pharmacokinetic properties

Estradiol, estra-1, 3, 5(10)-triene-3,17ß-diol is identical to human ovarian estradiol.

Absorption

Absorption of estradiol is dependent on the particle size: micronized estradiol is rapidly absorbed from the gastrointestinal tract with arithmetic mean Tmax values at steady-state of 3.9 hours.

The following table provides the arithmetic mean steady state pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for 1 mg dose of micronized estradiol. Data is presented as arithmetic mean (standard deviation).

Distribution

Estrogens can be found either unbound or bound. About 98– 99% of the estradiol dose binds to plasma proteins, from which about 30–52% to albumin and about 46–69% to the sex

hormonebindin­gglobulin (SHBG).

Biotransformation

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

In urine, the major compounds are the glucuronides of estrone and estradiol. The elimination half- life of estradiol and its main metabolites is between 10–16 h.

Estrogens are secreted in the milk of nursing mothers. Linearity/non-linearity

The mean estradiol exposure at steady-state after oral daily dosing of 2 mg micronized estradiol is approximately 2-fold greater than that after daily dosing of 1 mg micronized estradiol. Based on the elimination half-life of the micronized estradiol, it can be estimated that estradiol concentrations

reach steady-state approximately within one week following oral daily administration.

5.3 Preclinical safety data

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.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Tablet core:

Lactose Hypromellose Maize Starch

Colloidal anhydrous silica

Magnesium stearate

Film-coat:

Hypromellose Macrogol 400

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

The tablets are packed in blister strips of 28. The blister strips are made of PVC film with covering

Aluminium foil. Each carton contains 84 tablets.

6.6 Special precautions for disposal

Medicines no longer required should not be disposed of via wastewater or household waste. Any unused product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Abbott Laboratories Limited

Abbott House

Vanwall Business Park Vanwall Road Maidenhead

Berkshire SL6 4XE United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 00037/0683

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

28/12/2018