4.1. Therapeutic indications

Hormone replacement therapy for oestrogen deficiency symptoms in postmenopausal women.

4.2. Posology and method of administration

Adults:

This medicine is an oestrogen only HRT.

Conjugated oestrogens 0.3-1.25 mg daily, is the usual starting dose for women without a uterus. Continuous administration is recommended.

Treatment of Postmenopausal Symptoms

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see section 4.4) should be used.

Treatment to control menopausal symptoms should be initiated with 0.3 mg of conjugated oestrogens. If symptoms are not adequately controlled, higher doses of this medicine may be prescribed. Once treatment is established the lowest effective dose necessary for the relief of symptoms should be used. Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary.

Starting or Changing Treatment

In women who are not taking hormone replacement therapy or women who switch from a continuous combined hormone replacement therapy product, treatment may be started on any convenient day. In women transferring from a sequential hormone replacement therapy regimen, treatment should begin the day following completion of the prior regimen.

Concomitant progestogen use for women with a uterus

In women with a uterus, where the addition of a progestogen is necessary it should be added for at least 12-14 days every 28 day cycle to reduce the risk to the endometrium.

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

The benefits of the lower risk of endometrial hyperplasia and endometrial cancer due to adding progestogen should be weighed against the increased risk of breast cancer (see sections 4.4 and 4.8).

Forgotten tablet: If a tablet is forgotten, it should be taken as soon as the patient remembers, therapy should then be continued as before. If more than one tablet has been forgotten only the most recent tablet should be taken, the patient should not take double the usual dose to make up for missed tablets.

Missed pills may cause breakthrough bleeding in women with a uterus.

Elderly

There are no special dosage requirements for elderly patients, but as with all medicines, the lowest effective dose should be used.

Paediatric population

Safety and effectiveness in paediatric patients have not been established. Oestrogen treatment of prepubertal girls induces premature breast development and vaginal cornification, and may induce uterine bleeding.

Since large and repeated doses of oestrogen over an extended time period have been shown to accelerate epiphyseal closure, hormonal therapy should not be started before epiphyseal closure has occurred in order not to compromise final growth.

Method of administration

For Oral administration

Tablets should be taken whole; do not divide, crush, chew, or dissolve tablets in mouth.

4.3. Contraindications

1. Known, suspected or history of breast cancer

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

3. Undiagnosed genital bleeding

4. Untreated endometrial hyperplasia

5. Previous or current venous thromboembolism (e.g. deep vein thrombosis, pulmonary embolism)

6. Known thrombophilic disorders (e.g. protein C, protein S, or antithrombin deficiency, see section 4.4)

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

8. Acute liver disease or history of liver disease where the liver function tests have failed to return to normal

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

10. Porphyria

4.4. Special warnings and precautions for use

For the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.

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.

1. 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 women. 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.

2. Conditions that 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 this medicine, in particular:

- Leiomyoma (uterine fibroids) or endometriosis

- Risk factors for thromboembolic disorders (see below)

- Risk factors for oestrogen dependent tumours (e.g. first degree heredity for breast cancer)

- Hypertension

- Liver disorders (e.g. liver adenoma)

- Diabetes mellitus with or without vascular involvement

- Cholelithiasis

- Migraine or (severe) headaches

- Systemic lupus erythematosus (SLE)

- A history of endometrial hyperplasia (see below)

- Epilepsy

- Asthma

- Otosclerosis

3. Reasons for immediate withdrawal of therapy

Therapy should be discontinued if 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

4. Endometrial Hyperplasia and Carcinoma

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

The addition of a progestogen for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT.

For oral doses of conjugated equine oestrogens >0.625 mg the endometrial safety of added progestogens has not been demonstrated. The reduction in risk to the endometrium should be weighed against the increase in the risk of breast cancer of added progestogen (see 'Breast Cancer' below and section 4.8).

Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting appears after some time on therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to exclude endometrial malignancy.

Unopposed oestrogen stimulation may lead to pre-malignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis (but see above).

5. Breast Cancer

The overall evidence shows an increased risk of breast cancer in women taking combined oestrogen-progestogen or oestrogen-only HRT, that is dependent on the duration of taking HRT.

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

Results from a large meta-analysis showed that after stopping treatment, the excess risk will decrease with time and the time needed to return to baseline depends on the duration of prior HRT use. When HRT was taken for more than 5 years, the risk may persist for 10 years or more.

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

6. Ovarian Cancer

Ovarian cancer is much rarer than breast cancer.

Epidemiological evidence from a large meta-analysis suggests a slightly increased risk in women taking oestrogen-only or combined oestrogen-progestogen 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).

7. Venous thromboembolism

Hormone replacement therapy (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 a history of VTE or known thrombophilic states have an increased risk of VTE. 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.

Generally recognised risk factors for VTE include, use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (Body Mass Index >30kg/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 scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. If prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs 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 potential thromboembolic symptoms (e.g. painful swelling of a leg, sudden pain in the chest, dyspnoea).

8. Coronary Artery Disease (CAD)

There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestogen or oestrogen-only HRT. Randomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.

9. Ischaemic Stroke

Combined oestrogen-progestogen and oestrogen-only therapy are associated with an up to 1.5 fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age (see section 4.8).

In the WHI oestrogen-alone substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) compared to women receiving placebo (45 versus 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) versus those receiving placebo (18 versus 21 per 10,000 women-years).

Other Conditions

10. Oestrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction should be carefully observed.

11. The use of oestrogen may influence the laboratory results of certain endocrine tests and liver enzymes.

Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radio-immunoassay) or T3 levels (by radio-immunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.

Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin).

Some patients dependent on thyroid hormone replacement therapy may require increased doses in order to maintain their free thyroid hormone levels in an acceptable range. Therefore, patients should have their thyroid function monitored more frequently when commencing concurrent treatment in order to maintain their free thyroid hormone levels in an acceptable range.

12. A worsening of glucose tolerance may occur in patients taking oestrogens and therefore diabetic patients should be carefully observed while receiving hormone replacement therapy.

13. There is an increase in the risk of gallbladder disease in women receiving HRT (see Conditions that need supervision).

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

15. Oestrogens should be used with caution in individuals with severe hypocalcaemia

16. 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 or oestrogen-only HRT after the age of 65.

17. Exogenous oestrogens may induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema.

18. Laboratory monitoring

Oestrogen administration should be guided by clinical response rather than by hormone levels (e.g., estradiol, FSH).

19. This product contains lactose monohydrate and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

4.5. Interaction with other medicinal products and other forms of interaction

The metabolism of oestrogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 3A4 (CYP3A4) enzymes. Therefore, inducers or inhibitors of CYP3A4 may affect oestrogen drug metabolism. Inducers of CYP3A4, such as St. John's wort (Hypericum perforatum) preparations, phenobarbital, phenytoin, carbamazepine, rifampicin, rifabutin, nevirapine, efavirenz and dexamethasone , may reduce plasma concentrations of oestrogens, possibly resulting in a decrease in therapeutic effects and/or changes in the uterine bleeding profile. Inhibitors of CYP3A4, such as cimetidine, erythromycin, clarithromycin, ketoconazole, itraconazole, ritonavir, nelfinavir and grapefruit juice, may increase plasma concentrations of oestrogens and may result in side effects.

Interference with Laboratory and Other Diagnostic Tests

Laboratory test interactions

Increased platelet count decreased levels of antithrombin III, and increased plasminogen antigen and activity.

Oestrogens increase thyroid-binding globulin (TBG) leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels by column or by radioimmunoassay or T3 levels by radioimmunoassay. T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered.

Other binding proteins may be elevated in serum, i.e., corticosteroid binding globulin (CBG), sex hormone-binding globulin (SHBG) leading to increased circulating corticosteroid and sex steroids, respectively. Free or biologically active hormone concentrations may be decreased.

Increased plasma HDL and HDL2 cholesterol subfraction concentrations, reduced LDL cholesterol concentrations, increased triglyceride levels.

Impaired glucose tolerance.

The response to metyrapone may be reduced.

Effect of HRT with oestrogens on other medicinal products

Hormone contraceptives containing oestrogens have been shown to significantly decrease plasma concentrations of lamotrigine when co-administered due to induction of lamotrigine glucuronidation. This may reduce seizure control. Although the potential interaction between hormone replacement therapy and lamotrigine has not been studied, it is expected that a similar interaction exists, which may lead to a reduction in seizure control among women taking both medicinal products together.

4.6. Fertility, pregnancy and lactation

Pregnancy

This medicine is not indicated during pregnancy.

For women with a uterus

If pregnancy occurs during treatment with this medicine, it should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.

Breast-feeding

This medicine is not indicated during lactation.

4.7. Effects on ability to drive and use machines

No studies on the effect of ability to drive or use machines have been performed.

4.8. Undesirable effects

See also section 4.4.

Adverse drug reactions (ADRs)

The adverse reactions listed in the table are based on post-marketing spontaneous (reporting rate), clinical trials and class-effects.

System Organ Class

Common ADRs

(>1/100, < 1/10)

Uncommon ADRs

(>1/1000, <1/100)

Rare ADRs

(>1/10000, <1/1000)

Very Rare ADRs (<1/10000), isolated reports

Infections and infestations

Vaginitis, including vaginal candidiasis

Neoplasms benign and malignant (including cysts and polyps)

Fibrocystic breast changes; Ovarian cancer; Growth potentiation of benign meningioma

Enlargement of hepatic haemangiomas

Immune system disorders

Hypersensitivity

Anaphylactic/ anaphylactoid reactions, including urticaria and angioedema

Metabolism and nutrition disorders

Glucose intolerance

Exacerbation of porphyria; Hypocalcaemia

Psychiatric disorders

Depression

Changes in libido; Mood disturbances;

Irritability

Nervous system disorders

Dizziness; Headache; Migraine; Anxiety

Stroke; Exacerbation of epilepsy

Exacerbation of chorea

Eye disorders

Intolerance to contact lenses

Retinal vascular thrombosis

Cardiac disorders

Myocardial infarction

Vascular disorders

Venous thrombosis;

Pulmonary embolism

Superficial thrombophlebitis

Respiratory, thoracic and mediastinal disorders

Exacerbation of asthma

Gastrointestinal disorders

Nausea; Bloating; Abdominal pain

Vomiting; Pancreatitis; Ischaemic colitis

Hepatobiliary disorders

Gallbladder disease

Cholestatic jaundice

Skin and subcutaneous tissue disorders

Alopecia

Chloasma/melasma; Hirsutism; Pruritus; Rash

Musculoskeletal, connective tissue and bone disorders

Arthralgias; Leg cramps

Reproductive system & breast disorders

Abnormal uterine bleeding (Breakthrough bleeding/spotting); Breast pain, tenderness, enlargement, discharge; Leucorrhoea

Change in menstrual flow; Change in cervical ectropion and secretion

Dysmenorrhoea /pelvic pain; Galactorrhoea; Increased size of uterine leiomyomata

General disorders and administration site conditions

Oedema

Investigations

Changes in weight (increase or decrease); Increased triglycerides

Increases in blood pressure

Breast Cancer

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

• The increased risk in users of oestrogen-only therapy is lower than that seen in users of oestrogen-progestogen combinations.

• The level of risk is dependent on the duration of use (see section 4.4).

• Absolute risk estimations based on results of the largest randomised placebo-controlled trial (WHI-study) and the largest meta-analysis of prospective epidemiological studies are presented.

Largest meta-analysis of prospective epidemiological studies- Estimated additional risk of breast cancer after 5 years' use in women with BMI 27 (kg/m2)

Age at start HRT (years)

Incidence per 1000 never-users of HRT over a 5 year period (50-54 years)*

Risk ratio

Additional cases per 1000 HRT users after 5 years

Oestrogen only HRT

50

13.3

1.2

2.7

Combined oestrogen-progestogen

50

13.3

1.6

8.0

*Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2)

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

Estimated additional risk of breast cancer after 10 years' use in women with BMI 27 (kg/m2)

Age at start HRT

(years)

Incidence per 1000 never-users of HRT over a 10 year period (50-59 years)*

Risk ratio

Additional cases per 1000 HRT users after 10 years

oestrogen only HRT

50

26.6

1.3

7.1

Combined oestrogen-progestogen

50

26.6

1.8

20.8

*Taken from baseline incidence rates in England in 2015 in women with BMI 27 (kg/m2)

Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

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

Age range

(yrs)

Incidence per 1000 women in placebo arm over 5 years

Risk ratio & 95%CI

Additional cases per 1000 HRT users over 5 years (95%CI)

CEE oestrogen-only

50-79

21

0.8 (0.7 - 1.0)

-4 (-6 - 0)*

CEE+MPA oestrogen & progestogen‡

50-79

17

1.2 (1.0 - 1.5)

+4 (0 - 9)

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

‡When the analysis was restricted to women who had not used HRT prior to the study there was no increased risk apparent during the first 5 years of treatment: after 5 years the risk was higher than in non-users.

Endometrial Cancer

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 oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of oestrogen-only use and oestrogen dose, the increase in risk of endometrial cancer in 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 oestrogen-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)).

Ovarian cancer

Use of oestrogen-only or combined oestrogen-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 1.31-1.56). 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.

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

Age range (years)

Incidence per 1000 women in placebo arm over 5 years

Risk ratio and 95%CI

Additional cases per 1000 HRT users

Oral oestrogen-only*

50-59

7

1.2 (0.6-2.4)

1 (-3 - 10)

Oral combined oestrogen-progestogen

50-59

4

2.3 (1.2 - 4.3)

5 (1 - 13)

*Study in women with no uterus

Risk of coronary artery disease

• The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestogen HRT over the age of 60 (see section 4.4).

Risk of ischaemic stroke

• The use of oestrogen-only and oestrogen + 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 stroke* over 5 years' use

Age range (years)

Incidence per 1000 women in placebo arm over 5 years

Risk ratio and 95%CI

Additional cases per 1000 HRT users over 5 years

50-59

8

1.3 (1.1 1.6)

3 (1-5)

*no differentiation was made between ischaemic and haemorrhagic stroke.

Other adverse reactions reported in association with oestrogen/progestogen treatment including conjugated oestrogens:

• Oestrogen-dependent neoplasms benign and malignant, e.g. endometrial hyperplasia, endometrial cancer

• Venous thromboembolism, 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 sections 4.3 and 4.4.

• Myocardial infarction

• Gallbladder disease

• Skin and subcutaneous disorders: erythema multiforme, erythema nodosum, vascular purpura

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

• Exacerbation of otosclerosis

• Gynecomastia in males

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product.

Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at www.mhra.gov.uk/yellowcard.

4.9. Overdose

Symptoms of overdosage of oestrogen-containing products in adults and children may include nausea, vomiting, breast tenderness, dizziness, abdominal pain, drowsiness/ fatigue and withdrawal bleeding may occur in females. There is no specific antidote, and further treatment should be symptomatic.