4.1. Therapeutic indications

Hormone replacement therapy for oestrogen deficiency symptoms in postmenopausal women with an intact uterus.

4.2. Posology and method of administration

Posology

Adults:

This medicine is taken in a continuous combined 28-day regimen of one tablet daily with no break between packs.

In women who are not taking hormone replacement therapy or women who switch from another 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.

For treatment of postmenopausal symptoms: Take one tablet per day.

Breakthrough bleeding and spotting may occur in the early stages of this medicine therapy. If breakthrough bleeding persists and endometrial abnormality has been ruled out, a higher dose of treatment or cyclic therapy should be considered as an alternative.

The lowest dose and regimen that will control symptoms should be chosen.

Maintenance/Continuation/Extended treatment

For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see section 4.4) should be used. Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary.

The benefits of the lower risk of endometrial hyperplasia and endometrial cancer due to adding a 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.

Elderly:

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

Paediatric population

Not recommended.

Method of administration

This medicine is taken orally.

4.3. Contraindications

1. Hypersensitivity to the active substances or to any of the excipients of this medicine tablets listed in section 6.1.

2. Known, past or suspected breast cancer.

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

4. Undiagnosed genital bleeding.

5. Untreated endometrial hyperplasia.

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

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

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

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

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.

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 this medicine, in particular:

- Leiomyoma (uterine fibroids) or endometriosis

- Risk factors for thromboembolic disorders (see below)

- Risk factors for oestrogen dependent tumours (e.g. 1st degree heredity for breast cancer)

- Hypertension

- Liver disorders (e.g. liver adenoma)

- Diabetes mellitus with or without vascular involvement

- Cholelithiasis

- Migraine or (severe) headaches

- Systemic lupus erythematosus (SLE)

- A history of endometrial hyperplasia (see below)

- Epilepsy

- Asthma

- Otosclerosis

Reasons for immediate withdrawal of therapy

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

- Jaundice or deterioration in liver function

- Significant increase in blood pressure

- New onset of migraine-type headache

- Pregnancy

Endometrial hyperplasia and carcinoma

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

The addition of a progestogen for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT. Unless there is a previous diagnosis of endometriosis it is not recommended to add a progestogen in hysterectomised women.

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).

Break-through bleeding and spotting may occur during the first 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.

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 randomised placebo-controlled trial, the Women's Health Initiative study (WHI), and a meta-analysis of prospective epidemiological studies are consistent in finding an increased risk of breast cancer in women taking oestrogen-progestogen combinations for HRT that becomes apparent after about 3 (1-4) years (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.

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).

Meningioma

Meningiomas have been reported following long term administration of progestogens, including medroxyprogesterone acetate. Medroxyprogesterone should be discontinued if a meningioma is diagnosed. Caution is advised when recommending medroxyprogesterone to patients with a history of meningioma.

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 (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 scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where 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 4-6 weeks earlier, if this is possible. 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 anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.

If venous thromboembolism 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).

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 MPA.

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

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).

Other conditions

• Oestrogens/progestogens 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 this medicine is increased.

• 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.

• 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 usually 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 usually 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.

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

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

• A worsening of glucose tolerance may occur in some patients on oestrogen/progestogen therapy and therefore diabetic patients should be carefully observed while receiving hormone replacement therapy.

• 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.

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

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

The metabolism of oestrogens and progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).

Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones.

Herbal preparations containing St John's wort (Hypericum perforatum) may induce the metabolism of oestrogens and progestogens.

Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.

The response to metyrapone may be reduced.

Aminogluthimide administered concomitantly with MPA may significantly depress the bioavailability of MPA.

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. If pregnancy occurs during medication with this medicine treatment should be withdrawn immediately.

Clinically, data on a limited number of exposed pregnancies indicate no adverse effects of MPA on the foetus.

The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of oestrogens and progestogens indicate no teratogenic or foetotoxic effect.

Breast-feeding

This medicine is not indicated during lactation.

4.7. Effects on ability to drive and use machines

This medicine should not affect the ability to drive or use machinery.

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. Breast pain is a very common adverse event reported in ≥ 10% of patients.

System Organ Class

Very Common ADRs

( >1/10)

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

Vaginal candidiasis

Neoplasms benign and malignant (including cysts and polyps)

Fibrocystic breast changes, Ovarian cancer

Enlargement of hepatic hemangiomas

Immune system disorders

Anaphylactic/ anaphylactoid reactions, including urticaria and angioedema

Metabolism and nutrition disorders

Glucose intolerance

Exacerbation of porphyria; Hypocalcemia

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

Pulmonary embolism

Superficial thrombophlebitis

Respiratory, thoracic and mediastinal disorders

Exacerbation of asthma

Gastrointestinal disorders

Nausea; Bloating; Abdominal pain

Vomiting; Pancreatitis

Hepatobiliary disorders

Gallbladder disease

None

Cholestatic jaundice

Skin and subcutaneous tissue disorders

Alopecia; Acne; Pruritus

Chloasma/ melasma; Hirsutism; Pruritus; Rash

Musculoskeletal, connective tissue and bone disorders

Arthralgias; Leg cramps

Reproductive system & breast disorders

Breast pain

Breakthrough bleeding/ spotting, Dysmenorrhea; Breast tenderness, enlargement; Discharge

Change in menstrual flow; Change in cervical ectropion and secretion

Galactorrhoea; Increased size of uterine leiomyomata

General disorders and administration site conditions

Oedema

Investigations

Changes in weight (increase or decrease); Increased triglycerides

Increase in blood pressure

Breast cancer risk

• 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

Incidenceper 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 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 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 this medicine:

• 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 section 4.3 and 4.4.

• Myocardial infarction

• Stroke

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

• Probable dementia (see section 4.4)

• Exacerbation of otosclerosis

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.