ZUMENON Film-coated tablet Ref.[7703] Active ingredients: Estradiol

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 Zumenon, in particular:

• Leiomyoma (uterine fibroids) or endometriosis
• A history of, or risk factors for, thromboembolic disorders (see below)
• Risk factors for oestrogen dependent tumours, e.g. 1st degree heredity for breast cancer
• Hypertension
• Liver disorders (e.g. liver adenoma)
• Diabetes mellitus with or without vascular involvement
• Cholelithiasis
• Migraine or (severe) headache
• Systemic lupus erythematosus
• A history of endometrial hyperplasia (see below)
• Epilepsy
• Asthma
• Otosclerosis

Reasons for immediate withdrawal of therapy

Therapy should be discontinued in 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 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 cyclically 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 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 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 oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.

Breast cancer

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

Combined oestrogen-progestogen 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 oestrogen-progestogen for HRT that becomes apparent after about 3 years (see Section 4.8).

Oestrogen-only therapy: The WHI trial 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 substantially lower than that found in users of oestrogen-progestogen 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 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).

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 oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI > 30 kg/m²), pregnancy/postpartum period, systemic lupus erythematosus (SLE), and cancer. There is no consensus about the possible role of varicose veins in VTE.

As in all postoperative patients, prophylactic measures need 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 oestrogen-progestogen or oestrogen-only HRT.

Combined oestrogen-progestogen therapy

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.

Oestrogen-only

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

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 may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
• Women with pre-existing hypertriglyceridemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.
• Oestrogens increase thyroid binding globulin (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 oestrogen-only HRT after the age of 65.
• Patients with rare hereditary problems of galactose intolerance, total 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.

No interaction studies have been performed.

The efficacy of oestrogens might be impaired:

• The metabolism of oestrogens 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 (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 oestrogens and progestogens via the CYP450 3A4 pathway.

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

Oestrogens might interfere with the metabolism of other drugs:

Oestrogens 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.

Pregnancy

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

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

Lactation

Zumenon is not indicated during lactation.

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

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).

Infections and manifestations

Uncommon: Vaginal candidiasis

Immune system disorders

Uncommon: Hypersensitivity

Metabolism and nutrition disorders

Common: Weight increased, Weight decreased

Blood and the lymphatic system disorders

Very rare: Haemolytic anaemia

Psychiatric disorders

Uncommon: Nervousness, Depressed mood

Rare: Anxiety, libido decreased, libido increased

Nervous system disorders

Common: Headache

Uncommon: Dizziness

Rare: Migraine

Eye disorders

Uncommon: Visual disturbances

Rare: Intolerance to contact lenses

Cardiac disorders

Uncommon: Palpitations

Vascular disorders

Uncommon: Hypertension, Peripheral vascular disease, Varicose vein, Venous thromboembolism

Gastrointestinal disorders

Common: Nausea, Abdominal pain

Uncommon: Dyspepsia

Rare: Bloating, Vomiting

Hepatobiliary disorders

Uncommon: Gall bladder disorder

Skin and subcutaneous tissue disorders

Common: Rash, Pruritus

Uncommon: Urticaria Erythema nodosum,

Rare: Hirsutism, Acne

Musculoskeletal and connective tissue disorders

Common: Leg cramps

Uncommon: Back pain

Rare: Muscle cramps

Reproductive system and breast disorders

Common: Metrorrhagia, Uterine/vaginal bleeding including spotting, Pelvic pain

Uncommon: Change in cervical secretion, Menorrhagia, Breast pain/tenderness,

Rare: Breast enlargement, Premenstrual-like symptoms, Vaginal discharge, Dysmenorrhoea,

General disorders and administration site reactions

Common: Asthenia

Uncommon: Peripheral oedema, Oedema

Rare: Fatigue

Other adverse reactions have been reported in association with estradiol treatment (frequency unknown):

Neoplasms benign, malignant and unspecified (incl. cysts and polyps): Breast cancer^a, Oestrogen dependent neoplasms benign and malignant, e.g. endometrial cancer^b, ovarian cancer^c, Increase in size of leiomyoma

Nervous system disorders: Probable dementia over the age of 65 (see section 4.4), Chorea, Exacerbation of epilepsy

Vascular disorders: Stroke^f, Arterial thromboembolism, i.e. angina^e and myocardial infarction^e. For further information see sections 4.3 and 4.4., Venous thromboembolism^d, 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), Gastroesophageal reflux disease

Hepatobiliary disorders: Hepatic function abnormal, sometimes with jaundice

Skin and subcutaneous tissue disorders: Angioedema, chloasma, erythema multiforme, vascular purpura.

Renal and urinary disorders: Urinary incontinence

Reproductive system and breast disorders: Fibrocystic breast disease

a. 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 or 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):

^*1 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):

^* 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:

^*2 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.

b. Endometrial cancer risk

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 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)).

c. Ovarian cancer risk

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.

d. 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:

^*3 Study in women with no uterus

e. 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).

f. 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^*4 over 5 years' use:

^*4 no differentiation was made between ischaemic and haemorrhagic stroke.

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.

Not applicable.