INDIVINA

Indivina is a continuous combined HRT regimen in which oestrogen and progestagen are given every day without interruption. Posology One tablet each day orally without a tablet-free interval. Tablet should be taken approximately at the same time of the day.

5 mg tablet. Depending on the clinical response to treatment, the dosage can then be adjusted to individual needs. 5 mg is usually sufficient to prevent breakthrough bleeding. If breakthrough bleeding occurs and persists, and endometrial abnormality has been ruled out, the dose can be increased to 5 mg (Indivina 1mg/5 mg tablet).

If 1 mg of estradiol valerate (E2V) is not sufficient to alleviate oestrogen deficiency symptoms, the dose can be increased to 2 mg (Indivina 2 mg/5 mg tablet). In women with amenorrhea and not taking HRT or women who switch from another continuous combined HRT product, treatment with Indivina may be started on any day.

Women who switch from cyclic HRT regimen should start Indivina treatment one week after completion of the cycle. 1). If the patient has forgotten to take one tablet, the forgotten tablet is to be discarded. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.

4) should be used.

6% of users. Undesirable effects according to system organ class associated with HRT treatment are presented in the table below. e. deep leg or pelvic venous thrombosis Cerebral ischaemic events and pulmonary embolism)2 Respiratory, thoracic and mediastinal disorders Dyspnoea1, rhinitis1 Gastrointestinal disorders Nausea, vomiting, stomach cramps, flatulence Constipation, dyspepsia1, diarrhoea1, rectal disorder1 Abdominal pain, bloating (abdominal distension) Hepatobiliary disorders Alterations in liver function and biliary flow Cholestatic jaundice Skin and subcutaneous tissue disorders Acne, alopecia, dry skin, nail disorder1, skin nodule1, hirsutism1, erythema nodosum, urticaria Rash Eczema Musculoskeletal and connective tissue disorders Joint disorders, muscle cramps Renal and urinary disorders Increased urinary frequency/urgency, urinary incontinence1, cystitis1, urine discoloration1, haematuria1 Reproductive system and breast disorders Breast pain/tension, unscheduled vaginal bleeding or spotting, vaginal discharge, disorder of vulva/vagina, menstrual disorder Breast enlargement, breast tenderness, endometrial hyperplasia, uterine disorder1 Dysmenorrhe a, pre- menstrual like syndrome General disorders and administration site conditions Increased sweating Fatigue, abnormal laboratory test1, asthenia1, fever1, flu syndrome1, malaise1 1 Have been reported in single cases in clinical trials.

Given the small study population (n=611) it cannot be determined based on these results if the events are uncommon or rare. 4. 4). Breast cancer risk - An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestagen therapy for more than 5 years.

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

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. 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. 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 1 000 women with a uterus not using HRT.

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 1 000 women between the ages of 50 and 65.

Adding a progestagen to oestrogen-only therapy for […]

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).

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.

g. 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 - angioedema (hereditary/acquired).

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. 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 oestrogen-progestagen therapy in non-hysterectomised women prevents the excess risk associated with oestrogen-only HRT. - 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-progestagen or oestrogen-only HRT, that is dependent on the duration of taking HRT. 8). Oestrogen-only therapy - The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT.

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-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 oestrogen-only or combined oestrogen-progestagen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.

8). e. deep vein thrombosis or pulmonary embolism. 8). - Patients with a history of VTE or known thrombophilic states have an increased risk of VTE and HRT may add to this risk. 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 […]

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