ESTRADOT CONTI

Estradot Conti provides a continuous combined treatment with oestrogen and progestagen. Posology The oestrogen and the progestagen are given every day without interruption. Estradot Conti should be applied twice weekly, every three to four days.

Each patch should be applied to a different site. In women who are not taking HRT or women who switch from a continuous combined HRT, 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.

4). Thus, treatment should be started with the lower dose of Estradot Conti 30 μg/95 μg. If satisfactory control of symptoms is not obtained after 3 months of treatment, the dose may be increased with application of Estradot Conti 40 μg /130 μg.

Pediatric population There is no relevant use of Estradot Conti in the paediatric population. Method of administration Each patch should be applied to a different site. Recommended application sites are clean, free from any cream, dry and intact areas of skin on the dorsal region of the hip.

The site selected should be one at which little wrinkling of the skin occurs during movement of the body. Estradot Conti must not be applied on or near the breasts. The patch should not be exposed to the sun for long periods of time.

Once in place, the patch should be covered by the clothing. Immediately before use, the sachet is to be ripped open carefully at the incision close to the bag edge, and the patch is removed without damaging it (please note that the drying agent and oxygen absorber firmly attached to the inner surface of the sachet is for assuring product quality and not to be applied to the skin).

Caution should be exercised in bending the patch up and down at the perforation until the major part of the protective liner comes off the adhesive area. The free adhesive area is stuck to an intact, cleaned skin area on the back part of the hip.

Slightly lift the smaller part of the transdermal patch, so that the remainder of the protective liner can be removed and the patch affixed completely. Once the patch has been put on completely, pressure should be exercised with the palm for about one minute.

Any touching of the adhesive area should be avoided. Taking a shower or having a bath is possible with the patch. If the patch is correctly applied, it will adhere to the skin for the required dosing period without problems. In the event that a patch does come off, it should be replaced with a new patch for the rest of the dosing period.

The patch should then be changed again at the regular time to re-establish the patient´s routine schedule. Similarly, if the patch is not changed on the scheduled day, it should be replaced as soon as possible and changed again on the next scheduled day.

Forgetting a dose may increase the likelihood of break-through bleeding and spotting. 6.

The most frequent reported undesirable effects during treatment with Estradiol/Norethisterone acetate were breast tenderness and pain, reactions at the application site, dysmenorrhoea, irregular bleeding, and headache. Adverse events are listed below by system organ class and frequency.

The following undesirable effects may occur during treatment with Estradiol/Norethisterone acetate: Organ system Very common (≥ Common (≥ Uncommon (≥ Rare (≥ 1/10,000 Very rare Not known class 1/10) 1/100 to < 1/10) 1/1,000 to < 1/100) to < 1/1,000) (< 1/10,000) ** (cannot be estimated from the available data) Immune system disorders Hypersensitivity anaphylactic reaction Psychiatric disorders depression*, nervousness*, affect lability, mood changes libido disorder Nervous System disorders headache* dizziness*, insomnia* migraine, vertigo paresthesia Vascular disorders hypertension, varicose veins venous thromboembolis m Gastro- intestinal disorders nausea, abdominal distension*, diarrhoea*, dyspepsia*, flatulence, abdominal pain vomiting Hepatobiliary disorders gallbladder disorder, cholelithiasis jaundice cholestatic Skin and subcu- taneous tissue disorders application site reactions acne*, rash, pruritus*, dry skin, erythema skin discoloration Alopecia Musculo- skeletal and connective tissue disorders back pain*, pain in extremity* myastenia Reproductive system and breast disorders breast pain*, breast tenderness, dysmenorrhoea*, menstrual disorder* breast enlargement*, menorrhagia*, genital discharge*, irregular vaginal breast cancer uterine leiomyoma, fallopian tube cysts, endocervical polyps bleeding, uterine spasms, vaginal infection, endometrial hyperplasia General Disorders and administration site conditions pain, asthenia, oedema peripheral*, weight increased* Investigations transaminases increased (*) Adverse reactions associated to estrogen and progestagen have been found to be relatively less frequent with the lowest dosage strength (**) Reported in post-marketing experience 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 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) ‡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. *WHI study in women with no uterus, which did not show an increase in risk of breast cancer.

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. 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 progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. 2)). 4). 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.

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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. 4, Special warnings and precautions 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. 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 case a contraindication is discovered and in the following situations: • Jaundice or deterioration in liver function • Significant increase in blood pressure • New onset of migraine-like 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.

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.

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 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 (body mass index > 30 kg/m2), pregnancy/ postpartum period, systemic lupus erythematosus (SLE) and cancer.

There is no consensus about the possible role […]

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