GEPRETIX

Posology In women receiving oestrogen replacement therapy there is an increased risk of endometrial cancer which can be countered by progesterone administration. The recommended dose is 200mg daily at bedtime, for twelve days in the last half of each therapeutic cycle (beginning on Day 15 of the cycle and ending on Day 26).

Withdrawal bleeding may occur in the following week. Alternatively 100mg can be given at bedtime from Day 1 to Day 25 of each therapeutic cycle, withdrawal bleeding being less with this treatment schedule. Paediatric population There is no relevant use of Progesterone in the paediatric population.

Older people As for adults Method of administration This product is intended for oral use only. Progesterone should not be taken with food, and should be taken at bedtime. Concomitant food ingestion increases the bioavailability of micronized progesterone.

a. 5 spontaneously reported cases in every 1000 patients exposed to progesterone. b. 625 mg conjugated oestrogen, in a multicenter, randomised, double-blind, placebo-controlled clinical trial (Postmenopausal Oestrogen and Progestin Interventions (PEPI) Trial) in 875 postmenopausal women.

625 mg (only) (N=175) Placebo (N=174) Abdominal bloating 12 10 5Gastrointestinal disorders Abdominal pain 10 13 10 Headache 31 30 27Nervous system disorders Dizziness 15 5 9 Psychiatric disorders Depression 19 18 12 Breast tenderness 27 16 6 Hot flushes 11 14 35 Reproductive system and breast disorders Vaginal discharge 10 10 3 Joint pain 20 22 29Miscellaneous Urinary problems 11 10 9 Post-Marketing experience The information given below is based on extensive post marketing experience, primarily from oral administration of progesterone.

Adverse effects have been ranked under headings of frequency using the following convention: very common (≥1/10); common (≥1/100; <1/10); uncommon (≥1/1,000;<1/100); rare (≥1/10,000;<1/1,000); very rare (<1/10,000); frequency not known (cannot be estimated from the available data).

System organ class Frequency Not known (cannot be estimated from the available data) Gastrointestinal disorders Abdominal pain Nausea General disorders and administration site conditions Fatigue Nervous system disorders Headache Somnolence Dizziness Reproductive system and breast disorders Vaginal haemorrhage Skin and subcutaneous tissue disorders Pruritus c.

Description of selected adverse reactions Somnolence or transient dizziness may occur 1 to 3 hours after intake of the drug. Bedtime dosing and reduction of the dose may reduce these effects.

The following risks apply in relation to systemic oestrogen/progestogen treatment:

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

4). • Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented. Million Women study– Estimated additional risk of breast cancer after 5 years’ use. 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.

3 *WHI study in women with no uterus, which did not show an increase in risk of breast cancer Endometrial cancer risk Postmenopausal women with an uterus. The endometrial cancer risk is about 5 in every 1000 women with an 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 progesterone to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. 2)). 7 6 (5-7) #Overall risk ratio. The risk ratio is not constant but will increase with increasing duration on use Note: Since the background incidence of breast cancer differs by EU country, the number of additional cases of breast cancer will also change proportionately.

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.

e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in […]

Warnings • 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.

6) • in the treatment of premature labour, or • as a contraceptive. Precautions 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 • Depression • Photosensitivity 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 • Sudden or gradual, partial or complete loss of vision • Proptosis or diplopia • Papilloedema • Retinal vascular lesions 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. oestrogen Breakthrough bleeding and spotting may occur during the first months of treatment. 2). If breakthrough bleeding or spotting appears 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 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. 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.

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 (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 […]

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