ANGELIQ

Women who do not take hormone replacement therapy (HRT) or women who change from another continuous combined product may start treatment at any time. Women changing from a cyclic, sequential combined HRT regimen, treatment should begin the day following completion of the prior regimen.

Posology One tablet is taken daily. Each blister is for 28 days of treatment. Method of administration The tablets are to be swallowed whole with some liquid irrespective of food intake. Treatment is continuous, which means that the next pack follows immediately without a break.

The tablets should preferably be taken at the same time every day. If a tablet is forgotten it should be taken as soon as possible. If more than 24 hours have elapsed no extra tablet needs to be taken. If several tablets are forgotten, vaginal bleeding may occur.

For treatment of post menopausal symptoms, the lowest effective dose should be used. 4) should be used. Additional information on special populations Paediatric population Angeliq is not indicated for use in children and adolescents.

Geriatric patients There are no data suggesting a need for dosage adjustment in elderly patients. In women aged 65 years or older, see section

The table below reports adverse reactions by MedDRA system organ classes (MedDRA SOCs). The frequencies are based on clinical trial data. 5, 1, 2, or 3 mg). The most commonly reported adverse reactions were breast pain (> 10%) and during the first few months of treatment, bleeding and spotting (> 10%).

1). The frequency of bleeding decreases with the duration of treatment. System Organ Class Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1000 to < 1/100) Rare (< 1/1000) Blood and lymphatic system disorders Anemia Metabolism and nutrition disorders Weight increase or weight decrease, anorexia, increased appetite, hyperlipemia Psychiatric disorders Depression, emotional lability, nervousness Sleep disorder, anxiety, libido decreased Nervous system disorders Headache Paresthesia, concentration ability impaired, dizziness Vertigo Eye disorders Eye disorder, visual disturbance Ear and labyrinth disorders Tinnitus Cardiac disorders Palpitation Vascular disorders Embolism, venous thrombosis, hypertension, migraine, thrombophlebitis, varicose veins Respiratory, thoracic and mediastinal disorders Dyspnoea Gastrointestinal disorders Abdominal pain, nausea, abdomen enlarged Gastrointestinal disorder, diarrhea, constipation, vomiting, dry mouth, flatulence, taste disturbance Hepatobiliary disorders Liver function test abnormal Cholelithiasis Skin and subcutaneous tissue disorders Skin disorder, acne, alopecia, pruritus, rash, hirsutism, hair disorder Musculoskeletal and connective tissue disorders Pain in extremity, back pain, arthralgia, muscle cramps Myalgia Renal and urinary disorders Urinary tract disorder, urinary tract infection Reproductive system and breast disorders Benign breast neoplasm, breast enlargement, uterine fibroids enlarged, benign neoplasm of cervix uteri, menstrual disorder, vaginal discharge Breast carcinoma, endometrial hyperplasia, benign uterine neoplasm, fibrocystic breast, uterine disorder, ovarian disorder, cervix disorder, pelvic pain, vulvovaginal disorder, vaginal candidiasis, vaginitis, vaginal dryness Salpingitis, galactorrhoea System Organ Class Common (≥ 1/100 to < 1/10) Uncommon (≥ 1/1000 to < 1/100) Rare (< 1/1000) General disorders and administration site conditions Asthenia, localized oedema Generalized oedema, chest pain, malaise, sweating increased Chills The most appropriate MedDRA term is used to describe a certain reaction and its synonyms and related conditions.

Additional information on special populations The following, undesirable effects classified as at least possibly related to Angeliq treatment by the investigator, were recorded in 2 clinical studies in hypertensive women. Metabolism and nutrition disorders Hyperkalemia Cardiac disorders Cardiac failure, atrial flutter, QT interval prolonged, cardiomegaly Investigations Blood aldosterone increased.

The following undesirable effects have been reported in association with HRT products: Erythema nodosum, eythema multiforme, chloasma and hemorrhagic dermatitis. 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.

Any increased risk in users of oestrogen-only therapy is substantially lower than that seen in users of oestrogen-progestagen combinations. 4). Results of the largest randomised placebo-controlled trial (WHI study) and largest epidemiological study (MWS) are presented.

7 6 (5 - 7) a Taken from baseline incidences in developed countries. b 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 differs by EU country, the number of additional cases of breast cancer will also change proportionately. 5) +4 (0 - 9) a WHI study in women with no uterus, which did not show an increased in risk of breast cancer.

b 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 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 a progestagen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. 2)). Ovarian cancer Use of […]

4. 2. Pharmacokinetic properties). 3). 2). 3). g. g. g. 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. 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 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 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.

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

Some other studies, including the WHI trial, suggest that use of combined HRTs may be associated with a similar or slightly smaller risk (see […]

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