PREMPAK-C

Posology Adults:

Prempak-C is available for oral use in a sequential regimen for treatment of women with a uterus. 25 mg conjugated estrogens daily. One norgestrel tablet should be taken daily from day 17 to day 28 of estrogen therapy. Continuous estrogen administration is recommended.

For maintenance, the lowest effective dose should be used. 25mg conjugated estrogens daily depending on the response of the individual. One norgestrel tablet should be taken daily from day 17 to day 28 of estrogen therapy. 625 mg daily for most patients.

1). For most postmenopausal women therapy may be commenced at any convenient time although if the patient is still menstruating, commencement on first day of bleeding is recommended. In women transferring from another sequential hormone replacement therapy regimen, treatment should begin the day following completion of the prior regimen.

Withdrawal bleeding usually occurs within three to seven days after the last norgestrel tablet. 4) should be used. Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary. 8).

Forgotten tablet:

If a tablet is forgotten, it should be taken as soon as the patient remembers, therapy should then be continued as before. If more than one tablet has been forgotten only the most recent tablet should be taken. The patient should not take double the usual dose to make up for the forgotten tablet.

Missed pills may cause breakthrough bleeding.

Elderly:

There are no special dosage requirements for elderly patients, but, as with all medicines, the lowest effective dose should be used.

Paediatric population:

Not recommended. Method of administration For oral use only.

4. Adverse drug reactions (ADRs) The adverse reactions listed in the table are based on post-marketing spontaneous (reporting rate), clinical trials and class-effects. Breast pain is a very common adverse event reported in ≥ 10% of patients.

System Organ Class Common ADRs (>1/100, < 1/10) Uncommon ADRs (>1/1000, <1/100) Rare ADRs (>1/10000, <1/1000) Very Rare ADRs (<1/10000), isolated reports Infections and infestations Vaginitis Vaginal candidiasis Neoplasms benign and malignant (including cysts and polyps) Fibrocystic breast changes, Ovarian cancer Enlargement of hepatic hemangiomas Immune system disorders Anaphylactic/ anaphylactoid reactions, including urticaria and angioedema Metabolism and nutrition disorders Glucose intolerance Exacerbation of porphyria, Hypocalcaemia Psychiatric disorders Depression Changes in libido; Mood disturbances, Irritability Nervous system disorders Dizziness, Headache, Migraine, Anxiety Stroke, Exacerbation of epilepsy, Exacerbation of chorea Eye disorders Intolerance to contact lenses None Retinal vascular thrombosis Cardiac disorders Myocardial infarction Vascular disorders Pulmonary embolism, Deep vein thrombosis Superficial thrombophlebitis Respiratory, thoracic and mediastinal disorders Exacerbation of asthma Gastrointestinal disorders Nausea, Bloating, Abdominal pain Vomiting, Pancreatitis Hepatobiliary disorders Gallbladder disease Cholestatic jaundice Skin and subcutaneous tissue disorders Alopecia; Acne; Pruritus Chloasma/melas ma, Hirsutism, Pruritus; Rash Musculoskeletal , connective tissue and bone disorders Arthralgias, Leg cramps Reproductive system & breast disorders Breakthrough bleeding/ spotting Dysmenorrhea, Breast, tenderness / enlargement, Discharge Change in menstrual flow, Change in cervical ectropion and secretion Galactorrhoea, Increased size of uterine leiomyomata General disorders and administration site conditions Oedema Investigations Changes in weight (increase or decrease), Increased triglycerides Increase in blood pressure Breast cancer • An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined estrogen-progestogen therapy for more than 5 years.

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

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.

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. *Taken from baseline incidence rates in developed countries **WHI study in women with no uterus, which did not show an increase in risk of breast cancer Endometrial Cancer 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 estrogen-only use and estrogen 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 estrogen-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.

e. deep vein thrombosis or pulmonary embolism. 4). 3) 5 (1 - 13) *Study in women with no uterus Risk of coronary artery disease • The risk of coronary artery disease is slightly […]

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.

1. 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 women. 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. 2. Conditions that 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) headaches − Systemic lupus erythematosus (SLE) − A history of endometrial hyperplasia (see below) − Epilepsy − Asthma − Otosclerosis 3.

Reasons for immediate withdrawal of therapy Therapy should be discontinued if 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 4.

Endometrial Hyperplasia and carcinoma In women with an intact uterus the risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods. 8). After stopping treatment risk may remain elevated for at least 10 years.

The addition of a progestogen for at least 12 days per month/28 day cycle or continuous combined estrogen-progestogen therapy in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT. Unless there is a previous diagnosis of endometriosis it is not recommended to add a progestogen in hysterectomised women.

8). 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.

5. Breast Cancer The overall evidence suggests an increased risk of breast cancer in women taking combined estrogen progestogen and possibly also estrogen-only HRT, that is dependent on the duration of taking HRT. 8). For all HRT, an excess risk becomes apparent within a few years of use and increases with the duration of intake but returns to baseline within a few (at most five) years after stopping treatment.

HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer. 6. 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 estrogen-only or combined estrogen-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping.

8). 7. e. deep vein thrombosis or pulmonary embolism. 8). Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add to this risk. 3). Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition.

Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. Generally recognised risk factors for VTE include a personal or family history, use of estrogens, older age, major surgery, prolonged […]

1. 1 2. Known, past or suspected cancer of the breast 3. g. endometrial cancer) 4. Undiagnosed abnormal genital bleeding 5. Untreated endometrial hyperplasia 6. g. deep vein thrombosis, pulmonary embolism) 7. g. 4) 8. g. angina, myocardial infarction) 9.

Acute liver disease or history of liver disease where the liver function tests have failed to return to normal 10. Porphyria