Presentation and Status in Health Basket
Film Coated Tablets
Activelle is a continuous combined hormone replacement product intended for use in women with an intact uterus. One tablet should be taken orally once a day without interruption, preferably at the same time every day. For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration should be used. A switch to a higher dose combination product could be indicated if the response after 3 months is insufficient for satisfactory symptom relief. 2 In women with amenorrhea and not taking HRT or women transferring from another continuous combined HRT product, treatment with Activelle may be started on any convenient day. In women transferring from sequential HRT regimens, treatment should start right after their withdrawal bleeding has ended. If the patient has forgotten to take a tablet, the tablet should be taken as soon as possible within the next 12 hours. If more than 12 hours has passedis, the tablet should be discarded. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.
Progestogen. Dydrogesterone 10 mg. TABS: 20, 3x14x10 mg. In comb. with cont. estrogen ther: 1 tab dly for 14 consec. days/28 day cycle.
In comb. with cyclical estrogen ther: 1 tab dly dur. last 12-14 days estrogen ther. If inad. progestational response: 20 mg to be
Hormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in women more than one year after menopause. Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for other medicinal products approved for the prevention of osteoporosis. The experience treating women older than 65 years is limited.
Known, past or suspected breast cancer, Known, past or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer), Undiagnosed genital bleeding, Untreated endometrial hyperplasia, Previous or current venous thromboembolism (deep venous thrombosis, pulmonary embolism), Known thrombophilic disorders (e.g. protein C, protein S or antithrombin deficiency, Active or previous arterial thromboembolic disease (e.g. angina, myocardial infarction), Acute liver disease or a history of liver disease as long as liver function tests have failed to return to normal, Known hypersensitivity to the active substances or to any of the excipients, Porphyria.
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 checkups 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. Investigations, including appropriate imaging tools e.g. mammography, should be carried out in accordance with currently accepted screening practices, and 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. It should be taken into account that these conditions may recur or be aggravated during treatment with Activelle, in particular: Leiomyoma (uterine fibroids) or endometriosis, Risk factors for, thromboembolic disorders, Risk factors for estrogen dependent tumours, e.g. 1st degree heredity for breast cancer, Hypertension, Liver disorders (e.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-type headache, Pregnancy.
Endometrial hyperplasia & carcinoma: In women with an intact uterus, the risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods. The reported increase in endometrial cancer risk among estrogen only users varies from 2 to 12 fold greater compared with non-users, depending on the duration of treatmentand estrogen dose. After stopping treatment risk may remain elevated for more than 10 years. The addition of a progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined estrogen-progestagen therapy in non-hysterectomised women prevents the excess risk assosiated with estrogen only HRT. Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough bleeding or spotting continues after the first months of treatment, appears after some time during 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-progestagen and possibly also oestrogen-only HRT, that is dependent on the duration of taking HRT. The randomised placebo-controlled trial, the Women’s Health Initiative study (WHI), and epidemiological studies, are consistent in finding an increased risk of breast cancer in women taking combined oestrogen-progestagen for HRT. The excess risk becomes apparent after about 3 years of use but returns to baseline within a few (at most five) years after stopping treatment. 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. Long-term (at least 5 or10 years) use of estrogen-only HRT products has been associated with a slightly increased risk of ovarian cancer. Some studies, including the WHI trial, suggest that the long-term use of combined HRTs may confer asimilar or slightly smaller risk.
For full details see prescribing information.
Clinical Experience The most frequently reported adverse events in the clinical trials with Activelle were vaginal bleeding and breast pain/tenderness, reported in approximately 10% to 20% of patients. Vaginal bleeding usually occurred in the first months of treatment. Breast pain usually disappeared after a few months of therapy.
For full details see prescribing information.
The metabolism of oestrogens and progestagens may be increased by the concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepin) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz). Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John’s Wort (Hypericum perforatum) may induce the metabolism of oestrogens and progestagens. Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile. Drugs that inhibit the activity of hepatic microsomal drug metabolizing enzymes e.g. ketoconazole, may increase the circulating levels of the active substances in Activelle. Concomitant administration of cyclosporine and Activelle may cause increased blood levels of cyclosporine, creatinine and transaminases due to decreased metabolism of cyclosporine in the liver.
Pregnancy and Lactation
Pregnancy: Activelle is not indicated during pregnancy. If pregnancy occurs during medication with Activelle, treatment should be withdrawn immediately. Clinically, data on a limited number of exposed pregnancies indicate adverse effects of norethisterone on the foetus. At doses higher than normally used in OC and HRT formulations masculinisation of female foetuses was observed. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of oestrogens and progestagens, indicate no teratogenic or foetotoxic effect.
Lactation: Activelle is not indicated during lactation.
Overdose may be manifested by nausea and vomiting. Treatment should be symptomatic.