Activelle

/ Novo Nordisk

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.

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 this medical product, 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.
Venous thromboembolism
HRT is associated with a 1.3- to 3-fold risk of developing venous thromboembolism (VTE), i.e. deep vein thrombosis or pulmonary embolism. The occurrence of such an event is more likely in the first year of HRT than later.
Patients with known thrombophilic states have an increased risk of VTE and HRT may add to this risk. HRT is therefore contraindicated in these patients.
As in all postoperative patients, prophylactic measures need to be considered to prevent VTE following surgery. If prolonged immobilisation is to follow elective surgery, temporarily stopping HRT 4 to 6 weeks earlier is recommended. Treatment should not be restarted until the woman is completely mobilised.
In women with no personal history of VTE but with a first degree relative with a history of thrombosis at a young age, screening may be offered after careful counselling regarding its limitations (only a proportion of thrombophilic defects are identified by screening).
If a thrombophilic defect is identified which segregates with thrombosis in family members or if the defect is ‘severe’ (e.g. antithrombin, protein S, or protein C deficiencies or a combination of defects), HRT is contraindicated.
Women already on chronic anticoagulant treatment require careful consideration of the benefit-risk of use of HRT.
If VTE develops after initiating therapy, the drug should be discontinued.
For full details see prescribing information.
Smoking: This product should not be prescribed to a woman who is a smoker, especially if she is older than 35, without careful medical evaluation.
Ischaemic stroke: Combined oestrogen-progestagen and oestrogen-only therapy are associated with an up to 1.5-fold increase in risk of ischaemic stroke. The relative risk does not change with age or time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age.
Other conditions:
* Oestrogens may cause fluid retention, and therefore patients with cardiac or renal dysfunction should be carefully observed.
* Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or hormone replacement therapy, since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with oestrogen therapy in this condition.
* Exogenous oestrogens may induce or exacerbate symptoms of hereditary and acquired angioedema.
* Oestrogens increase thyroid binding globulin (TBG), leading to increased circulating total thyroid hormone, as measured by protein-bound iodine (PBI), T4 levels (by column or by radioimmunoassay) or T3 levels (by radioimmunoassay). T3 resin uptake is decreased, reflecting the elevated TBG. Free T4 and free T3 concentrations are unaltered. Other binding proteins may be elevated in serum, i.e. corticoid binding globulin (CBG), sex-hormone-binding globulin (SHBG) leading to increased circulating corticosteroids and sex steroids, respectively. Free or biological active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin and ceruloplasmin).
* HRT use does not improve cognitive function. There is some evidence of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65.
ALT elevations: During clinical trials with patients treated for hepatitis C virus (HCV) infections with the combination regimen ombitasvir/paritaprevir/ritonavir and dasabuvir with and without ribavirin, ALT elevations greater than 5 times the upper limit of normal (ULN) were significantly more frequent in women using ethinylestradiol-containing medicinal products such as CHCs. Additionally, also in patients treated with glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir, ALT elevations were observed in women using ethinylestradiol-containing medications such as CHCs. Women using medicinal products containing oestrogens other than ethinylestradiol, such as estradiol, and ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin had a rate of ALT elevation similar to those not receiving any oestrogens; however, due to the limited number of women taking these other oestrogens, caution is warranted for co-administration with the following combination drug regimens: ombitasvir/paritaprevir/ritonavir and dasabuvir with or without ribavirin, glecaprevir/pibrentasvir or sofosbuvir/velpatasvir/voxilaprevir.
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: 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.