Estrofem 2mg 28 tablets

Instructions for use 1. Name of medicinal product Estrofem® 2 mg film-coated tablets 2. Qualitative and quantitative composition Each film-coated tablet contains 2 mg estradiol (as estradiol hemihydrate). Excipient with known effect: lactose monohydrate. See section 6.1 for a full list of excipients. 3. Pharmaceutical form Film-coated tablets. Blue, film-coated, round, biconvex tablets embossed with NOVO280. Diameter 6 mm. 4. Clinical particulars 4.1 Therapeutic indications Hormone replacement therapy for symptoms of estrogen deficiency in postmenopausal women. Prevention of osteoporosis in postmenopausal women at risk of future fractures who are intolerant of or for whom other medicinal products approved for the prevention of osteoporosis are contraindicated. Estrofem® is particularly intended for women who have undergone hysterectomy and therefore do not require combined estrogen/progestogen therapy. Experience in the treatment of women aged over 65 years is limited. 4.2 Posology and method of administration Estrofem® is an estrogen-only preparation for hormone replacement. Estrofem® is taken orally, one tablet daily, without interruption. The lowest effective dose should be used for the shortest possible time to treat menopausal symptoms and to continue HRT (see also section 4.4). Dose adjustment upwards or downwards of Estrofem® is indicated if the response is insufficient to achieve satisfactory symptom relief after three months or if tolerability is unsatisfactory. Prevention of bone mineral loss is usually achieved with 1-2 mg estradiol daily, so higher doses are not usually used for long-term osteoporosis prevention. In women without a uterus, Estrofem® can be initiated on any convenient day. In women with a uterus who are amenorrhoeic and switching from sequential HRT, Estrofem® can be started on day 5 of bleeding and only in combination with a progestogen for at least 12-14 days; when switching from continuous-combined HRT, Estrofem® can be started with a progestogen on any convenient day. The type and dose of progestogen should ensure adequate inhibition of estrogen-induced endometrial proliferation (see also section 4.4). If a patient forgets to take a tablet, the tablet should be taken as soon as possible within the next 12 hours. If more than 12 hours have passed, the tablet should be discarded. Missing a tablet in women with a uterus may increase the probability of heavy bleeding and spotting. Unless there is a prior diagnosis of endometriosis, the addition of a progestogen is not recommended in women who have undergone hysterectomy. 4.3 Contraindications - Known, past or suspected breast cancer - Known, past or suspected estrogen-dependent malignant tumours (e.g. endometrial cancer) - Undiagnosed vaginal bleeding - Untreated endometrial hyperplasia - Current or past history of venous thromboembolism (deep vein thrombosis, pulmonary embolism) and confirmed thrombophilic disorders (e.g. deficiency of Protein C, Protein S or Antithrombin) (see section 4.4). - Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction) - Acute liver disease or history of liver disease if liver function tests have not returned to normal. - Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 4.4 Special warnings and precautions for use When used for the treatment of postmenopausal symptoms, hormone replacement therapy should only be initiated for symptoms that adversely affect quality of life. In all cases, risks and benefits should be carefully re-evaluated at least annually and HRT should only be continued as long as the benefit outweighs the risk. Experience in the treatment of women with premature menopause (due to ovarian dysfunction or surgical removal) is limited, as is limited evidence regarding the risks associated with HRT in the treatment of premature menopause. Due to the low absolute risk in younger women, the benefit-risk balance may be more favourable for these women than for older women. Medical examination/monitoring Before initiating or re-initiating HRT, a full personal and family history should be taken. A physical examination, including breast and pelvic examination, is indicated, taking into account contraindications and precautions for use. Periodic check-ups are recommended during treatment, the nature and frequency of which should be adapted to the individual. Women should be advised to report immediately any changes in their breasts to their doctor or nurse (see 'Breast cancer' below). Investigations, including instrumental investigations such as mammography, should be carried out in accordance with currently accepted screening practices and modified to individual clinical need. Conditions requiring 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 requires close supervision. These conditions may recur or be aggravated during treatment with Estrofem®, in particular: - Leiomyoma (uterine fibroids) or endometriosis - Risk factors for thromboembolic disorders (see below) - Risk factors for estrogen-dependent tumours, e.g. a first-degree family history of breast cancer - Hypertension - Liver disorders (e.g. hepatic adenoma) - Diabetes mellitus with or without vascular complications - Cholelithiasis - Migraine or severe headache - Systemic lupus erythematosus - History of endometrial hyperplasia (see below) - Epilepsy - Asthma - Otosclerosis. Reasons for immediate withdrawal of therapy Therapy should be discontinued on discovery of the contraindication and in the following circumstances: - Jaundice or impairment of liver function - Significant increase in blood pressure - Onset of migraine-type headache - Pregnancy Endometrial hyperplasia and cancer In women with an intact uterus, the risk of endometrial hyperplasia and cancer increases with prolonged use of unopposed estrogens. The risk of endometrial cancer is increased 2-12 fold among users of estrogen-only therapy compared to non-users, depending on the duration of treatment and the dose of estrogen (see section 4.8). The risk may remain elevated for at least 10 years after cessation of treatment. Addition of a progestogen for at least 12 days per cycle in non-hysterectomised women prevents the excess risk associated with estrogen-only HRT. Heavy bleeding and spotting may occur during the first months of treatment in women with an intact uterus. If heavy bleeding or spotting develops after some time on therapy or continues after cessation of treatment, the cause should be investigated, including endometrial biopsy to exclude endometrial malignancy. Estrogen stimulation, unopposed by progestogen, may lead to pre-malignant or malignant transformation in residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy for endometriosis if they are known to have residual endometriosis. Breast cancer Evidence suggests that there is an increased risk of breast cancer in women taking combined estrogen-progestogen or estrogen-only HRT, which is dependent on the duration of HRT use. The Women's Health Initiative (WHI) trial found no increased risk in women who had undergone hysterectomy using estrogen-only HRT. Observational studies have mostly reported a small increase in the risk of breast cancer diagnosis, which is lower than in users of estrogen-progestogen combinations (see section 4.8). Results from large meta-analyses show that after stopping HRT, the excess risk decreases with time and the time to return to baseline levels depends on the duration of prior HRT use. When HRT has been used for over 5 years, the risk may persist for 10 years or longer. HRT, particularly combined estrogen-progestogen treatment, increases the density of mammographic images, which may adversely affect radiological detection of breast cancer. Ovarian cancer Ovarian cancer is much rarer than breast cancer. Large meta-epidemiological evidence shows a slightly increased risk in women using estrogen-only or combined estrogen-progestogen HRT, which becomes apparent within 5 years of use and decreases over time after cessation. Venous thromboembolism HRT is associated with a 1.3-3 fold increased risk of developing venous thromboembolism, i.e. deep vein thrombosis or pulmonary embolism. The probability of developing such an event is higher in the first year of HRT than later (see section 4.8). Patients with confirmed thrombophilic conditions have an increased risk of VTE events and HRT further increases this risk. Therefore, HRT is contraindicated in such patients (see section 4.3). In general, recognised risk factors for VTE events include use of estrogens, older age, surgery, prolonged immobilisation, obesity (body mass index >30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus and cancer. There is no consensus on the possible role of varicose veins in VTE. As with all post-operative patients, prophylactic measures to prevent VTE should be considered after surgery. If prolonged immobilisation follows elective surgery, it is recommended that HRT be temporarily discontinued 4-6 weeks beforehand. Treatment should only be resumed after the woman is fully mobile. In women who do not have a personal history of VTE but have a history of thrombosis at a young age, screening should be considered after discussion of its limitations (screening identifies only a subset of thrombophilic defects). If a thrombophilic defect is identified that segregates with thrombosis in family members or if the defect is 'severe' (e.g. Antithrombin, Protein S, Protein C deficiency or combined deficiencies), HRT is contraindicated. For women already on chronic anticoagulant therapy, a careful risk-benefit assessment of HRT is required. If VTE develops after starting therapy, the product should be discontinued. Patients should be advised to contact their doctor immediately if they experience potential symptoms of thromboembolism (e.g. painful swelling of a leg, sudden chest pain, dyspnoea). Coronary artery disease There is no evidence from randomised controlled trials on protection against myocardial infarction in women with or without coronary artery disease who were on combined estrogen-progestogen or estrogen-only HRT. Randomised controlled data show no increased risk of coronary artery disease in hysterectomised women using estrogen-only therapy. Ischaemic stroke Combined estrogen-progestogen and estrogen-only therapy is associated with a 1.5-fold increased risk of ischaemic stroke. The relative risk does not change with age and time since menopause. However, as the baseline risk of stroke is strongly age-dependent, the overall risk of stroke in women using HRT will increase with age (see section 4.8). Other conditions Estrogens may cause fluid retention and therefore patients with cardiac or renal dysfunction require careful observation. Women with pre-existing hypertriglyceridaemia should be observed closely during estrogen replacement or HRT, as rare cases of significant increase in plasma triglycerides, leading to pancreatitis, have been reported in women with this condition during estrogen therapy. Estrogens increase sex hormone-binding globulin (SHBG), leading to increased total circulating thyroid hormone as measured by protein-bound iodine, T4 levels (by column or radioimmunoassay) or T3 levels (by radioimmunoassay). T3 resin uptake is decreased, reflecting the increased SHBG. Free T4 and free T3 concentrations are unchanged. Other binding proteins may be increased in serum (e.g. corticosteroid binding globulin, sex hormone-binding globulin), leading to increased circulating corticosteroids and sex steroids. Free or biologically active hormone concentrations are unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin). The use of HRT does not improve cognitive function. There is some evidence of an increased risk of probable dementia in women who start continuous combined or estrogen-only HRT after the age of 65. Estrofem® tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. 4.5 Interactions with other medicinal products and other forms of interaction The metabolism of estrogens may be increased when used concomitantly with substances known to induce drug-metabolising enzymes, particularly cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepine) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz). The strong inhibitors ritonavir and nelfinavir, on the other hand, exhibit inhibitory properties when used with steroid hormones. Herbal preparations containing St. John's Wort (Hypericum perforatum) may induce the metabolism of estrogens. Clinically, increased metabolism of estrogens may lead to decreased effect and changes in the pattern of uterine bleeding. 4.6 Fertility, pregnancy and lactation Pregnancy Estrofem® is not indicated during pregnancy. If pregnancy occurs during treatment with Estrofem®, treatment should be discontinued immediately. Most of the available epidemiological studies to date have shown no teratogenic or fetotoxic effects following accidental fetal exposure. Breast-feeding Estrofem® is not indicated during breast-feeding. 4.7 Effects on ability to drive and use machines Estrofem® has no known effect on the ability to drive and use machines. 4.8 Undesirable effects Clinical experience In clinical trials, less than 10% of patients experienced adverse drug reactions. The most common adverse reactions were breast tenderness. Breast pain, abdominal pain, oedema and headache. The adverse reactions listed below have occurred during treatment with Estrofem® in clinical trials. Common >1/100 and <1/10 Psychiatric disorders · Depression. Nervous system disorders: · Headache. Gastrointestinal disorders: · Abdominal pain or nausea. Musculoskeletal and connective tissue disorders: · Leg cramps. Reproductive system and breast disorders: · Breast tenderness, breast enlargement or breast pain. General disorders and administration site conditions: · Oedema. Investigations: · Weight increased. Uncommon >1/1,000 and <1/10 Ocular disorders: · Visual disturbances. Vascular disorders: · Venous embolism. Gastrointestinal disorders: · Dyspepsia · Vomiting · Flatulence or bloating. Hepatobiliary disorders · Cholelithiasis. Skin and subcutaneous tissue disorders: · Rash or urticaria. Post-marketing experience In addition to the adverse drug reactions mentioned above, the following reactions have been reported spontaneously and are considered likely to be associated with Estrofem® treatment. The frequency of these spontaneous adverse drug reactions is very rare (<1/10,000, unknown (cannot be estimated from the available data)). Post-marketing experience is subject to under-reporting, particularly for trivial and well-known adverse reactions. The frequencies presented should be interpreted in this context: · Immune system disorders: Generalized hypersensitivity reactions (e.g. anaphylactic reaction/shock) · Nervous system disorders: Exacerbation of migraine, stroke, dizziness, depression · Gastrointestinal disorders: Diarrhoea · Skin and subcutaneous tissue disorders: Alopecia · Reproductive system and breast disorders: Irregular vaginal bleeding* · Investigations: Increased blood pressure. The following adverse reactions are associated with estrogen treatment: · Myocardial infarction, congestive heart failure · Venous thromboembolism, i.e. deep vein thrombosis of the leg or pelvis and pulmonary embolism · Gallbladder disease · Skin and subcutaneous disorders: Chloasma, erythema multiforme, erythema nodosum, vascular purpura, pruritus · Vaginal candidiasis · Estrogen-dependent benign and malignant neoplasms, e.g. endometrial cancer (see section 4.4), endometrial hyperplasia and increase in size of uterine fibroids* · Insomnia · Epilepsy · Decreased libido (not otherwise specified) · Worsening of asthma · Probable dementia (see section 4.4). *In women who have not undergone hysterectomy. Breast cancer risk The increased risk in users of estrogen-only therapy is lower than in users of estrogen-progestogen combinations. The level of risk is dependent on the duration of use (see section 4.4). Based on results from the large randomised placebo-controlled trial (WHI trial) and the largest meta-analysis of prospective epidemiological studies, absolute risk estimates are presented below. Largest meta-analysis of prospective epidemiological studies Estimated additional risk of breast cancer from 5 years of use in women with a BMI of 27 (kg/m2) Estrogen-only HRT Age at start of HRT (years): 50 Cases per 1,000 users who have never used HRT over a 5-year period (50-54 years)*: 13.3 Relative risk: 1.2 Additional cases per 1,000 HRT users over 5 years: 2.7 Combined estrogen-progestogen Age at start of HRT (years): 50 Cases per 1,000 users who have never used HRT over a 5-year period (50-54 years)*: 13.3 Relative risk: 1.6 Additional cases per 1,000 HRT users over 5 years: 8.0 *Based on baseline incidence rates in England in 2015 in women with a BMI of 27 (kg/m2) Note: As the background incidence of breast cancer varies in different EU countries, the number of additional breast cancer cases will also vary proportionally. Estimated additional risk of breast cancer from 10 years of use in women with a BMI of 27 (kg/m2) Estrogen-only HRT Age at start of HRT (years): 50 Cases per 1,000 users who have never used HRT over a 10-year period (50-59 years)*: 26.6 Relative risk: 1.3 Additional cases per 1,000 HRT users over 10 years: 7.1 Combined estrogen-progestogen Age at start of HRT (years): 50 Cases per 1,000 users who have never used HRT over a 10-year period (50-59 years)*: 26.6 Relative risk: 1.8 Additional cases per 1,000 HRT users over 10 years: 20.8 *Based on baseline incidence rates in England in 2015 in women with a BMI of 27 (kg/m2) Note: As the background incidence of breast cancer varies in different EU countries, the number of additional breast cancer cases will also vary proportionally. US WHI studies - Additional risk of breast cancer after 5 years of use. CEE estrogen-only Age range (years): 50-79 Cases per 1,000 women in placebo group over 5 years: 21 Relative risk and 95% confidence interval: 0.8 (0.7-1.0) Additional cases per 1,000 HRT users (95% confidence interval): -4 (-6-0)* CEE+MPA estrogen-progestogen** Age range (years): 50-79 Cases per 1,000 women in placebo group over 5 years: 17 Relative risk and 95% confidence interval: 1.2 (1.0-1.5) Additional cases per 1,000 HRT users (95% confidence interval): -4 (0-9) *WHI trial in women without a uterus, which showed no increase in breast cancer risk **When the analysis was restricted to women who had not used HRT prior to the study, no increased risk was apparent during the first 5 years of treatment. After 5 years the risk was higher than in non-users. Endometrial cancer risk In women with an intact uterus, the risk of endometrial cancer is approximately 5 per 1,000 women with a uterus who do not use HRT. Estrogen-only HRT is not recommended in women with a uterus as it increases the risk of endometrial cancer (see section 4.4). Depending on the duration of unopposed estrogen use and the dose of estrogen, the increase in risk of endometrial cancer in epidemiological studies has ranged from 5 to 55 additional cases diagnosed per 1,000 women aged 50-65 years. Prevention of this increased risk is possible by adding a progestogen to estrogen-only therapy for at least 12 days each cycle. In the Million Women Study, 5 years of use of combined HRT (sequential or continuous) did not increase the risk of endometrial cancer (relative risk 1.0 (0.8-1.2)). Ovarian cancer risk The use of estrogen-only or combined estrogen-progestogen HRT is associated with a slightly increased risk of ovarian cancer diagnosis (see section 4.4). A meta-analysis of 52 epidemiological studies reported an increased risk of ovarian cancer in women who were currently using HRT compared to women who had never used HRT (relative risk 1.43, 95% confidence interval 1.31-1.56). For women aged 50-54 years using HRT for 5 years, this leads to approximately 1 additional case per 2,000 users. In women aged 50-54 years not using HRT, approximately 2 in 2,000 women will be diagnosed with ovarian cancer over a 5-year period. Risk of venous thromboembolism HRT is associated with a 1.3 to 3-fold increased relative risk of developing venous thromboembolism, i.e. deep vein thrombosis or pulmonary embolism. The probability of developing such an event is higher in the first year of HRT use (see section 4.4). Results from WHI studies are presented below. WHI studies - Additional risk of venous thromboembolism after 5 years of use Oral estrogen-only Age range (years): 50-59 Cases per 1,000 women in placebo group over 5 years: 7 Relative risk and 95% confidence interval: 1.2 (0.6-2.4) Additional cases per 1,000 HRT users over a 5-year period (95% confidence interval): 1 (-3-10) Oral combined estrogen-progestogen Age range (years): 50-59 Cases per 1,000 women in placebo group over 5 years: 4 Relative risk and 95% confidence interval: 2.3 (1.2-4.3) Additional cases per 1,000 HRT users over a 5-year period (95% confidence interval): 5 (1-13) *Trial in women without a uterus. Risk of coronary artery disease The risk of coronary artery disease is slightly increased in users of estrogen-progestogen HRT aged over 60 years (see section 4.4). Risk of ischaemic stroke The use of estrogen-only and estrogen-progestogen therapy is associated with a 1.5-fold increased risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased with HRT use. This risk is not dependent on age or duration of use, but the baseline risk is strongly age-related. The overall risk of stroke in women using HRT increases with age (see section 4.4). WHI studies - Additional risk of ischaemic stroke* after 5 years of use Age range (years): 50-59 Cases per 1,000 women in placebo group over 5 years: 8 Relative risk and 95% confidence interval: 1.3 (1.1 – 1.6) Additional cases per 1,000 HRT users over a 5-year period (95% confidence interval): 3(1-5) *Ischaemic and haemorrhagic strokes were not differentiated. 4.9 Overdose Symptoms of overdose may include nausea and vomiting. There is no specific antidote and treatment should be symptomatic. 5 Pharmacological properties 5.1 Pharmacodynamic properties Pharmacotherapeutic group: Natural and semi-synthetic estrogens, plain, ATC code: G03CA03. The active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to human endogenous estradiol. It replaces the loss of estrogen production in menopausal women and alleviates menopausal symptoms. Relief of menopausal symptoms is achieved within the first few weeks of treatment. Estrogens prevent bone loss after menopause or oophorectomy. The estrogen deficiency during menopause is associated with increased bone turnover and reduced bone mass. The effect of estrogens on bone mineral density is dose-dependent. Protection is effective as long as treatment is ongoing. After cessation of HRT, bone mass loss occurs at the same rate as in untreated women. Evidence from the WHI trial and meta-analysed trials shows that HRT, alone or in combination with a progestogen - predominantly when used in healthy women - reduces the risk of hip, vertebral and other osteoporotic fractures. HRT also prevents fractures in women with low bone density and/or established osteoporosis, but evidence for this is limited. The effects of Estrofem® on bone mineral density were investigated in a two-year randomised, double-blind, placebo-controlled trial in women with premature postmenopause (n=166, including 41 receiving Estrofem 1 mg and 42 Estrofem 2 mg). Estrofem® 1 mg and 2 mg significantly prevented bone loss at the lumbar spine and total hip compared to women receiving placebo. The mean percentage difference in bone mineral density change compared to placebo was 4.3% and 5.3% for 1 mg and 2 mg respectively at the lumbar spine, and 4.0% and 3.9% at the femoral neck. The corresponding figures were 3.3% and 3.2% after 2 years of treatment. The percentage of women who maintained or gained bone mineral density at the lumbar spine during treatment was 61% and 68% in women treated with 1 mg and 2 mg Estrofem® respectively. 5.2 Pharmacokinetic properties Orally administered micronised 17β-estradiol, which is the active substance in Estrofem®, is rapidly and effectively absorbed from the gastrointestinal tract, reaching peak plasma concentrations of approximately 44 pg/mL (range 30-53 pg/mL) within 4-6 hours after administration of 2 mg. The half-life of 17β-estradiol is approximately 14-16 hours. 17β-estradiol and its metabolites are excreted in urine (90-95%) as biologically inactive glucuronide and sulfate conjugates and in faeces (5-10%) mainly in unconjugated form. 5.3 Preclinical safety data Acute toxicity of estrogens is low. Significant differences between animal species and between animals and humans in preclinical results do not provide sufficient predictive value for the use of estrogens in humans. In experimental animals, estradiol or estradiol valerate showed embryolethal effects even at relatively low doses; malformations of the genitourinary tract and feminisation of male fetuses were observed. Based on traditional studies of repeated dose toxicity, genotoxicity and carcinogenic potential, the available preclinical data do not reveal any special risk to humans other than those discussed in other sections of the instructions. 6 Pharmaceutical particulars 6.1 List of excipients Tablet core: Lactose monohydrate Maize starch Hydroxypropylcellulose Talc Magnesium stearate Coating: Hypromellose, Indigo carmine (E132), Talc, Titanium dioxide (E171) and Macrogol 400. Pharmaceutical product group II, dispensed on prescription form No. 3. 6.2 Incompatibilities Not applicable. 6.3 Shelf life The shelf life is indicated on the label and carton after "Expiry date". 6.4 Special precautions for storage Store below 30°C. Do not freeze. 6.5 Container type and contents 1x28 tablets or 3x28 tablets in calendar dial packs. A calendar pack with 28 tablets consists of the following three parts: · A coloured, opaque polypropylene base · A transparent polystyrene ring-shaped cap · A coloured opaque polystyrene central dial. Not all pack sizes may be marketed. 6.6 Special precautions for disposal Any unused medicinal product or waste material should be disposed of in accordance with local requirements. 7. Manufacturer Novo Nordisk A/S Novo Alle DK-2880 Bagsværd Denmark Patient information How to use the calendar pack 1. Set the daily reminder Rotate the inner disc to set the day of the week opposite the small plastic divider. 2. Remove the first day's tablet Break the plastic divider and remove the first tablet. 3. Move the dial Forward the transparent dial one position clockwise each day as indicated by the arrow. Remove the next tablet. Remember to only remove 1 tablet per day. You can only rotate the transparent dial after removing the tablet from the slot. The trade mark Estrofem® belongs to Novo Nordisk Health Care AG, Switzerland. © 2021 Novo Nordisk A/S