- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyOne tablet daily to be taken orally. Elleste Solo 1 mg may be taken continuously in hysterectomised women. In women with a uterus, a progestogen should be added for 12 - 14 days each cycle to oppose the production of an oestrogen-stimulated hyperplasia of the endometrium. Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestogen in hysterectomised women. Therapy may start at any time in women with established amenorrhoea or who are experiencing long intervals between spontaneous menses. In patients who are menstruating, it is advised that therapy starts on the first day of bleeding. Patients changing from a cyclical or continuous sequential preparation should complete the cycle and may then change to Elleste Solo 1 mg without a break in therapy. Patients changing from a continuous combined preparation may start therapy at any time if amenorrhoea is established, or otherwise start on the first day of bleeding. Elleste Solo tablets are available in two strengths: Elleste Solo 1 mg (containing 1 mg estradiol) and Elleste Solo 2 mg (containing 2 mg estradiol). For initiation and continuation of treatment of post-and peri-menopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used. Elleste Solo 2 mg is additionally indicated for prevention of osteoporosis in postmenopausal women at high risk of future fractures and who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.Missed or Extra Tablet: If a tablet is missed it should be taken within 12 hours of when normally taken; otherwise the tablet should be discarded, and the usual tablet should be taken the following day. A missed dose may lead to break-through bleeding or spotting in non-hysterectomised women. If one extra tablet is taken inadvertently, the usual tablet should be taken the following day.
ElderlyThere are no special dosage requirements for elderly patients.
Paediatric populationNot to be used in children.
Method of administrationFor oral use.
Medical Examination/Follow UpBefore 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 (see 'Breast Cancer' below). Investigations, including mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Conditions Which Need SupervisionIf 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 Elleste Solo 1 mg, in particular: - Leiomyoma (uterine fibroids) or endometriosis - Risk factors for thromboembolic disorders (see below) - Risk factors for oestrogen 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 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
Endometrial Hyperplasia and CarcinomaIn 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 oestrogen-only users varies from 2-to 12-fold greater compared with non-users, depending on the duration of treatment and oestrogen dose (see Section 4.8). 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. 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. Unopposed oestrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to oestrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, if they are known to have residual endometriosis.
Breast CancerThe 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.
Combined oestrogen-progestogen therapy• 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-progestogen for HRT that becomes apparent after about 3 years (see Section 4.8)
Oestrogen-only therapy• The WHI trial found no increase in the risk of breast cancer in hysterectomised women using oestrogen-only HRT. Observational studies have mostly reported a small increase in risk of having breast cancer diagnosed that is substantially lower than that found in users of oestrogen-progestogen combinations (see Section 4.8).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 CancerOvarian 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 the use of combined HRTs may be associated with a similar, or slightly smaller risk (see Section 4.8).
Venous ThromboembolismHRT is associated with a 1.3-3 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 (see Section 4.8).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 (see Section 4.3). Generally recognised risk factors for VTE include, use of oestrogens, older age, major surgery, prolonged immobilisation, obesity (BMI>30 kg/m2), pregnancy/postpartum period, systemic lupus erythematosus (SLE) and cancer. There is no consensus about the possible role of varicose veins in VTE. As in all postoperative patients, prophylactic measures need 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 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. Patients should be told to contact their doctors immediately when they are aware of a potential thromboembolic symptom (e.g., painful swelling of a leg, sudden pain in the chest, dyspnea).
Coronary Artery Disease (CAD)There is no evidence from randomised controlled trials of protection against myocardial infarction in women with or without existing CAD who received combined oestrogen-progestogen or oestrogen-only HRT.
Combined oestrogen-progestogen therapyThe relative risk of CAD during use of combined oestrogen+progestogen HRT is slightly increased. As the baseline absolute risk of CAD is strongly dependent on age, the number of extra cases of CAD due to oestrogen+progestogen use is very low in healthy women close to menopause, but will rise with more advanced age.
Oestrogen-onlyRandomised controlled data found no increased risk of CAD in hysterectomised women using oestrogen-only therapy.
Ischaemic StrokeCombined oestrogen-progestogen 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 (see Section 4.8).
Other ConditionsOestrogens 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. 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 radio-immunoassay) or T3 levels (by radio-immunoassay). 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-1-antitrypsin, ceruloplasmin). HRT 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.Patients with rare hereditary disorders of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Pregnancy:Elleste Solo 1 mg is not indicated during pregnancy. If pregnancy occurs during medication with Elleste Solo 1 mg treatment should be withdrawn immediately. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to oestrogens indicate no teratogenic or foetotoxic effects.
Lactation:Elleste Solo 1 mg is not indicated during lactation.
|Organ System Class||Common ADRs, >1/100,<1/10||Uncommon ADRs >1/1,000, <1/100||Rare ADRs >1/10,000, <1/1,000|
|Infections and infestations||Vaginal candidiasis|
|Metabolism and nutrition disorders||Weight fluctuation|
|Psychiatric disorders||Mood alterations including anxiety and depressed mood, libido disorder|
|Reproductive system and breast disorders||Metrorrhagia, uterine leiomyoma, breast tenderness, breast enlargement|
|Gastrointestinal disorders||Nausea, abdominal pain||Dyspepsia, vomiting, flatulence|
|Hepatobiliary disorders||Gallbladder disorder, cholelithiasis|
|Nervous System disorders||Headache||Dizziness, migraine|
|Skin and subcutaneous tissue disorders||Alopecia, hirsutism, rash, pruritus|
|Musculoskeletal and connective tissue disorders||Muscle spasms|
|Vascular disorders||Hypertension||Venous thromboembolism* Thrombophlebitis|
|General disorders and administration site conditions||Oedema|
Breast Cancer Risk• An up to 2-fold increased risk of having breast cancer diagnosed is reported in women taking combined oestrogen-progestogen 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-progestogen combinations.• The level of risk is dependent on the duration of use (see Section 4.4).• Results of the largest randomised placebo-controlled trial (WHI-study) and largest epidemiological study (MWS) are presented.
Million Women study Estimated additional risk of breast cancer after 5 years' use
|Age range (years)||Additional cases per 1000 never-users of HRT over a 5 year period*2||Risk ratio#||Additional cases per 1000 HRT users over 5 years (95%CI)|
|Oestrogen only HRT|
|#Overall risk ratio. The risk ratio is not constant but will increase with increasing duration of 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.|
|Age range (yrs)||Incidence per 1000 women in placebo arm over 5 years||Risk ratio & 95%CI Additional cases per 1000 HRT||users over 5 years (95%CI)|
|CEE+MPA oestrogen & progestogen|
Endometrial Cancer Risk
Postmenopausal women with a uterusThe endometrial cancer risk is about 5 in every 1000 women with a uterus not using HRT. In women with a uterus, use of oestrogen-only HRT is not recommended because it increases the risk of endometrial cancer (see Section 4.4).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 progestogen to oestrogen-only therapy for at least 12 days per cycle can prevent this increased risk. In the Million Women Study the use of five years of combined (sequential or continuous) HRT did not increase risk of endometrial cancer (RR of 1.0 (0.8-1.2)).
Ovarian CancerUse of oestrogen-only or combined oestrogen-progestogen HRT has been associated with a slightly increased risk of having ovarian cancer diagnosed (see Section 4.4).A meta-analysis from 52 epidemiological studies reported an increased risk of ovarian cancer in women currently using HRT compared to women who have never used HRT (RR 1.43, 95% CI 1.31-1.56). 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.
Risk of Venous ThromboembolismHRT is associated with a 1.3-3-fold increased relative 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 using HT (see Section 4.4). Results of the WHI studies are presented:
WHI Studies - Additional risk of VTE over 5 years' use
|Age range (years)||Incidence per 1000 women in placebo arm over 5 years||Risk ratio and 95%CI||Additional cases per 1000 HRT users over 5 years|
|50-59||7||1.2 (0.6-2.4)||1 (-3 10)|
|Oral combined oestrogen-progestogen|
|50-59||4||2.3 (1.2 4.3)||5 (1 - 13)|
Risk of Coronary Artery DiseaseThe risk of coronary artery disease is slightly increased in users of combined oestrogen-progestogen HRT over the age of 60 (see Section 4.4).
Risk of Ischaemic Stroke• The use of oestrogen-only and oestrogen + progestogen therapy is associated with an up to 1.5 fold increased relative risk of ischaemic stroke. The risk of haemorrhagic stroke is not increased during use of HRT.• This relative risk is not dependent on age or on duration of use, but as the baseline risk is strongly age-dependent, the overall risk of stroke in women who use HRT will increase with age, see Section 4.4.
WHI studies combined - Additional risk of ischaemic stroke*5 over 5 years' use
|Age range (years)||Incidence per 1000 women in placebo arm over 5 years||Risk ratio and 95%CI||Additional cases per 1000 HRT users over 5 years|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
|Plasma Unconjugated Estradiol (mean)||Plasma Unconjugated Estrone(mean)|
|AUC0-48h||950 pg.h/ml||2700 pg.h/ml|
|Cmax||45 pg/ml||140 pg/ml|
|Tmax||5.0 h||4.0 h|
EstradiolReadily and fully absorbed from the GI tract when given orally, peak levels are generally observed 3-6 hours after ingestion, but by 24 hours concentrations have returned to baseline. Estradiol is converted to estrone and estriol primarily in the liver. These are excreted into the bile and undergo enterohepatic recirculation and further degradation before being excreted in the urine (90-95%) as biologically inactive glucuronide and sulphate conjugates or in the faeces (5-10%), mostly unconjugated.
Tablet core:Lactose monohydrateMaize starchPovidone 25Talc (purified)Magnesium stearate Film-coating material: Hydroxypropylmethyl cellulose (E464)Titanium dioxide (E171)Macrogol 400
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