- estradiol hemihydrate
POM: Prescription only medicine
This information is intended for use by health professionals
Medical examination/follow-upBefore initiating or re-instituting 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 appropriate imaging tools, e.g. 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 Femoston-conti 0.5 mg/2.5 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 Meningioma
Reasons for immediate withdrawal of therapyTherapy 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 and 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 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 can prevent the excess risk associated with oestrogen-only HRT.• Breakthrough 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.
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-progestogen HRT, which becomes apparent within 5 years of use and diminishes over time after stopping. Some other studies, including the WHI trial suggest that use of combined HRTs may be associated with a similar or slightly smaller risk (see section 4.8).
Venous thromboembolism• HRT 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 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 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 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, dyspnoea).
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 therapy:The 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-only:Randomised 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 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. 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-l-antitrypsin, 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. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.This oestrogen-progestogen combination treatment is not a contraceptive.
The efficacy of oestrogens and progestogens might be impaired: The metabolism of oestrogens and progestogens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically P450 enzymes, such as anticonvulsants (e.g. phenobarbital, carbamazepin, phenytoin) 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 progestogens. Clinically, an increased metabolism of oestrogens and progestogens may lead to decreased effect and changes in the uterine bleeding profile.
PregnancyFemoston-conti 0.5 mg/2.5 mg is not indicated during pregnancy. If pregnancy occurs during medication with Femoston-conti 0.5 mg/2.5 mg treatment should be withdrawn immediately. There are no adequate data from the use of estradiol/dydrogesterone in pregnant women. The results of most epidemiological studies to date relevant to inadvertent fetal exposure to combinations of oestrogens and progestogens indicate no teratogenic or foetotoxic effect.
LactationFemoston-conti 0.5 mg/2.5 mg is not indicated during lactation.
FertilityFemoston-conti 0.5 mg/2.5 mg is not indicated during fertility.
|MedDRA system organ class||Very common ≥1/10||Common ≥1/100 to <1/10||Uncommon ≥1/1,000 to <1/100||Rare ≥1/10,000 to <1/1,000|
|Infections and infestations||Vaginal candidiasis||Cystitis- like symptoms|
|Neoplasms benign, malignant and unspecified||Increase in size of leiomyoma|
|Blood and the lymphatic system disorders||Haemolytic anaemia*|
|Immune system disorders||Hypersensitivity|
|Psychiatric disorders||Depression, nervousness||Influence on libido|
|Nervous system disorders||Headache||Migraine, dizziness||Meningioma*|
|Eye disorders||Steepening of corneal curvature*, contact lenses intolerance*|
|Cardiac disorders||Myocardial infarction|
|Vascular disorders||Venous thromboembolism*, hypertension, peripheral vascular disease, varicose vein||Stroke*|
|Gastrointestinal disorders||Abdominal pain||Nausea, vomiting, abdominal distension (including flatulence)||Dyspepsia|
|Hepatobiliary disorders||Abnormal hepatic function occasionally with jaundice asthenia or malaise, and abdominal pain, gall bladder disorder|
|Skin and subcutaneous tissue disorders||Allergic skin reactions ( e.g. rash, urticaria, pruritus)||Angio-edema, vascular purpura, erythema nodosum*, Chloasma or melasma, which may persist when drug is discontinued*|
|Musculoskeletal and connective tissue disorders||Back pain||Leg cramps*|
|Reproductive system and breast disorders||Breast pain/tenderness||Menstrual disorders (including postmenopausal spotting, metrorrhagia, menorrhagia, oligo-/ amenorrhoea, irregular menstruation, dysmenorrhoea), pelvic pain, cervical discharge||Breast enlargement, premenstrual syndrome|
|General disorders and administration site reactions||Asthenic conditions (asthenia, fatigue, malaise), peripheral oedema|
|Investigations||Increased weight||Decreased weight|
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 perioda||Risk ratio #||Additional cases per 1000 HRT users over 5 years (95%CI)|
|Oestrogen only HRT|
|50 - 65||9 - 12||1.2||1-2 (0 - 3)|
|50 - 65||9 - 12||1.7||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.|
|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)|
|50 - 79||21||0.8 (0.7 1.0)||-4 (-6 0)b|
|CEE+MPA oestrogen & progestogen|
|50 - 79||17||1.2 (1.0 1.5)||+4 (0 9)|
Endometrial cancer riskPostmenopausal women with a uterus:The 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 the 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- to 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 HRT (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|
|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 strokeThe 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 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 stroked 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||8||1.3 (1.1 - 1.6)||3 (1 - 5)|
Other adverse reactions have been reported in association with oestrogen/progestogen treatment
Neoplasms benign, malignant and unspecified:Oestrogen dependent neoplasms both benign and malignant, e.g. endometrial cancer, ovarian cancer. Increase in size of meningioma.
Immune system disorders:Systemic lupus erythematosusMetabolism and nutrition disorders:Hypertriglyceridemia
Nervous system disorders:Probable dementia, chorea, exacerbation of epilepsy
Vascular disorders:Arterial thromboembolism
Gastrointestinal disorders:Pancreatitis (in women with pre-existing hypertriglyceridemia)
Skin and subcutaneous tissue disorders:Erythema multiforme
Renal and urinary disorders:Urinary incontinence
Reproductive system and breast disorders:Fibrocystic breast disease, uterine cervical erosion
Congenital, familial and genetic disorders:Aggravated porphyria
Investigations:Total thyroid hormones increased Reporting of suspected adverse reactions Reporting 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 via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard. a Taken from baseline incidence rates in developed countries b WHI study in women with no uterus, which did not show an increase in risk of breast cancer c Study in women with no uterus d no differentiation was made between ischaemic and haemorrhagic stroke.
EstradiolThe active ingredient, synthetic 17β-estradiol, is chemically and biologically identical to endogenous human estradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms.
DydrogesteroneDydrogesterone is an orally-active progestogen having an activity comparable to parenterally administered progesterone.As oestrogens promote the growth of the endometrium, unopposed oestrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
Clinical trial information• Relief of oestrogen-deficiency symptoms and bleeding patterns • Relief of menopausal symptoms was achieved during the first few weeks of treatment. With Femoston-conti 0.5 mg/2.5 mg the reduction of moderate to severe hot flushes was statistically significant versus placebo from week 4 onward. The number of moderate to severe hot flushes decreased further until end of treatment period in week 13. In two studies amenorrhoea (no bleeding or spotting) was seen in 91% and in 88% of the women respectively during months 10-12 of treatment. Irregular bleeding and or spotting appeared in 10% and 21% of the women during the first 3 months of treatment and in 9% and in 12% during months 10-12 of treatment.
Estradiol• Absorption:Absorption of estradiol is dependent on the particle size: micronized estradiol is readily absorbed from the gastrointestinal tract.The following table provides the mean steady state pharmacokinetic parameters of estradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized estradiol. Data is presented as mean (SD).
|Estradiol 0.5 mg|
|Cmax (pg/mL)||34.8 (30.4)||182 (110)||Cmax (ng/mL)||6.98 (3.32)|
|Cav (pg/mL)||21.5 (16.0)||-||-||-|
|AUC0- (pg.h/mL)||516 (383)||2959 (2135)||AUC0- (ng.h/mL)||82.0 (42.6)|
Dydrogesterone• Absorption:Following oral administration, dydrogesterone is rapidly absorbed with a Tmax between 0.5 and 2.5 hours. The absolute bioavailability of dydrogesterone (oral 20 mg dose versus 7.8 mg intravenous infusion) is 28 %. The following table provides the mean steady state pharmacokinetic parameters of dydrogesterone (D) and dihydrodydrogesterone (DHD). Data is presented as mean (SD).
|Dydrogesterone 2.5 mg|
|Cmax (ng/mL)||0.759 (0.313)||18.9 (7.22)|
|Cmin (ng/mL)||0.0309 (0.0209)||-|
|Cav (ng/mL)||0.117 (0.0455)||-|
|AUC0- (ng.h/mL)||2.81 (1.09)||90.4 (44.1)|
|Blister packs:||28 film-coated tablets 84 film-coated tablets 280 (10 x 28) film-coated tablets|
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