- 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
Starting FemostonIn women who are not taking hormone replacement therapy and who are amenorrhoeic, or women who switch from a continuous combined hormone replacement therapy, treatment may be started on any convenient day. In women transferring from a cyclic or continuous sequential HRT regimen, treatment should begin the day following completion of the prior regimen. If the patient has regular menstruation periods, treatment is started within five days of the start of bleeding.
AdministrationFor the first 14 days during a 28-cycle, one tablet containing oestradiol is taken daily; during the following 14 days one tablet containing oestradiol and dydrogesterone is taken.After a cycle of 28 days, on the 29th day, a new 28-day cycle begins. This means that the treatment should be taken continuously without a break between packs. Femoston can be taken with or without food.The days of the week are printed on the back of the blister strips. Firstly, the tablets from the part marked with arrow 1 should be taken, then all the tablets from the part marked with arrow 2 should be taken.If a dose has been forgotten, it should be taken as soon as possible. When more than 12 hours have elapsed, it is recommended to continue with the next dose without taking the forgotten tablet. The likelihood of breakthrough bleeding or spotting may be increased.Paediatric population:There is no relevant indication for the use of Femoston in the paediatric population.
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 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, 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 in cases where 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 progestagen cyclically for at least 12 days per month/28 day cycle or continuous combined oestrogen-progestagen 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.
Breast cancerThe 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. Combined oestrogen-progestogen therapyThe randomised placebo-controlled trial, the Womens 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 that becomes apparent after about 3 years (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-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.Oestrogen-only therapyThe 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 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.- 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 ages, major surgery, prolonged immobilisation, severe 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 chronic anticoagulant treatment require careful consideration of the benefit-risk 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-progestagen or oestrogen-only HRT.
Combined oestrogen-progestagen therapyThe relative risk of CAD during use of combined oestrogen+progestagen 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+progestagen 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-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 (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 hypertriglyceridemia 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 use does not improve cognitive function. There is some evidence of increased risk of possible 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, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.• Women who may be at risk of pregnancy should be advised to adhere to non-hormonal contraceptive methods.
Oestrogens might interfere with the metabolism of other drugs:Oestrogens per se may inhibit CYP450 drug-metabolising enzymes via competitive inhibition. This is in particular to be considered for substrates with a narrow therapeutic index, such as:- tacrolimus and cyclosporine A (CYP450 3A4, 3A3)- fentanyl (CYP450 3A4)- theophylline (CYP450 1A2).Clinically this may lead to an increased plasma level of the affected substances up to toxic concentrations. Thus, careful drug monitoring for an extended period of time might be indicated and a dosage decrease of tacrolimus, fentanyl, cyclosporin A and theophylline may be necessary.
|MedDRA system organ class||Very common ≥1/10||Common ≥1/100, <1/10||Uncommon ≥1/1,000, <1/100||Rare ≥1/10,000, <1/1,000|
|Infections and infestations||Vaginal candidiasis||Cystitis-like syndrome|
|Neoplasms benign, malignant and unspecified||Increase in size of leiomyoma|
|Immune system disorders||Hypersensitivity|
|Psychiatric disorders||Depression, Nervousness||Influence on libido|
|Nervous system disorders||Headache||Migraine, Dizziness|
|Cardiac disorders||Myocardial infarction|
|Vascular disorders||Hypertension, Peripheral vascular disease, Varicose vein, Venous thromboembolism|
|Gastrointestinal disorders||Abdominal pain||Nausea, Vomiting, 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)||Angioedema, Vascular purpura|
|Musculoskeletal and connective tissue disorders||Back pain|
|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-progestagen 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-progestagen 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*1||Risk ratio & 95%CI#||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 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.|
US WHI studies - additional risk of breast cancer after 5 years' use
|Age range (years)||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)*2|
|CEE+MPA oestrogen & progestagen|
|50-79||17||1.2 (1.0 1.5)||+4 (0 9)|
Endometrial cancerPostmenopausal 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 between the ages of 50 and 65. Adding a progestagen 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 (R.R of 1 .0 (0.8-1.2)).
Ovarian cancerUse of oestrogen-only or combined oestrogen-progestagen 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|
|50-59||7||1.2 (0.6-2.4)||1 (-3 10)|
|Oral combined oestrogen-progestagen|
|50-59||4||2.3 (1.2 4.3)||5 (1 - 13)|
Risk of coronary artery disease• The risk of coronary artery disease is slightly increased in users of combined oestrogen-progestagen HRT over the age of 60 (see section 4.4).
Risk of ischaemic stroke• The use of oestrogen-only and oestrogen + progestagen 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*4 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||8||1.3 (1.1-1.6)||3 (15)|
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.
OestradiolThe active ingredient, synthetic 17β-oestradiol, is chemically and biologically identical to endogenous human oestradiol. It substitutes for the loss of oestrogen production in menopausal women, and alleviates menopausal symptoms. Oestrogens prevent bone loss following menopause or ovariectomy.
DydrogesteroneDydrogesterone is an orally-active progestagen 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 progestagen greatly reduces the oestrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
Clinical trial informationRelief of oestrogen-deficiency symptoms and bleeding patterns.- Relief of menopausal symptoms was achieved during the first few weeks of treatment.- Regular withdrawal bleeding with Femoston 1/10 occurred in approximately 75-80% of women with a mean duration of 5 days. Withdrawal bleeding usually started on the day of the last pill of the progestagen phase. Break-through bleeding and/or spotting occurred in approximately 10% of the women; amenorrhoea (no bleeding or spotting) occurred in 21-25% of the women for months 10 to 12 of treatment.- With Femoston 2/10, approximately 90% of women had regular withdrawal bleeding. The start day and duration of bleeding, and the number of women with intermittent bleeding was the same as with Femoston 1/10, amenorrhoea occurred in 7-11% of the women for months 10 to 12 of treatment.Prevention of osteoporosis - Oestrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. - The effect of oestrogens on the bone mineral density is dose-dependent. Protection appears to be effective for as long as treatment is continued. After discontinuation of HRT, bone mass is lost at a rate similar to that in untreated women.- Evidence from the WHI trial and meta-analysed trials shows that current use of HRT, alone or in combination with a progestagen given to predominantly healthy women reduces the risk of hip, vertebral, and other osteoporotic fractures. HRT may also prevent fractures in women with low bone density and/or established osteoporosis, but the evidence for that is limited.- After two years of treatment with Femoston 2/10, the increase in lumbar spine bone mineral density (BMD) was 6.7% ± 3.9% (mean ± SD). The percentage of women who maintained or gained BMD in lumbar zone during treatment was 94.5%. For Femoston 1/10 the increase in lumbar spine BMD was 5.2% ± 3.8% (mean ± SD), and the percentage of women with no change or an increase in lumbar spine BMD was 93%.- Femoston also had an effect on hip BMD. The increase after two years of treatment with 1mg oestradiol was 2.7% ± 4.2% (mean ± SD) at femoral neck, 3.5% ± 5.0% (mean ± SD) at trochanter and 2.7%± 6.7% (mean ± SD) at Wards triangle. After two years of treatment with 2mg oestradiol these figures were respectively, 2.6% ± 5.0%; 4.6% ± 5.0% and 4.1% ± 7.4%. The percentage of women who maintained or gained BMD in the 3 hip areas after treatment with 1mg oestradiol was 67-78% and 71-88% after treatment with 2mg oestradiol.
Oestradiol• AbsorptionAbsorption of oestradiol is dependent on the particle size: micronized oestradiol is readily absorbed from the gastrointestinal tract. The following table provides the mean steady state pharmacokinetic parameters of oestradiol (E2), estrone (E1) and estrone sulphate (E1S) for each dose of micronized oestradiol. Data is presented as mean (SD).
|Cmax (pg/mL)||71 (36)||310 (99)||Cmax (ng/mL)||9.3 (3.9)|
|Cmin (pg/mL)||18.6 (9.4)||114 (50)||Cmin (ng/mL)||2.099 (1.340)|
|Cav (pg/mL)||30.1 (11.0)||194 (72)||Cav (ng/mL)||4.695 (2.350)|
|AUC0-24 (pg.h/mL)||725 (270)||4767 (1857)||AUC0-24 (ng.h/mL)||112.7 (55.1)|
Dydrogesterone• AbsorptionFollowing oral administration, dydrogesterone is rapidly absorbed with a Tmax between 0.5 and 2.5 hours. The absolute bioavailability of dydrogesterone (oral 20mg dose versus 7.8mg intravenous infusion) is 28%.The following table provide the mean steady state pharmacokinetic parameters of dydrogesterone (D) and dihydrodydrogesterone (DHD). Data is presented as mean (SD).
|Cmax (ng/mL)||2.54 (1.80)||62.50 (33.10)|
|Cmin (ng/mL)||0.13 (0.07)||3.70 (1.67)|
|Cav (ng/mL)||0.42 (0.25)||13.04 (4.77)|
|AUC0-t (ng.h/mL)||9.14 (6.43)||311.17 (114.35)|
|Opadry Y-l-7000 white:||hypromellose, polyethylene glycol 400, titanium dioxide (E171)|
|Opadry OY-8243 grey:||hypromellose, polyethylene glycol 400, titanium dioxide(E171), iron oxide black (E172)|
|Blister packs:||28 film-coated tablets 84 film-coated tablets|
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