Summary of Product Characteristics Updated 20-May-2016 | Orion Pharma (UK) Limited
|Estradiol valerate Medroxyprogesterone acetateExcipient with known effect: Lactose monohydrate||2 mg5 mg79.5 mg|
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 Indivina, in particular:- Leiomyoma (uterine fibroids) or endometriosis- A history of or risk factors for thromboembolic disorders (see below)- 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- Hereditary angiodema
Reasons for immediate withdrawal of therapy:Therapy should be discontinued in case a contra-indication is discovered and in the following situations:- Jaundice or deterioration of 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 estrogens 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 treatment and estrogen 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 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 of 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-progestagen 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-progestagen 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-progestagen 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 estrogen-progestagen 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 (see Section 4.8).- Patients with a history of VTE or 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 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-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 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 (see section 4.8).
Other conditions- Estrogens 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 estrogen therapy in this condition.- Estrogens 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).- Chloasma may occasionally occur, especially in women with a history of chloasma gravidarum. Women with a tendency to chloasma should minimise exposure to the sun or ultraviolet radiation whilst taking HRT.- 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, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
PregnancyIndivina is not indicated during pregnancy. If pregnancy occurs during medication with Indivina, treatment should be withdrawn immediately. Data on limited number of exposed pregnancies indicate no adverse effects of medroxyprogesterone acetate on the foetus. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of estrogens and progestagen indicate no teratogenic or foetotoxic effect.
BreastfeedingIndivina is not indicated during lactation.
|Organ system class||Common ADRs, ≥1/100 <10||Uncommon ADRs, ≥1/1000 <1/100||Rare ADRs, ≥1/10 000 <1/1 000||Adverse events reported post marketing with frequency not known (cannot be estimated from the available data)|
|Neoplasms benign, malignant and unspecified (incl cysts and polyps)||Benign breast neoplasm, benign endometrial neoplasm||Uterine fibroids|
|Immune system disorders||Hypersensitivity reaction||Exacerbation of hereditary angioedema|
|Metabolism and nutrition disorders||Oedema, weight increase, weight decrease||Increased appetite, hypercholesterolemia1|
|Psychiatric disorders||Depression, nervousness, lethargy||Anxiety, insomnia, apathy, emotional lability, impaired concentration, changes in mood or libido, euphoria1, agitation1|
|Nervous system disorders||Headache, dizziness||Migraine, paraesthesia, tremor1|
|Eye disorders||Visual impairment, dry eye1||Contact lense intolerance|
|Vascular disorders||Hot flushes||Hypertension1, superficial phlebitis1, purpura1||Venous thromboembolism (i.e. deep leg or pelvic venous thrombosis and pulmonary embolism)2||Cerebral ischaemic events|
|Respiratory, thoracic and mediastinal disorders||Dyspnoea1, rhinitis1|
|Gastrointestinal disorders||Nausea, vomiting, stomach cramps, flatulence||Constipation, dyspepsia1, diarrhoea1, rectal disorder1||Abdominal pain, bloating (abdominal distension)|
|Hepatobiliary disorders||Alterations in liver function and biliary flow||Cholestatic jaundice|
|Skin and subcutaneous tissue disorders||Acne, alopecia, dry skin, nail disorder1, skin nodule1, hirsuitism1, erythema nodosum, urticaria||Rash||Eczema|
|Musculoskeletal and connective tissue disorders||Joint disorders, muscle cramps|
|Renal and urinary disorders||Increased urinary frequency/urgency, urinary incontinence1, cystitis1, urine discoloration1, haematuria1|
|Reproductive system and breast disorders||Breast pain/tension, unscheduled vaginal bleeding or spotting, vaginal discharge, disorder of vulva/vagina, menstrual disorder||Breast enlargement, breast tenderness, endometrial hyperplasia, uterine disorder1||Dysmenorrhea, pre-menstrual like syndrome|
|General disorders and administration site conditions||Increased sweating||Fatigue, abnormal laboratory test1, asthenia1, fever1, flu syndrome1, malaise1|
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*||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)*|
|CEE+MPA oestrogen & progestagen|
|50-79||17||1.2 (1.0 1.5)||+4 (0 9)|
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 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 (RR of 1.0 (0.8-1.2)).
Ovarian cancer riskUse 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 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-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* 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)|
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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Relief of estrogen deficiency symptoms and bleeding patterns- Relief of menopausal symptoms was achieved during the first few weeks of treatment.- Amenorrhoea was seen in 91% of women receiving 1 mg estradiol valerate and in 80% of women receiving 2 mg estradiol valerate after 10-12 months of treatment. Irregular bleeding and/or spotting appeared in 41% of the women receiving 1 mg estradiol valerate and 51% of women receiving 2 mg estradiol valerate during the first three months of treatment and in 9% of the women receiving 1 mg estradiol valerate and in 20% of women receiving 2 mg estradiol valerate during 10-12 months of treatment.
Prevention of osteoporosis- Estrogen deficiency at menopause is associated with an increasing bone turnover and decline in bone mass. The effect of estrogens on bone mineral density (BMD) 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 4 years of treatment with Indivina combinations containing the 1 mg dose, the increase in lumbar spine bone mineral density (BMD) was 6.2 ± 0.5% (mean ± SD). The percentage of women who maintained or gained BMD in lumbar zone during treatment was 86.6 %. - Indivina combinations containing the 1 mg dose also had an effect on hip BMD. The increase after 4 years was 2.9 ± 0.4% (mean ± SD) at femoral neck. The percentage of women who gained BMD in hip zone during treatment was 80.4 %.- After 4 years of treatment with Indivina combinations containing the 2 mg dose, the increase in lumbar spine BMD was 7.4 ± 0.4% (mean ± SD). The percentage of women who gained BMD in lumbar zone during treatment was 95.8 %. - Indivina combinations containing the 2 mg dose also had an effect on hip BMD. The increase after 4 years was 2.9 ± 0.4% (mean ± SD) at femoral neck. The percentage of women who gained BMD in hip zone during treatment was 72.3 %.
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