Summary of Product Characteristics Updated 03-May-2016 | Orion Pharma (UK) Limited
Method of administrationTridestra consists of 91 tablets in a blister pack bearing calendar markings. Dosage is according to the calendar pack. One tablet should be taken daily without a break between packs. The dosage during days 1 to 70 (inclusive) of the cycle is 2 mg estradiol valerate (white tablets). From day 71 to day 84 (inclusive) it is 2 mg of estradiol valerate and 20 mg of medroxyprogesterone acetate (blue tablets). From day 85 to day 91 (inclusive) a placebo preparation (yellow tablets) is taken when a menstrual like bleed occurs.For initiation and continuation of treatment of peri- and postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used.Women with amenorrhoea who are not taking HRT or who are switching to Tridestra from continuous combined HRT product, may start treatment on any day. Women who are still having periods may start treatment 5 days after the start of the period.Women who are switching from a cyclic or continuous sequential HRT product to Tridestra treatment may start one week after completion of the cycle (28 days) ie at the end of a withdrawal bleed. If the patient has forgotten to take one tablet, it should be taken within 12 hours otherwise the forgotten tablet should be discarded and the usual tablet taken the following day. Missing a dose may increase the likelihood of breakthrough bleeding and spotting.Unless there is a previous diagnosis of endometriosis, it is not recommended to add a progestagen in hysterectomised women.
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 Tridestra, 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• Hereditary angioedema
Reasons for immediate withdrawal of therapyTherapy 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 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 of therapy, or continues after treatment has been discontinued, the reason should be investigated, which may include endometrial biopsy to excluded 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 including the Million Women Study (MWS), are consistent in reporting findings of 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).In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestagen was added, either sequentially or continuously, and regardless of type of progestagen. There was no evidence of a difference in risk between the different routes of administration.In the WHI study, the continuous combined conjugated equine estrogen and medroxyprogesterone acetate (CEE + MPA) product used was associated with breast cancers that were slightly larger in size and more frequently had local lymph node metastases compared to placebo.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.
Ovarian cancer• Ovarian 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. One randomised controlled trial and epidemiological studies found a two- to threefold higher risk for users compared with non-users, For non-users it is estimated that the number of cases of VTE that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 8 per 1000 women aged between 60-69 years. It is estimated that in healthy women who use HRT for 5 years, the number of additional cases of VTE over a 5 year period will be between 2 and 6 (best estimate = 4) per 1000 women aged 50-59 years and between 5 and 15 (best estimate = 9) per 1000 women aged 60-69 years. 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). Personal or strong family history of thromboembolism or recurrent spontaneous abortion should be investigated in order to exclude a thrombophilic predisposition. Until a thorough evaluation of thrombophilic factors has been made or anticoagulant treatment initiated, use of HRT in such patients should be viewed as contraindicated. Those women already on anticoagulant treatment require careful consideration of the benefit-risk of use of HRT. • Generally recognised risk factors for VTE include, use of oestrogen, older age, major surgery, prolonged immobilization, a personal history or family history, 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.• The risk of VTE may be temporarily increased with prolonged immobilisation, major trauma or major surgery. As in all postoperative patients, scrupulous attention should be given to prophylactic measures to prevent VTE following surgery. Where prolonged immobilisation is liable to follow elective surgery, particularly abdominal or orthopaedic surgery to the lower limbs, consideration should be given to temporarily stopping HRT 4 to 6 weeks earlier, if possible. Treatment should not be restarted until the woman is completely mobilised. • 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 (eg, 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. Two large clinical trials (WHI and HERS i.e. Heart and Estrogen/progestin Replacement Study) showed a possible increased risk of cardiovascular morbidity in the first year of use and no overall benefit. For other HRT products there are only limited data from randomised controlled trials examining effects in cardiovascular morbidity and mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.
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). One large randomised clinical trial (WHI-trial) found, as a secondary outcome, an increased risk of ischaemic stroke in healthy women during treatment with continuous combined conjugated estrogens and MPA. For women who do not use HRT, it is estimated that the number of cases of stroke that will occur over a 5 year period is about 3 per 1000 women aged 50-59 years and 11 per 1000 women aged 60-69 years. It is estimated that for women who use conjugated estrogens and MPA for 5 years, the number of additional cases will be between 0 and 3 (best estimate = 1) per 1000 users aged 50-59 years and between 1 and 9 (best estimate = 4) per 1000 users aged 60-69 years. It is unknown whether the increased risk also extends to other HRT products.
Other conditions• Oestrogens may cause fluid retention and, therefore, patients with cardiac or renal dysfunction should be carefully observed. Patients with terminal renal insufficiency should be closely observed, since it is expected that the level of circulating active ingredients of Tridestra is increased. • Women with pre-existing hypertriglyceridaemia should be followed closely during oestrogen replacement or HRT, 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).• Chloasma may occasionaly 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 from the WHI trial of increased risk of probable dementia in women who start using continuous combined or oestrogen-only HRT after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.
PregnancyTridestra is not indicated during pregnancy. If pregnancy occurs during medication with Tridestra treatment should be withdrawn immediately. Clinically, data on a limited number of exposed pregnancies indicate no adverse effects of medroxyprogesterone acetate on the foetus. The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of oestrogens and progestogen indicate no teratogenic or foetotoxic effect.
Breast-feedingTridestra is not indicated during lactation.
|Organ system class||Common ADRs, ≥1/100 <1/10||Uncommon ADRs, ≥1/1000 <1/100||Rare ADRs,≥1/10000 <1/1000||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, hirsutism1 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|
Other adverse reactions have been reported in association with estrogen-progestagen treatment:• Myocardial infarction • Gall bladder disease • Skin and subcutaneous disorders: chloasma, erythema multiforme • Pancreatitis (see section 4.4) • Probable dementia over the age of 65 (see section 4.4)
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*2||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.|
*Taken from baseline incidence rates in developed countries
US WHI studies - additional risk of breast cancer after 5 years' use
|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)*3|
|CEE+MPA oestrogen & progestagen|
|50-79||17||1.2 (1.0 1.5)||+4 (0 - 9)|
Postmenopausal women with a uterusThe endometrial cancer risk is about 5 in every 1000 women with an 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 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*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|
|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.
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