- 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 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
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). Investigation, 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 ethinylestradiol tablets, in particular:• Risk factors for estrogen dependent tumours e.g. 1st degree heredity for breast cancer• Leimyoma (uterine fibroids) or endometriosis• A history of, or risk factors for, thromboembolic disorders (see below)• Hypertension• Liver disorders (e.g. liver adenoma)• Diabetes Mellitus with or without vascular involvement• Cholelithiasis• Otosclerosis• Asthma• Migraine or (severe) headache and epilepsy• Systemic Lupus erythematosis• Hyperplasia of the endometrium (see below)
Reasons for immediate withdrawal of therapy• Jaundice or deterioration in liver function• Significant increase in blood pressure• New onset of migraine-type headache• Pregnancy
Endometrial hyperplasiaThe risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see Section 4.8). The addition of a progestogen for at least 12 days of the cycle in non-hysterectomised women greatly reduces this risk.The reduction in risk to the endometrium should be weighed against the increase in the risk of breast cancer of added progestogen (see 'Breast cancer' below and in Section 4.8)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 estrogen stimulation may lead to premalignant or malignant transformation in the residual foci of endometriosis. Therefore, the addition of progestogens to estrogen replacement therapy should be considered in women who have undergone hysterectomy because of endometriosis, especially if they are known to have residual endometriosis (but see above).
Breast cancerA randomised placebo-controlled trial, the Women's Health Initiative study (WHI) and epidemiological studies, including the Million Women Study (MWS), have reported an increased risk of breast cancer in women taking oestragens, estrogen-progestogen combinations or tibolone for HRT for several years (See Section 4.8). For all HRT, an excess risk becomes apparent within a few years of use and increases with duration of intake but returns to baseline within a few (at most five) years after stopping treatment.In the MWS, the relative risk of breast cancer with conjugated equine estrogens (CEE) or estradiol (E2) was greater when a progestogen was added, either sequentially or continuously, and regardless of type of progestogen. 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.HRT, especially estrogen-progestogen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.
Ovarian CancerLong-term (at least 5 to 10 years) use of estrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain whether long-term use of combined HRT confers a different risk than estrogen-only products.
Venous thromboembolismHRT is associated with a higher relative 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 three fold 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.Generally recognised risk factors for VTE include a personal history or family history, severe obesity (BMI > 30 kg/m2) and systemic lupus erythematosus (SLE). There is no consensus about the possible role of varicose veins in VTE.Patients with a history of VTE or known thrombophilic states have an increased risk of VTE. HRT may add further to this risk. Personal or strong family history of recurrent 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.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 (e.g., painful swelling of a leg, sudden pain in the chest, dyspnoea).
StrokeOne 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 continuous estrogens and medroxyprogesterone acetate (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.
Coronary Artery Disease (CAD)There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated estrogens and MPA. 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 limited data from randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.
Other conditions• Estrogens 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 in Ethinylestradiol Tablets is increased.• Women with pre-existing hypertriglyceridemia should be followed closely during estrogen 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-I-antitrypsin, ceruloplasmin).• There is no conclusive evidence for improvement of cognitive function. There is some evidence from the WHI trial of increased risk of probable dementia in women who start using continuous combined CEE and MPA after the age of 65. It is unknown whether the findings apply to younger post-menopausal women or other HRT products.• Patients with rare hereditary problems of galactose intolerance, the Lapp-lactose deficiency, or glucose-galactose malabsorption should not take this medicine.
Breast cancerAccording to evidence from a large number of epidemiological studies and one randomised placebo-controlled trial, the Women's Health Initiative (WHI), the overall risk of breast cancer increases with increasing duration of HRT use in current or recent HRT users.For estrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was estrogen-only HRT) and from the epidemiological Million Women Study (MWS) are similar at 1.35 (95%CI 1.21 1.49) and 1.30 (95%CI 1.21 1.40), respectively.For estrogen plus progestogen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with estrogens alone.The MWS reported that, compared to never users, the use of various types of estrogen-progestogen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 2.12) than use of estrogens alone (RR = 1.30, 95%CI: 1.21 1.40) or use of tibolone (RR=1.45; 95%CI 1.25- 1.68).The WHI trial reported a risk estimate of 1.24 (95%CI 1.01 1.54) after 5.6 years of use of estrogen-progestogen combined HRT (CEE + MPA) in all users compared with placebo.The absolute risks calculated from the MWS and the WHI trial are presented below:The MWS has estimated, from the known average incidence of breast cancer in developed countries, that:• For women not using HRT, about 32 in every 1000 are expected to have breast cancer diagnosed between the ages of 50 and 64 years.• For 1000 current or recent users of HRT, the number of additional cases during the corresponding period will be• For users of estrogen-only replacement therapy - between 0 and 3 (best estimate = 1.5) for 5 years' use - between 3 and 7 (best estimate = 5) for 10 years' use.• For users of estrogen plus progestogen combined HRT, - between 5 and 7 (best estimate = 6) for 5 years' use - between 18 and 20 (best estimate = 19) for 10 years' use.The WHI trial estimated that after 5.6 years of follow-up of women between the ages of 50 and 79 years, an additional 8 cases of invasive breast cancer would be due to estrogen-progestogen combined HRT (CEE + MPA) per 10,000 women years.According to calculations from the trial data, it is estimated that:• For 1000 women in the placebo group, - about 16 cases of invasive breast cancer would be diagnosed in 5 years. • For 1000 women who used estrogen + progestogen combined HRT (CEE + MPA), the number of additional cases would be - between 0 and 9 (best estimate = 4) for 5 years' use.The number of additional cases of breast cancer in women who use HRT is broadly similar for women who start HRT irrespective of age at start of use (between the ages of 45-65) (see section 4.4).
Endometrial cancerIn women with an intact uterus, the risk of endometrial hyperplasia and endometrial cancer increases with increasing duration of use of unopposed estrogens. According to the data from epidemiological studies, the best estimate of the risk of endometrial cancer is that for women not using HRT, about 5 in every 1000 are expected to have endometrial cancer diagnosed between the ages of 50 and 65. Depending on the duration of treatment and estrogen dose, the reported increase in endometrial cancer risk among unopposed estrogen users varies from 2-to 12-fold greater compared with non- users. Adding a progestogen to estrogen-only therapy greatly reduces this this increased risk.Other adverse reactions have been reported in association with estrogen treatment;Genito-urinary tract: endometrial neoplasia, endometrial cancer, intermenstrual bleeding, increase in the size of uterine fibromyomata, endometrial proliferation or aggravation of endometriosis, excessive production of cervical mucus.Breast: tenderness, pain, enlargement, secretion.Gastro-intestinal tract: nausea, vomiting, cholelithiasis, cholestatic jaundice.Cardiovascular system: hypertension, thrombosis, thrombophlebitis, thromboembolism, myocardial infarction, stroke.Venous thromboembolism, i.e. deep leg or pelvic venous thrombosis and pulmonary embolism, is more frequent among hormone replacement therapy users than among non-users. For further information, see section 4.3 Contraindications and 4.4 Special warnings and precautions for use.Skin: erythema nodosum, erythema multiforme, vascular purpura, rash, chloasma.Eyes: corneal discomfort if contact lenses are used.CNS: headache, migraine, mood changes (elation or depression), probable dementia (see Section 4.4).Metabolic: sodium and water retention, reduced glucose tolerance and change in body weight, hypercalcaemia.In men: feminisation, gynaecomastia, testicular atrophy and impotence. 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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard.
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