- 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
Maintenance/Continuation/Extended treatmentFor initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4 Special warnings and special precautions for use) should be used. Patients should be re-evaluated periodically to determine if treatment for symptoms is still necessary.The benefits of the lower risk of endometrial hyperplasia and endometrial cancer due to adding a progestogen should be weighed against the increased risk of breast cancer (see section 4.4 Special warnings and special precautions for use and section 4.8 Undesirable effects) Forgotten tablet: If a tablet is forgotten, it should be taken as soon as the patient remembers, therapy should then be continued as before. If more than one tablet has been forgotten only the most recent tablet should be taken, the patient should not take double the usual dose to make up for missed tablets. Missed pills may cause breakthrough bleeding.Elderly:There are no special dosage requirements for elderly patients, but, as with all medicines, the lowest effective dose should be used.Children:Not recommended
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 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 mammography, should be carried out in accordance with currently accepted screening practices, modified to the clinical needs of the individual.
Conditions that 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 Premique Low Dose, in particular:− Leiomyoma (uterine fibroids) or endometriosis− A family history of, or other 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) headaches− Systemic lupus erythematosus (SLE)− A history of endometrial hyperplasia (see below)− Epilepsy− Asthma− Otosclerosis
Reasons for immediate withdrawal of therapyTherapy should be discontinued if 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 HyperplasiaThe risk of endometrial hyperplasia and carcinoma is increased when estrogens are administered alone for prolonged periods (see section 4.8 Undesirable effects). The addition of a progestogen for at least 12 days of the cycle in non-hysterectomised women greatly reduces this risk. Unless there is a previous diagnosis of endometriosis it is not recommended to add a progestogen in hysterectomised women.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 section 4.8 Undesirable effects). 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 CancerA randomised 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 estrogens, estrogen-progestogen combinations or tibolone for HRT for several years (see Section 4.8 Undesirable effects). For all HRT, an excess risk becomes apparent within a few years of use and increases with the 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.
Venous thromboembolismHormone replacement therapy (HRT) 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 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. Generally recognised risk factors for VTE include a personal or family history and severe obesity (Body Mass Index >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 to this risk. 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.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 4-6 weeks earlier, if this is possible. Treatment should not be restarted until the woman is completely mobilised.If venous thromboembolism develops after initiating therapy the drug should be discontinued. Patients should be told to contact their doctors immediately when they are aware of potential thromboembolic symptoms (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 cardiovascular benefit with continuous combined conjugated estrogens and MPA. Two large clinical trials (WHII 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 randomised controlled trials examining effects in cardiovascular morbidity or mortality. Therefore, it is uncertain whether these findings also extend to other HRT products.
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 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.
Ovarian CancerLong term (at least 5 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 different risk than estrogen-only products.
Other Conditions• Estrogens/progestogens 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 Premique Low Dose is increased.• The use of estrogen may influence the laboratory results of certain endocrine tests and liver enzymes.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 usually 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 biologically active hormone concentrations are usually unchanged. Other plasma proteins may be increased (angiotensinogen/renin substrate, alpha-I-antitrypsin, ceruloplasmin). Some patients dependent on thyroid hormone replacement therapy may require increased doses in order to maintain their free thyroid hormone levels in an acceptable range. Therefore, patients should have their thyroid function monitored more frequently when commencing concurrent treatment in order to maintain their free thyroid hormone levels in an acceptable range.• There is an increase in the risk of gallbladder disease in women receiving HRT (see conditions that need supervision)• A worsening of glucose tolerance may occur in some patients on estrogen/progestogen therapy and therefore diabetic patients should be carefully observed while receiving hormone replacement therapy.This product contains lactose and sucrose. Patients with rare hereditary problems of galactose intolerance, fructose intolerance, the Lapp lactase deficiency, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.• 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 should be used with caution in individuals with severe hypocalcaemia• 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.
Adverse drug reactions (ADRs)The adverse reactions listed in the table are based on post-marketing spontaneous (reporting rate), clinical trials and class-effects. Breast pain is a very common adverse event reported in ≥ 10% of patients.
|System Organ Class||Very Common ADRs( >1/10)||Common ADRs( >1/100, < 1/10)||Uncommon ADRs( >1/1000, <1/100)||Rare ADRs( >1/10000, <1/1000)||Very Rare ADRs ( <1/10000), isolated reports|
|Infections and infestations||Vaginitis||Vaginal candidiasis|
|Neoplasms benign and malignant (including cysts and polyps)||Fibrocystic breast changes Ovarian cancer||Enlargement of hepatic hemangiomas|
|Immune system disorders||Anaphylactic/ anaphylactoid reactions, including urticaria and angioedema|
|Metabolism and nutrition disorders||Glucose intolerance||Exacerbation of porphyria; hypocalcemia|
|Psychiatric disorders||Depression||Changes in libido; Mood disturbances||Irritability|
|Nervous system disorders||Dizziness; Headache; Migraine; Anxiety||Stroke; Exacerbation of epilepsy||Exacerbation of chorea|
|Eye disorders||Intolerance to contact lenses||Retinal vascular thrombosis|
|Cardiac disorders||Myocardial infarction|
|Vascular disorders||Pulmonary embolism||Superficial thrombophlebitis|
|Respiratory, thoracic and mediastinal disorders||Exacerbation of asthma|
|Gastrointestinal disorders||Nausea; Bloating; Abdominal pain||Vomiting; Pancreatitis|
|Hepatobiliary disorders||Gallbladder disease||None||Cholestatic jaundice|
|Skin and subcutaneous tissue disorders||Alopecia; acne; Pruritis||Chloasma/melasma; Hirsutism; Pruritus; Rash|
|Musculoskeletal, connective tissue and bone disorders||Arthralgias; Leg cramps|
|Reproductive system & breast disorders||Breast pain||Breakthrough bleeding/spotting dysmenorrhea, breast, tenderness, enlargement, discharge||Change in menstrual flow; Change in cervical ectropion and secretion||Galactorrhoea; Increased size of uterine leiomyomata|
|General disorders and administration site conditions||Oedema|
|Investigations||Changes in weight (increase or decrease) Increased triglycerides||Increase in blood pressure|
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|
|o between 0 and 3 (best estimate = 1.5) for 5 years' use|
|o between 3 and 7 (best estimate = 5) for 10 years' use.|
|• For users of estrogen plus progestogen combined HRT|
|o between 5 and 7 (best estimate = 6) for 5 years' use|
|o between 18 and 20 (best estimate = 19) for 10 years' use.|
|• For 1000 women in the placebo group.|
|o About 16 cases of invasive breast cancer would be diagnosed in 5 years.|
|• For 1000 women who used estrogen plus progestogen combined HRT (CEE + MPA), the number of additional cases would be|
|o Between 0 and 9 (best estimate = 4) for 5 years' use.|
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 data from epidemiological studies, the best estimate of the risk 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 increased risk. Other adverse reactions reported in association with estrogen/progestogen treatment including Premique:• Estrogen-dependent neoplasms benign and malignant, e.g. endometrial hyperplasia, endometrial cancer• 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 Contra-indications and 4.4 Special Warnings and Precautions for Use.• Myocardial infarction• Stroke• Skin and subcutaneous disorders: erythema multiforme, erythema nodosum, vascular purpura• Probable dementia (see section 4.4 Special warnings and special precautions for use)• Exacerbation of otosclerosis
Conjugated EstrogensThe active ingredients are primarily the sulphate esters of estrone, equilin sulphates, 17α-estradiol and 17β-estradiol. These substitute for the loss of estrogen production in menopausal women, and alleviate menopausal symptoms.
Progestogen:As estrogens promote the growth of the endometrium, unopposed estrogens increase the risk of endometrial hyperplasia and cancer. The addition of a progestogen reduces but does not eliminate the estrogen-induced risk of endometrial hyperplasia in non-hysterectomised women.
Relief of estrogen-deficiency symptomsIn a 1-year clinical trial (n=2,808), vasomotor symptoms were assessed for efficacy during the first 12 weeks of treatment in a subset of symptomatic women (n=241) who had at least 7 moderate or severe hot flushes daily or 50 moderate to severe hot flushes during the week before randomisation. Premique 0.625mg/2.5mg (conjugated estrogens/medroxyprogesterone acetate) was shown to be statistically better than placebo at weeks 4, 8 and 12 for relief of both frequency and severity of moderate to severe vasomotor symptoms.In two clinical trials, the incidence of amenorrhoea (no bleeding or spotting) increased over time in women treated with Premique 0.625 mg/2.5 mg. Amenorrhoea was seen in 68% of women at cycle 6 and 77% of women at cycle 12. Breakthrough bleeding and/or spotting appeared in 48% during the first 3 months, and in 24% of women during months 10-12 of treatment.
AbsorptionConjugated estrogens are soluble in water and are well absorbed from the gastrointestinal tract after release from the drug formulation. However Premique Low Dose contains a formulation of medroxyprogesterone acetate (MPA) that is immediately released and conjugated estrogens that are slowly released over several hours. MPA is well absorbed from the gastrointestinal tract. Table 1 summarises the mean pharmacokinetic parameters for unconjugated and conjugated estrogens, and medroxyprogesterone acetate following administration of 2 Premique Low Dose 0.3 /1.5 mg and 2 Premique Low Dose 0.45/1.5 mg tablets to healthy postmenopausal women.
DistributionThe distribution of exogenous estrogens is similar to that of endogenous estrogens. Estrogens are widely distributed in the body and are generally found in higher concentrations in the sex hormone target organs. Estrogens circulate in the blood largely bound to sex hormone binding globulin (SHBG) and albumin. MPA is approximately 90% bound to plasma proteins but does not bind to SHBG.
MetabolismExogenous estrogens are metabolised in the same manner as endogenous estrogens. Circulating estrogens exist in a dynamic equilibrium of metabolic interconversions. These transformations take place mainly in the liver. Estradiol is converted reversibly to estrone, and both can be converted to estriol, which is the major urinary metabolite. Estrogens also undergo enterohepatic recirculation via sulphate and glucuronide conjugation in the liver, biliary secretion of conjugates into the intestine, and hydrolysis in the gut followed by reabsorption. In postmenopausal women a significant proportion of the circulating estrogens exists as sulphate conjugates, especially estrone sulphate, which serves as a circulating reservoir for the formation of more active estrogens. Metabolism and elimination of MPA occur primarily in the liver via hydroxylation, with subsequent conjugation and elimination in the urine.
ExcretionEstradiol, estrone and estriol are excreted in the urine along with glucuronide and sulphate conjugates. Most metabolites of MPA are extracted as glucuronide conjugates with only minor amounts secreted as sulphates.
Table 1 Pharmacokinetic parameters for Premique Low Dose
|Drug||2 x 0.3 mg CE/1.5 mg MPA Combination (n=30)||2 x 0.45 mg CE/1.5 mg MPA Combination (n=61)|
|PK Parameter Arithmetic Mean (%CV)||Cmax(pg/mL)||tmax(h)||t1/2(h)||AUC(pg.h/mL)||Cmax(pg/mL)||tmax(h)||t1/2(h)||AUC(pg.h/mL)|
|Estrone||79 (35)||9.4 (86)||51.3 (30)||5029 (45)||91 (30)||9.8 (47)||48.9 (28)||5786 (42)|
|BA*-Estrone||56 (46)||9.4 (86)||19.8 (39)||1429 (49)||67 (37)||9.8 (47)||21.5 (49)||2042 (52)|
|Equilin||30 (43)||7.9 (42)||14.0 (75)||590 (42)||35 (40)||8.5 (34)||16.4 (49)||825 (44)|
|PK Parameter Arithmetic Mean (%CV)||Cmax(pg/mL)||tmax(h)||t1/2(h)||AUC(ng.h/mL)||Cmax(ng/mL)||tmax(h)||t1/2(h)||AUC(ng.h/mL)|
|Total Estrone||2.4 (38)||7.1 (27)||26.5 (33)||62 (48)||3.0 (37)||8.2 (39)||25.9 (23)||78 (40)|
|BA*- Total Estrone||2.2 (36)||7.1 (27)||16.3 (32)||41 (44)||2.8 (36)||8.2 (39)||16.9 (36)||56 (39)|
|Total Equilin||1.5 (47)||5.5 (29)||11.5 (24)||22 (41)||1.9 (42)||7.2 (33)||12.2 (25)||31 (52)|
|PK Parameter Arithmetic Mean (%CV)||Cmax(ng/mL)||tmax(h)||t1/2(h)||AUC(ng.h/mL)||Cmax(ng/mL)||tmax(h)||t1/2(h)||AUC(ng.h/mL)|
|MPA||1.2 (42)||2.8 (61)||42.3 (34)||29.4 (30)||1.2 (42)||2.7 (52)||47.2 (41)||32.0 (36)|
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