Estradiolis+Noretisterono acetatas, 2mg+1mg, plėvele dengtos tabletės
Vartojimas: vartoti per burną
Registratorius: Novo Nordisk A/S, Danija
Sudedamosios medžiagos: Estradiolis+Noretisterono acetatas
Summary of Product Characteristics
- Name of the Medicinal ProductKliogest® film-coated tablet
- Qualitative and Quantitative CompositionEach film-coated tablet contains:Estradiol 2 mg (as estradiol hemihydrate) Norethisterone acetate 1 mgFor excipients, see 6.1.
- Pharmaceutical FormFilm-coated tablet White, film-coated, biconvex tablet, engraved with NOVO 281. Diameter 6 mmorYellow, film-coated, biconvex tablet, engraved with NOVO 286. Diameter 6 mm
- Clinical Particulars4.1Therapeutic IndicationsHormone Replacement Therapy (HRT) for oestrogen deficiency symptoms in women more than one year after menopause. Prevention of osteoporosis in postmenopausal women at high risk of future fractures who are intolerant of, or contraindicated for, other medicinal products approved for the prevention of osteoporosis.The experience of treating women older than 65 years is limited.4.2Posology and Method of AdministrationKliogest® is a continuous combined hormone replacement product intended for use in women with an intact uterus. One tablet should be taken orally and once a day without interruption, preferably at the same time every day.For initiation and continuation of treatment of postmenopausal symptoms, the lowest effective dose for the shortest duration (see also Section 4.4) should be used. In women with amenorrhea and not taking HRT or women transferring from another continuous combined HRT product, treatment with Kliogest® may be started on any convenient day. However, when women switch from a sequential HRT-product to Kliogest it is recommended to start treatment after the bleeding episode, i.e. the same day as start of a new treatment cycle with sequential HRT was planned.If the patient has forgotten to take one tablet, the forgotten tablet is to be discarded. Forgetting a dose may increase the likelihood of breakthrough bleeding and spotting.4.3Contraindications-Known, past or suspected breast cancer -Known or suspected oestrogen-dependent malignant tumours (e.g. endometrial cancer)-Undiagnosed genital bleeding-Untreated endometrial hyperplasia-Previous idiopathic or current venous thromboembolism (deep venous thrombosis, pulmonary embolism)-Active or recent arterial thromboembolic disease (e.g. angina, myocardial infarction) -Acute liver disease, or history of liver disease as long as liver function tests have failed to return to normal-Known hypersensitivity to the active substances or to any of the excipients -Porphyria4.4 Special Warnings and Precautions for UseFor the treatment of postmenopausal symptoms, HRT should only be initiated for symptoms that adversely affect quality of life. In all cases, a careful appraisal of the risks and benefits should be undertaken at least annually and HRT should only be continued as long as the benefit outweighs the risk.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 (Please see the “Breast Cancer” section below). Investigations, 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 Kliogest®, in particular:- Leiomyoma (uterine fibroids) or endometriosis- A history of, or 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-OtosclerosisReasons for immediate withdrawal of therapyTherapy should be discontinued in case 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-PregnancyEndometrial hyperplasiaThe risk of endometrial hyperplasia and carcinoma is increased when oestrogens are administered alone for prolonged periods (see Section 4.8). The addition of a progestagen for at least 12 days per cycle in non-hysterectomised women greatly reduces this risk.Breakthrough bleeding and spotting may occur during the first months of treatment. If breakthrough 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 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 oestrogens, oestrogen-progestagen 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 oestrogens (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 oestrogen 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 oestrogen-progestagen combined treatment, increases the density of mammographic images which may adversely affect the radiological detection of breast cancer.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 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 history or family history, 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 four to six 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, dyspnea).Coronary artery disease (CAD) There is no evidence from randomised controlled trials of cardiovascular benefit with continuous combined conjugated oestrogens and medroxyprogesterone (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 only 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. 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 oestrogens 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 oestrogens 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 oestrogen-only HRT products in hysterectomised women has been associated with an increased risk of ovarian cancer in some epidemiological studies. It is uncertain that long-term use of combined HRT leads to any risk increase for ovarian cancer.Other conditionsOestrogens 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 Kliogest® will increase. 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-immuno-assay) 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.Kliogest® tablets contain lactose. Patients with rare hereditary galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
- 4.5Interaction with Other Medicaments and Other Forms of InteractionsThe metabolism of oestrogens and progestagens may be increased by concomitant use of substances known to induce drug-metabolising enzymes, specifically cytochrome P450 enzymes, such as anticonvulsants (e.g. phenobarbital, phenytoin, carbamazepin) and anti-infectives (e.g. rifampicin, rifabutin, nevirapine, efavirenz).Ritonavir and nelfinavir, although known as strong inhibitors, by contrast exhibit inducing properties when used concomitantly with steroid hormones. Herbal preparations containing St John’s Wort (Hypericum perforatum) may induce the metabolism of oestrogens and progestagens.Clinically, an increased metabolism of oestrogens and progestagens may lead to decreased effect and changes in the uterine bleeding profile.Drugs that inhibit the activity of hepatic microsomal drug metabolizing enzymes e.g. ketoconazole, may increase circulating levels of the active substances in Kliogest®.
- 4.6Pregnancy and LactationKliogest® is not indicated during pregnancy.If pregnancy occurs during medication with Kliogest®, treatment should be withdrawn immediatelyData on a limited number of exposed pregnancies indicate adverse effects of norethisterone on the foetus. At doses higher than normally used in OC and HRT formulations masculinisation of female foetuses was observed.The results of most epidemiological studies to date relevant to inadvertent foetal exposure to combinations of oestrogens and progestagens indicate no teratogenic or foetotoxic effect.LactationKliogest® is not indicated during lactation4.7Effects on Ability to Drive and Use MachinesNo effects known.4.8Undesirable EffectsClinical experience:The most frequently reported adverse events in the clinical trials with Kliogest® were vaginal bleedings and breast pain/tenderness, reported in approximately 10% to 30% of patients. Vaginal bleedings usually occurred in the first months of treatment. Breast pain usually disappears after a few months of therapy. All adverse events observed in the randomised clinical trials with a higher frequency in patients treated with Kliogest® or similar HRT products as compared to placebo and which on an overall judgement are possible related to treatment are presented in the table below.
System organ class
Very common >1/10
Infections and infestations
Genital candidiasis or vaginitis, see also “Reproductive system and breast disorders
Immune system disorders
Hypersensi-tivity, see also “Skin and subcutaneous tissue disorders
Metabolism and nutrition disorders
Fluid retention, see also “General disorders and administration site conditions
Depression or depression aggravated
Nervous system disorders
Headache, migraine or migraine aggravated
Pulmonary embolism Thrombo-phlebitis deep
NauseaAbdominal pain, abdominal distension or abdominal discomfort
Flatulence or bloating
Skin and subcutaneous tissue disorders
Alopecia, hirsutism or acnePruritus or urticaria
Musculoskeletal, connective tissue and bone disorders
Back pain Leg cramps
Reproductive system and breast disorders
Breast pain or breast tendernessVaginal haemorrhage
Breast oedema or breast enlargementUterine fibroids aggravated or uterine fibroids re-occurrence or uterine fibroids
General disorders and administration site conditions
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 oestrogen-only HRT, estimates of relative risk (RR) from a reanalysis of original data from 51 epidemiological studies (in which >80% of HRT use was oestrogen-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 oestrogen plus progestagen combined HRT, several epidemiological studies have reported an overall higher risk for breast cancer than with oestrogens alone. The MWS reported that, compared to never users, the use of various types of oestrogen-progestagen combined HRT was associated with a higher risk of breast cancer (RR = 2.00, 95%CI: 1.88 – 2.12) than use of oestrogens 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 oestrogen-progestagen 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 oestrogen-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.
- 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 oestrogen-progestagen combined HRT (CEE + MPA) per 10,000 women years. According to calculations from the trial data, it is estimated that:
- about 16 cases of invasive breast cancer would be diagnosed in 5 years.
- For 1000 women who used oestrogen + progestagen combined HRT (CEE + MPA), the number of additional cases would be
- 4.9OverdoseOverdose may be manifested by nausea and vomiting. Treatment should be symptomatic.
- For users of oestrogen-only replacement therapy
- Pharmaceutical Particulars6.1List of excipientsTablet core:Lactose monohydrateMaize starchGelatinTalcMagnesium stearateFilm-coating:White tablets:Hypromellose TriacetinTalcYellow tablets:HypromelloseTalcTitanium dioxide (E171)Yellow iron oxide (E172)Propylene glycol 6.2Incompatibilities Not applicable6.3Shelf Life4 years.
- Special Precautions for StorageDo not store above 25ºC. Do not refrigerate. Keep the container in the outer carton6.5Nature and Contents of Container1 x 28 tablets or 3 x 28 tablets in calendar dial packs.The calendar dial pack with 28 tablets consists of the following 3 parts:-The base made of coloured non-transparent polypropylene-The ring-shaped lid made of transparent polystyrene-The center-dial made of coloured non-transparent polystyreneNot all pack sizes may be marketed.
- Instructions for UseNo special requirements.
- Marketing Authorization NumberAs registered locally
- Date of First Authorization/Renewal of the AuthorizationAs registered locally
- Date of Revision of the TextSeptember 2005
|Tarptautinis pavadinimas||Estradiolis+Noretisterono acetatas|
|Vaisto forma||plėvele dengtos tabletės|
|Vartojimas||vartoti per burną|
|Registratorius||Novo Nordisk A/S, Danija|
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