Evian® (Eviana® )

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceEstradiol + Norethisterone acetateEstradiol + Norethisterone acetate
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    • Dosage form: & nbspfilm-coated tablets
    Composition:

    1 tablet contains:

    active substances: Estradiol (as hemihydrate) 0.5 mg and norethisterone acetate 0.1 mg;

    Excipients: lactose monohydrate 37.5 mg, corn starch 37.5 mg, giprolose 3.2 mg, talc 0.8 mg, magnesium stearate 0.4 mg;

    tablet shell: hypromellose 2.28 mg, triacetin 0.12 mg.

    Description:

    The tablets covered with a film cover of white color, round, biconcave, on one side engraving "NOVO 291 ", on the other - the symbol of the company (bull Apis).

    Pharmacotherapeutic group:antimycotics combined (estrogen + progestogen)
    ATX: & nbsp

    G.03.F.B.05   Norethisterone and estrogen

    Pharmacodynamics:

    Estradiol: synthetic 17β-Extradiol, identical to the woman's ovary produced by endogenous estradiol, eliminates estrogen deficiency in postmenopausal women and softens the symptoms of menopause, and also prevents bone loss during menopause or ovariectomy.

    Norethisterone: Since estrogens stimulate the growth of the endometrium, the use of exclusively estrogen increases the risk of endometrial hyperplasia and endometrial cancer.

    The addition of progestogen significantly reduces the estrogen-induced risk of endometrial hyperplasia in women who have not undergone hysterectomy.

    Attenuation of menopausal symptoms occurs in the first weeks of treatment. In the third week of the medication, the mean frequency of moderate and severe hot flushes was significantly lower (p <0.001) in the group of patients receiving 0.5 mg of estradiol statistically compared with that in the placebo group. This decline persisted until the end of the study (24 weeks).

    Eviana® is a combined preparation for HRT, containing 17β-estradiol and norethisterone (in the form of acetate), which prevents the development of regular withdrawal bleeding associated with cyclic or sequential HRT. In 89% of women, development of amenorrhea (absence of bleeding and spotting bleeding) was noted six months after the start of treatment. In the first six months of treatment bleeding and / or spotting spotting can be observed in 11-15% of women.

    It is known that combined therapy with estrogens and progesterone increases the density of the mammogram, which may have a negative effect on the radiological study for the detection of breast cancer. Six months after the start of the treatment with Eviana®, an increase in breast density during mammography was not observed.

    Deficiency of estrogen during the menopause is associated with a decrease in bone mineral density. The effect of estrogens on the mineral density of bones depends on the dose. It is believed that this effect persists as long as the treatment continues. After the termination of HRT, the bone mass is reduced to the same extent as in women who have not undergone treatment.

    Studies show that the widespread use of HRT alone estrogen or in combination with progestogen, prescribed mainly to healthy women, reduces the risk of fractures of the hip joint, spine and other fractures due to osteoporosis. HRT can also prevent fractures in women whose bone mineral density is low and / or with diagnosed cases of osteoporosis, but the evidence supporting this assumption is limited.

    The effect of estrogens on the mineral density of bones depends on the dose and therefore the effect of the Evian® preparation may be less than that observed with higher doses of estradiol.

    Act 17β-estradiol 0.5 mg per bone mineral density was studied in two biennial randomized, double-blind, placebo-controlled studies and with participation of women in menopause (n= 327, including 44 women who took 17β-estradiol 0.5 mg and n= 171 in another study, including 40 women taking 17β-estradiol 0.5 mg). All women received a calcium supplement 500-1000 mg / day. 17β-estradiol 0.5 mg significantly prevented the loss of bone mass in the lumbar spine, hip joints, radius, and the whole body in patients who took 17β-estradiol 0.5 mg for 2 years. In the first study (n= 327), the percentage of bone mineral density in the lumbar spine, in the femoral neck and femoral spit was 2.26 ± 2.76%, 0.26 ± 2.86% and 1.74 ± 4.12% (mean ±SD). In comparison with the baseline, the percentage change in bone mineral density in the second study (n= 171) in the lumbar region of the spine, in the femoral neck and femoral spit were 0.17 ± 3.28%, 1.76 ± 4.23%, 0.97 ± 5.71% and 0.74 ± 6, respectively, 41%.Percentage of women whose bone mineral density persisted or increased in the first study (n= 327) during treatment 17β-estradiol 0.5 mg in the lumbar spine, in the neck of the femur and femoral spit, were 74%, 57% and 67% respectively.

    In the second study (n= 171) conducted during 2 years, this percentage was 41%, 69%, 56% and 44% respectively.

    Biochemical bone markers showed a decrease in bone resorption in both studies.

    Pharmacokinetics:

    After taking the drug Evian® inside micronized 17β-estradiol is rapidly absorbed in the gastrointestinal tract, undergoes primary metabolism in the liver and small intestine and reaches a peak concentration in the blood plasma of approximately 24 pg / ml, a coefficient of variation of 38% (after taking two Evian® tablets), 5-8 hours. Half-life 17β-Extradiol from the body is about 15 hours. The drug circulates in the blood as a complex with albumin (61%) and globulin binding sex hormones (SHGG) (37%). In the free form in the blood circulates only about 1-2% 17β-estradiol.

    17β-Extradiol is metabolized, mainly,in the liver, and also outside it - in the intestine and target organs, with the formation of less active or inactive metabolites, including estrone, catechol estrogens, as well as sulphates and glucuronides of estrogen.

    The bulk of estrogens are excreted as inactive metabolites by the kidneys, and also with bile, in which they undergo hydrolysis and are absorbed back (enterohepatic recirculation).

    After taking Eviana ® inside norethisterone acetate is rapidly absorbed and transformed into norethisterone (NET). The MET is subjected to primary metabolism in the liver and small intestine and reaches a maximum plasma concentration of approximately 2.4 ng / ml after about 0.5-1.5 hours, the CV coefficient of 41% (after the introduction of two Evian® tablets) . The final half-life of norethisterone is about 9-11 hours. NET creates a complex with albumin (61%) and globulin binding sex hormones SHGG (36%). The most important metabolites are the α5-dihydro-NET and tetra-NET isomers, which are excreted mainly with urine in the form of sulfates or conjugated glucuronides.

    Norethisterone does not affect the pharmacokinetic properties of estradiol.

    The study of the pharmacokinetics of the drug in elderly patients was not conducted.

    Preclinical safety data

    Estrogens have a low acute toxicity index. In view of the significant differences between individual species of experimental animals, as well as between animals and humans, the results of preclinical studies are of limited importance for predicting efficacy in humans. Animal studies have shown that estradiol and estradiol valerate even in relatively low doses can cause embryo death, as well as the development of congenital malformations of the genitourinary tract and feminization of the male fetus.

    Norethisterone, as well as other gestagens, causes virilization of the female fetus in rats and monkeys. In high doses norethisterone can cause death of the embryo.

    Pre-clinical data, based on data on pharmacological safety, genotoxicity and oncogeneity, did not reveal a specific risk for humans, except for those effects that are considered in other sections of the manual.

    Indications:

    Hormone replacement therapy (ERT) for symptoms of estrogen deficiency in postmenopausal women, no earlier than one year after the onset of menopause.

    Contraindications:

    - Breast cancer or a suspicion of it, as well as breast cancer in the anamnesis;

    - diagnosed (including in the anamnesis) estrogen-dependent malignant neoplasms (including endometrial cancer) or suspicion of them;

    - bloody discharge (bleeding) from the vagina of an unclear etiology;

    - untreated endometrial hyperplasia;

    - deep vein thrombophlebitis, thrombosis, pulmonary embolism, or idiopathic thromboembolism in history;

    - diseases accompanied by arterial thromboembolism (including angina pectoris, myocardial infarction);

    - acute liver disease or liver disease in an anamnesis, in which the liver function was not normalized;

    - hypersensitivity to the active substance or other components included in the preparation;

    - porphyria;

    - pregnancy;

    - lactation.

    The experience of treating women over the age of 65 is limited.

    Carefully:

    If early or currently diagnosed any of the diseases listed below and / or worsened during pregnancy or previous hormonal treatment,the patient should be under close medical supervision, as such diseases can recur / aggravate during the treatment with Eviana®:

    - leiomyoma or endometriosis;

    - risk factors for thromboembolism or thromboembolism in the anamnesis (see "Special instructions");

    - risk factors for the development of estrogen-dependent tumors (eg, breast cancer in relatives of the first degree of kinship);

    - arterial hypertension;

    - liver diseases (including liver adenoma);

    - diabetes mellitus with or without vascular disease;

    - cholelithiasis;

    - migraine or severe headaches;

    - systemic lupus erythematosus;

    - endometrial hyperplasia in the anamnesis (see "Special instructions");

    - epilepsy;

    - bronchial asthma;

    - otosclerosis.

    Pregnancy and lactation:

    The use of Eviana® during pregnancy and during breastfeeding is contraindicated. In the case of pregnancy on the background of treatment with Eviana ® - treatment should be immediately stopped.

    Limited data on the use of Eviana ® during pregnancy indicate the adverse effects of norethisterone on the fetus. The use of hormones in doses that are used for oral contraception, HRT or higher leads to masculinization of the female fetus.

    The results of most epidemiological studies on the unintended effects on the fetus of combined therapy with estrogens and progesterones indicate that it has no teratogenic or fetotoxic effect.

    Dosing and Administration:

    Evian® tablets are designed for continuous combined hormone replacement therapy for HRT in women with an unrefined uterus. The drug is taken orally 1 tablet per day without interruption, preferably at the same time of day.

    In the treatment of postmenopausal symptoms, the drug should be started and resumed at the lowest effective dose for short-term therapy (see also section Special instructions for use and warnings).

    If there is an insufficient response to therapy after three months, the transition to a higher-dose drug should be discussed.

    Patients with amenorrhea who do not receive HRT or who take another combination drug in continuous mode can start taking Evian® tablets on any convenient day.

    When transferring patients from the cyclic mode of HRT, treatment should be started immediately after the end of menstrual bleeding caused by withdrawal of the drug.

    If you miss a new tablet the missed tablet should be taken as soon as possible within the next 12 hours. If the drug is delayed for more than 12 hours, the missed tablet should be discarded. Skipping the next dose can cause breakthrough uterine bleeding or the appearance of spotting spotting. Unused medication should be disposed of in accordance with local regulations.

    Side effects:

    The most frequently reported side effects during clinical trials of Evian® were vaginal bleeding. According to the results of a six-month clinical study of bleeding or the appearance of spotting bleeding from the vagina, 11% of patients were registered during the first month of taking the drug, 15% at the 4th month of therapy and 11% at the end of the clinical trial. A higher frequency side effects were observed among patients receiving Eviana® treatment, compared with patients receiving placebo. Below are all the side effects that are generally believed to have a possible association with the treatment.

    Very often: (> 1/10 - more than 1 for 10)

    Disorders from the reproductive system and mammary glands:

    - Bleeding from the vagina

    Often: (> 1/100; <1/10 - more than 1 per 100, but less than 1 for 10)

    Impaired nervous system:

    - Headache

    Disorders from the gastrointestinal tract:

    - Nausea

    - Abdominal pain

    Disturbances from the musculoskeletal system and connective tissue:

    - Backache

    - Pain in the cervical spine

    - Pain in the extremities

    Disorders from the reproductive system and mammary glands:

    - Endometrial hyperplasia

    - Vulvovaginal mycoses

    Rarely: (> 1/1000; <1/100 - more than 1 per 1000, but less than 1 per 100)

    Immune system disorders:

    - Hypersensitivity (see also Disturbances from the skin and subcutaneous fat)

    Metabolic disorders:

    - Fluid retention in the body (see also General disorders and reactions at the site of administration)

    Mental disorders:

    - Depressive conditions or severe depression

    - Increased excitability

    Impaired nervous system:

    - Migraine

    - Dizziness

    Disorders from the gastrointestinal tract:

    - Bloating

    - Dyspepsia

    Disturbances from the skin and subcutaneous fat:

    - Alopecia

    - Acne

    - Skin itching or urticaria

    Disturbances from the musculoskeletal system and connective tissue:

    - Cramps in the calf muscles

    Disorders from the reproductive system and mammary glands:

    - Soreness of the mammary glands

    - Discomfort in the area of ​​mammary glands

    Common disorders and reactions at the site of administration:

    - Peripheral edema

    Mammary cancer (see section "Special instructions")

    The risk of developing breast cancer among women currently taking or taking HRT in the recent past increases in proportion to the increase in HRT.

    Endometrial cancer (see section "Special instructions")

    In women with an unrefined uterus, the risk of developing hyperplasia and endometrial cancer increases with prolonged use of estrogens without the adverse effect of progestogerone. Addition of progesterones to estrogen significantly reduces the risk of developing endometrial cancer.

    Adverse reactions that occurred with other preparations containing estradiol / norethisterone acetate (1 mg / 0.5 mg):

    - Benign and malignant neoplasms (including cysts and polyps): endometrial cancer.

    - Mental disorders: insomnia, anxiety, decreased libido, increased libido.

    - Disturbances from the nervous system: dizziness.

    - Disorders from the side of the organ of vision: visual impairment.

    - Disorders from the cardiovascular system: severe arterial hypertension.

    - Disorders from the gastrointestinal tract: indigestion, vomiting.

    - Hepatobiliary disorders: cholecystitis, cholelithiasis, severe form of cholelithiasis, recurrence of cholelithiasis.

    - Disturbances from the skin and subcutaneous fat: seborrhea, rash, angioedema

    - Violations of the reproductive system and mammary glands: endometrial hyperplasia, manifestations of vulvovaginal candidiasis.

    - Other: weight loss, increased blood pressure.

    Reports of the following adverse reactions have been reported in literary sources in connection with the mention of hormonal replacement therapy with estrogens / progestogens:

    - Estrogen-dependent neoplasms - benign and malignant, including endometrial cancer.

    - Venous thromboembolism, that is, deep vein thrombosis of the lower limbs or pelvic organs, as well as pulmonary embolism, is much more common in women who underwent HRT than in women who did not take hormone replacement therapy (for more details see sections Contraindications and Special instructions for use).

    - Myocardial infarction and stroke.

    - Cholelithiasis.

    - Disturbances from the skin and subcutaneous fat: hyperpigmentation of the skin, erythema multiforme, erythema nodosum, vascular purpura.

    - Possible dementia (more detailed information can be found in the section Special instructions).

    Overdose:

    Overdose may cause nausea and vomiting.

    Treatment is symptomatic.

    Interaction:

    With the simultaneous use with inductors of microsomal enzymes, especially cytochrome P450 enzymes, such as anticonvulsants (for example, phenobarbital, phenytoin, carbamazepine) and anti-infective drugs (for example, rifampicin, rifabutin, nevirapine, efavirenz), it is possible to accelerate the metabolism of estrogens and progesterones. On the contrary, ritonavir and nelfinavir, although they are strong inhibitors, with simultaneous use with steroid hormones show inducing properties.

    Phytopreparations, which include St. John's wort (Hypericum perforatum), can stimulate the metabolism of estrogens and progestogens.

    Elevated metabolism of estrogens and progestogens can clinically be manifested by a decrease in the effect of the drug and a change in the character of uterine bleeding.

    Medicinal products that inhibit the activity of microsomal liver enzymes, including ketoconazole, can increase the concentration of circulating active components of Eviana ®.

    Special instructions:

    Treatment of estrogen-dependent symptoms of postmenopausal HRT should be started only in cases of their adverse effect on the quality of life of women. To assess the ratio of benefits and risks of treatment with the drug, every 3 to 4 months (but at least once every 6 months), taking into account the individual characteristics of the patient, to conduct a medical examination, using clinical and laboratory data. HRT should be continued only as long as the benefits exceed the risk.

    Medical examination / control

    Before starting / resuming HRT, you should collect an anamnesis and study the patient's medical history, conduct the necessary examination (including pelvic organs and mammary glands), read the contraindications and special precautions for using the drug. Women should be advised to report any changes in the mammary glands to the doctor or nurse for the purpose of timely follow-up, including mammography.

    Reasons for immediate withdrawal of treatment

    Treatment should be discontinued if there are contraindications and the following conditions:

    - Jaundice or liver dysfunction

    - Significant increase in blood pressure

    - A new attack of a migraine headache

    - Pregnancy

    Endometrial hyperplasia

    With prolonged monotherapy with estrogens, the risk of developing hyperplasia and endometrial carcinoma increases (see also section Side effect). To reduce the risk in women with unoperated uterus, it is necessary to combine therapy with progestogen for at least 12 days during the cycle.

    During the first months of treatment with the drug, breakthrough bleeding and spotting can be noted.If such bleeding or discharge occurs some time after initiation of therapy or continues after discontinuation of the drug to determine their cause and exclude malignancy of the endometrium, an endometrial biopsy may be required.

    Endometrial cancer

    A maximum assessment of the risk of developing endometrial cancer in women not receiving HRT, based on epidemiological studies, shows that approximately 5 out of every 1,000 women aged 50-65 years will have endometrial cancer. Depending on the duration of treatment and the dose of estrogen, the risk of developing endometrial cancer among women receiving HRT with estrogen, without the adverse effect of progestogen, is 2-12 times higher than that of women who have not been accepted HRT.

    Mammary cancer

    Data from the randomized placebo-controlled study of the Women's Health Initiative (WHI), as well as epidemiological research, including a large-scale study of women's health "Million Women" (MWS), indicate an increased risk of developing breast cancer in women who have had HRT for several years with estrogens,estrogens in combination with progestogens or tibolone (see also section Side effect). The degree of additional risk becomes apparent after several years of HRT use and increases with prolonged treatment. However, the increased risk is reduced to the baseline in a few years (in most cases, after 5 years) after discontinuation of treatment.

    In women receiving estrogen replacement monotherapy, the values ​​of the relative risk (RR) of development of breast cancer obtained from a reanalysis of 51 epidemiological studies (in which> 80% of patients received hormone replacement therapy only estrogens) and the results of the epidemiological study "One Million Women" (MWS), are comparable and are 1.35 (95% CI: 1.21-1.49) and 1.30 (95% CI: 1.21-1.40), respectively.

    According to several epidemiological studies, the overall risk of developing breast cancer is higher with combined HRT with estrogens and progestogen than with estrogen alone.

    The results of the "One Million Women" (MWS) show that when comparing women who never received HRT, patients,(RR = 2.00, 95% CI: 1.88-2.12) than women receiving estrogen alone (RR = 1.30, 95 % CI: 1.21-1.40) or tibolone (RR = 1.45, 95% CI: 1.25-1.68).

    According to a study of "Million Women" (MWS) the magnitude of the risk of developing breast cancer after 5.6 years of combined HRT use with estrogen and progestogen (KLE + MPA) is comparable to the placebo group and is 1.24 (95% CI: 1.01-1.54).

    The magnitude of the absolute risk of developing breast cancer, calculated from the data of the study "Million women" (MWS) and the project "Women's Health" (WHI), are presented below:

    According to a study of "Million Women" (MWS), based on the known average incidence of breast cancer in women in advanced economies:

    The expected incidence of breast cancer among women aged 50-64 years who do not take HRT will be 32 out of every 1000 women.

    Among women taking HRT now or in the recent past, the number of additional cases of breast cancer in terms of 1000 women for a certain period will be:

    Among patients receiving estrogen replacement therapy 0-3 cases per 1000 women (an average of 1.5) with a duration of 5 years of substitution therapy,

    3-7 cases per 1000 women (an average of 5) with a duration of therapy of 10 years.

    Among patients who received combined HRT with estrogens and progestogen 5-7 cases per 1000 women (mean 6) with a duration of 5 years of replacement therapy,

    18-20 cases per 1000 women (an average of 19) with a duration of therapy of 10 years.

    According to the study "Women's Health" (WHI), After 5.6 years, the number of additional cases of development of invasive breast cancer in women aged 50-79 years, who had combined HRT with estrogen and progestogen (GLE ± MPA), was 8 cases for every 10,000 patient-years.

    Based on the clinical trial, it was calculated that:

    Of every 1,000 women in the placebo group After 5 years, approximately 16 women will be diagnosed with invasive breast cancer.

    Of every 1000 women who received combined HRT with estrogen and progestogen (CLA + MPA), the number of additional cases of breast cancer will be 0-9 cases (an average of 4) with a duration of 5 years of replacement therapy.

    In the study MWS the relative risk of breast cancer was higher when added to therapy with conjugated equine estrogens (EML) orEstradiol (E2), taken both in cyclic and continuous mode, progestogen, and did not depend on the type of progestogen.

    Data confirming a significant difference in the incidence of breast cancer, depending on the method of administration of the drug, are absent.

    In the study WHI it was found that with the development of breast cancer against a background of continuous replacement therapy with a combined preparation containing conjugated equine estrogens and medroxyprogesterone acetate (KLE + MPA), the neoplasm is somewhat larger and more often metastasizes to the regional lymph nodes, compared with the placebo group.

    Against the backdrop of HRT, especially with combined therapy with estrogens and progestogens, the density of the mammogram (mammogram) may increase, which may contradict the radiographic signs of breast cancer.

    In general, the number of additional cases of breast cancer in women aged 45-60 years who take combined HRT is comparable to that of women who are just starting HRT and does not depend on the age at which HRT is started.

    Venous thromboembolism

    HRT is associated with a higher relative risk of venous thromboembolism (VTE) - deep vein thrombosis or pulmonary embolism. In the conducted studies, a 2-3 fold increase in the risk of VTE during HRT was established. It has been established that for 5-year period in non-treated patients, the number of cases of VTE is about 3 per 1000 women aged 50-59 years and 8 per 1000 at the age of 60-69 years. It is estimated that in healthy women who underwent a 5-year course of HRT, the number of additional cases of VTE for 5 years is 2-6 (on average 4) per 1000 women aged 50-59 years and 5-15 (an average of 9 ) per 1,000 women aged 60-69 years. The probability of occurrence of VTE is greater in the first year of HRT than in the following. As a rule, the risk factors for venous thromboembolism include cases of VTE in the anamnesis (including in the immediate family) and the corresponding changes in the coagulogram, significant obesity (body mass index> 30 kg / m), systemic lupus erythematosus. There is no consensus on the possible role of varicose veins in the development of VTE. HRT may increase the risk. It is necessary to analyze all cases of thromboembolism and / or spontaneous abortions in a personal or family anamnesis, to exclude a predisposition to thrombophilia.Until the appropriate examination is carried out, HRT is contraindicated. The appointment of HRT to women taking anticoagulants is only possible taking into account the benefit / risk ratio of HRT use. The risk of VTE may temporarily increase with prolonged immobilization, including due to trauma, surgical intervention, in the postoperative period. When planning operations, it is necessary to consider the desirability of terminating HRT 4-6 weeks prior to intervention in each specific case. Treatment should not be resumed until the coagulogram is normalized and mobility restored. If VTE develops after the start of treatment, HRT should be discontinued. The patient should suspend HRT and immediately inform their attending physician if symptoms such as soreness and / or swelling of the lower limb, sudden chest pain, shortness of breath occur. Cardiac ischemia

    Conducted randomized controlled studies did not reveal a reduction in the incidence of cardiovascular disease in the context of continuous combination therapy with conjugated estrogens and medroxyprogesterone acetate (MPA).Data from two large clinical trials (WHI and HERS - "Heart and replacement therapy with estrogen / progesterone") showed a possible increase in the risk of developing cardiovascular diseases during the first year of treatment and the lack of a common clinical advantage. To evaluate other drugs for HRT, there is a limited number of randomized controlled trials; studying the impact on cardiovascular morbidity and mortality. Therefore, it is not clear whether these data also apply to other HRT preparations.

    Violation of cerebral circulation / stroke

    In a large randomized clinical trial of WHI an increase in the risk of cerebrovascular accident in healthy women with combined HRT (KLE + MPA) has been established. So, in the absence of HRT, the number of cases of cerebral circulation impairment per 1000 women within 5 years was about 3 - at the age of 50-59 years and about 11 - at the age of 60-69 years. For 1000 women who used conjugated estrogens and MPA during. 5 years, the number of additional cases of cerebral circulation disorder ranged from 0 to 3 (on average 1) - at the age of 50-59 years and 1-9 (on average 4) - at the age of 60-69 years. It is not known whether such an increase in risk extends to other HRT preparations.

    Ovarian Cancer

    According to some epidemiological studies, the use of estrogen in the form of monotherapy or in combination with progestogen for 5-10 years is accompanied by an increased risk of ovarian cancer.

    Other states

    Estrogens can lead to fluid retention in the body, which can worsen the condition of patients with impaired heart or kidney function. When taking Eviana ® in the terminal stage of renal failure, the level of circulating active components increases.

    Also, women with hypertriglyceridemia in the anamnesis are subject to a thorough examination and observation in the HRT process, since in the treatment with estrogens, a significant increase in triglyceride levels in the plasma, leading to pancreatitis, is possible.

    Estrogens increase the concentration of thyroxin-binding globulin, which leads to an increase in the total concentration of circulating thyroid hormones, determined by the content of protein-bound iodine, thyroxine (by column chromatography or radioimmunoassay), triiodothyronine (in radioimmunoassay).The concentrations of free thyroxin and triiodothyronine remain unchanged.

    Concentrations of other binding proteins of blood serum can be increased, incl. corticoid-binding globulin and globulin binding sex hormones, which leads to an increase in the concentration of circulating corticosteroids and sex hormones. Concentrations of free or biologically active hormones do not change.

    The concentration of other plasma proteins, angiotensinogen / renin, alpha1-antitrypsin, ceruloplasmin, can also increase.

    There is insufficient evidence to improve cognitive function. Moreover, with behavior WHI - studies showed an increased risk of possible dementia in combination (CLA + MPA) HRT in women over 65 years of age. It is not known whether this applies to other HRT preparations and / or HRT in younger postmenopausal women.

    Eviana® contains lactose. Before prescribing this drug to patients with rare hereditary diseases - congenital lactase deficiency, lactose intolerance and glucose-galactose malabsorption, the severity of this condition should be carefully assessed.If the drug is prescribed for such patients, they should be under careful medical supervision.

    Effect on the ability to drive transp. cf. and fur:

    Unknown.

    Form release / dosage:

    Tablets, film-coated, 0.5 mg / 0.1 mg.

    Packaging:

    28 tablets, film-coated, packed in a plastic calendar disk. 1 calendar disc in a cardboard box with instructions for use.

    Packing with a calendar disk of 28 tablets consists of three parts:

    Basis of colored opaque polypropylene Lid in the form of a circle of transparent polystyrene Central dial of colored opaque polystyrene.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C. Do not store in the refrigerator.

    Keep out of the reach of children.

    Shelf life:

    30 months.

    Do not use after expiry date.

    Terms of leave from pharmacies:On prescription
    Registration number:PL-000749
    Date of registration:29.09.2011
    Date of cancellation:2016-09-29
    The owner of the registration certificate:Novo Nordisk A / SNovo Nordisk A / S Denmark
    Manufacturer: & nbsp
    Representation: & nbspNOVO NORDISK TOVNOVO NORDISK TOVDenmark
    Information update date: & nbsp01.10.2015
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