CleiGest® (Kliogest®)

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Active substanceEstradiol + Norethisterone acetateEstradiol + Norethisterone acetate
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  • CleiGest®
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    Novo Nordisk A / S     Denmark
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    GEDEON RICHTER, OJSC     Hungary
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    Novo Nordisk A / S     Denmark
    • Dosage form: & nbspfilm-coated tablets
    Composition:

    1 tablet contains:

    active substances: Estradiol (in the form of estradiol hemihydrate) 2 mg and norethisterone 1 mg;

    Excipients: lactose monohydrate - 37.4 mg; corn starch - 37.4 mg; gelatin - 1.0 mg; talc - 0.8 mg; magnesium stearate - 0.4 mg;

    film sheath: hypromellose - 0.821 mg; triacetin - 0.043 mg.

    Description:

    Round biconvex tablets of white color, film-coated, with engraving "NOVO 281".

    Pharmacotherapeutic group:The antimycotactic means combined (estrogen + gestagen)
    ATX: & nbsp

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

    Pharmacodynamics:

    A combined preparation containing estrogen and progestogen for continuous hormone replacement therapy (HRT).

    Estradiol: synthetic 17β-Extradiol, is chemically and biologically identical to human endogenous estradiol.Eliminates estrogen deficiency in postmenopausal women and softens the symptoms of menopause. Also prevents the reduction of bone mass during the 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 the symptoms of menopause occurs within the first few weeks of treatment.

    Cliogest® is a combination drug for continuous hormone replacement therapy (HRT), which is prescribed to avoid the withdrawal of regular bleeding associated with cyclic or sequential HRT.

    Amenorrhea (cessation of regular menstrual bleeding and spotting discharge) occurs in 94% of women during 10-12 months of treatment. Menstruation bleeding and / or the appearance of smearing excretions were observed in 30% of women during the first three months of treatment and in 6% in the period from 10 to 12 months of treatment.Deficiency of estrogen during the menopause is associated with an increase in the rate of bone tissue renewal and a decrease in bone mineral density. The effect of estrogens on bone mineral density is dose-dependent. It is believed that this effect persists as long as the treatment continues. After the termination of HRT, the decrease in bone mass occurs in the same degree as in women who have not undergone treatment. Study WHI and meta-analyzes of various 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 caused by 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 effects of Cleigoest® on the mineral density of bones were shown with the participation of women in menopause (n = 327, including 48 women receiving Cleiopester®). All women received an additional 1000 mg of calcium daily.In women taking Cleiopest®, the loss of bone mass in the lumbar spine, hips, radius and throughout the body was significantly lower compared to women taking placebo with calcium supplementation. After 2 years of treatment, women who have bone mineral density in the lumbar region spine, in the neck of the femur and the femoral spit survived or increased during the treatment with Cliogest®, were 91%.

    Pharmacokinetics:

    After oral administration 17β-estradiol in micronized form occurs its rapid absorption in the gastrointestinal tract. Primary metabolism 17β-estradiol in the body is carried out in the liver and other organs of the digestive system. A maximum plasma concentration of approximately 44 pg / ml (30-53 pg / ml) is achieved 6 hours after the administration of one Cleiopester® tablet. Half-life 17β-Extradiol is about 18 hours. It circulates in the blood as a complex with globulin, binding sex hormones SHGG (37%), and albumin (61%), and only 1-2% remains unbound. Metabolism 17β-estradiol occurs mainly in the liver and intestines,as well as in target organs and includes the formation of less active and inactive metabolites, including estrone, catechol estrogens and various estrogen sulfates and glucuronides.

    Estrogens are excreted together with bile, where they are partially hydrolyzed and again enter the intestinal-hepatic blood flow (recirculation), and the bulk of estrogens is excreted from the body together with urine in a biologically inactive form.

    After oral administration norethisterone rapidly absorbed and converted into norethisterone (NET). The primary metabolism of norethisterone is also carried out in the liver and other gastrointestinal organs. The maximum plasma concentration, approximately 9 ng / ml (6-11 ng / ml), is achieved 1 hour after taking 1 mg. The half-life is approximately 10 hours. NET binds to SHBG (36%) and albumin (61%). The most important metabolites of NET are isomers of 5α- dihydro-NET and tetrahydro-NET, which are excreted mainly with urine in the form of sulfate or conjugates of glucuronides.

    In elderly people, pharmacokinetic studies have not been conducted.

    Indications:

    Replacement hormone therapy (HRT) in women with symptoms of estrogen deficiency that have been in the postmenopausal period for more than a year.

    Prevention of osteoporosis in postmenopausal women in the presence of a high risk of fracture in those patients who do not tolerate or which are contraindicated in other drugs intended for the prevention of osteoporosis.

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

    Contraindications:

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

    - established or suspected estrogen-dependent tumor (including endometrial cancer);

    - pathological hemorrhages from the genitals of unclear etiology;

    - untreated endometrial hyperplasia;

    - recent or in active phase venous thromboembolic diseases (deep vein thrombophlebitis, thrombosis or pulmonary embolism);

    - recently transferred or in the active phase arterial thromboembolic diseases (including angina pectoris, myocardial infarction);

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

    - congenital lactase deficiency, lactose intolerance, glucose-galactose malabsorption;

    - breast cancer (established in the anamnesis, as well as a suspicion of it);

    - porphyria.

    Carefully:

    If the patient has any of the diseases listed below and / or if the disease has occurred earlier and / or worsened during pregnancy or previous hormonal treatment, then the patient must be under close medical supervision. It should be taken into account that these diseases can recur or worsen during the treatment with Cliogest®, especially in the following diseases:

    - Leiomyoma (uterine fibroadenoma) or endometriosis.

    - Risk factors for thromboembolism or thromboembolism in the anamnesis (see below).

    - Risk factors for the development of estrogen-dependent tumors (for example, the presence of relatives of the first degree of kinship, suffering from breast cancer).

    - Arterial hypertension.

    - Diseases of the liver (including liver adenoma).

    - Diabetes mellitus with or without vascular disease.

    - Chololithiasis.

    - Migraines or severe headaches.

    - Systemic lupus erythematosus.

    - Endometrial hyperplasia in the anamnesis (see below).

    - Epilepsy.

    - Bronchial asthma.

    - Otosclerosis.

    Pregnancy and lactation:

    Reception Cleigoest® is not indicated during pregnancy.

    If pregnancy occurs against the background of treatment with Cleigoest®, then treatment should be immediately stopped.

    Data based on a limited number of pregnancies, during which patients took hormonal drugs, indicate the adverse effect of norethisterone on the fetus. At doses exceeding those commonly used in HRT, masculinization of female fetuses was observed.

    The results of most of the epidemiological studies conducted to date, relating to the unintentional effects on the fetus of combined estrogen and progestogen compositions, indicate the absence of teratogenic and fetotoxic effects.

    Reception Cleigoest® is not indicated during breastfeeding.

    Dosing and Administration:

    Cliogest® is a drug for permanent, consistent use in HRT in women with an intact uterus. Take 1 tablet orally 1 time per day without interruption, preferably at the same time each day.

    To start and continue (resume) the treatment of menopausal symptoms, the lowest effective dose should be used with the shortest duration (see "Special instructions").

    Women with amenorrhea who do not take HRT drugs or women who switch from another combined continuous HRT course can begin treatment with Cliogest® on any convenient day. Women who undergo successive regimens of HRT should be treated immediately after they have resumed bleeding.

    If the patient forgot to take one pill, then the forgotten pill should not be taken. Bypassing the drug may increase the chance of resuming vaginal bleeding and the appearance of smearing vaginal discharge.

    In all cases, a careful assessment of the risk-benefit ratio should be made at least once a year, and continued HRT only as long as the benefits of using the drug exceed the risk of associated side effects.

    Side effects:

    Clinical experience

    The side effects most frequently encountered in clinical trials of Cleigoest® include vaginal bleeding and pain / tenderness in the mammary glands, reported by approximately 10% to 30% of patients. Vaginal bleeding usually occurred during the first months of treatment.The pain in the mammary glands usually disappeared after several months of treatment. All adverse events observed in randomized clinical trials of Cleigoest® or similar HRT with a higher frequency than placebo, and which may be associated with HRT, are presented below.

    Violations of the genitals and mammary gland

    Very often (> 1/10): pain or pain in the mammary glands; vaginal bleeding.

    Often (> 1/100; <1/10): swelling or enlargement of the mammary glands; increase or relapse of uterine fibroadenoma or the development of a primary uterine fibroadenoma.

    Infections and invasions

    Often (> 1/100; <1/10): vaginal candidiasis or vaginitis.

    Disorders from the metabolism and nutrition

    Often (> 1/100; <1/10): fluid retention.

    Disorders of the psyche

    Often (> 1/100; <1/10): Depression or worsening of depression.

    Infrequently (> 1/1 000; <1/100): nervousness.

    Disturbances from the nervous system

    Often (> 1/100; <1/10): headache, migraine, or exacerbation of migraine.

    Disorders from the gastrointestinal tract

    Often (> 1/100; <1/10): nausea, abdominal pain, bloating, or abdominal discomfort.

    Infrequently (> 1/1 000; <1/100): flatulence or bloating.

    Disturbances from musculoskeletal and connective tissue

    Often (> 1/100; <1/10): back pain; cramps in the calf muscles.

    General disorders and disorders at the site of administration

    Often (> 1/100; <1/10): peripheral edema; increase in body weight.

    Infrequently (> 1/1 000; <1/100): no effect of the drug.

    Immune system disorders

    Infrequently (> l/l 000; <1/100): hypersensitivity reactions.

    Vascular disorders

    Infrequently (> l / l 000; <1/100): thrombophlebitis of superficial veins.

    Rarely (> l/l 0000; <1/1000): pulmonary embolism; deep vein thrombophlebitis.

    Disturbances from the skin and subcutaneous tissues

    Infrequently (> l/l 000; <1/100): alopecia, hirsutism, or acne; an itchy rash or hives.

    Experience in the post-marketing use of the drug

    In addition to the aforementioned adverse reactions that occur with the use of Cleigoest®, the side reactions listed below, which are generally believed to relate to Cleigoest®, are listed below.

    The incidence of such adverse reactions can be classified as very rare (<1/10000 patient-years):

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

    - Disorders of the psyche: insomnia, anxiety, changes in libido

    - Disturbances from the nervous system: dizziness, impaired cerebral circulation

    - Disturbances on the part of the organ of vision: visual impairment

    - Vascular disorders: exacerbation of hypertension

    - Heart Disease: myocardial infarction

    - Disorders from the gastrointestinal tract: dyspepsia, vomiting

    - Disorders from the liver and biliary tract: cholecystitis, cholelithiasis, exacerbation of cholelithiasis

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

    - Violations from the genitals and the breast: endometrial hyperplasia, vulvovaginal itching

    - General disorders, and disorders at the site of administration: weight loss, increased blood pressure

    Mammary cancer

    According to a large number. epidemiological studies and one randomized, placebo-controlled study conducted by the Women's Right to Health organization (WHI, Women’s Health Initiative study), the overall risk of developing breast cancer increases with the duration of HRT.

    The relative risk assessment, obtained by re-analysis of the original data 51 epidemiological studies (in which more than 80% of women undergoing HRT with estrogen only), and the result of the analysis of the MWS, Million Women Study, are almost the same: 1.35 (95% confidence interval, 1.21-1.49) and 1.30 ( confidence interval 95%, 1.21-1.40), respectively.

    The results of individual epidemiological studies indicate, in general, a higher risk of developing breast cancer in women undergoing combined hormone replacement therapy (estrogen plus progestogen) compared with those taking estrogens alone.

    Research data MWS show that compared to women who have never undergone HRT, the use of different types of combined (estrogen plus progestogen) HRT is associated with a higher risk of developing breast cancerRR = 2.00, at 95% confidence interval: 1.88-2.12) compared with those who took only estrogens (RR = 1.30, with 95% confidence interval 1.21-1.40) or took tibolone (RR= 1.45, 95% confidence interval: 1.25-1.68).

    According to the research WHI for all women who underwent a course of combined HRT with estrogens plus progestogen (CEE + MRA) for 5.6 years, the risk was 1.24 (95% confidence interval: 1.01-1.54) compared with placebo.Absolute risk indicators calculated from data MWS and WHI, are presented below:

    Using the known proportion of the disease of women with breast cancer in developed countries, in the study MWS found that:

    - Breast cancer is diagnosed in about 32 out of 1,000 women who do not use HRT, between the ages of 50 and 64 years.

    - For 1000 women undergoing or recently undergoing HRT, the number of additional cases of breast cancer development during the relevant period will be:

    With substitution therapy only estrogen

    • between 0 and 3 (the most accurate estimate = 1.5) with a 5-year course
    • between 3 and 7 (the most accurate estimate = 5) with a 10-year course

    When combined, estrogen plus progestogen, HRT

    • between 5 and 7 (the most accurate estimate = 6) with a 5-year course
    • between 18 and 20 (the most accurate estimate = 19) with a 10-year course.

    In the study conducted WHI, it was found that after a course of treatment of 5.6 years in women between the ages of 50 and 79 years, the development of 8 additional cases of invasive breast cancer per 10 000 women can be due to a combined, estrogen plus progestogen, HRT (CEE + MRA). Based on the calculations carried out in the study, it is established that:

    - For 1,000 women taking placebo, approximately 16 cases of invasive breast cancer can be diagnosed within 5 years.

    - For 1000 women who took a combined, estrogen plus progestogen, HRT (CEE + MRA), the number of additional cases could range from 0-9 (the most accurate estimate = 4) in 5 years of use.

    The number of additional cases of breast cancer in women who take HRT is similar for women who started HRT, regardless of age at the start of therapy (between 45 and 65 years of age) (see "Special instructions").

    Endometrial cancer

    The risk of endometrial hyperplasia and endometrial cancer in women with an intact uterus increases with the duration of intake of exclusively estrogen. According to epidemiological studies on the most accurate risk assessment, it is expected that approximately 5 out of 1000 women who do not undergo HRT can be diagnosed with endometrial cancer between the ages of 50 and 65 years. Depending on the duration of treatment and the dose of estrogen, the increased risk of developing endometrial cancer among patients taking exclusively estrogen, according to available data, varies from 2 to 12 times, compared to patients not taking estrogens.The addition of progestogen to monotherapy with estrogen alone significantly reduces this risk.

    Other adverse reactions reported in connection with treatment with the estrogen / progestogen combination are:

    - Disturbances from the skin and subcutaneous tissues: chloasma, exudative polymorphic erythema, erythema nodosum, vascular purpura.

    - Possible dementia (see "Special instructions").

    Overdose:

    Overdose may cause nausea and vomiting.

    Treatment - symptomatic.

    Interaction:

    Metabolism of estrogens and progestogens can increase with the concomitant use of substances known as inducers of drug metabolism isozymes, in particular cytochrome P450 isoenzymes such as antiepileptic agents (eg, phenobarbital, phenytoin, carbamazepine) and antibiotics (for example, rifampicin, rifabutin, nevirapine, efavirenz). Although ritonavir and nelfinavir are known as potent inhibitors, with concomitant use with steroid hormones, they exhibit stimulating properties on the metabolism of estrogens and progestogens.

    Herbal preparations containing St. John's Wort (perforated)Hypericum perforatum), can also stimulate the metabolism of estrogens and progestogens.

    Clinically, increased metabolism of estrogens and progestogens can lead to a decrease in the effectiveness of the action and changes in the nature of uterine bleeding.

    Drugs that inhibit the activity of hepatic microsomal enzymes of drug metabolism, for example, ketoconazole, can increase the concentration of the active substances of Cleigoest®.

    Special instructions:

    When deciding whether to use HRT for the treatment of postmenopausal symptoms, it should only be started if there are symptoms that reduce the patient's quality of life. The frequency of medical examinations is individual, but at least 1 time in 6 months - to assess the need for further HRT. In all cases, it should at least continue HRT only as long as the advantage outweighs the risk.

    Medical examination / control

    Before starting or resuming HRT, the patient's medical history and family history should be studied. In this case, you should conduct a physical examination (including pelvic organs and mammary glands) and take into account contraindications and special precautions during use.During the treatment it is recommended to conduct periodic examinations of the patient, the frequency 'and the volume of which must be selected for each patient individually.

    Women should be advised to report their observed changes in the mammary glands to the doctor or nurse (see below section "Breast Cancer"). In accordance with the currently accepted screening practice, examinations, including mammography, adjusted according to individual clinical indications should be carried out.

    Reasons for immediate withdrawal of treatment

    Treatment should be interrupted if a contraindication is found in the following situations:

    - Jaundice or liver dysfunction

    - Significant increase in blood pressure

    - A new attack of a migraine headache

    - Pregnancy

    Endometrial hyperplasia

    The risk of developing hyperplasia and endometrial cancer increases when certain estrogens are administered for a long period of time (see "Side effect"). The addition of progestogen to women who have not undergone hysterectomy for at least 12 days per cycle significantly reduces this risk.The development of bleeding and the appearance of spotting can occur during the first months of treatment. If the development of bleeding or the appearance of smearing secretions occurs some time after the start of treatment or continues after discontinuation of treatment, then the cause of this phenomenon should be investigated, for which an endometrial biopsy is done to exclude the possibility of malignant formation in the endometrium.

    Mammary cancer

    Randomized, placebo-controlled trial WHI (Women’s Health Initiative study), as well as epidemiological studies, including MWS (Million Women Study), showed that there is an increased risk of developing breast cancer in women taking estrogens, estrogen-progestogen combinations or tibolone in the process of HRT for several years (see "Side effects"). In all cases of HRT over several years the risk is higher than normal and it increases with the duration of admission, but returns to its initial state for several years (maximum five) after discontinuation of treatment.

    In the study MWS the relative risk of breast cancer,associated with the administration of conjugated equine estrogens or estradiol (E2), was higher when the progestogen was added either sequentially or permanently, regardless of the type of progestagen. Data on the existence of a difference in risk for different routes of drug intake are not available. In the study WHI Continuous use of the combined preparation on the basis of conjugated equine estrogen and medroxyprogesterone acetate (MPA) was associated with the development of breast cancer, which was slightly larger in size, and metastases to regional lymph nodes were more frequent than in placebo. In HRT, especially with the combined treatment of estrogen-progestogen, there is an increase in the density of mammographic images, which can make it difficult to radiological detection of breast cancer.

    Venous thromboembolism

    HRT is associated with a higher relative risk of venous thromboembolism (VTE), namely vein thrombosis or pulmonary embolism.

    In one randomized controlled trial and in epidemiological studies, a two to threefold increase in the risk for patients using HRT was found in comparison with those who did not undergo this course of treatment.It was found that for women who did not undergo this course of treatment, the number of cases of VTE occurring over a 5-year period is approximately 3 per 1000 women aged 50-59 years and 8 per 1000 women aged 60-69 years. According to a rough estimate in healthy women who used HRT for 5 years, the number of additional cases of VTE for 5 years is 2-6 (the most accurate estimate = 4) per 1,000 women aged 50-59 years and 5-15 (the most accurate estimate = 9) per 1,000 women aged 60-69 years. The onset of this event is more likely in the first year of HRT than in the following period.

    The generally recognized risk factors for developing VTE include a severe degree of obesity in the personal or family history (body mass index> 30 kg / m2) and systemic lupus erythematosus. There is no consensus on the possible role of varicose veins in the development of VTE.

    Patients with a history of VTE or known thrombophilic status have an increased risk of developing VTE. HRT may increase the risk. It is necessary to investigate serious cases of thromboembolism or recurring cases of spontaneous abortion in a personal or family anamnesis in order to exclude a predisposition to thrombophilia.Until a thorough evaluation of thrombophilic factors or anticoagulant treatment is initiated, the appointment of HRT to such patients should be considered contraindicated. For the appointment of HRT to those women who are already taking anticoagulants, you must carefully weigh the benefit / risk ratio of HRT use. The risk of VTE may temporarily increase with prolonged immobilization, extensive trauma or radical surgery. In the postoperative period careful attention should be given to preventive measures to prevent cases of VTE. If the planned operation entails a state of prolonged immobilization, in particular, it may occur with abdominal intervention or orthopedic surgery of the lower limbs, consideration should be given to the possibility temporarily, for 4-6 weeks before surgery, suspend HRT. Treatment should not be resumed until the woman has acquired full mobility. If VTE develops after the start of treatment, medication should be discontinued. Immediately, as soon as the patient noticed a possible thromboembolic symptom (painful edema of the lower limb,sudden chest pain, shortness of breath), he should inform his doctor about it.

    Cardiac ischemia

    Based on randomized controlled trials, conclusions can not be drawn about the benefits of continuous use of equine estrogens and MPA. Two large clinical studies (WHI [Women’s Health Initiative study] and HERS [Heart and oestrogen/progestin Replacement Study]) showed the possibility of an increased risk of cardiovascular morbidity in the first year of the combination and generally showed no benefit. For other HRT preparations, only limited data are available from the results of randomized, controlled trials evaluating their effect on the incidence of the cardiovascular system or mortality.

    Therefore, it remains unclear whether this influence also extends to other HRT preparations.

    Violation of cerebral circulation

    A large randomized, clinical trial (WHI) identified as a secondary result an increased risk of developing ischemic stroke in healthy women who underwent continuous treatment with a combination of equine estrogens and MPA.According to the evaluation, in women who have not undergone HRT, the number of cases of cerebral circulation that may occur during 5 years is approximately 3 per 1,000 women aged 50-59 years and 11 cases per 1000 women aged 60-69 years . In those women who took a combination of conjugated estrogens and MPA for 5 years, the number of additional cases of cerebral circulation disorder ranges from 0 to 3 (the most accurate estimate is 1) per 1,000 women aged 50-59 years and 1-9 cases per 1000 women aged 60-69 years (the most accurate estimate = 4). Data on whether this increased risk for other HRT drugs are unknown.

    Ovarian Cancer

    Prolonged use (at least for 5-10 years) of only estrogen preparations for HRT in women with a distant uterus is associated in some epidemiological studies with an increased risk of ovarian cancer. It remains unclear whether prolonged use of combined HRT drugs increases the risk of ovarian cancer compared to the risk associated with the use of only estrogen-containing drugs.

    Other states

    Estrogens can lead to fluid retention in the body, and therefore patients with dysfunction of the cardiovascular system or kidneys should be closely monitored.Patients with terminal renal insufficiency should be closely monitored, as the level of circulating active components is expected to increase with the use of Cliogest®.

    Women with hypertriglyceridemia who are history should be closely monitored in HRT, as there are reports that, in this condition, rare cases of a significant increase in triglyceride levels in plasma that lead to pancreatitis are noted in estrogen treatment.

    Estrogens increase the concentration of thyroxine-binding globulin, which leads to an increase in the total concentration of circulating thyroid hormones, determined by the content of protein-bound iodine, the concentration of thyroxine (determined by column chromatography or radioimmunoassay) or triiodothyronine. (determined by 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, globulins, binding sex hormones,which leads to an increase in the concentration of circulating corticosteroids and sex hormones, respectively. Concentrations of free or biologically active hormones do not change.

    The concentration of other plasma proteins (angiotensinogen / renin substrate, alpha 1-antitrypsin, ceruloplasmin) can also increase.

    There is no conclusive evidence of improvement cognitive function. There is some evidence in the WHI study of the existence of the risk of possible dementia in women who, after age 65, have begun to take a combined drug containing equine estrogens and IPA. It is not known whether this applies to women at a younger age in the postmenopausal state or to other HRT preparations.

    Cleiopest® tablets contain lactose, so it should not be taken to patients with such rare congenital diseases as glucose intolerance and galactose, lactase deficiency, and galactose malabsorption syndrome.

    Cliogest® does not have a contraceptive effect.

    Effect on the ability to drive transp. cf. and fur:Unknown.
    Form release / dosage:Tablets, film-coated, 2 mg of estradiol + 1 mg of norethisterone acetate.
    Packaging:

    For 28 tablets in a plastic calendar disk.

    On 1 calendar disk together with the instruction on application in a cardboard bundle.

    Storage conditions:

    Store at a temperature not exceeding 25 ° C.

    Do not freeze.

    Keep the disc with tablets in a cardboard box.

    Keep out of the reach of children.

    Shelf life:

    4 years.

    Do not use after expiry date.

    Terms of leave from pharmacies:On prescription
    Registration number:П N013451 / 01
    Date of registration:28.09.2011
    Expiration Date:Unlimited
    Date of cancellation:2017-01-31
    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: & nbsp29.01.2018
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