Divigel (Divigel®)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceEstradiolEstradiol
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  • Divigel
    gel externally 
    Orion Corporation     Finland
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    • Dosage form: & nbspgel for external use
    Composition:

    Active ingredient estradiol hemihydrate, respectively. Estradiol 1 mg;

    Excipients: carbomers (carbopol 974 P), trolamine, propylene glycol, ethyl alcohol (96%), water purified to 1.0 g.

    Description:ABOUTunconfined opalescent gel.

    Pharmacotherapeutic group:Estrogen
    ATX: & nbsp

    G.03.C.A.03   Estradiol

    Pharmacodynamics:The active substance of the preparation Divigel, synthetic 17-estradiol, is chemically and biologically identical to the endogenous human estradiol produced in the body of ovarian women, from the first menstruation to the menopause. Estrogens form a complex with specific receptors found in the cells of various target organs - in the uterus, vagina, urethra, breast, liver, hypothalamus, pituitary. The receptor-ligand complex interacts with the estrogen-effector elements of the genome and specific intracellular proteins that induce the synthesis of i-RNA, proteins and the release of cytokines and growth factors.

    Has a feminizing effect on the body.Stimulates the development of the uterus, fallopian tubes, vagina, stroma and ducts of the mammary glands, pigmentation in the nipple and genital area, the formation of secondary sex characteristics by the female type, the growth and closure of the epiphyses of long tubular bones. Rejection facilitates timely and regular endometrial bleeding, in high concentrations causes endometrial hyperplasia, suppresses lactation, inhibits bone resorption, stimulate the synthesis of several transport proteins (thyroxine-binding globulin; transcortin; transferrin binding globulin sex Gaumont) fibrinogen. Has procoagulant action, increases the synthesis of hepatic vitamin K-dependent coagulation factors (II, VII, IX, X), reduces the concentration of antithrombin III.

    It increases concentration of thyroxine in the blood, iron, copper and others. It has antiatherosclerotic action, increases the amount of HDL, LDL, and reduces cholesterol, triglycerides concentration increases. Modulating progesterone receptor sensitivity and sympathetic regulation of smooth muscle tone, stimulates transition intravascular fluid in the tissue and causes a compensatory delay sodium and water.In large doses, it prevents the degradation of endogenous catecholamines, competing for the active receptors of catechol-O-methyltransferase.

    After menopause, only a small amount of estradiol (from estrone in the liver and adipose tissue) is formed in the body. The decrease in the content of estradiol produced in the ovaries is accompanied in many women by vasomotor and thermoregulatory instability ("hot flushes" to the skin of the face), sleep disorders, and progressive mucosal atrophy organs of the genitourinary system.

    Due to estrogen deficiency, osteoporosis develops (mainly the spine). After ingestion, a greater amount of estradiol before it enters the bloodstream is metabolized in the lumen (microflora) and intestinal wall, as well as in the liver (which leads to unphysiologically high concentrations of estrone in plasma, and with prolonged therapy to cumulation of estrone and estrone sulfate) . The effects of the accumulation of these metabolites in the body for a long time have not yet been elucidated. It is known that oral administration of estrogens causes an increase in protein synthesis (incl.renin), which leads to an increase in blood pressure (BP).

    Pharmacokinetics:The preparation is a gel for external use on an alcohol-based basis. When applied to the skin, alcohol evaporates rapidly and estradiol penetrates through the skin, getting into the circulatory system. Application of the preparation Divigel to an area of ​​200-400 cm2 (the size of one or two palms) does not affect the amount of absorbed estradiol. However, if the DIVIGEL preparation is applied over a large area, the degree of absorption is significantly reduced. In some ways estradiol is retained in the subcutaneous tissues, from where it is gradually released into the bloodstream.

    Transdermal application allows to avoid the first stage of hepatic metabolism, due to which the variations in the concentration of estradiol in the blood plasma with the use of the preparation Divigel are insignificant.

    Transdermal administration of 0.5, 1.0 and 1.5 mg of estradiol (0.5, 1.0 and 1.5 g of the DIVIGEL preparation) is accompanied by an average maximum concentration of Cmax in plasma of 143, 247 and 582 pmol / l, respectively. Average concentrations of Caverage during the interval between doses are 75, 124 and 210 pmol / l, respectively. Mean minimum concentrations Cmin are 92, 101 and 152 pmol / l, respectively. Against the background of using the Divigel, the ratio of estradiol / estrone is maintained at a level of 0.4 to 0.7, whereas when oral estrogens are used, it usually decreases to <0.2.

    The bioavailability of estradiol in the use of the DIVIGEL preparation is 82%.

    Metabolism and excretion of estradiol in transdermal administration is similar to the metabolism of natural estrogens.

    Do not cumulate.

    Indications:

    Hormone replacement therapy with symptoms of estrogen deficiency; Treatment of climacteric syndrome associated with natural or artificial menopause, which developed as a result of surgical intervention.

    Contraindications:

    -​ Hypersensitivity to estradiol and / or any of the excipients of the drug.

    -​ Breast cancer (diagnosed, suspected or in history).

    -​ Diagnosed or suspected estrogen-dependent malignant tumors of the genital organs (including, endometrial cancer).

    -​ Bleeding from the vagina of an unclear etiology.

    -​ Untreated endometrial hyperplasia.

    -​ Revealed acquired or hereditary predisposition to venous or arterial thrombosis, including an antithrombin III deficiency, protein C deficiency, protein S deficiency).

    -​ Venous thrombosis and thromboembolism are currently or in history (including thrombosis and deep vein thrombophlebitis, pulmonary embolism).

    -​ Active or recently transferred arterial thromboembolic diseases (including angina pectoris, myocardial infarction).

    -​ Congenital hyperbilirubinemia (syndromes Gilbert, Dubin-Johnson, Rotor).

    -​ Benign or malignant liver tumors are currently or in the anamnesis.

    -​ Cholestatic jaundice or severe cholestatic itching (including an increase in their manifestations during an earlier pregnancy or on the background of taking sexual drugs).

    - Acute liver disease or a history of liver disease, if the results of functional liver tests have not returned to normal.

    "Porphyria."

    Carefully:Carefully Diphygel should be used for such diseases as uterine myoma, endometriosis, the presence of risk factors for thromboembolic disorders, the presence of risk factors for estrogen-dependent tumors (breast cancer in first-line relatives), arterial hypertension, liver diseases (including,adenoma of the liver) with normal liver function tests, diabetes mellitus with or without diabetic angiopathy, cholelithiasis, migraine or severe headache, systemic lupus erythematosus, endometrial hyperplasia in the anamnesis, epilepsy, bronchial asthma, otosclerosis, heart failure, renal failure, ischemic disease heart disease (IHD), sickle cell anemia, history of history of Chloasma, history of hypertriglyceridemia, hereditary angioedema.

    Experience in women over 65 is limited.

    Pregnancy and lactation:

    The drug Divigel is not indicated for use during pregnancy. If during pregnancy with the drug Divigel becomes pregnant, the treatment should be stopped immediately.

    The results of most epidemiological studies conducted to date and concerning the accidental effects of estrogen on the fetus do not indicate a teratogenic or fetotoxic effect.

    The drug Divigel is not indicated for use during breastfeeding.

    Dosing and Administration:

    The drug Divigel is a gel for transdermal application.The drug Divigel can be used for long-term and cyclic therapy. The usual starting dose is 1.0 mg of estradiol (1.0 g of gel, respectively) per day, but the choice of the initial dose may be based on the severity of the symptoms. Depending on the clinical picture, the dose can be changed after 2-3 cycles individually from 0.5 g to 1.5 g per day, which corresponds to 0.5 to 1.5 mg of estradiol per day.

    At the beginning and continuation of the treatment of postmenopausal symptoms, the lowest effective dose should be administered during the least prolonged period.

    The use of the drug Divigel without the addition of progestogen is possible only in patients with a deleted uterus.

    Patients with an "intact" (unoperated) uterus during treatment with Dvigel are recommended to be prescribed gestagen - at least 12-14 consecutive days during a month or 28-day cycle. After the course of gestagen use, menstrual bleeding should occur. With extraordinary or prolonged uterine bleeding it is necessary to establish the cause of their occurrence.

    In women who underwent hysterectomy, the addition of progestogen in the absence of an anamnesis of endometriosis is not recommended.

    In women who did not previously use drugs for hormone replacement therapy (HRT), and in women who switch to the DIVIGEL preparation from a combined drug for HRT with a continuous regimen of treatment, the treatment with DIVIGEL can be started at any convenient day for the patient. In women switching to the DIVIGEL preparation with a continuous sequential HRT regimen, treatment should begin after the completion of the previous regimen.

    If the patient has forgotten to apply the gel, you should do this as soon as possible, however no later than within 12 hours from the time of application. If more than 12 hours have passed, the application of the DIVIGEL preparation should be postponed until the next time. With irregular use of the drug (missed doses), there may be "breakthrough" bleeding and "spotting" bleeding.

    Mode of application

    The gel is usually applied once a day to clean, dry skin of the lower part of the anterior wall of the abdomen, lumbar region, shoulders, forearms, or alternately on the right or left buttocks, alternating between application sites. The drug Divigel should not be applied to the mammary glands, face, genital area, or to irritated areas of the skin. The area of ​​application should be equal to 1-2 palms.After applying the drug, you should wait a few minutes until the gel dries (2-3 min). Place the application of the gel can not be rinsed for 1 hour. Avoid accidental contact with Divigel in the eyes. Wash hands immediately after applying the gel.

    Additional information for special groups of patients

    The experience of using the drug Divigel in women over 65 years is limited.

    Indications for use of the drug Divigel in children are absent.

    Side effects:

    During the first few months of treatment, there may be "breakthrough" bleeding, "spotting" bleeding and soreness or an increase in the mammary glands. As a rule, these effects are transient and usually disappear on the background of ongoing treatment. Undesirable drug reactions have been reported, in particular, in three Phase III clinical trials. The following are undesirable drug reactions noted in clinical trials (only those cases that were possibly associated with transdermal use of estradiol at a dose of 50 μg or 100 μg per day), as well as undesirable drug reactions observed in the post-marketing period.In general, it can be expected that adverse drug reactions may occur in 76% of patients. In clinical trials, local reactions and pain in the mammary glands occurred in more than 10% of patients.

    The frequency of side effects of the drug is assessed as follows:

    Frequent: 1/100, 1/10

    Infrequent: 1/1000, 1/100

    Rare: 1/10 000, 1/1000

    The frequency is unknown (noted in the post-marketing period).

    Benign, malignant and unspecified neoplasms (including cysts and polyps): infrequent - benign neoplasm of the breast, benign neoplasm of the endometrium; frequency unknown - myoma of the uterus.

    Disorders from the immune system: infrequent - hypersensitivity reactions; frequency unknown - exacerbation of hereditary angioedema.

    Disorders of nutrition and metabolism: frequent - edema, weight gain, weight loss; infrequently - increased appetite, hypercholesterolemia1.

    Mental disorders: frequent - Depression, nervousness, drowsiness; infrequent - anxiety, insomnia, apathy, emotional lability, impaired concentration, changes in libido and mood, euphoria1, agitation1.

    Nervous system disorders: frequent - headache, dizziness; infrequent - migraine, paresthesia, tremor1.

    Disorders from the side of the organ of vision: infrequent - visual impairment1, dry eye syndrome1; rare - intolerance to contact lenses.

    Disorders from the heart: infrequent - a feeling of palpitations.

    Violations from the vessels: frequent - "tides"; infrequently - increase of blood pressure1, superficial phlebitis1, purple1; rare - venous thromboembolism (including deep vein thrombosis of the lower limbs and small pelvis and pulmonary embolism); frequency unknown cerebral ischemic disorders.

    Disturbances from the respiratory system, chest and mediastinal organs: infrequent - dyspnea1, rhinitis1.

    Disorders from the gastrointestinal tract: frequent - nausea, vomiting, stomach cramps, flatulence; infrequent - constipation, indigestion1, diarrhea1, disorders of the rectum1; frequency unknown - Pain in the abdomen, bloating.

    Disorders from the liver and biliary tract: rare - violations of the liver, cholestasis; frequency unknown - cholestatic jaundice.

    Disturbances from the skin and subcutaneous tissues: infrequent - Acne, alopecia, dry skin, pathology of nails1, cutaneous nodules1, hirsutism1; rare - rash; frequency unknown - contact dermatitis, eczema.

    Disorders from the musculoskeletal and connective tissue: infrequent - pathology of the joints, muscle spasms.

    Disorders from the kidneys and urinary tract: infrequent - Frequent urination, urinary retention, incontinence1, cystitis1, change in color of urine1, hematuria.

    Disorders from reproductive system and mammary glands: frequent - Acyclic bleeding from the vagina or "smearing" bloody discharge, vaginal discharge, vulvovaginitis, menstrual irregularities, pain or tenderness of the mammary glands; infrequent - enlargement of mammary glands, tenderness in palpation of the mammary glands, endometrial hyperplasia, uterine disorders1; rare - dysmenorrhea, a condition reminiscent of premenstrual syndrome.

    General disorders and disorders at the site of administration: frequent - skin irritation, itching at the site of application, pain, increased sweating; infrequent - fatigue, asthenia1, fever1, influenza-like syndrome1, malaise1.

    Laboratory and instrumental data: infrequent - deviations from the norm of the results of laboratory tests1.

    1) Observed in clinical studies in isolated cases. Given the small size of the population (n = 611), based on these results, it is impossible to determine whether these phenomena were infrequent or rare.

    Against the background of treatment with estrogens / gestagens, there were other undesirable reactions:

    - Benign and malignant estrogen-dependent neoplasms, in particular, endometrial cancer.

    - Myocardial infarction and stroke.

    - Disorders from the skin and subcutaneous tissue: chloasma, erythema multiforme, erythema nodal, thrombocytopenic purpura.

    - There is an increased risk of developing dementia at the onset of HRT at the age of over 65.

    In women who use combined estrogen-progestational drugs for more than 5 years, there is an increased risk of diagnosing breast cancer by a factor of 2.

    Due to the content of propylene glycol in the formulation, Divigel can cause skin irritation.

    Risk of ovarian cancer

    The use of HRT in the form of estrogen monotherapy or combined estrogen-progestogen therapy was associated with a slightly increased risk of ovarian cancer (see section Special instructions).A meta-analysis of 52 epidemiological studies indicates an increased risk of ovarian cancer in women currently using HRT compared to women who have never taken HRT (RR 1.43, 95% CI 1.31-1.56). Among women aged 50 to 54 years who take HRT for 5 years, this results in approximately 1 additional case for 2000 women. Among women aged 50 to 54 who did not take HRT, approximately 2 women in 2000 had ovarian cancer diagnosed within 5 years.

    Overdose:

    Symptoms: pain in the mammary glands, a sense of anxiety, irritability, nausea, vomiting, in some cases - metrorrhagia.

    In case of transdermal administration, an overdose is unlikely. Treatment is symptomatic. The gel should be washed off the skin.

    Symptoms disappear when the dose decreases or when the drug is withdrawn.

    Interaction:

    Metabolism of estradiol is accelerated by simultaneous reception with barbiturates, tranquilizers (anxiolytics), narcotic analgesics, means for anesthesia, some antiepileptic drugs (carbamazepine, phenytoin), inducers of microsomal enzymes of the liver; herbal preparations containing St. John's Wort.

    The concentration of estradiol in the blood also decreases with the simultaneous use of phenylbutazone and certain antibiotics and antiviral drugs (ampicillin, rifampicin, rifabutin, nevirapine, efavirenz).

    Ritonavir and nelfinavir, also known as strong inhibitors, when combined with sex hormones, on the contrary, exhibit inducing properties.

    The effect of estradiol is enhanced by the intake of folic acid and thyroid hormone preparations.

    With transdermal administration, the effect of "primary" passage through the liver can be avoided, so the effect of preparations for HRT with transdermal application of estrogens, possibly to a lesser extent than with oral administration, depends on the effect of inducers of microsomal liver enzymes.

    In clinical practice, increased estrogen metabolism can lead to a weakening of the effect and changes in the character of uterine bleeding.

    Estradiol:

    -​ increases the effectiveness of lipid-lowering drugs;

    -​ weaken the effect of drugs of male sex hormones; hypoglycemic, diuretic, antihypertensive drugs and anticoagulants.

    Special instructions:

    In the treatment of postmenopausal symptoms, HRT should be started only if there are symptoms adversely affecting the quality of life. It should be at least once a year to conduct a detailed assessment of the risks and benefits and appoint HRT only if the benefit exceeds the risk.

    Data on the risks associated with HRT for the treatment of early menopause are limited. However, given the low absolute risk of HRT in young women, the ratio of benefits and risks in such women may be more favorable than in older women.

    Before starting or re-appointing HRT, you must collect a complete personal and family history. A medical examination should be conducted to identify possible contraindications and to observe the necessary precautions when taking the drug (including examination of pelvic organs and mammary glands). During the treatment it is recommended to conduct periodic examinations, the frequency and methods included in it are determined for each case individually. Studies, including mammography, should be conducted in accordance with accepted norms and adapted to the individual clinical needs of each individual case.

    During the patient's admission of drugs for HRT, a thorough evaluation of all the benefits and risks of therapy should be conducted.

    Conditions that require observation

    If any of the following conditions are present, previously met and / or worsened during pregnancy or previous hormonal therapy, the patient should be under constant medical supervision. It should be taken into account that these conditions can, in rare cases, recur or aggravate during treatment with DIVIGEL, in particular: uterine myoma or endometriosis; risk factors for thromboembolic disease; risk factors for estrogen-dependent tumors (presence of relatives of the first line of kinship with breast cancer); arterial hypertension; liver disease (eg, liver adenoma); diabetes mellitus with or without diabetic angiopathy; cholelithiasis; migraine and / or severe headache; systemic lupus erythematosus; endometrial hyperplasia in the anamnesis; epilepsy; bronchial asthma; otosclerosis, hereditary angioedema.

    Causes of immediate cessation of therapy

    Therapy should be discontinued if contraindications and / or in the following situations are detected: jaundice or impaired liver function; marked increase in blood pressure; newly emerged seizures of migraine-like headache; pregnancy.

    Hyperplasia and endometrial cancer

    The risk of hyperplasia and endometrial cancer increases with estrogen for a long time. According to available data, the risk of developing endometrial cancer in women using only estrogens increases 2-12 times compared to women who do not use estrogens, depending on the duration of treatment and the dose of estrogens. After cessation of treatment, the increased risk may persist for at least 10 years. To reduce the risk, it is necessary to combine estrogen therapy in women with an unreplacable uterus with gestagens for at least 12 days during the treatment cycle or take combined estrogen-progestogen preparations continuously.

    During the first months of treatment, there may be "breakthrough" bleeding and "spotting" bleeding. If "breakthrough" bleeding or "spotting" spotting occurs after a certain period of treatment or continues after the withdrawal of treatment,it is necessary to conduct a survey to determine the causes of their occurrence, including endometrial biopsy (to exclude the malignant neoplasm of the endometrium).

    The use of drugs for HRT containing only estrogen can lead to precancerous or malignant transformation of residual foci of endometriosis. Thus, women who underwent a hysterectomy due to endometriosis should be provided with the addition of progestogens to estrogen replacement therapy in order to prevent endometrial cancer if it is known that they have residual foci of endometriosis.

    Mammary cancer

    The available data generally indicate an increased risk of breast cancer in women receiving combined estrogen-progestational medications and, possibly, also estrogen-only preparations for HRT; this risk depends on the duration of HRT use.

    The use of combined estrogen-progestogen drugs for HRT

    In a randomized placebo-controlled study (the Women's Health Initiative, WHI) and in epidemiological studies, concurrent data on the increased risk of breast cancer in women,receiving combined estrogen-progestational drugs for HRT; increased risk was detected after about 3 years of treatment.

    Application of drugs for HRT containing only estrogen

    The WHI study found no increased risk of developing breast cancer in women who underwent a hysterectomy and used hormone-eluting drugs containing only estrogen.

    In observational studies, in most cases, there is a slight increase in the risk of diagnosing breast cancer, which is significantly lower than in women using estrogen and progestogen combinations.

    Additional risk begins to appear after several years of treatment, but returns to baseline within a few (not more than five) years after cessation of treatment.

    HRT, in particular combined estrogen-progestogen, leads to an increase in the density of mammographic images, which can prevent radiographic detection of breast cancer.

    Ovarian Cancer

    Ovarian cancer is less common than breast cancer. Epidemiological data,obtained from a large meta-analysis indicate a slightly increased risk in women taking estrogen monotherapy or combined estrogen-progestogen HRT; the risk becomes apparent within 5 years of use and decreases with time after discontinuation. Several other studies, including the WHI study, suggest that the use of combined HRT may be associated with a similar or slightly lower risk (see Side-Effects section).

    Thromboembolism

    In women receiving HRT, there is a higher risk of venous thromboembolism (VTE), in particular, deep vein thrombosis or pulmonary embolism, compared with women who did not receive HRT 1.3-3 times. The probability is higher in the first year of HRT than in subsequent years.

    The main risk factors: individual or family history, the use of estrogen, serious surgery, prolonged immobilization, severe obesity (body mass index more than 30 kg / m2), systemic lupus erythematosus, advanced age, pregnancy and the postpartum period, malignant neoplasms.

    There is no consensus on the possible role of varicose veins in developmentVTE.

    The risk of VTE increases with prolonged immobilization, extensive injuries or extensive surgical interventions. The intake of drugs for HRT should be discontinued 4 to 6 weeks before the planned surgical operations on the abdominal organs or orthopedic operations on the lower limbs. Treatment can be resumed after a complete recovery of motor ability.

    Women who do not have a history of VTE, but who have first-degree relatives who have survived thrombosis at a young age, can be screened after a detailed discussion of its limitations (screening reveals only a few thrombophilic disorders). If there is a thrombophilic disorder manifested by thrombosis in family members, as well as in the presence of "severe" defects (such as deficiency of antithrombin, protein S or protein C, or a combination of defects), HRT is contraindicated.

    Women who are already receiving continuous treatment with anticoagulants require a thorough evaluation of the ratio of the benefits and risks of HRT.

    If VTE develops after the start of treatment, the drug should be discontinued.Patients should be advised to immediately contact a physician if there are potential symptoms of thromboembolism (soreness and / or swelling of the lower limb, sudden chest pains, shortness of breath).

    Cardiac ischemia

    In randomized controlled trials, no data were obtained on the prophylactic effect of myocardial infarction in women with or without IHD who received combined estrogen-progestational medications for HRT or estrogens alone.

    The use of combined estrogen-progestogen drugs for HRT

    When combined estrogen-progestational drugs for HRT are used, there is a slight increase in the relative risk of coronary heart disease. Since the initial absolute risk of CHD depends largely on age, the number of additional cases of IHD caused by the use of estrogens in combination with gestagens in healthy women approaching menopause is extremely small, but increases with age.

    The use of drugs for HRT that contain only estrogen

    In randomized controlled trials, there was no evidence of an increased risk of coronary heart disease in patients who underwent a hysterectomy and who receivedPreparations for HRT containing only estrogen.

    Ischemic stroke

    HRT combined estrogen-progestogen and estrogen alone is associated with an increased risk of ischemic stroke by almost 1.5 times. Relative risk does not change with age and depending on the time that has passed since the onset of menopause. However, since the baseline risk of stroke largely depends on age, the overall risk of stroke in women receiving HRT will increase with age.

    Impaired renal function

    Estrogens cause fluid retention in the body. Patients with cardiac or renal failure should be under constant medical supervision.

    Diabetes

    Estrogens increase sensitivity to insulin and increase its excretion. Patients with diabetes mellitus in the first months of HRT are shown a constant control of the concentration of glucose in the blood.

    Cholelithiasis

    Admission of estrogen increases the risk of cholelithiasis.

    Hypertriglyceridemia

    A careful observation should be made in the history of HRT in women with hypertriglyceridemia in the anamnesis, since in this condition, when the estrogen therapy is used, rare cases of a sharp increase in the concentration of triglycerides in the plasma, leading to the development of pancreatitis.

    Effect on thyroid function

    Estrogens increase the concentration of thyroxine-binding globulin, leading to an increase in the total concentration of circulating thyroid hormones.

    Chloasma

    In some cases, chloasma may develop, especially in women who have a history of chloasma during pregnancy. Women with a tendency to develop chloasma, against the background of HRT, should minimize exposure to sun or ultraviolet radiation.

    Effect on cognitive function

    HRT does not improve cognitive function. There is a slight increase in the risk of developing dementia at the onset of HRT at the age of over 65.

    The drug Divigel is not a contraceptive drug, it is necessary to use adequate non-hormonal methods of contraception during the drug intake.

    Effect on the ability to drive transp. cf. and fur:Does not affect.
    Form release / dosage:Gel for external use 0,1%.
    Packaging:

    Primary packaging: 0.5 or 1.0 g of gel in single-dose three-layer bags of laminated aluminum (inner layer - polyethylene, middle layer - aluminum, outer layer - polyester).

    Secondary packaging: for 28 or 91 single-dose package in a cardboard box with a nested instruction for use.

    Storage conditions:

    Store the drug at a temperature of not more than + 25 ° C.

    Keep out of the reach of children.

    Shelf life:

    3 years.

    Do not use after the expiration date printed on the package!

    Terms of leave from pharmacies:On prescription
    Registration number:П N015526 / 01
    Date of registration:14.01.2009
    Expiration Date:Unlimited
    The owner of the registration certificate:Orion CorporationOrion Corporation Finland
    Manufacturer: & nbsp
    Representation: & nbspOrion Pharma LLCOrion Pharma LLC
    Information update date: & nbsp20.11.2017
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