Tepadina (Tepadina)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceThioridazineThioridazine
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    • Dosage form: & nbsplyophilizate for the preparation of concentrate for the preparation of a solution for infusions
    Composition:
    1 bottle contains:
    The active ingredient is thiotepa 15 mg or 100 mg.
    Description:

    Lyophilized compact mass or powder from white to almost white.

    Pharmacotherapeutic group:antitumor agent - alkylating compound
    ATX: & nbsp

    N.05.A.C.02   Thioridazine

    Pharmacodynamics:
    An antitumor agent that alkylates a compound of a group of nitrogen mustard gas. Oppresses hemopoiesis, disrupts the exchange of nucleic acids and blocks mitosis, forming complex bonds with DNA. The effect of the drug is associated with the formation of an unstable ethyleneimine radical, which, like in the case of "radiotherapy," causes the destruction of the bonds of many intracellular molecular structures, including DNA. Due to high myeloablative properties thiotepa enhances immunosuppression and mieloablation, thus speeding up,transplant engraftment; this reduces the "graft versus leukemia" (RTAP) response associated with the "graft versus host" (GVHD) reaction.

    Pharmacokinetics:
    Distribution: the preparation is a 'highly lipophilic
    compound. The apparent volume of distribution varies from 40.8 l / m2 to 75 l / m2. The apparent volume of thiotepa distribution does not depend on the administered dose. Free, fraction, not bound, with proteins in plasma, is 70-90%; is slightly associated with gamma globulin and albumin (10-30%). After intravenous administration, the concentration of the drug in the cerebrospinal fluid is almost equal to that in the blood plasma. The average ratio of the area under, the concentration-time curve (AUC) in the cerebrospinal fluid to the blood plasma is 0.93.
    Metabolism:, Thiotepa is rapidly metabolized in the liver. Metabolites are found in the urine 1 hour after the infusion. Metabolites are active alkylating agents. Thiotepa desulfurization by means of, cytochrome P450, isoenzymes "of the liver, CYP2B and, CYP3A, to its main and active metabolite - triethylene phosphoramide (TEPA). �?
    Excretion: clearance of the drug - from 11.4 to -23.2 l / h / m2; The period, 1 half-life (T1 / 2) '- from 1.5 to 4.1 hours. " It is excreted by the kidneys (85%) in; mainly in the form of metabolites. It is almost completely excreted by the kidneys in 6-8 hours.
    The pharmacokinetics of the drug in pediatric patients (from 2 to 12 years) does not differ from the pharmacokinetics in adult patients. There are no data on the pharmacokinetics of the drug in patients with chronic renal and / or hepatic insufficiency.
    Indications:
    The drug Tepadina is shown in the complex therapy, in combination with other chemotherapeutic drugs:
    as a preparatory therapy for hematologic diseases in
    adults and. children before allogeneic and autologous, transplantation;
    hematopoietic stem cells, (TSCC), with or without total irradiation
    whole organism;
    - for the treatment of solid tumors in adults and children in combination with, high doses of chemotherapeutic drugs, supported by transplantation of hematopoietic stem cells.

    Contraindications:
    Hypersensitivity to the components of the drug; simultaneous reception of a vaccine against yellow fever; simultaneous administration with live antiviral and bacterial vaccines; pregnancy; lactation period

    Carefully:
    Inhibition of bone marrow function (including on the background of concomitant radiation or chemotherapy), acute infectious diseases of viral, fungal or bacterial nature, severe renal and / or hepatic insufficiency (no experience of use), cardiovascular diseases.

    Dosing and Administration:

    Intravenously drip. The duration of intravenous infusion should be 2-4 hours.,
    The prepared solution is administered as an intravenous infusion through a central venous catheter. , It is recommended to administer the solution using systems for transfusion of solutions with a filter diameter of 0.2 μm.
    The permanent catheter is washed with 5 ml of 0.9% sodium chloride solution.
    The dose of the drug depends on the age of the patient, the type of transplantation, the disease.
    In renal and hepatic insufficiency, - as well as to persons in old age, correction of the dosing regimen is not required.
    Adults:
    In autologous transplantation of hematopoietic stem cells (TSCC):
    Hematological diseases
    The recommended dose: from 125 mg / m2 / day (3.38 mg / kg / day) to 300 mg / m2 / day. (8.10 mg / kg / day) once a day, for 2-4 days before administration. , autologous TSCC,depending on the chosen combination with other chemotherapeutic preparations. Selected dose not must
    exceed the maximum cumulative dose of 900 mg / m2 (24.32 mg / kg) for the entire period of preparatory therapy.
    LYMPHOMA . ' ' . .
    The recommended dose: from 125 mg / m2 / day (3.38 mg / kg / sweet) to 300 mg / m2 / day, (8.10 mg / kg / day) once a day, for 2-4 days before the autologic TSCA, depending on the chosen combination with other chemotherapeutic preparations. Selected dose not must
    exceed the maximum cumulative dose of 900 mg / m2 (24.32 mg / kg) for the entire period of preparatory therapy.
    LYMPHOMA OF THE CENTRAL NERVOUS SYSTEM '
    The recommended dose: 185. mg / m2 / day (5 mg / kg / day) once a day for 2 days before the autologous TSCS, depending on the combination chosen with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose,
    '370 mg / m2 (10 mg / kg) for the entire period of preparatory therapy.
    MULTIPLE MYELOMA . -
    . The recommended dose: from 150 mg / m2 / day (4.05 mg / kg / day) to 250 mg / m2 / day (6.76 mg / kg / day) once a day, "for 3 days before carrying out, autologous TTSK, depending, on the chosen combination with others "t! * chemotherapy drugs.. The dose should not exceed the maximum cumulative dose of 750 mg / m2 (20.27 mg / kg) for the entire period of preparatory therapy.
    Solid tumors
    The recommended dose: from 120 mg / m2 / day (3.24 mg / kg / day) to 250 mg / m2 / day; .
    (6.76 mg / kg / day), once a day or divided into 2 infusions per day, for 2-5 days before autologous TSCS, depending on. selected combination with other chemotherapeutic drugs.
    The dose should not exceed the maximum cumulative dose of 800 mg / m2 (21.62 mg / kg) for the entire period of preparatory therapy.
    MAMMARY CANCER
    The recommended dose: from 120 mg / m2 / day (3.24 mg / kg / day) to 250 mg / m2 / day (6.76 mg / kg / day), once a day, for 3-5 days before carrying out autologous TTSK, depending, on, the chosen combination with other chemotherapeutic-preparations. , Dosage, dose: should not. exceed the maximum cumulative dose of 800 mg / m2 (21.62 mg / kg) for the whole. period of preparatory therapy.
    TUMORS OF CENTRAL NERVOUS SYSTEM
    The recommended dose: from 125 mg / m2 / day (3.38 mg / kg / day) to 250 mg / m2 / day (6.76 mg / kg / day), once a day or divided into 2 infusions per day, for 3-4 days before the autologous TTSK, depending on the chosen combination with other chemotherapeutic drugs.The dose should not exceed the maximum cumulative dose of 750 mg / m2 (20.27 mg / kg) for the entire period of preparatory therapy.
    ovarian cancer.
    The recommended dose: 250 mg / m2 / day (6.76 mg / kg / day) once a day, c. , within 2 days before the autologous TSCA. Dosage, the dose should not exceed the maximum cumulative dose of 500 mg / m2, (13.51 mg / kg) for the entire period of preparatory therapy.
    HYMNOGENOGENIC TUMORS
    The recommended dose: from 150 mg / m2 / day (4.05 mg / kg / day) to 250 mg / m2 / day (6.76 mg / kg / day) once a day, for 3 days prior to administration . autologous TSCC, depending on the chosen combination with other: chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 750 mg / m2 (20.27 mg / kg) for the entire period of preparatory therapy / v
    In 'allogeneic transplantation of hematopoietic stem cells (TSCC): ' :
    'Hematological diseases
    The recommended dose: from 185 mg / m2 / day (5 mg / kg / day) to 481 mg / m2 / day (13 mg / kg / day), once a day or divided into 2 infusions per day for 1-3 days before the allogeneic TSCC, in, depending on the chosen combination with other chemotherapeutic drugs.,,
    . The dose should not exceed the maximum cumulative dose of 555 mg / m2 (15 mg / kg) for the entire period of preparatory therapy.
    LYMPHOMA ,
    Recommended dose: 370 mg / m2 / day (10 mg / kg / day) divided into 2 infusions per day before allogeneic TSCA. The dose should not exceed the maximum cumulative dose of 370 mg / m2 (10 mg / kg) for the entire period of preparatory therapy.
    MULTIPLE MYELOMA
    The recommended dose is 185 mg / m2 / day (5 mg / kg / day) once a day before the allogeneic TSCC. The dose should not exceed
    the maximum cumulative dose, 185 mg / m2 (5 mg / kg). behind. the whole period '(preparatory therapy)
    ;LEUKEMIA
    The recommended dose is from 85 mg / m2 / day (5 mg / kg / day) to 481 mg / m2 / day (13 mg / kg / day), once a day or divided into 2 infusions. day; during, 1-2 days of forwarding by carrying out allogeneic; TGSC, in "depending on the chosen combination with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 555 mg / m2 (15 mg / kg) for the entire period of preparatory therapy
    THALASSEMIA
    Recommended dose: 370 mg / m2 / day (10 mg / kg / day), divided; for - 2 infusions per day, before the allogeneic LSCA.The dose chosen1 '/ should not exceed the maximum cumulative dose of 370 mg / m2 (10 mg / kg)' for the entire period of preparatory therapy.
    Children
    In 'autologous transplants of hematopoietic stem cells (TSCC)
    Solid tumors. '-'. . D
    The recommended dose: from 150 mg / m2 / day (6 mg / kg / day) to 350 mg / m2 / day <
    (14 mg / kg / day) once a day for 2-3 days before autologous TSCS, depending on the combination chosen with other chemotherapeutic drugs. The selected dose should not exceed the maximum cumulative dose of 1050 mg / m2 (42 mg / kg) for the whole (the period of preparatory therapy)
    TUMORS OF CENTRAL NERVOUS SYSTEM
    The recommended dose: from 250 mg / m2 / day (10 mg / kg / day) to 350 mg / m2 / day (14 mg / kg / day) once a day, for 3 days before, autologous TSCA, in depending on the chosen combination with other ', chemotherapeutic drugs. The selected, / dose, should not exceed the maximum cumulative dose of 1050 mg / m2 (42 mg / kg) for the entire period of preparatory therapy.
    With allogenic transplantation of hematopoietic stem cells. (TSCC):
    Hematological diseases. . ' �?
    The recommended dose: from 125 mg / m2 / day (5 mg / kg / day) to 250 mg / m2 / day,
    (10 mg / kg / day), once a day, or divided into 2 infusions per day, for 1-3 days before allogeneic TSCS, depending on the combination chosen with other chemotherapeutic drugs. The dose should not exceed the maximum cumulative dose of 375 mg / m2 (15 mg / kg) for the entire period of preparatory therapy. '
    LEUCEMIA /
    Recommended dose: 250 mg / m2 / day (10 mg / kg / day), divided into 2 infusions per day, before the allogeneic TSCA. The dose should not exceed the maximum cumulative dose of 250 mg / m2 (10 mg / kg) for the entire period of preparatory therapy.
    THALASSEMIA
    The recommended dose: from 200 mg / m2 / day (8 mg / kg / day) to 250 mg / m2 / day (10 mg / kg / day), divided into 2 infusions per day, before allogeneic TSCA. The dose should not exceed the maximum cumulative dose of 250 mg / m2 (10 mg / kg) for the entire period of preparatory therapy. f,
    REFRACTORY CYTOPENDS
    Recommended dose: 125 mg / m2 / day (5 mg / kg / day); once a day, in "3 days before the allogeneic TSCC. The dose should not exceed the maximum cumulative dose of 375 mg / m2 (15 mg / kg) for the entire period of preparatory therapy.
    , HEREDITARY DISEASES
    The recommended dose: 125 mg / m2 / day (5 mg / kg / day), once a day, for 2 days before the allogeneic TSCC. The dose should not exceed the maximum cumulative dose of 250 mg / m2 (10 mg / kg) for the entire period of preparatory therapy.
    SERPOVIDNA-CELLULAR ANEMIA,
    Recommended dose: 250'mg / m2 / day (10; mg / kg / day), divided by. .
    2 infusions per day before the allogeneic TSCC. The dose should not exceed the maximum cumulative dose of 250 mg / m2 (10 mg / kg) \ for the entire period of preparatory therapy. .
    Preparation of solution for infusion.
    A drug. is dissolved by addition in vials. water for. injections of 1.5 ml and 10 ml respectively for dosages of 15 mg and 100 mg, followed by thorough mixing. The resulting clear, colorless solution. without visible mechanical inclusions (otherwise the solution can not be used), 0.9% solution of sodium chloride is dissolved in 500 ml of the solution before the injection (the final concentration of the drug should be 0.5 to 1 mg / 1 ml). .
    In the preparation of a solution for infusions, the use of gloves is recommended.If the solution accidentally gets on the skin, immediately wash the area with soap and water. If the drug accidentally gets on the mucous membranes, they must be thoroughly rinsed under a stream of water.

    Side effects:

    Very frequent> 10%; frequent> 1% and <10%; not frequent> 0,1% and <1%. .
    Adults:
    Infectious and parasitic diseases: very frequent - increase, predisposition to infection, sepsis; not frequent - a syndrome of toxic shock:
    Benign, - malignant and unspecified neoplasms (including cysts and polyps): frequent - secondary 'malignant tumor caused by treatment.
    On the part of the organs of hematopoiesis and lymphatic system: very frequent - leukopenia, thrombocytopenia, febrile neutropenia, anemia, pancytopenia, granulocytopenia
    On the part of the immune system, "very frequent, - an acute reaction" transplant against the host, "a chronic" graft versus host "reaction, frequent - hypersensitivity
    From the endocrine system: frequent - hypopituitarism
    (insufficiency of pituitary gland function)
    On the part of metabolism: very frequent - anorexia, decreased appetite, hyperglycemia.
    Mental disturbances: very frequent - changes in the mental state, confused * consciousness; frequent - anxiety, not frequent - delirium, increased excitability, hallucinations, agitation.
    From the nervous system: very frequent - dizziness, headache, blurred vision, encephalopathy, convulsions, paresthesia; frequent, - intracranial, aneurysm, extrapyramidal disorders, cognitive disorders, cerebral hemorrhage.
    From the side - the organ, the view: very, very frequent - conjunctivitis; frequent - cataract. .
    From the side of the hearing organ and labyrinthine disorders: very frequent '- hearing impairment, ototoxicity, tinnitus. .
    From the heart: very frequent - arrhythmia; frequent - tachycardia, heart failure; not frequent - cardiomyopathy, myocarditis. : .
    From the vascular system: very frequent, - lymphatic edema, arterial hypertension; frequent - bleeding, embolism. .
    On the part of the respiratory system: very frequent - idiopathic syndrome of pneumonia, epistaxis; frequent - pulmonary edema, cough, pneumonitis is not frequent - hypoxia.
    From the gastrointestinal tract: very frequent - nausea, stomatitis, esophagitis, vomiting, diarrhea, dyspepsia, abdominal pain, enteritis, colitis;
    frequent - constipation, gastrointestinal, perforation, intestinal obstruction; not frequent - gastrointestinal ulcer. .
    , On the part of the liver and biliary tract: 'very frequent - venokljuzionnaya. liver disease, hepatomegaly (liver enlargement), jaundice.
    From the skin: very frequent - rash, prurite, alopecia; frequent - erythema; not frequent - a violation of pigmentation, erythrodermic. psoriasis. '
    From the musculoskeletal system :, very frequent - back pain, myalgia, arthralgia.
    From the side of the urinary system: very frequent - hemorrhagic. cystitis; frequent - dysuria, oliguria ,. renal failure, cystitis, hematuria.
    From the reproductive system and breast: very frequent, azoospermia, amenorrhea, vaginal bleeding; frequent - menopausal symptoms; not frequent - female infertility, male infertility. '
    Other: very frequent - pyrexia, asthenia, chills, general edema, inflammation or pain at the injection site, inflammation of the mucous membranes; frequent - multiorgan insufficiency, pain.
    Laboratory and instrumental studies: very frequent -
    increase, body weight, increased bilirubin concentration in plasma,
    increased transaminase activity, increased activity of amylase; * frequent increase in plasma concentration of creatinine; urea, - / activity of gamma-glutamyltransferase alkaline, phosphatase; aspartate aminotransferase.
    Children:
    Infectious, and parasitic diseases: very frequent - increased predisposition to infection, sepsis; frequent - thrombocytopenic purpura.
    Benign, malignant and unspecified neoplasms (including cysts and polyps): frequent - a secondary malignant tumor.
    From the organs of hematopoiesis and lymphatic system: very frequent - thrombocytopenia, febrile neutropenia, anemia, pancytopenia, granulocytopenia. .
    From the immune system: very, very frequent - acute reaction
    "transplant versus host," a chronic "graft versus host" reaction.
    On the part of the endocrine system: very frequent - hypopituitarism, hypogonadism, hypothyroidism.
    From the side of metabolism: very frequent anorexia, hyperglycemia. 'Mental disturbances: very frequent - changes in the mental state; frequent - mental disorders caused by the general condition of the body.
    From the nervous system: very frequent headache,
    encephalopathy; convulsions, cerebral hemorrhage, memory impairment ;, paresis; frequent - ataxia. ,
    From the side, the organ of hearing and labyrinthine disturbances: very frequent - hearing impairment.
    From the heart: very much. frequent. heart failure'; frequent - cardiovascular insufficiency, heart disease. .
    From the side of the vascular system: very frequent - bleeding; frequent - hypertension. -
    On the part of the respiratory system: very frequent - pneumonitis; Frequent - idiopathic pneumonia syndrome, pulmonary hemorrhage, pulmonary edema, - Nasal bleeding, hypoxia, respiratory arrest.
    From the gastrointestinal tract: very frequent - nausea, stomatitis, vomiting, diarrhea, abdominal pain; frequent - enteritis, intestinal obstruction.
    From the side of the liver and biliary tract, ways: very frequent - veno-occlusive disease of the liver; frequent - liver failure.
    On the part of the skin: very frequent - rash,, erythema, desquamation, impaired pigmentation.
    From the musculoskeletal, apparatus: very frequent - delay - growth.
    From the urinary system: very frequent - functional disorders of the bladder; frequent - renal failure, hemorrhagic cystitis.
    Other: very frequent - pyrexia, inflammation of the mucous membranes, pain.
    multiple organ failure
    Laboratory and instrumental research: very frequent -
    an increase in the concentration of bilirubin in the plasma, an increase in transaminase / creatinine activity in the plasma, an increase in activity of aspartate aminotransferase, an increase in the activity of alanine aminotransferase; frequent - an increase in the concentration of urea in the plasma ,. disturbance, electrolyte balance of blood, increase in prothrombin time.

    Overdose:
    Symptoms: myoablation and. pancytopenia. The emergence of data
    diseases can only be established with, help: laboratory, research.
    Treatment: symptomatic. There is no specific antidote. '

    Interaction:
    Thiotepa is metabolized by isoenzymes of the liver, CYP2B6 and CYP3A4. - Co-administration with inhibitors of CYP2B6 isoenzymes (eg, clopidogrel and ticlopidine) or CYP3A4 (eg, azole, antifungal agents, macrolides such as erythromycin,
    clarithromycin, telithromycin and protease inhibitors) can increase the concentration of thiotepa in plasma and potentially reduce the concentrationactive metabolite TEPA. . Joint injection of cytochrome P450 inducers. (eg, rifampicin, , carbamazepine, phenobarbital), can .increase thiotepa metabolism, which will lead to an increase in the concentration of the active metabolite in the plasma.Thiotepa is a weak inhibitor of the isoenzyme CYP2B6 and can potentially increase1 in plasma concentrations of ... substances metabolized by the CYP2B6 isoenzyme such as ifosfamide, tamoxifen, bupropion, efavirenz and cyclophosphamide. The CYP2B6 isozyme catalyzes the biotransformation of the cyclophosphamide into its active form, 4-hydroxycyclophosphamide (4-OHPP) and, thus, co-administration,. , with the preparation of thioteps of these preparations may lead to a decrease in the concentration of the active 4-ONRS. Therefore, during the 'joint use of the thiotepa preparation and these drugs should be' conducted clinical control.
    Contraindicated simultaneous use: the vaccine against yellow fever - the risk of a fatal systemic disease caused by the vaccine.
    It is not recommended simultaneous reception: with other living attenuated. vaccines. The risk of * a systemic 'disease caused by a vaccine, which can be fatal, is increasing.This risk is increased in patients who have decreased immunity due to the - underlying disease. It is necessary to use an inactive vaccine, in, if so. there is (poliomyelitis). Also, simultaneous administration with phenytoin is not recommended, since it is possible to reduce the gastrointestinal absorption of phenytoin and, as a consequence, increase the risk of seizures. There is also a risk of increasing toxicity or decreasing the effectiveness of thioteps due to increased hepatic metabolism of phenytoin. Cyclosporin, tacrolimus: cause an increase in immunosuppression with a risk of lymphoproliferation.
    Alkylating chemotherapeutic drugs, including thiotepu, inhibit the activity of pseudocholonesterase in plasma from 35% to 70%. The action of succinyl-choline can be increased by 5-15 minutes. Contraindicated is the one-time use of the drug, with cyclophosphamide. The drug is necessary. enter after completion, a course of infusions of cyclophosphamide. ^ Concurrent use, thioteps and myelosuppressive and myelotoxic drugs (eg, cyclophosphamide, melphalan, busulfan, fludarabine, thiosulphane) may increase the risk of hematologic adverse reactions in.. as a result, the toxic effect of these drugs.
    In the case of a malignant tumor, the risk of thrombosis increases, so patients are often prescribed anticoagulant therapy. Individual variability of the state of the blood coagulation system in patients and the possibility of interaction between oral anticoagulants and antitumor chemotherapeutic. means requires frequent analysis of INR (the international normalized attitude) when they are simultaneously assigned.

    Special instructions:
    In all patients with therapy with Tepadin at recommended doses, deep depression of bone marrow function develops, so it is necessary to monitor the total blood count with calculating the leukocyte count and platelet count, while counting white blood cell and platelet cells during therapy with Tepadina and At least 30 days after transplantation / must be done daily. For, the treatment of hematological toxicity can be used colony-stimulating. factors; transfusion of platelet and erythrocyte mass.
    'In patients with hepatic insufficiency; after transplantation 'it is recommended to regularly monitor activity in the plasma of transaminase, alkaline, phosphatase and bilirubin concentration for the purpose of early diagnosis of hepatotoxicity.
    Patients previously exposed to radiation therapy or who received 3 or more cycles of chemotherapy or previous transplantation of progenitor cells are under an increased risk of developing hepatic venous-occlusive diseases.
    Preliminary irradiation of the brain or craniocerebral irradiation can cause severe toxic reactions (eg, encephalopathy). The drug increases the risk of developing a secondary malignant tumor, since it is a carcinogen. .
    During the treatment and for at least three months, before or after taking chemotherapeutic immunosuppressants, the patient should not be given live viral and bacterial vaccines.
    Women, and men during treatment and, at least for one year. After, should use reliable methods of contraception. Before the start of treatment in women of childbearing age, pregnancy must be excluded. To men,Before starting treatment with Tepadina, it is recommended to consider the issue of cryopreservation of sperm.

    Effect on the ability to drive transp. cf. and fur:
    studies on the effect of the drug on the ability to drive the car and other mechanisms have not been carried out, however, such frequent side effects of the drug as dizziness, headache and blurry vision may affect the performance of these actions, therefore, it is necessary to refrain from driving and driving other potentially hazardous activities.

    Form release / dosage:
    Lyophilizate for the preparation of concentrate for the preparation of a solution for infusions 15 mg, 100 mg.

    Packaging:
    For 15 mg of lyophilizate in a transparent glass vial with a volume of 3 ml, capped with a rubber stopper in gray, unclosed by an aluminum cap with a blue "flip top" cap. 100 mg of lyophilizate in a 10 ml transparent glass vial, sealed with a rubber stopper of gray color and closed with an aluminum cap with a red "flip top" cap. ' ,
    1 bottle with instructions for use in a cardboard pack.

    Storage conditions:
    At a temperature of 2 to 8 ° C. Do not freeze. '
    Keep out of the reach of children.

    Shelf life:
    18 months.
    Concentrate - at a temperature of 2 to 8 ° C for 8 hours. , Diluted solution - at a temperature of 2 to 8 ° C for 24 hours. Do not use after the expiration date.

    Terms of leave from pharmacies:On prescription
    Registration number:LP-001134
    Date of registration:03.11.2011
    Manufacturer: & nbsp
    Information update date: & nbsp10.09.2015
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