Active substanceMethotrexateMethotrexate
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  • Dosage form: & nbsplyophilizate for solution for injection
    Composition:1 bottle contains:

    active substance: methotrexate in terms of anhydrous substance-500 mg, 1000 mg auxiliary substance: sodium hydroxide - 88 mg, 176 mg.

    Description:Porous mass from yellow to dark yellow color of heterogeneous color. In the light it is unstable, hygroscopic.
    Pharmacotherapeutic group:Antitumour agent, antimetabolite
    ATX: & nbsp

    L.01.B.A   Analogues of folic acid

    L.01.B.A.01   Methotrexate

    Pharmacodynamics:Methotrexate - antitumor, cytostatic agent of the group of antimetabolites-analogues of folic acid. It inhibits dihydrofolate reductase involved in the reduction of dihydrofolic acid into tetrahydrofolic acid (a carrier of the single-carbon groups necessary for the synthesis of purine nucleotides and their derivatives). It inhibits the synthesis, repair of deoxyribonucleic acid (DNA) and cellular mitosis (in the S phase). Especially sensitive to the action of methotrexate tissue with high cell proliferation: tumor tissue, bone marrow, embryonic cells, epithelial cells of the mucous membranes. Along with the antitumor has an immunosuppressive effect.
    Pharmacokinetics:Time to reach the maximum concentration (Cmax) with intramuscular injection 30-60 minutes. The connection with plasma proteins is about 50%. When used in therapeutic doses, regardless of the route of administration, it practically does not penetrate the blood-brain barrier, after intrathecal injection in the cerebrospinal fluid, high concentrations are achieved.Penetrates into breast milk. Metabolized mainly in the liver with the formation of pharmacologically active polyglutamine form, inhibiting dihydrofolate reductase and thymidine synthesis. The half-life period in the initial phase is 2-4 hours, and in the final phase - 3-10 hours when using conventional doses and 8-15 hours - when using high doses of the drug. In chronic renal failure, both phases of excretion of methotrexate can be significantly prolonged. It is excreted mainly by the kidneys in unchanged form by glomerular filtration and tubular secretion (with intravenous administration of 80-90% is excreted within 24 hours), with bile is excreted up to 10% (followed by reabsorption in the intestine). The excretion of methotrexate in patients with impaired renal function, expressed as ascites or transudate, is significantly slower. With repeated administration, it accumulates in tissues in the form of metabolites.
    Indications:

    - trophoblastic tumors;

    - Acute leukemia (especially lymphoblastic and myeloblast variants);

    - Neuroleukemia (prevention and treatment);

    - non-Hodgkin's lymphomas, including lymphosarcoma;

    - Breast cancer, squamous cell carcinoma of the head and neck, lung cancer, skin cancer,cervical cancer, vulvar cancer, esophageal cancer, kidney cancer, bladder cancer, ovarian cancer, testicular cancer, penile cancer, retinoblastoma, medulloblastoma;

    - osteogenic sarcoma and soft tissue sarcoma;

    - mushroom mycosis (far advanced stages);

    - severe forms of psoriasis, psoriatic arthritis, rheumatoid arthritis, dermatomyositis, systemic lupus erythematosus, ankylosing spondylitis (with ineffective standard therapy).

    Contraindications:Povppennaya sensitivity to methotrexate and / or any other component of the drug; severe anemia, leukopenia, neutropenia, thrombocytopenia; marked renal and / or liver failure; pregnancy and the period of breastfeeding. There are no age restrictions for application.
    Carefully:Pleural or peritoneal effusions, dehydration, infectious diseases of a viral, fungal or bacterial nature, a gout or urate nephrolitoliasis in anamnesis, previous radiation or chemotherapy, simultaneous use of methotrexate at a dose of 15 mg / week or more with acetylsalicylic acid.
    Pregnancy and lactation:Methotraxate is contraindicated during pregnancy and lactation.
    Dosing and Administration:Intravenously, intramuscularly, intraarterially, intrathecally. The contents of the vial are dissolved with a sterile isotonic sodium chloride solution immediately before use. 1 gram (1000 milligrams) methotrexate diluted 0.9% isotonic saline, 20 ml to a concentration of 50 mg / ml.

    The resulting solution methotrexate if necessary may be further diluted in an isotonic sodium chloride solution or 5% dextrose solution.

    Doses above 100 mg / m2 administered only intravenously, the pre-diluted lyophilizate methotrexate, further diluted with 5% dextrose. When prescribing high doses of the drug (above 100 mg / m2) necessarily the subsequent introduction of calcium folinata.

    For the intrathecal administration of methotrexate solution was diluted lyophilisate 50 mg / ml, further diluted to a concentration of 1 mg / ml in 0.9% isotonic sodium chloride solution.

    Malignant neoplasms

    Vero-methotrexate is a part of many chemotherapy regimens, therefore, when selecting the route of administration, regimen and dosage in each individual case, one should be guided by the data of specialized literature.The following dosing regimens are used in adults and children: Trophoblastic tumors: 15-30 mg intramuscularly, daily for 5 days with an interval of one or more weeks (depending on signs of toxicity). Treatment rates are usually repeated 3 to 5 times to a total dose of 300-400 mg.

    Leukemia and lymphoma: 200-500 mg / m2 by intravenous infusion once every 2-4 weeks.

    Neuroleukemia: 12 mg / m2 for 15-30 seconds intrathecally 1 or 2 times a week.

    When treating children, the dose is selected depending on the age of the child: children under the age of 1 year are prescribed 6 mg, children aged 1 year 8 mg, children 2 years 10 mg, children 3 years and over -12 mg.

    Before administration, it is necessary to remove cerebrospinal fluid in a volume approximately equal to the volume of the drug to be injected.

    With caution, enter intrathecally. Exceeding the recommended dose with intrathecal administration significantly increases the risk of significant manifestations of toxicity. Caution: do not enter calcium folinate intrathecally!

    Solid tumors: in combination with other antitumor drugs 30-40 mg / m2 intravenously sprayed once a week.

    When high-dose therapy is administered from 2 to 15 g / m2 a 4-6 hour intravenous infusion at intervals of 1-5 weeks followed by optional introduction of calcium folinate which typically begin 24 hours after the start of infusion and methotrexate administered every 6 hours in a dose of 3-40 mg / m2 (usually 15 mg / m2) and above, depending on the concentration of methotrexate in the blood serum for 48-72 hours (see instructions for the use of calcium folinate).

    Precautions for use.

    Methotrexate is a cytotoxic drug, so care must be taken when handling it.

    When high doses of methotrexate are administered, careful monitoring of the patient's condition is necessary to detect early signs of toxic reactions early.

    With care, enter intertecally. Exceeding the recommended dose with intrathecal administration significantly increases the risk of significant manifestations of toxicity.

    High-dose therapy (at a dose of 2 g / m2 and above) should be performed only by an experienced chemotherapist under the control of methotrexate concentration in plasma under steady-state conditions.Normal decrease in the content of methotrexate in blood plasma is considered 2 times as compared to the initial value in 22 hours after the administration. Increase in plasma concentrations of creatinine (by 50% or more from the original) and / or bilirubin requires intensive detoxification therapy.

    During therapy with methotrexate in elevated and high doses, it is necessary to monitor the pH of the urine: on the day of administration and in the next 2-3 days, the urine reaction should be alkaline. This is achieved by intravenous drip injection of a mixture consisting of 40 ml of 4.2% sodium bicarbonate solution and 400-800 ml of 0.9% sodium chloride solution on the eve, on the day of treatment and subsequent 2-3 days. Treatment with methotrexate in high and high doses should be combined with enhanced hydration (up to 2 liters of fluid per day).

    For the treatment of psoriasis methotrexate appoint only patients with severe disease that can not be treated by other types of therapy.

    To timely detect symptoms of intoxication during treatment with methotrexate, it is necessary to monitor the parameters of peripheral blood (1 time per week), the functional state of the liver and kidneys.

    With the development of diarrhea and ulcerative stomatitis, methotrexate therapy must be interrupted due to the high risk of developing hemorrhagic enteritis and perforation of the intestinal wall, which can lead to the death of the patient.

    In patients with impaired liver function, the period of excretion of methotrexate is increased, therefore, in such patients therapy should be carried out with extreme caution, with the use of reduced doses.

    Impaired renal function is dose dependent. Risk of impairment is elevated in patients with reduced renal function or with dehydration, as well as in patients taking other nephrotoxic drugs.

    Men and women of childbearing age should be treated with methotrexate and at least 3 months after the use of reliable methods of contraception.

    Side effects:

    From the hematopoiesis: leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, anemia.

    From the digestive system: anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, pharyngitis, enteritis, diarrhea, erosive and ulcerative lesions and bleeding from the gastrointestinal tract, with prolonged daily use - a violation of liver function,increased activity of "liver" transaminases, periportal, fibrosis and cirrhosis of the liver, liver necrosis, fatty liver, pancreatitis.

    From the nervous system: encephalopathy (especially with the introduction of multiple doses intrathecally, as well as in patients who received radiation therapy on the head area), fatigue, weakness, confusion, ataxia, tremor, irritability, convulsions, coma. Acute side effects caused by intrathecal administration of methotrexate may include dizziness, blurred vision, headache, back pain, stiff neck, seizures, hemiparesis.

    From the respiratory system: interstitial pneumonitis, pulmonary fibrosis, exacerbation of pulmonary infections.

    From the urinary system: cystitis, nephropathy, impaired renal function (increased level of creatinine, hematuria).

    On the part of the reproductive system: violation of the process of oogenesis, spermatogenesis, decreased libido / impotence, changes in fertility.

    From the skin and skin appendages: cutaneous erythema and / or rash, itching, hives, telangiectasia, furunculosis,depigmentation or hyperpigmentation, acne, skin peeling, folliculitis, alopecia (rarely), increased photosensitivity, exacerbation of radiation dermatitis.

    From the sense organs: conjunctivitis, excessive lacrimation, cataract, photophobia, cortical blindness (at high doses), visual impairment.

    Allergic reactions: fever, chills, rash, hives, anaphylaxis, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

    Other: malaise, decreased resistance to infectious diseases, osteoporosis, hyperuricemia, vasculitis, arthralgia / myalgia.

    Overdose:Symptoms: No, is diagnosed by the concentration of methotrexate in plasma.

    Treatment: the introduction of a specific antidote - calcium folinate whenever possible immediately, preferably within the first hour, at a dose equal to or greater than the dose of methotrexate; subsequent doses are administered as needed, depending on the serum concentration of methotrexate. To prevent the precipitation of methotrexate and / or its metabolites in the renal tubules, the body is hydrated and alkalinized with urine, which accelerates the excretion of methotrexate.

    In case of an overdose with intrathecal injection, immediately after an overdose is detected, repeated lumbar punctures should be performed to ensure rapid drainage of cerebrospinal fluid, possibly neurosurgical intervention with ventricululumbral perfusion. All these procedures should be performed against a background of intensive maintenance therapy and systemic administration of large doses of calcium folinate.

    Attention: do not enter calcium folinate intrathecally!

    Interaction:With the simultaneous use of methotrexate (in high doses) with various non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid and other salicylates, azaprospan, diclofenac, indomethacin and ketoprofen the toxicity of methotrexate may increase, and in some cases a potentially toxic effect, sometimes even fatal, is possible. With special precautions and appropriate monitoring, it is possible to use methotrexate in low doses (7.5-15 mg per week) in combination with NSAIDs, in particular in the treatment of rheumatoid arthritis.

    The simultaneous use of sulfonamides, sulfonylurea derivatives, phenytoin, phenylbutazone, aminobenzoic acid, probenecid, pyrimethamine or trimethoprim, a number of antibiotics (penicillins, tetracyclines, chloramphenicol), indirect anticoagulants and lipid-lowering drugs (colestramine) increases the toxicity of methotrexate.

    Retinoids, azathioprine, sulfasalazine risk of developing hepatotoxicity. Multivitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate therapy.

    Asparaginase is a methotrexate antagonist.

    Anesthesia using dinitrogen oxide can lead to the development of -non-predictable severe myelosuppression and stomatitis.

    The appointment of amiodarone to patients receiving methotrexate therapy can cause skin ulceration.

    Methotrexate reduces the clearance of theophylline.

    In several patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (metoksalen and ultraviolet irradiation), skin cancer was detected.

    Caution should be exercised with the simultaneous administration of erythrocyte mass and methotrexate.

    The combination with radiotherapy can increase the risk of soft tissue necrosis.

    Methotrexate may reduce the immunological response to vaccination. With simultaneous administration with live vaccine, severe antigenic reactions can develop.

    Effect on the ability to drive transp. cf. and fur:Care should be taken when driving vehicles and performing - potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.
    Form release / dosage:Lyophilizate for the preparation of solution for injection 500 mg and 1000 mg.
    Packaging:Lyophilizate containing 500 mg of active substance in glass bottles with a capacity of 20 ml and lyophilizate containing 1000 mg of active substance in glass bottles with a capacity of 50 ml. One bottle together with instructions for use in a pack of cardboard. For 30, 50 bottles with instructions for use, based on one instruction for 5 bottles, in a box of cardboard (for hospitals).
    Storage conditions:In the dark place at a temperature of no higher than 30 ° 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:P N002098 / 03-2003
    Date of registration:30.05.2008 / 30.12.2011
    Expiration Date:Unlimited
    The owner of the registration certificate:LENS-PHARM, LLC LENS-PHARM, LLC Russia
    Manufacturer: & nbsp
    Information update date: & nbsp01.02.2017
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