Tablets "Methotrexate" is an antitumor, cytostatic agent of the antimetabolite group. It has an immunosuppressive effect.
Methotrexate 2.5 mg. Additives: sugar (sucrose) - 43.97 mg, potato starch - 21.82 mg, talc - 680 mcg, calcium stearate - 340 mcg, crospovidone - 340 mcg, povidone - 350 mcg. Composition of the shell: sugar (sucrose) - 32.5865 mg , magnesium hydroxycarbonate hydrate - 20.457 mg, wheat flour - 16.144 mg, povidone - 166 mcg, gelatin - 138 mcg, dye azorubine (E122) (carmoisin, dye acid red 2C) - 16.6 mcg, titanium dioxide - 450 mcg, wax - 27.9 mcg, talc - 14 mcg.
An antitumor, cytostatic agent of the group of antimetabolites, suppresses dihydrofolate reductase involved in the reduction of dihydrofolic acid to tetrahydrofolic acid (carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives). Inhibits synthesis, DNA repair and cell mitosis. Particularly sensitive to the action of rapidly proliferating tissues: cells of malignant tumors, bone marrow, embryonic cells, epithelial cells of the intestinal mucosa, bladder, oral cavity. Along with anti-tumor has immunosuppressive effect.
Oral absorption depends on the dose: when taken 30 mg / m2 is well absorbed, the average bioavailability is 60%. Absorption is reduced when taken in doses exceeding 80 mg / m2. In children with leukemia, absorption ranges from 23% to 95%. The time to reach Cmax - from 40 minutes to 4 hours. Food slows down the absorption and reduces Cmax. Communication with plasma proteins is about 50%, mainly with albumin. After distribution in tissues, high concentrations of methotrexate in the form of polyglutamates are found in the liver, kidneys, and especially in the spleen, in which methotrexate can be kept for several weeks or even months. When taken in therapeutic doses practically does not penetrate the blood-brain barrier. Penetrates into breast milk. After oral administration, it is partially metabolized by the intestinal flora, the main part - in the liver (regardless of the route of administration) with the formation of a pharmacologically active polyglutamine form, which also inhibits dihydrofolate reductase and thymidine synthesis.T1 / 2 in patients receiving less than 30 mg / m2 of the drug in the initial phase is 2-4 hours, and in the final phase (which is long) - 3-10 hours when using small and 8-15 hours - when using large doses drug. In chronic renal failure, both phases of the elimination of the drug can be significantly prolonged. It is mainly excreted by the kidneys in unchanged form by glomerular filtration and tubular secretion, and up to 10% is excreted in the bile (with subsequent reabsorption in the intestine). Removal of the drug in patients with impaired renal function, ascites or transudate expressed is significantly slowed down. When reintroduced accumulates in tissues in the form of polyglutamates.
It is used when using low doses for the treatment of: trophoblastic tumors, acute lymphoblastic leukemia, non-Hodgkin's lymphomas, advanced stages of fungal mycosis, severe forms of psoriasis, with rheumatoid arthritis, when other methods of therapy are ineffective.
The use of methotrexate is contraindicated during pregnancy and lactation, with marked changes in kidney and liver function, with hematological disorders (such as bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia), in the acute stage of infectious diseases, immunodeficiency syndrome, and with increased sensitivity to methotrexate or other parts of the pill, for children up to 3 years old. With care. With ascites, pleural effusion, gastric ulcer and duodenal ulcer, ulcerative colitis, dehydration, gout or nephrolithiasis in history, previously radiotherapy or chemotherapy, infectious diseases of viral, fungal or bacterial nature.
Application for violations of liver function. Use of methotrexate is contraindicated for marked changes in liver function. Application for violations of renal function. Use of methotrexate is contraindicated for marked changes in kidney function. Excretion of the drug in patients with impaired renal function is significantly slowed down. When you re-enter accumulates in the tissues in the form of polyglutamate. Use in children Use of methotrexate is contraindicated in children under 3 years of age.
Use during pregnancy and lactation
It has a teratogenic effect: it can cause fetal death, congenital deformities. If a woman becomes pregnant during therapy with methotrexate, it is necessary to decide on the termination of pregnancy due to the risk of adverse effects on the fetus. Methotrexate is excreted in breast milk; breastfeeding should be discontinued for the entire course of treatment.
Dosage and administration
Methotrexate pills used inside. Doses and terms of treatment are set individually depending on the chemotherapy regimen. Trophoblastic tumors: 15-30 mg orally, daily for 5 days with an interval of one or more weeks (depending on signs of toxicity). The course of treatment is usually repeated 3 to 5 times. At 50 mg 1 time in 5 days with an interval of at least 1 month. The course of treatment requires 300-400 mg. Acute lymphoblastic leukemia (as part of complex therapy): 3.3 mg / m 2 in combination with prednisone until remission is reached, then 15 mg / m 2 2 times a week or 2.5 mg / kg every 14 days. Non-Hodgkin's lymphomas (as part of complex therapy): 15-20 mg / m 2 for 1 dose 2 times a week. 7.5 mg / m 2 daily for 5 days. Rheumatoid arthritis: the initial dose is usually 7.5 mg once a week, which is taken at one time or divided into three doses with an interval of 12 hours. To achieve the optimal effect, the weekly dose may be increased, and it should not exceed 20 mg. When the optimal clinical effect is achieved, the dose should be reduced to the lowest effective dose. The optimal duration of treatment is not known. Psoriasis: therapy with methotrexate is carried out in doses of 10 to 25 mg per week. The dose is usually increased gradually, when the optimal clinical effect is reached, the dose reduction is started until the lowest effective dose is reached. Fungal mycosis: 25 mg 2 times a week. Dose reduction or cancellation of the drug is determined by the patient's response and hematological parameters.
On the part of the hemopoietic system: anemia (including aplastic), thrombocytopenia, leukopenia, neutropenia, agranulocytosis, eosinophilia, pancytopenia, lymphoproliferative diseases, hypogammaglobulinemia, lymphadenopathy. On the digestive system, anorexia, anorexia, for example, if there is a problem, an anorexia, a mode, a mode, a mode, is used, anchorage, anorexia, a redness, anorexia, etc., if a route has a redox cell size, anorexia, anorexia, anorexia, eosinophilia.stomatitis, gingivitis, pharyngitis, enteritis, erosive and ulcerative lesions and bleeding from the gastrointestinal tract (including melena, hematemesis), hepatotoxicity (acute hepatitis, fibrosis and cirrhosis, hepatic failure, hypoalbuminemia, increased activity of hepatic transaminases, pancreatitis) nervous system: headache, dizziness, drowsiness, dysarthria, aphasia, hemiparesis, paresis, cramps; when used in high doses, transient cognitive impairment, emotional lability; unusual cranial sensitivity, encephalopathy (including leukoencephalopathy). On the part of the organ of vision: conjunctivitis, visual impairment (including transient blindness). On the part of the cardiovascular system: pericarditis, pericardial effusion, lowering blood pressure, thromboembolism (including arterial thrombosis, cerebral vascular thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolism). On the respiratory system: rarely - pulmonary fibrosis, respiratory failure, alveolitis, interstitial pneumonitis (including fatal), chronic obstructive pulmonary disease (COPD), symptoms of potentially serious interstitial pneumonia - dry non-productive cough, shortness of breath, fever. From the genitourinary system: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria, disorder spermato-and ovogenesis, transient oligospermia, decreased libido, impotence, dysmenorrhea, vaginal discharge, gynecomastia, infertility, miscarriage, fetal death, fetal development defects. On the skin side: erythematous rash, itching, rash, photosensitivity, impaired skin pigmentation, alopecia, ecchymosis, telangiectasia, acne, abrasions, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis, ulceration and necrosis of the skin, exfoliative dermatitis. In the treatment of psoriasis - a burning sensation of the skin, painful erosive plaques on the skin. On the side of the musculoskeletal system: arthralgia, myalgia, osteoporosis, osteonecrosis, fractures. New formations: lymphoma (including reversible). General reactions: allergic reactions down to anaphylactic shock , allergic vasculitis, tumor lysis syndrome, soft tissue necrosis, sudden death,life-threatening opportunistic infections (including Pneumocystis pneumonia), cytomegalovirus (CMV) infections (including CMV pneumonia), sepsis (including fatal), nocardiosis, histoplasmosis, cryptoccosis, infections caused by Herpes zoster and Herpes simplex (including including disseminated herpes), diabetes mellitus, increased sweating.
There are no specific symptoms of an overdose of methotrexate, it is diagnosed by the concentration of methotrexate in plasma. Treatment: Administration of a specific antidote - calcium folinate whenever possible immediately, preferably within the first hour, in 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 the urine is alkalinized, which speeds up the release of methotrexate. To minimize the risk of nephropathy as a result of sedimentation of the drug or its metabolites in the urine, it is necessary to additionally determine the urine pH before each injection and every 6 hours throughout the entire period of use of calcium folinate as an antidote, until plasma methotrexate concentration drops below 0.05 μmol / l, to ensure a pH above 7.
Interaction with other drugs
Increases the anticoagulant activity of coumarin or indanedione derivatives and / or increases the risk of bleeding by reducing the synthesis of procoagulant factor in the liver and disturbed platelet formation. allopurinol, colchicine, sulfinpyrazon); the use of uricosuric anti-gouty drugs may increase the risk of nephropathy associated with increased formation of uric acid during treatment with methotrexate (it is preferable to use allopurinol). Simultaneous administration of salicylates, phenylbutazone, phenytoin, sulfonamides, sulfonylurea derivatives, aminobenzoic acid, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, tetracycline, chloramphenicol),indirect anticoagulants and lipid-lowering drugs (Kolestiramine) increases toxicity by displacing methotrexate from albumin and / or reducing tubular secretion, which in some cases may cause the development of severe toxic effects, sometimes even fatal. Non-steroidal anti-inflammatory drugs (NSAIDs) the background of high doses of methotrexate increase the concentration and slow down the elimination of the latter, which can lead to death from severe hematological and gastrointestinal neck intoxication. It is recommended to stop taking phenylbutazone for 7-12 days, piroxicam for 10 days, diflunisal and indomethacin for 24-48 h, ketoprofen and NSAIDs with a short T1 / 2 for 12-24 h before the infusion of methotrexate in moderate and high doses and for at least 12 hours (depending on the concentration of methotrexate in the blood) after its completion. Caution should be exercised when combining NSAIDs with low doses of methotrexate (possibly reducing the excretion of methotrexate by the renal tubules). Drugs that block tubular secretion (for example, probenecid) increase the toxicity of methotrexate by reducing its excretion by the kidneys. Antibiotics poorly absorbed in the gastrointestinal tract (tetracyclines, chloramphenicol) reduce the absorption of methotrexate and disrupt its metabolism due to the suppression of normal intestinal microflora. sulfasalazine, ethanol and other hepatotoxic drugs increase the risk of developing hepatotoxicity. L-asparaginase reduces the severity of the antitumor effect and methotrexate by inhibiting cell replication. Anesthesia using dinitrogen oxide can lead to the development of unpredictable severe myelosuppression and stomatitis. Use of cytarabine 48 hours before or within 10 minutes after initiation of methotrexate therapy may cause the development of synergistic cytotoxic effect (correction of dosage regimen based on the control of hematological parameters). Hematotoxic drugs increase the risk of hematotoxicity metotreksata.Metotreksat reduces teofilina.Neomitsin clearance for oral administration can reduce the absorption of methotrexate.Several patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (methoxen and ultraviolet irradiation (UFO)) have been diagnosed with skin cancer. Combination with radiation therapy may increase the risk of bone marrow suppression. Methotrexate can reduce the immune response to vaccination with live and inactivated viral vaccines. Folate-containing drugs (including multivitamins) can reduce the effectiveness of methotrexate therapy. Purpose of amiodarone to patients receiving methotrexate for psoriasis can cause skin manifestation.
Methotrexate is a cytotoxic drug, so care must be taken when handling it. The drug should be prescribed by a doctor who has experience with methotrexate and is familiar with its properties and characteristics of the action. Due to the possible development of severe and even fatal adverse reactions, patients should be fully informed by the doctor about possible risks and recommended safety measures. Patients undergoing therapy with methotrexate should be properly monitored so that signs of possible toxic effects and adverse reactions are detected and evaluated in a timely manner. Before starting or resuming therapy with methotrexate, a complete general blood count should be performed with a platelet count, a biochemical blood test with enzyme values determined liver, bilirubin, serum albumin, chest x-ray, kidney function Duration: tests for tuberculosis and hepatitis. To detect symptoms of intoxication in time, it is necessary to monitor the state of peripheral blood (the number of leukocytes and platelets: first every other day, then every 3-5 days during the first month, then 1 time in 7-10 days, during remission - once every 1-2 weeks., liver transaminase activity, kidney function (urea nitrogen, creatinine clearance and / or serum creatine), serum uric acid concentration, periodically x-ray chest organs, examination oral mucosa and pharynx for the presence of ulceration before each use.Monitoring of bone marrow hematopoiesis is recommended before treatment, 1 time during the treatment period and at the end of the course. Metotrexate can potentially lead to the development of symptoms of acute or chronic hepatotoxicity (including fibrosis and cirrhosis of the liver). Chronic hepatotoxicity usually develops after long-term use of methotrexate (usually for 2 or more years) or a total cumulative dose of at least 1.5 g is reached and may lead to an unfavorable outcome. The hepatotoxic effect may also be due to the burdened concomitant history (alcoholism, obesity, diabetes mellitus) and old age. Due to the toxic effects of the drug on the liver during treatment, one should refrain from prescribing other hepatotoxic drugs to patients except in cases of obvious need. Patients taking other hepatotoxic drugs (for example, leflunomide) should be carefully monitored. In order to objectify liver function, along with biochemical parameters, a liver biopsy is recommended before or after 2-4 months after starting treatment; with a total cumulative dose of 1.5 g and after each additional 1-1.5 g. With moderate liver fibrosis or any degree of cirrhosis, therapy with methotrexate is canceled; for mild fibrosis, it is usually recommended to repeat the biopsy after 6 months. During initial therapy, minor histological changes in the liver are possible (minor portal inflammation and fatty changes), which is not a reason for refusing or discontinuing treatment, but indicates the need for caution when using the drug. hemorrhagic enteritis and perforation of the intestinal wall, which can lead to the death of the patient. too long sun exposure, or abused UV lamp (photosensitivity reaction is possible). Due to its effect on the immune system, methotrexate can worsen the response to vaccination and affect the results of immunological tests.It is necessary to refuse immunization (if it is not approved by the doctor) in the range from 3 to 12 months after taking the drug; other family members of the patient living with him should refuse to immunize with oral polio vaccine (avoid contact with people who received the polio vaccine, or wear a protective mask that covers the nose and mouth). Patients of childbearing age of both sexes and their partners should use reliable contraceptive measures during treatment with methotrexate and after treatment for at least 3 months - men and at least one ovulation cycle - women. After the course of treatment with high doses of methotrexate, it is recommended that Calcium folinate Since methotrexate can affect the central nervous system (feeling tired, dizzy), patients taking the drug should refrain from Xia from operating a vehicle or potentially dangerous machinery.