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An antitumor, cytostatic agent of the group of antimetabolites, suppresses dihydrofolate reductase, which is 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. Rapidly proliferating tissues are especially sensitive to the action: 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 taking 30 mg / m2 well absorbed, the average bioavailability - 60%. Absorption is reduced when taken in doses exceeding 80 mg / m2.
In children with leukemia, absorption ranges from 23% to 95%. 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 drug in the initial phase is 2-4 hours, and in the final phase (which is long) - 3-10 hours with small and 8-15 hours with high doses of the drug. In chronic renal failure, both phases of drug withdrawal can be significantly prolonged.
Excreted mainly by the kidneys in unchanged form by glomerular filtration and tubular secretion, up to 10% is excreted in the bile (with subsequent reabsorption in the intestine). Removal of the drug in patients with impaired renal function, severe ascites or transudate is significantly slowed down. When reintroduced accumulates in tissues in the form of polyglutamates.
- Acute lymphoblastic leukemia and non-Hodgkin lymphomas;
- trophoblastic tumors;
- mushroom mycosis in advanced stages;
- severe forms of psoriasis;
- rheumatoid arthritis (with the failure of other therapies).
1 tablet contains:
Active substances: methotrexate 2.5 mg.
Excipients: sugar (sucrose) - 43.97 mg, potato starch - 21.82 mg, talc - 680 mcg, calcium stearate - 340 mcg, crospovidone - 340 mcg, povidone - 350 mcg.
Shell composition: sugar (sucrose) - 32.5865 mg, magnesium hydroxycarbonate hydrate - 20.457 mg, wheat flour - 16.144 mg, povidone - 166 μg, gelatin - 138 μg, dye azorubine (E122) (carmoisin, dye acid red 2C) - 16.6 mcg, titanium dioxide - 450 mcg, wax - 27.9 mcg, talc - 14 mcg.
Methotrexate is marketed under different brands and generic names, and comes in different dosage forms:
|Brand name||Manufacturer||Country||Dosage form|
|Methotrexate-Ebeve||Ebeve Pharma||Austria||solution concentrate|
|Metorthrit®||K.O.Romparm Company S.R.L||Romania||solution|
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Dosage and Administration
Methotrexate pills used inside. Doses and terms of treatment are set individually depending on the chemotherapy regimen.
- 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.
- on 50 mg 1 time in 5 days with an interval not less than 1 month. The course of treatment requires 300-400 mg.
Acute lymphoblastic leukemia (as part of complex therapy):
- 3.3 mg / m2 in combination with prednisone to achieve remission, then 15 mg / m2 once a week or 2.5 mg / kg every 14 days.
Non-Hodgkin lymphomas (as part of complex therapy):
- 15-20 mg / m2 for 1 reception 2 times a week;
- 7.5 mg / m2 daily for 5 days.
The initial dose is usually 7.5 mg once a week, which is taken at once or divided into three doses at intervals of 12 hours. To achieve an optimal effect, the weekly dose may be increased, but it should not exceed 20 mg. When the optimal clinical effect is achieved, the dose should be lowered until the lowest effective dose is reached. The optimal duration of treatment is not known. In juvenile chronic arthritis for children, doses of 10-30 mg / m are effective.2/ week (0.3-1 mg / kg).
Methotrexate therapy 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 begins until the lowest effective dose is reached.
- 25 mg 2 times a week. Dose reduction or cancellation of the drug is determined by the patient's response and hematological parameters.
From the hemopoietic system: anemia (including aplastic), thrombocytopenia, leukopenia, neutropenia, agranulocytosis, eosinophilia, pancytopenia, lymphoproliferative diseases, hypogammaglobulinemia, lymphadenopathy.
From the digestive system: anorexia, nausea, vomiting, stomatitis, gingivitis, pharyngitis, enteritis, erosive and ulcerative lesions and bleeding from the gastrointestinal tract (including melena, hematemesis), hepatotoxicity (acute hepatitis, fibrosis and cirrhosis of the liver, hepatic failure, hypoalbuminemia, increased activity "transaminase), pancreatitis.
From the nervous system: headache, dizziness, drowsiness, dysarthria, aphasia, hemiparesis, paresis, convulsions; 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).
Since 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 part of 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 kidney failure, azotemia, cystitis, hematuria, proteinuria, impaired spermato-and ovogenesis, transient oligospermia, decreased libido, impotence, dysmenorrhea, vaginal discharge, gynecomastia, infertility, miscarriage, fetal death, fetal developmental defects.
On the part of the skin: erythematous rash, skin itchiness, urticaria, photosensitivity, impaired skin pigmentation, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis, skin necrosis, skin skin necrosis, skin skin necrosis, skin necrosis, skin necrosis, erythema multiforme In the treatment of psoriasis - a burning sensation of the skin, painful erosive plaques on the skin.
From the musculoskeletal system: arthralgia, myalgia, osteoporosis, osteonecrosis, fractures.
Neoplasm: lymphoma (including reversible).
General reactions: allergic reactions up to anaphylactic shock, allergic vasculitis, tumor lysis syndrome, soft tissue necrosis, sudden death, life-threatening opportunistic infections (including pneumocystic pneumonia), cytomegalovirus (CMV) infections (including CMV pneumonia), sepsis (in including fatal), nocardiosis, histoplasmosis, cryptococcosis, infections caused by Herpes zosteri and Herpes simplex (including disseminated herpes), diabetes mellitus, increased sweating.
The use of methotrexate is contraindicated:
- during pregnancy and lactation;
- with marked changes in renal function and liver;
- in hematological disorders (such as bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia);
- in the acute stage of infectious diseases;
- in immunodeficiency syndrome;
- in case of hypersensitivity to methotrexate or other components of the tablet;
- children up to 3 years.
Carefully: with ascites, pleural effusion, gastric ulcer and duodenal ulcer, ulcerative colitis, dehydration, gout or nephrolithiasis in history, previous radiotherapy or chemotherapy, infectious diseases of viral, fungal or bacterial nature.
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 impaired platelet formation.
Increases the concentration of uric acid in the blood, therefore, in the treatment of patients with concomitant hyperuricemia and gout, a dose adjustment of anti-gouty medicines (allopurinol, colchicine, sulfinpyrazon) may be required; 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 taking of a salmon / or reduction of tubular secretion, which in some cases may cause the development of severe toxic effects, sometimes even fatal.
Non-steroidal anti-inflammatory drugs (NSAIDs) with 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 intoxication. It is recommended to stop taking phenylbutazone for 7-12 days, piroxicam for 10 days, diflunisal and indomethacin for 24-48 hours, ketoprofen and NSAIDs with a short T1 / 2 for 12-24 hours before the administration 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 must be exercised when combining NSAIDs with low doses of methotrexate (possibly reduced removal 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 the normal intestinal microflora.
Retinoids, azathioprine, Sulfasalazinee, ethanol and other hepatotoxic drugs increase the risk of developing hepatotoxicity.
L-asparaginase reduces the severity of the anti-tumor effect of methotrexate by inhibiting cell replication.
Anesthesia with dinitrogen oxide can lead to the development of unpredictable severe myelosuppression and stomatitis.
The use of cytarabine 48 hours before or within 10 minutes after the start of therapy with methotrexate may cause the development of a synergistic cytotoxic effect (correction of the dosing regimen is recommended based on the control of hematological parameters).
Hematotoxic drugs increase the risk of methotrexate hematotoxicity.
Methotrexate reduces theophylline clearance.
Neomycin for oral administration may reduce the absorption of methotrexate. In several patients with psoriasis or fungal mycosis, treated with methotrexate in combination with PUVA therapy (methoxen and ultraviolet radiation), skin cancer was detected.
Combination with radiation therapy may increase the risk of bone marrow depression. 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.
The administration of amiodarone to patients receiving methotrexate therapy for psoriasis may cause skin manifestation.
Pregnancy and Lactation
It has a teratogenic effect: 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, for the period of the entire course of treatment breastfeeding should be stopped.
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 adequately 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 complete blood count should be performed with platelet count, a biochemical blood test with values for liver enzymes, bilirubin, serum albumin, chest x-ray, kidney function tests, and if necessary, tests for tuberculosis and hepatitis.
For timely detection of symptoms of intoxication, 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 once every 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 fluoroscopy of the chest organs, examination of the oral mucosa and pharynx e ulceration before each use. Monitoring the status of bone marrow hematopoiesis is recommended before treatment, 1 time during the treatment period and at the end of the course.
Methotrexate 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 can 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.
For the objectification of liver function, along with biochemical parameters, it is recommended to conduct a liver biopsy before beginning or 2-4 months after the start of 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 stopping treatment, but indicates the need for caution when using the drug
With the development of diarrhea and ulcerative stomatitis, therapy with methotrexate must be interrupted due to the high risk of hemorrhagic enteritis and perforation of the intestinal wall, which can lead to the death of the patient.
Do not expose unprotected skin to prolonged sun exposure or to abuse the 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 apply reliable contraceptive measures during treatment with methotrexate and after treatment for at least 3 months - men and at least one ovulation cycle - women.
After a course of treatment with high doses of methotrexate, calcium folinate is recommended to reduce its toxicity.
Impact on the ability to drive vehicles and other mechanisms that require high concentration of attention
Since methotrexate can affect the central nervous system (feeling tired, dizzy), patients taking the drug should refrain from driving or potentially dangerous machinery.
The specific symptoms of an overdose of methotrexate are absent, it is diagnosed by the concentration of methotrexate in the 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 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 administration 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.
- Brand name: Methotrexate
- Active ingredient: Methotrexate
- Dosage form: pills, coated.
- Manufacturer: Ozone
- Avascular necrosis of bone after adult acute lymphocytic leukemia treatment with methotrexate, vincristine, L-asparaginase, and dexamethasone (MOAD)
- Postsurgical sequential methotrexate, fluorouracil, and leucovorin for advanced colorectal carcinoma: A preliminary study
- Randomized comparison of moderate-dose methotrexate infusions to oral methotrexate in children with intermediate risk acute lymphoblastic leukemia: A Childrens Cancer Group study
- Sinushistiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): Response to methotrexate and mercaptopurine
- Intermediate-dose methotrexate versus cranial irradiation in childhood acute lymphoblastic leukemia: A ten-year follow-up
- Fractionated cyclophosphamide and back to back high dose methotrexate and cytosine arabinoside improves outcome in patients with stage III high grade small non-cleaved cell lymphomas (Snccl): A randomized trial of the pediatric oncology group
- Systemic near-fatal anaphylactic reaction after intrathecal methotrexate administration
- Long-term remission induced by corticosteroids, cyclophosphamide, and methotrexate in a patient with natural killer cell leukemia
- Successful rescue by oral cholestyramine of a patient with methotrexate nephrotoxicity: Nonrenal excretion of serum methotrexate
- Cutaneous side effects of medium dose methotrexate in children with acute lymphoblastic leukaemia
- Adult and two children with fetal methotrexate syndrome
- Developmental delay in fetal aminopterin/methotrexate syndrome
- FLR1 gene (ORF YBR008c) is required for benomyl and methotrexate resistance inSaccharomyces cerevisiae and its benomyl-induced expression is dependent on Pdr3 transcriptional regulator
- Meningeal carcinomatosis in patients with breast carcinoma: Clinical features, prognostic factors, and results of a high-dose intrathecal methotrexate regimen
- Anaphylactoid reactions to methotrexate
- Ifosfamide, etoposide, cytarabine, and methotrexate as salvage chemotherapy in relapsed or refractory aggressive non-Hodgkin's lymphoma
- Low dose methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone with zalcitabine in patients with acquired immunodeficiency syndrome-related lymphoma: Effect on human immunodeficiency virus and serum interleukin-6 levels over time
- A phase I trial of a modified, dose intensive FAMTX regimen (High dose 5-fluorouracil + doxorubicin + high dose methotrexate + leucovorin) with oral uridine rescue
- Influence of methotrexate dose intensity on outcome of patients with high grade osteogenic osteosarcoma: Analysis of the literature
- Methotrexate bound to carbon particles used for treating cancers with lymph node metastases in animal experiments and a clinical pilot study
- Mitoxantrone, 5-fluorouracil, and high dose leucovorin (NFL) versus intravenous cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) in first-line chemotherapy for patients with metastatic breast carcinoma : A randomized Phase II trial
- A Phase II trial of methotrexate, vinblastine, doxorubicin, and cisplatin in the treatment of metastatic carcinoma of the uterine cervix
- Influence of Methotrexate Dose Intensity on Outcome of Patients with High Grade Osteogenic Osteosarcoma : Analysis of the literature
- A comparative study of the long term psychosocial functioning of childhood acute lymphoblastic leukemia survivors treated by intrathecal methotrexate with or without cranial radiation