Methotrexate, 2.5mg 50 pcs.

• acute lymphoblastic leukemia and non-Hodgkin’s lymphoma;
• trophoblastic tumors;
• Fungal mycosis in advanced stages.
• Fungal mycosis in advanced stages;
• severe forms of psoriasis;
• rheumatoid arthritis (when other therapies fail).

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Active ingredient

Composition

1 tablet contains:

Active substances:

Methotrexate 2.5 mg.

Associates:

sugar (sucrose) – 43.97 mg,

potato starch – 21.82 mg,

Talc – 680 µg,

calcium stearate – 340 µg,

crospovidone – 340 µg,

povidone – 350 µg.

Composition of the shell:

sugar (sucrose) – 32.5865 mg, magnesium hydroxycarbonate hydrate – 20.457 mg, wheat flour – 16.144 mg, povidone – 166 µg, gelatin – 138 µg, azorubin dye (E122) (carmoisine, acid red dye 2C) – 16.6 µg, titanium dioxide – 450 µg, wax – 27.9 µg, talc – 14 µg.

How to take, the dosage

Methotrexate tablets are used orally. Doses and timing of treatment are set individually depending on the chemotherapy regimen.

Trophoblastic tumors:

Acute lymphoblastic leukemia (as part of complex therapy):

Non-Hodgkin lymphoma (as part of combination therapy):

Rheumatoid arthritis:

The starting dose is usually 7.5 mg once weekly, taken once daily or divided into three doses at 12-hour intervals. For optimal effect, the weekly dose may be increased, but should not exceed 20 mg. When optimal clinical effect is achieved, dose reduction should be initiated until the lowest effective dose is achieved. The optimal duration of therapy is not known. In juvenile chronic arthritis, doses of 10-30 mg/m2/week (0.3-1 mg/kg) are effective in children.

Psoriasis:

Methotrexate therapy is given in doses of 10 to 25 mg/week. The dose is usually increased gradually; when optimal clinical effect is achieved, dose reduction is started until the lowest effective dose is achieved.

Fungal mycosis:

Interaction

Increases aithikoagulant activity of coumarin or indandion derivatives and/or increases the risk of bleeding by reducing the synthesis in the liver of procoagulant factor and impairment of platelet formation.

Increases the concentration of uric acid in the blood, therefore, when treating patients with concomitant hyperuricemia and gout it may be necessary to adjust the dose of antipodagric agents (allopurinol, colchicine, sulfinpyrazone); use of uricosuric antipodagric drugs may increase the risk of nephropathy associated with increased uric acid formation during treatment with methotrexate (allopurinol is preferable). Concomitant use of salicylates, phenylbutazone, phenytoin, sulfonamides, sulfonylurea derivatives, aminobenzoic acid, pyrimethamine or trimethoprim, some antibiotics (penicillin, tetracycline, chloramphenicol), Indirect anticoagulants and hypolipidemic drugs (colestyramine) increase toxicity due to displacement of methotrexate from binding to albumin and/or decrease in tubular secretion, which in some cases may cause development of severe toxic effect, sometimes even with lethal outcome.

Non-steroidal anti-inflammatory drugs (NSAIDs) against a background of high doses of methotrexate increase the concentration and delay elimination of the latter, which can lead to death from severe hematological and gastrointestinal intoxication. It is recommended to stop phenylbutazone 7-12 days, pyroxicam 10 days, diflunisal and indomethacin 24-48 h, ketoprofen and NSAIDs with short T1/2 12-24 h before methotrexate infusion in moderate and high doses and for at least 12 h (depending on methotrexate concentration in blood) after its completion. Caution should be exercised when combining NSAIDs with low doses of methotrexate (renal tubular excretion of methotrexate may decrease). Medicinal products that block renal tubular secretion (e.g. probenecid) increase methotrexate toxicity by reducing its excretion by the kidneys.

Antibiotics that are poorly absorbed in the gastrointestinal tract (tetracyclines, chloramphenicol) reduce absorption of methotrexate and disrupt its metabolism by inhibiting normal gut flora.

Retinoids, azathioprine, sulfasalazine, ethanol and other hepatotoxic drugs increase the risk of hepatotoxicity.

L-asparaginase reduces the anti-tumor effects of methotrexate by inhibiting cell replication.

The administration of anesthesia with dinitrogen oxide may lead to the development of unpredictable severe myelosuppression and stomatitis.

The use of cytarabine 48 hours before or within 10 minutes after initiation of methotrexate therapy may be associated with a synergistic cytotoxic effect (dosing adjustment is recommended based on hematologic monitoring).

Hematotoxic drugs increase the risk of hematotoxicity of methotrexate.

Methotrexate decreases theophylline clearance.

Intravenous neomycin may decrease the absorption of methotrexate. Several patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (methoxalen and ultraviolet irradiation (UVI)) have been found to have skin cancer.

Combination with radiation therapy may increase the risk of bone marrow suppression. Methotrexate may decrease the immune response to live and inactivated viral vaccines.

Folate-containing medications (including multivitamins) may decrease the effectiveness of methotrexate therapy.

Prescribing amiodarone to patients receiving methotrexate therapy for psoriasis may cause skin eruptions.

Special Instructions

Methotrexate is a cytotoxic drug, so care must be taken when handling it. The drug should be prescribed by a physician experienced in the use of methotrexate and familiar with its properties and characteristics of action. Because of the possibility of severe or even fatal adverse reactions, patients should be fully informed by their physician about the possible risks and the recommended precautions. Patients on methotrexate therapy should be appropriately monitored to ensure that signs of possible toxic effects and adverse reactions are identified and evaluated in a timely manner.

Before starting or resuming methotrexate therapy, a complete blood count with platelet count, biochemical blood counts to determine liver enzymes, bilirubin, serum albumin, chest x-ray, renal function tests, and tests for tuberculosis and hepatitis should be performed if necessary.

For timely detection of intoxication symptoms it is necessary to monitor the peripheral blood (number of leukocytes and platelets: first every day, then every 3-5 days during the first month, then once every 7-10 days, in remission period – once every 1-2 weeks.), “hepatic” transaminase activity, kidney function (urea nitrogen, creatinine clearance and/or serum creatinine), serum uric acid concentration, periodic chest x-ray examination, examination of the oral and pharyngeal mucosa for ulceration before each use. Monitoring of the state of bone marrow hematopoiesis is recommended before treatment, once during treatment and at the end of the course.

Methotrexate has the potential to cause symptoms of acute or chronic hepatotoxicity (including liver fibrosis and cirrhosis). Chronic hepatotoxicity usually develops after long-term use of methotrexate (usually for 2 or more years) or reaching a total cumulative dose of at least 1.5 g and may lead to an adverse outcome. Hepatotoxic effect may also be due to a concomitant history (alcoholism, obesity, diabetes mellitus) and old age. Due to the toxic effect of the drug on the liver, patients should be refrained from prescribing other hepatotoxic drugs during treatment, except in cases of obvious necessity. Patients taking other hepatotoxic drugs (e.g., leflunomide) should be closely monitored.

To objectify liver function along with biochemical parameters, a liver biopsy is recommended before or 2-4 months after treatment initiation; at a total cumulative dose of 1.5 g and after each additional 1-1.5 g. For moderate liver fibrosis or any degree of cirrhosis, methotrexate therapy is discontinued; for mild fibrosis, a repeat biopsy is usually recommended after 6 months. Minor histologic changes to the liver (minor portal inflammation and fatty changes) are possible during initial therapy, which is not a reason for discontinuing or stopping treatment, but indicates that caution should be exercised when using the drug.

In case of diarrhea and ulcerative stomatitis, methotrexate therapy should be stopped due to high risk of hemorrhagic enteritis and bowel wall perforation, which can lead to death of the patient.

Perhaps do not expose unprotected skin to prolonged exposure to sunlight or abuse a UVB lamp (photosensitization reaction possible). Due to its effect on the immune system, methotrexate may impair the response to vaccinations and affect immunological test results. Vaccination should be stopped (unless approved by doctor) between 3 and 12 months after taking the vaccine; other family members who are living with the patient should stop receiving oral polio vaccine (avoid contacts with people who have received polio vaccine or wear a mask that covers the mouth and nose). Patients of childbearing age of both sexes and their partners should use reliable contraception during methotrexate treatment and after treatment for at least 3 months for men and at least one ovulation cycle for women.

After treatment with high-dose methotrexate, the use of calcium folinate is recommended to reduce its toxicity.

Influence on the ability to drive vehicles and other mechanisms requiring increased concentration

As methotrexate can affect the central nervous system (feeling of fatigue, dizziness), patients taking the drug should refrain from driving vehicles or potentially dangerous mechanisms.

Contraindications

The use of methotrexate is contraindicated:

With caution: with ascites, pleural effusion, gastric and duodenal ulcers, ulcerative colitis, dehydration, history of gout or nephrolithiasis, previous radiation therapy or chemotherapy, infectious diseases of viral, fungal or bacterial nature.

Side effects

Blood system disorders: anemia (including aplastic), thrombocytopenia, leukopenia, neutropenia, agranulocytosis, eosinophilia, pancytopenia, lymphoproliferative diseases, hypogammaglobulinemia, lymphadenopathy.

Digestive system disorders: Anorexia, nausea, vomiting, stomatitis, gingivitis, pharyngitis, enteritis, erosive ulcerative lesions and bleeding from the GI tract (including melena, hematemesis), hepatotoxicity (acute hepatitis, liver fibrosis and cirrhosis, liver failure, hypoalbuminemia, increased activity of “liver” transaminases), pancreatitis.

Nervous system disorders: headache, dizziness, somnolence, dysarthria, aphasia, hemiparesis, paresis, convulsions; when used in high doses – transient cognitive impairment, emotional lability; unusual cranial sensitivity, encephalopathy (including leukoencephalopathy).

VIight: conjunctivitis, visual impairment (including transient blindness).

Cardiovascular system disorders: pericarditis, pericardial effusion, decreased BP, thromboembolism (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolism).

Respiratory system disorders: rare – 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.

Urogenital system disorders: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria, impaired spermatogenesis and ovogenesis, transient oligospermia, decreased libido, impotence, dysmenorrhea, vaginal discharge, gynecomastia, sterility, miscarriage, fetal death, fetal defects.

Skin disorders: erythematous rash, skin itching, urticaria, photosensitivity, skin pigmentation disorders, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis, skin ulceration and necrosis, exfoliative dermatitis. In the treatment of psoriasis – a burning sensation of the skin, painful erosive plaques on the skin.

Musculoskeletal system: arthralgia, myalgia, osteoporosis, osteonecrosis, fractures.

Novoplasms: lymphoma (including reversible).

General reactions: Allergic reactions up to and including 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), nocardiasis, histoplasmosis, cryptococcosis, infections caused by Herpes zoster and Herpes simplex (including disseminated herpes), diabetes, excessive sweating.

Overdose

There are no specific symptoms of methotrexate overdose, diagnosed by plasma concentration of methotrexate.

Treatment: Administration of specific antidote – calcium folinate if 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 concentration of methotrexate in blood serum.

In order to prevent precipitation of methotrexate and/or its metabolites in the renal tubules, the body is hydrated and the urine is alkalized, which accelerates excretion of methotrexate. To minimize the risk of nephropathy as a result of precipitation of the drug or its metabolites in the urine, the urine pH should be additionally determined before each administration and every 6 h throughout the duration of calcium folinate as an antidote until the plasma concentration of methotrexate is below 0.05 µmol/L, to ensure a pH above 7.

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