Methotrexate-teva

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METHOTREXATE-TEVA (METHOTREXATE-TEVA)

Composition:

Active substance: methotrexate;

1 ml of solution contains methotrexate 100 mg;

Excipients: sodium hydroxide, hydrochloric acid diluted (if necessary), water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: clear solution, ranging in color from orange to brown, practically free from mechanical particles.

Pharmacotherapeutic group. Antimetabolites. Structural analogues of folic acid. ATC code L01BA01.

Pharmacological Properties

Pharmacodynamics

Methotrexate is a folic acid antagonist that competitively inhibits dihydrofolate reductase, an enzyme responsible for converting folic acid into tetrahydrofolic acid. Inhibition of tetrahydrofolate formation limits the availability of one-carbon fragments required for purine synthesis and the conversion of deoxyuridylate to thymidylate during DNA synthesis, resulting in suppression of cellular repair and replication processes.

Pharmacokinetics

After parenteral administration, methotrexate is actively transported across cell membranes and distributed throughout the body tissues, with higher concentrations accumulating in the kidneys, gallbladder, spleen, liver, and skin. Methotrexate competes with reduced folates for active transport across cell membranes via a unidirectional, carrier-mediated active transport process. Approximately 50% of the drug in the blood is protein-bound and may be retained for several weeks in the kidneys and liver. Sustained plasma concentrations and tissue accumulation of methotrexate can be achieved through daily repeated dosing. Following parenteral administration, drug concentrations in cerebrospinal fluid do not reach therapeutic levels. Methotrexate crosses the placenta and is excreted into breast milk. The highest ratio of methotrexate concentration in breast milk to plasma concentration is 0.08:1.

Methotrexate undergoes hepatic and intracellular metabolism to form polyglutamate derivatives, which can be converted back to methotrexate by hydrolytic enzymes.

The drug is primarily eliminated via the kidneys through glomerular filtration and active tubular secretion. A small amount is excreted in bile and eliminated in feces. A significant correlation has been observed between methotrexate clearance and creatinine clearance.

Clinical characteristics.

Indications.

Trophoblastic tumors (choriocarcinoma, chorionadenoma, hydatidiform mole), acute lymphoblastic leukemia, neuroleukemia, osteosarcoma, non-Hodgkin’s lymphoma, Burkitt’s lymphoma, advanced stages of head and neck cancer, breast cancer, advanced stages of mycosis fungoides, severe forms of psoriasis, severe cases of rheumatoid arthritis.

Contraindications.

Hypersensitivity to the components of the drug, pregnancy (when used for non-oncological indications) or breastfeeding, poor nutritional status, hepatic insufficiency, renal insufficiency (creatinine clearance < 20 ml/min), disorders of the hematopoietic system (particularly bone marrow hypoplasia, leukopenia, thrombocytopenia, or severe anemia), alcohol abuse, pulmonary toxicity caused by methotrexate, severe acute or chronic infections (e.g., tuberculosis or AIDS), mucosal ulcers of the oral cavity or gastrointestinal tract, immunodeficiency syndrome (when used in patients with psoriasis or rheumatoid arthritis), vaccination with live vaccines during methotrexate therapy.

Special safety precautions.

When preparing injectable methotrexate, protective gloves, mask, and protective goggles should be used. Preparation of methotrexate, as with any cytostatic medicinal product, must be carried out in a room with vertical ventilation. Spilled medication should be washed off with sufficient amount of water.

Interaction with other medicinal products and other types of interactions.

Nonspecific anti-inflammatory drugs (NSAIDs) should not be administered before or during high-dose methotrexate therapy (> 10 mg methotrexate per week). Fatal cases due to severe hematological disorders and hemorrhage have been reported in association with concomitant use of high-dose methotrexate and certain NSAIDs.

Probenecid, weak organic acids (e.g., loop diuretics) and pyrazoles (phenylbutazone) may slow down methotrexate excretion, leading to increased serum concentration and enhanced hematological toxicity. The risk of toxic effects also increases with combined use of low-dose methotrexate and NSAIDs or salicylates. The potential toxicity of methotrexate is particularly increased when used concomitantly with NSAIDs and diuretics. In rheumatology, combination of low-dose methotrexate with NSAIDs is usually applied. Close monitoring of the patient is required when these drugs are used concomitantly.

Protein-bound methotrexate may be displaced by salicylates, NSAIDs (e.g., phenylbutazone), sulfonamides, hypoglycemic agents, diuretics, phenytoin, barbiturates, tranquilizers, oral contraceptives, tetracyclines, chloramphenicol, aminopyrine derivatives, p-aminobenzoic acid, doxorubicin, bleomycin, cyclophosphamide, aminoglycosides, allopurinol, vincristine, hydrocortisone, prednisone, asparaginase, and cytarabine. Increased plasma concentration of unbound methotrexate may enhance toxic effects.

High-dose methotrexate should be used with caution in combination with potentially nephrotoxic agents (e.g., cisplatin).

Pharmacokinetic interactions between methotrexate and anticonvulsants, as well as between methotrexate and 5-fluorouracil, should be taken into account.

Methotrexate should be used cautiously in combination with potentially hepatotoxic substances (e.g., alcohol, leflunomide, azathioprine, sulfasalazine, and retinoids). Regular alcohol consumption and use of additional hepatotoxic drugs increase the likelihood of hepatotoxic effects of methotrexate.

Oral antibiotics (including tetracyclines, chloramphenicol, and broad-spectrum antibiotics not absorbed by the body, so-called intestinal antiseptics) may reduce methotrexate absorption or affect enterohepatic circulation due to inhibition of intestinal flora or suppression of bacterial metabolism.

Penicillins may reduce methotrexate excretion, potentially increasing toxicity. Antibiotics such as penicillins, glycopeptides, sulfonamides, ciprofloxacin, and cephalothin may reduce renal clearance of methotrexate, leading to increased serum concentration and enhanced toxic effects on the hematopoietic system and gastrointestinal tract.

When concomitant therapy with drugs that may cause adverse effects on the bone marrow (e.g., sulfonamides, trimethoprim/sulfamethoxazole, chloramphenicol, pyrimethamine) is used, the possibility of more pronounced hematological disorders should be considered.

Concomitant use of metamizole and methotrexate may enhance the hematotoxic effect of methotrexate, especially in elderly patients. Therefore, such concomitant use should be avoided.

When used in combination with other cytostatic agents, pharmacodynamic interaction may occur, manifested by increased therapeutic activity and enhanced toxicity.

In patients undergoing wave therapy, interaction with radioactive substances is possible.

Patients receiving methotrexate should not be vaccinated with live vaccines. Partial or full protection can be achieved with inactivated vaccines.

Due to possible effects on the immune system, methotrexate use may lead to inaccurate results in vaccination and laboratory tests (immunological procedures to detect immune response).

Vitamin solutions containing folic acid may reduce the efficacy of systemically administered methotrexate. High doses of calcium folinate may reduce the efficacy of intrathecally administered methotrexate. Folic acid deficiency may enhance methotrexate toxicity.

In some cases, potentiation of bone marrow suppression has been reported in patients treated with methotrexate in combination with folate antagonists (trimethoprim, sulfamethoxazole). The use of methotrexate in combination with sulfonamides is not recommended.

The use of nitrous oxide enhances the effect of methotrexate on folate metabolism, leading to increased toxicity (e.g., severe unpredictable myelosuppression, stomatitis, and, in case of intrathecal administration, severe unpredictable neurotoxicity). Although this effect can be mitigated by administration of calcium folinate, concomitant use of nitrous oxide and methotrexate should be avoided.

Methotrexate may reduce the clearance of theophylline.

During methotrexate therapy, excessive consumption of beverages containing caffeine or theophylline (coffee, caffeinated drinks, black tea) should be avoided, as this may reduce the efficacy of methotrexate due to possible interaction between methotrexate and methylxanthines.

When methotrexate is used in combination with leflunomide, the risk of developing pancytopenia may increase. Methotrexate increases plasma levels of mercaptopurines. Therefore, dose adjustment may be necessary when using this combination.

Combination of methotrexate with immunomodulating agents should be used with caution, especially in orthopedic surgery, where susceptibility to infection is increased.

Toxic effects of methotrexate are generally not enhanced when used concomitantly with other antirheumatic drugs (e.g., gold salts, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine).

When methotrexate is used concomitantly with proton pump inhibitors (e.g., omeprazole, pantoprazole), interaction may occur. Omeprazole may reduce renal clearance of methotrexate, while pantoprazole may inhibit renal elimination of the metabolite 7-hydroxymethotrexate, which may be accompanied by development of myalgia and tremor.

When used in combination with sulfasalazine, the effect may be potentiated due to inhibition of folic acid synthesis by sulfasalazine (resulting in increased frequency of adverse effects).

Special precautions for use.

Treatment with methotrexate must be carried out under the supervision of a qualified oncologist experienced in the use of antineoplastic chemotherapeutic agents.

Treatment of psoriasis and rheumatoid arthritis should be conducted only under the supervision of a dermatologist and rheumatologist, respectively.

During methotrexate therapy, patients must be under close monitoring to allow timely detection of signs of potential toxic effects and adverse reactions. Due to the risk of severe or even fatal toxic reactions, patients should be thoroughly informed about possible complications and recommended preventive measures.

Administration of doses exceeding 20 mg per week is associated with a significant increase in toxicity, particularly bone marrow suppression.

Recommended investigations and preventive measures. Prior to initiating methotrexate therapy or resuming treatment after interruption, the following should be performed: complete blood count with white blood cell differential and platelet count, liver enzyme levels, bilirubin, serum albumin, chest X-ray, and renal function tests. When clinically indicated, tests to exclude tuberculosis and hepatitis should be performed.

During methotrexate therapy (at least once a month for the first 6 months and every 3 months thereafter), the following monitoring is recommended: oral and pharyngeal examination for mucosal changes; complete blood count with white blood cell differential, platelet count, and hematocrit; urinalysis and renal function tests; liver enzyme activity assessment; chest X-ray is recommended.

Patients with pleural effusion or ascites should be treated prior to initiating therapy to prevent prolonged methotrexate elimination half-life and development of toxic effects.

Even at usual therapeutic doses, methotrexate may cause sudden bone marrow suppression. In case of significant decrease in leukocyte or platelet counts, methotrexate therapy should be discontinued immediately and symptomatic supportive treatment initiated. Severe leukopenia during methotrexate therapy may lead to infectious complications. In such cases, therapy should be discontinued and appropriate antibacterial treatment initiated. In cases of severe bone marrow suppression, blood or platelet transfusions may be required. Patients should be instructed to promptly report any signs or symptoms suggestive of infection. Careful monitoring of leukocyte and platelet counts is necessary when methotrexate is used concomitantly with hematotoxic drugs (e.g., leflunomide).

Like other cytotoxic agents, methotrexate may cause tumor lysis syndrome in patients with rapidly proliferating tumors. Appropriate symptomatic treatment should be administered to prevent or reduce manifestations of this condition.

For psoriasis treatment, the following monitoring is recommended: monthly blood tests; liver and renal function tests every 1–3 months. Monitoring is usually more frequent during antineoplastic therapy. At the beginning of treatment, after dose adjustments, or during periods of increased risk of methotrexate accumulation (e.g., dehydration), more frequent medical evaluations are recommended.

When methotrexate is used for oncological indications, particular attention should be paid to signs of liver damage. Methotrexate therapy should not be initiated or should be suspended in case of any abnormalities in liver function tests or liver biopsy. Liver test parameters usually normalize within two weeks, after which treatment may be resumed at the physician’s discretion. Signs of liver fibrosis or cirrhosis require discontinuation of therapy. Further investigations are needed to determine whether serial liver biochemical tests or type III procollagen peptide tests are sufficient for early detection of hepatotoxicity. Such assessments should be individualized, considering the absence or presence of risk factors such as prior alcohol abuse, persistent elevation of liver enzymes, history of liver disease, familial hereditary liver disorders, diabetes, obesity, prior treatment with hepatotoxic drugs or exposure to hepatotoxic chemicals, prolonged methotrexate therapy, or cumulative dose of 1.5 g or more. Persistent elevation of liver enzyme activity warrants consideration of dose reduction or discontinuation of further therapy. Transient increases in transaminase levels (up to 2–3 times the upper limit of normal) have been reported in some patients. Persistent elevation of liver enzymes necessitates dose reduction or discontinuation of methotrexate therapy. Since methotrexate is hepatotoxic, other hepatotoxic drugs should not be prescribed during treatment unless absolutely necessary. Alcohol consumption should be avoided or significantly limited. Particular caution is required in patients receiving concomitant therapy with other hepatotoxic and hematotoxic agents (e.g., leflunomide), and liver enzyme levels should be closely monitored.

When methotrexate is used for non-oncological indications, treatment should not be initiated or should be suspended in case of persistent or significant abnormalities in liver function tests, non-invasive fibrosis tests, or liver biopsy results. Transient increases in transaminase levels (2–3 times above the upper limit of normal) have been reported in 13–20% of patients. Prolonged elevation of liver enzymes and/or decreased serum albumin may indicate severe hepatotoxicity. In case of persistent elevation of liver enzymes, dose reduction or discontinuation of methotrexate should be considered. Histological changes, fibrosis, and, more rarely, liver cirrhosis may occur without prior abnormalities in liver function tests. Cases of liver cirrhosis have been reported in patients with normal transaminase levels. Therefore, in addition to liver function tests, non-invasive diagnostic methods for liver monitoring should be considered. Liver biopsy should be considered on an individual basis, taking into account comorbidities, medical history, and biopsy-related risks. Risk factors for hepatotoxicity include prior alcohol abuse, persistent elevation of liver enzymes, history of liver disease, familial hereditary liver disorders, diabetes, obesity, prior use of hepatotoxic drugs or exposure to hepatotoxic substances, and prolonged methotrexate therapy. Additional hepatotoxic drugs should not be used during methotrexate therapy except when absolutely necessary. Alcohol consumption should be avoided. Liver enzyme levels should be closely monitored in patients receiving concomitant hepatotoxic therapy. Particular caution is advised in patients with insulin-dependent diabetes mellitus, as cases of liver cirrhosis have been reported without any elevation in transaminase levels.

Methotrexate should be used with caution in patients with infectious diseases, peptic ulcers, nonspecific ulcerative colitis, infants, and elderly patients.

Methotrexate may cause kidney damage and lead to renal failure. Regular monitoring of renal function, including urine alkalinity, and measurement of serum methotrexate levels are recommended. In cases of nephrotoxicity, methotrexate therapy should be discontinued.

In patients with possible renal impairment (e.g., elderly patients), methotrexate doses should be reduced. This is particularly important when methotrexate is used concomitantly with drugs affecting its excretion, causing kidney damage (e.g., nonsteroidal anti-inflammatory drugs), or potentially causing hematological disorders. Dehydration may potentiate methotrexate toxicity. Alkalinization of urine and increased diuresis are recommended, especially during high-dose therapy.

Fatal cases due to interstitial pneumonia and isolated cases of interstitial lung disease have been reported. Lung disease associated with methotrexate use at doses exceeding 7.5 mg per week may occur at any stage of treatment and can be life-threatening. This condition is not always reversible. Symptoms of lung disease or nonspecific pneumonitis (dyspnea, cough (especially dry and non-productive), fever) occurring during methotrexate therapy are often accompanied by eosinophilia and may indicate potentially severe damage, requiring discontinuation of therapy and thorough patient evaluation (including chest X-ray) to exclude infection. These symptoms should be monitored at every patient visit. In cases of methotrexate-induced pneumonitis, immediate discontinuation of therapy and corticosteroid treatment may be required. Reinitiation of methotrexate therapy after toxic lung injury is contraindicated.

Additionally, pulmonary alveolar hemorrhage has been reported with methotrexate use for rheumatological and related indications. This hemorrhage may also be associated with vasculitis and other comorbid conditions. In suspected cases of pulmonary alveolar hemorrhage, rapid diagnostic evaluation is required.

Diarrhea and ulcerative stomatitis require discontinuation of therapy due to the risk of hemorrhagic enteritis and fatal outcome from intestinal perforation.

For patients undergoing long-term therapy (e.g., psoriasis patients), there are no known carcinogenic factors. Data on carcinogenic effects in patients treated with methotrexate for rheumatoid arthritis are limited.

Photosensitivity. Photosensitivity, manifesting as increased sensitivity to sunburn, has been observed in some individuals taking methotrexate (see section "Adverse reactions"). Exposure to intense sunlight or UV radiation should be avoided unless medically indicated. Patients should use appropriate sun protection measures.

Radiation dermatitis and sunburn may occur after methotrexate use. Psoriatic lesions may worsen with combined UV exposure.

Cases of malignant lymphoma development have been reported in patients receiving low-dose methotrexate. In some cases, lymphoma regressed after methotrexate discontinuation without the need for cytotoxic therapy. In such cases, methotrexate therapy should first be discontinued. If remission does not occur, appropriate treatment should be initiated.

Concomitant use of folate antagonists (e.g., trimethoprim/sulfamethoxazole) may rarely cause acute pancytopenia.

Concurrent use of methotrexate with radiation therapy may increase the risk of soft tissue necrosis and osteonecrosis.

In children receiving methotrexate, periodic cognitive function tests are recommended to detect cognitive disorders at an early stage.

Since methotrexate affects the immune system, it may alter response to vaccination and affect immunological test results. Vaccination may be ineffective if administered during methotrexate therapy. Particular caution is required in patients with inactive chronic infections (e.g., herpes zoster, tuberculosis, hepatitis B or C) due to possible reactivation. Live vaccines should not be administered during methotrexate therapy. Generalized infections after smallpox vaccination have been reported in patients receiving methotrexate.

In cases of vomiting, diarrhea, or stomatitis that may lead to dehydration, methotrexate therapy should be withheld until the patient's condition normalizes.

The drug should be used with caution or avoided in patients with pre-existing blood disorders. In psoriasis treatment, methotrexate should be discontinued immediately in case of significant reduction in blood cell counts. Methotrexate therapy in cancer patients may be continued only if the potential benefit outweighs the risk of severe myelosuppression. Myelosuppression may also occur after intrathecal methotrexate administration. Patients with severe granulocytopenia and fever require immediate evaluation and usually parenteral broad-spectrum antibiotics.

For psoriasis treatment, methotrexate use should be limited to severe, disabling, and difficult-to-treat cases, only when other therapies are insufficiently effective, and only after biopsy confirmation and/or dermatologist consultation.

Vitamin preparations or other products containing folic acid, folinic acid, or their derivatives may reduce methotrexate efficacy.

Cases of encephalopathy/leukoencephalopathy have been reported in oncology patients receiving methotrexate, and such events cannot be excluded in non-oncology patients. Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving methotrexate, mostly in combination with other immunosuppressive agents. PML may be fatal and should be considered in the differential diagnosis of immunosuppressed patients with new or worsening neurological symptoms.

High-dose therapy. During high-dose treatment, folinic acid should be administered concomitantly. Serum methotrexate concentrations are appropriate indicators for determining the duration of folinic acid therapy. Residual methotrexate levels should be assessed 48 hours after the start of methotrexate infusion. If the residual methotrexate level is < 0.5 µmol/L, additional folinic acid administration is not required.

Fertility. Oligospermia, menstrual cycle disturbances, and amenorrhea have been reported during and for some time after methotrexate therapy. Methotrexate may impair fertility by affecting spermatogenesis and oogenesis during treatment. These effects are generally reversible after therapy discontinuation.

Teratogenicity. Methotrexate causes embryotoxicity, abortions, and congenital anomalies in humans. Therefore, women of childbearing potential must be informed about possible effects on fertility, pregnancy loss, and congenital malformations (see section "Pregnancy or breastfeeding"). When used for non-oncological indications, pregnancy must be excluded before initiating therapy. Effective contraception must be used by women of reproductive age during treatment and for at least 6 months after methotrexate discontinuation.

Pregnancy or breastfeeding.

Women of childbearing potential/Contraception in women

Women should not become pregnant during methotrexate therapy. Effective contraception must be used during treatment and for at least 6 months after therapy discontinuation. Women of reproductive age must be informed about the risk of methotrexate's adverse effects on the fetus, and pregnancy must be excluded by appropriate methods (e.g., pregnancy test) before initiating therapy. Pregnancy tests should be performed during treatment as clinically needed (e.g., after any contraceptive failure).

Contraception in men

There are no data on methotrexate levels in semen. Genotoxicity of methotrexate has been observed in animal studies; therefore, genotoxic effects on sperm cannot be completely ruled out. Limited clinical data do not indicate an increased risk of congenital malformations or miscarriage after paternal exposure to low methotrexate doses (< 30 mg per week). Data are insufficient to assess the risk of congenital malformations or miscarriage after paternal exposure to higher doses.

As a precautionary measure, sexually active male patients or their partners should use reliable contraception during treatment and for at least 3 months after methotrexate discontinuation. Men should not donate sperm during treatment or for 3 months after methotrexate discontinuation.

Pregnancy

Methotrexate use for non-oncological indications during pregnancy is contraindicated. If a patient becomes pregnant during methotrexate therapy or within 6 months after therapy discontinuation, she must be informed about the risk of adverse effects on the fetus. Ultrasound examinations should be performed to confirm normal fetal development.

Reproductive toxicity of methotrexate has been observed in animal studies, particularly in the first trimester. Teratogenic effects of methotrexate have been reported, including fetal death, miscarriages, and/or congenital anomalies (e.g., craniofacial, cardiovascular, central nervous system, and limb malformations).

Methotrexate is a potent human teratogen. Exposure during pregnancy increases the risk of spontaneous abortions, intrauterine growth retardation, and congenital malformations.

• Spontaneous abortions were reported in 42.5% of pregnant women who used low-dose methotrexate (< 30 mg per week), compared to 22.5% in patients using other drugs.
• Major congenital defects occurred in 6.6% of live-born children whose mothers used low-dose methotrexate (< 30 mg per week) during pregnancy, compared to approximately 4% in children whose mothers used other drugs.

There are insufficient data on methotrexate use during pregnancy at doses exceeding 30 mg per week, but a higher rate of spontaneous abortions and congenital malformations is expected, particularly at doses typically used for oncological indications.

Normal pregnancies have been reported after methotrexate discontinuation prior to conception.

For oncological indications, methotrexate should not be administered during pregnancy, especially during the first trimester. The benefit of treatment versus potential risk to the fetus must be carefully evaluated in each case. If methotrexate is used during pregnancy or if a patient undergoing methotrexate therapy becomes pregnant, she must be informed about the risk of adverse effects on the fetus.

Breastfeeding

Methotrexate is excreted in breast milk. Due to the potential for serious adverse reactions in infants, methotrexate is contraindicated during breastfeeding. Breastfeeding must be discontinued during methotrexate therapy.

Fertility

Methotrexate affects spermatogenesis and oogenesis and may reduce fertility. Oligospermia, menstrual cycle disturbances, and amenorrhea have been reported. These effects are generally reversible after therapy discontinuation.

For patients receiving methotrexate for oncological indications who plan to have children, consultation with genetic counseling centers is recommended, preferably before starting therapy. Men should consider sperm cryopreservation prior to therapy initiation due to the potential genotoxicity of methotrexate.

Ability to affect reaction speed when driving or operating machinery.

Since methotrexate may cause fatigue, somnolence, dizziness, visual disturbances, paresis, and hemiparesis, the drug may have a slight or moderate adverse effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Dosage and duration of treatment are determined individually depending on the chemotherapy regimen, indications, and patient tolerance. Treatment must be administered by a physician experienced in the use of methotrexate and who understands the risks associated with methotrexate therapy.

Methotrexate, solution for injection, does not contain any antimicrobial preservatives and therefore cannot be used from the same vial for subsequent doses.

When reconstituted with 0.9% sodium chloride solution or 5% glucose solution for infusion, chemical and physical stability of the prepared injection solution has been demonstrated for 24 hours at 15–25 °C.

Trophoblastic tumors. For patients without metastases or with trophoblastic tumors not posing a risk, the daily dose is 15–30 mg administered intramuscularly for 5 consecutive days. Such courses may be repeated 3–5 times as needed, with intervals of 1 week or longer.

For patients at high risk of developing trophoblastic tumors, combination therapy is often required, including 300 mg/m² of methotrexate followed by leucovorin (folinic acid).

Therapeutic efficacy is assessed by monitoring serum chorionic gonadotropin concentrations.

Acute lymphoblastic leukemia. Methotrexate should be used as part of combination therapy in acute lymphoblastic leukemia at a dose of 15–30 mg/m² administered intramuscularly or intravenously once weekly. Acute lymphoblastic leukemia in children must be treated according to a standardized chemotherapy protocol. The treatment protocol includes induction, consolidation, and reinduction phases and is regulated by the relevant order of the country's regulatory authority.

Neuroleukemia. The drug should be administered intrathecally at intervals of not less than 1 week. The maximum concentration for intrathecal administration is 1 mg/mL. The solution may be diluted with 0.9% sodium chloride solution. Dosage for intrathecal administration: for children aged 3 years and older – 12 mg.

For adults, the dose should not exceed 15 mg. Treatment should continue until cerebrospinal fluid cytology normalizes, after which one additional dose is recommended, followed by prophylactic doses equivalent in amount to therapeutic doses but with strictly individualized intervals.

Osteosarcoma. In the treatment of osteosarcoma, methotrexate should be administered at high doses (8–12 g/m²) in combination with other cytostatic agents, followed by leucovorin therapy (see section "High-dose methotrexate").

Lymphomas (including Burkitt’s lymphoma). At stages I–II, methotrexate may in some cases achieve long-term remission even when administered orally. At stage III, methotrexate should be used in combination with other antineoplastic agents. Treatment at all stages requires multiple therapy cycles with 7–10 day intervals. The dose of methotrexate in combination therapy is 0.625–2.5 mg/kg daily. Children with non-Hodgkin’s lymphoma should be treated according to the acute lymphoblastic leukemia treatment protocol.

Head and neck cancer. In monotherapy, administer 40 mg/m² once weekly until therapeutic effect is achieved. Folinic acid should not be used in this case.

Breast cancer. Methotrexate is administered intravenously at a dose of 10–60 mg/m². In advanced cases, it is usually administered in combination with other antineoplastic agents. The same regimens are used for adjuvant therapy after mastectomy and/or radiotherapy.

cutaneous T-cell lymphoma (Mycosis fungoides). Methotrexate is administered intramuscularly at a dose of 50 mg once weekly or 25 mg twice weekly.

In half of cases, methotrexate therapy leads to clinical remission. Dose reduction or discontinuation is determined by the patient's response and hematological parameters.

Psoriasis. Treatment of psoriasis in women should begin immediately after the end of the menstrual cycle. One week prior to starting methotrexate therapy, a test dose of 5–10 mg should be administered parenterally to detect idiosyncratic reactions.

For adults, the dosing regimen is as follows: 10–25 mg intramuscularly or intravenously once weekly. The dose should be gradually increased; once optimal clinical effect is achieved, the dose should be gradually reduced to the lowest effective level. Optimal results are achieved in most patients after 2–3 months, with improvement seen within 4 weeks of treatment. Discontinuation of the drug leads to symptom recurrence within 2 weeks to 6 months.

Rheumatoid arthritis. When methotrexate is administered intravenously or intramuscularly, the initial weekly dose for adult patients is 10 mg. If necessary, this dose may be gradually increased by 2.5 mg weekly up to a maximum of 25 mg. One week prior to starting methotrexate therapy, a test dose of 5–10 mg should be administered parenterally to detect idiosyncratic reactions.

Improvement is observed in most patients within 4–6 weeks. Clinical response is typically achieved after 6 months, after which dose adjustments may be needed to maintain optimal clinical response.

Relapse of rheumatoid arthritis may occur after discontinuation of therapy.

For the treatment of psoriasis and rheumatoid arthritis, methotrexate should be administered only once weekly. Dosing errors in methotrexate use may result in serious adverse reactions, including fatal outcomes. Careful attention must be paid to this section of the instructions for medical use.

High-dose methotrexate. At least 24 hours prior to methotrexate administration, oral sodium bicarbonate should be administered: 1 g every 4–6 hours. This should continue for at least 24 hours after the last dose of leucovorin. Prior to starting methotrexate therapy, urine pH should be above 7.5, creatinine clearance should exceed 60 mL/min, and serum creatinine concentration should be less than 120 µmol/L. Diuresis should exceed 2000 mL/m²/day.

Methotrexate dosage varies from 200 to 12,000 mg/m². This dosage may be administered intravenously at a concentration of 2.5 to 25 mg/mL, diluted in 0.9% sodium chloride solution in volumes ranging from 100 mL to 1 L. Infusion duration ranges from 30 minutes to 6 hours. Within 24 hours after such therapy, leucovorin therapy should be initiated to protect normal cells from the toxic effects of methotrexate.

Leucovorin dosage depends on the methotrexate dose. The standard rescue regimen includes 15 mg of leucovorin administered intravenously every 3 hours during the first 24 hours, followed by 15 mg of leucovorin orally every 6 hours for the next 24 hours. Leucovorin therapy may be discontinued when plasma methotrexate concentration falls below 10⁻⁷ mol/L. In cases of elevated serum creatinine or low creatinine clearance, the leucovorin dose should be increased. An alternative rescue regimen includes administering leucovorin at 5% of the total methotrexate dose given to the patient (maximum leucovorin dose: 500 mg) in 200 mL of 0.9% sodium chloride solution over 2 hours, starting 24 hours after the initiation of methotrexate infusion. After this, 15 mg of leucovorin should be administered orally every 6 hours for 3 days.

Dose adjustment.

If leukocyte or platelet counts decrease on the first day of therapy, the methotrexate dosage in standard therapy (40 mg/m²) should be adjusted according to the table below, based on the lowest value observed.

Percentage of normal dose	White blood cell count, mm3	Platelet count, mm3
100	> 3500	> 125000
50	2500–3500	75000–125000
0	< 2500	< 75000

If the leukocyte count is 2500-3500 per 1 mm³ and/or the platelet count is 75,000-125,000 per 1 mm³, treatment should be discontinued for one week. If blood parameters normalize, treatment may be continued. If blood parameters do not normalize, the drug dosage should be reduced.

Methotrexate should not be administered to patients with a creatinine clearance of less than 60 ml/min. In case of hepatotoxic effects, treatment should be discontinued.

Special patient groups

Patients with renal impairment

Patients with renal impairment require dose reduction. The dose should be adjusted as follows:

Creatinine clearance (ml/min)	Percentage of dose to be administered
> 50	100 % of dose
20-50	50 % of dose
< 20	methotrexate not to be used

Patients with hepatic impairment

Methotrexate should be administered with great caution or not administered at all to patients with clinically significant current or pre-existing liver disease, especially if associated with excessive alcohol consumption. Methotrexate administration is contraindicated if bilirubin levels exceed 5 mg/dL (85.5 µmol/L) (see section "Contraindications").

Patients with pathological fluid accumulation

Methotrexate elimination is reduced in patients with pathological fluid accumulation (third-space fluid), such as ascites or pleural effusion, which may lead to prolonged methotrexate plasma half-life and unexpected toxicity. Pleural effusion and ascites should be drained prior to initiating methotrexate therapy. The methotrexate dose should be adjusted according to serum methotrexate concentration.

Elderly patients

A dose reduction should be considered in elderly patients due to age-related decline in hepatic and renal function, as well as decreased folate stores associated with increasing age.

Children

The drug may be used in children with acute lymphoblastic leukemia, neuroleukemia, and non-Hodgkin's lymphoma only as part of combination therapy. Use of the drug for treatment of children under 3 years of age is not recommended due to lack of data on efficacy and safety in this patient group.

Overdose

Symptoms of overdose manifest as an intensification of one or more adverse reactions. With continued treatment, toxic effects become more pronounced. The most commonly observed symptoms are related to hematopoietic and gastrointestinal system suppression: leukopenia, thrombocytopenia, anemia, pancytopenia, neutropenia, bone marrow suppression, mucositis, stomatitis, ulcerative lesions of the oral mucosa, nausea, vomiting, ulcerative gastrointestinal tract lesions, and gastrointestinal bleeding. In some patients, signs of overdose may be absent. There have been reports of fatal outcomes due to sepsis, septic shock, renal failure, and aplastic anemia.

The specific antidote for methotrexate is calcium folinate.

In case of accidental overdose, calcium folinate should be administered intravenously or intramuscularly in a dose equal to or higher than the methotrexate dose, no later than one hour after methotrexate administration. Subsequently, additional doses of calcium folinate should be administered until serum methotrexate concentration falls below 10⁻⁷ mol/L.

Intrathecal overdose should be treated immediately with lumbar puncture, followed by ventriculolumbar perfusion and systemic therapy with folinic acid. If necessary, general supportive measures and blood transfusions may be performed.

In cases of significant overdose, hydration and urinary alkalinization are required to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Standard hemodialysis and peritoneal dialysis do not significantly enhance methotrexate elimination. Effective clearance of methotrexate can be achieved with intensive intermittent hemodialysis using high-flux dialyzers.

Adverse Reactions

The frequency and severity of adverse reactions depend on the dose and frequency of methotrexate administration. Since severe adverse reactions may occur even at low doses, regular and frequent medical monitoring is required. Most adverse reactions are reversible if detected early. If adverse reactions occur, the dose should be reduced or therapy discontinued, and appropriate measures taken (see section "Overdose"). If methotrexate treatment is resumed, it should be continued cautiously, with careful assessment of the necessity of therapy and increased vigilance for possible recurrence of toxic effects.

The most common adverse effects during methotrexate therapy are ulcerative stomatitis, leucopenia, nausea and gastrointestinal disturbances, general malaise, sudden weakness, fever, chills, somnolence, and decreased immunity. Overall, the occurrence of severe adverse effects and their intensity depend on the dosage and frequency of drug administration.

Infections and infestations: pneumonia, herpes zoster, opportunistic infections (sometimes with fatal outcomes), cystitis, vaginitis, sepsis, cytomegalovirus infections, pharyngitis, Pneumocystis pneumonia, nocardiosis, histoplasmosis, cryptococcosis, herpes hepatitis, disseminated simple herpes, furunculosis.

Benign, malignant and unspecified neoplasms (including cysts and polyps): lymphoma, lymphoproliferative disorders (some cases of lymphoma and other lymphoproliferative disorders which resolved in some cases after discontinuation of methotrexate therapy; in a recent study, methotrexate therapy was not found to increase the incidence of lymphomas), tumor lysis syndrome.

Gastrointestinal disorders: gingivitis, pharyngitis, stomatitis, inflammation and ulceration of the mucous membranes of the mouth and throat (particularly within the first 24–48 hours after methotrexate administration), anorexia, nausea, vomiting, diarrhea (particularly within the first 24–48 hours after methotrexate administration), hematemesis, vomiting with blood, gastrointestinal ulcers and hemorrhage, dyspepsia, enteritis, malabsorption, abdominal pain, melena, toxic megacolon.

Blood and lymphatic system disorders: anemia, leucopenia and/or thrombocytopenia, pancytopenia, agranulocytosis, bone marrow suppression, megaloblastic anemia, aplastic anemia, blood formation disorders, neutropenia, lymphadenopathy, lymphoproliferative disorders (partially reversible), eosinophilia.

Hepatobiliary disorders: marked elevation of liver transaminases (ALT, AST), increased alkaline phosphatase and bilirubin levels, hepatotoxicity, fibrosis, cirrhosis (frequently observed despite regular monitoring and normal liver enzyme values), diabetic metabolism, fatty liver degeneration, decreased serum albumin levels, acute hepatitis, recurrence of chronic hepatitis, acute liver degeneration, herpetic hepatitis, liver failure, liver atrophy, liver necrosis.

Immune system disorders: hypogammaglobulinemia, immunosuppression, anaphylactic reactions, including anaphylactic shock.

Metabolism and nutrition disorders: diabetes mellitus.

Psychiatric disorders: mood disturbances, loss of libido, insomnia.

Nervous system disorders: headache, vertigo-type dizziness, somnolence, fatigue, severe visual disturbances, apathy, confusion, depression, mood changes, transient cognitive disorders, speech disorders (including dysarthria, aphasia), sensory disturbances, hemiparesis, paresis, seizures, leukoencephalopathy/encephalopathy, pain, muscular asthenia, paresthesia/hypoesthesia, taste disturbances (metallic taste), meningeal signs (paralysis, vomiting), acute aseptic meningitis; with intravenous administration, leukoencephalopathy has been observed in patients with osteosarcoma and in individuals who received craniospinal radiotherapy; acute neurological syndromes (abnormal behavior, focal sensorimotor disturbances, and abnormal reflexes) occur in patients receiving high-dose methotrexate; with intrathecal administration, chemical arachnitis with symptoms such as headache, back pain, nuchal rigidity, and fever elevation; paresis, usually temporary, involving paralysis of upper and lower limbs affecting one or more spinal nerves; leukoencephalopathy with anxiety, mania, insomnia, ataxia, dementia, and sometimes severe seizures.

Eye disorders: eye irritation, visual disturbances, blurred vision, conjunctivitis, transient blindness, vision loss, retinopathy.

Cardiac and vascular disorders: arterial hypotension, thromboembolic events (including arterial thrombosis, thrombophlebitis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism), vasculitis, pericarditis, exudative pericarditis, pericardial tamponade.

Respiratory, thoracic and mediastinal disorders: interstitial alveolitis/pneumonitis (often with eosinophilia) with pulmonary complications and associated fatal cases (regardless of dose and duration of methotrexate therapy): typical symptoms may include general illness, dry irritating cough, dyspnea which may progress to dyspnea at rest, chest pain, fever (in case of suspected development of such complications, methotrexate therapy should be immediately discontinued and infectious causes (including pneumonia) excluded); pulmonary fibrosis, chronic interstitial lung diseases, dyspnea, pleuritis, pharyngitis, apnea, bronchial asthma, Pneumocystis carinii-induced pneumonia, chronic obstructive pulmonary diseases, infections, including pneumonia; pleural effusion, alveolitis. Cases of pulmonary alveolar hemorrhage have been reported with methotrexate use for rheumatological and related indications.

Renal and urinary disorders: inflammation and ulceration of the bladder, severe nephropathy or renal failure, azotemia, dysuria, hematuria, oliguria, anuria, electrolyte imbalance, proteinuria.

Reproductive system disorders: disturbances of oogenesis and spermatogenesis, oligospermia, menstrual cycle disturbances and vaginal discharge, infertility, miscarriages, fetal developmental abnormalities, suppressed spermatogenesis, impotence, vaginal ulcers, vaginal inflammation, loss of libido, gynecomastia.

Skin and subcutaneous tissue disorders: exanthema, erythema, erythematous rashes, pruritus, urticaria, ulcers, increased photosensitivity, enhanced skin pigmentation, abnormal pigmentation, hair loss, alopecia, ecchymosis, telangiectasia, acne, vasculitis, herpes-like skin rashes, toxic epidermal necrolysis (Lyell's syndrome), Stevens-Johnson syndrome, erythema multiforme, sudden psoriasis, increased rheumatic nodules, herpes zoster, painful lesions of psoriatic plaques, petechiae, increased nail pigmentation, acute paronychia, furunculosis, nocardial, histoplasma, and cryptococcal mycosis, disseminated simple herpes, allergic vasculitis, hidradenitis, skin desquamation/exfoliative dermatitis.

Musculoskeletal and connective tissue disorders: arthralgia, myalgia, osteoporosis, stress fractures, osteonecrosis of the jaw (secondary to lymphoproliferative disorders).

Other: local tissue damage (formation of sterile abscess, lipodystrophy) at the injection site following intramuscular or subcutaneous administration, mucositis, increased fatigue, malaise, fever, edema, impaired wound healing, sudden death.

Shelf life. 2.5 years.

Storage conditions. Store in the original packaging at a temperature not exceeding 25 °C, protected from light and out of reach of children.

Incompatibility. Methotrexate should not be mixed in the same container with other medicinal products.

Packaging. 10 ml in a vial, 1 vial per carton.

Prescription category. Prescription only.

Manufacturer. Pharmachemie B.V.

Manufacturer's address and place of business. Swensweg 5, 2031 GA Haarlem, The Netherlands.