Methotrexate "ebewe"

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT METHOTREXATE "EBEWE" (METHOTREXATE "EBEWE")

Composition:

Active substance: methotrexate;

1 ml of concentrate contains 100 mg of methotrexate;

Excipients: sodium hydroxide, water for injections.

Pharmaceutical form. Concentrate for solution for infusion.

Main physicochemical properties: clear yellow solution. During storage, the colour of the solution may change to orange-yellow.

Pharmacotherapeutic group.

Antineoplastic agents. Antimetabolites. Structural analogues of folic acid.

ATC code L01B A01.

Pharmacological properties.

Pharmacodynamics.

Methotrexate is a folic acid derivative and belongs to the class of cytotoxic antimetabolites. It acts during the S-phase of the cell cycle and competitively inhibits the enzyme dihydrofolate reductase, thereby preventing the reduction of dihydrofolate to tetrahydrofolate, which is essential for DNA synthesis and cell replication. Rapidly proliferating tissues, such as malignant tumors, bone marrow, fetal cells, oral and intestinal mucosa, and bladder cells, are generally more sensitive to methotrexate. Since malignant tissue proliferation is faster than normal, methotrexate can disrupt its development without causing irreversible damage to healthy tissues.

Pharmacokinetics.

Approximately 50% of methotrexate is protein-bound in plasma. After distribution, methotrexate accumulates predominantly in the liver, kidneys, and spleen in the form of polyglutamates, which can be retained for weeks to months. When administered in low doses, only a minimal amount of methotrexate penetrates into the cerebrospinal fluid. The terminal elimination half-life of methotrexate varies widely (3–17 hours), averaging 6–7 hours. In patients with a third space distribution (pleural effusion, ascites), the elimination half-life of methotrexate may be up to four times longer.

Approximately 10% of the administered dose is metabolized in the liver. The main metabolite of methotrexate is 7-hydroxymethotrexate.

Methotrexate is primarily excreted unchanged by the kidneys (via glomerular filtration and active secretion in the proximal tubules).

Approximately 5–20% of methotrexate and 1–5% of 7-hydroxymethotrexate are excreted in bile. There is significant enterohepatic recirculation of methotrexate.

In patients with impaired renal function, methotrexate elimination is considerably slower. It is unknown whether hepatic impairment affects methotrexate elimination.

Clinical characteristics.

Indications.

The medicinal product Methotrexate "Ebewe", concentrate for solution for infusion, 100 mg/mL is indicated for the treatment of adults and children aged 3 years and older.

Methotrexate "Ebewe" at low (single dose < 100 mg/m² body surface area [BSA]) and medium-high doses (single dose 100–1000 mg/m² BSA) is indicated for the treatment of the following oncological diseases:

Malignant trophoblastic tumors (benign gestational trophoblastic disease, choriocarcinoma):

• as monotherapy in women at low risk;
• in combination with other cytostatic agents in women at high risk;

Breast cancer:

• in combination with other cytostatic agents for adjuvant therapy following tumor resection or mastectomy, and for palliative treatment in advanced stages;

Head and neck cancer:

• for palliative monotherapy in metastatic disease or in case of recurrence;

Non-Hodgkin's lymphoma:

• for the treatment of intermediate- or high-grade non-Hodgkin's lymphoma in combination with other cytostatic agents;

Acute lymphoblastic leukemia:

• as part of combination therapy protocols in combination with other cytostatic agents, for maintenance therapy during remission and for prophylaxis and treatment of carcinomatous meningitis.

Methotrexate "Ebewe" at high doses (single dose >1000 mg/m² BSA) is indicated for the treatment of the following oncological diseases:

• Non-Hodgkin's lymphoma predominantly localized in the central nervous system, prior to radiotherapy;
• Acute lymphoblastic leukemia;
• Prophylaxis and treatment of carcinomatous meningitis.

For the treatment of severe, generalized, therapy-resistant psoriasis, psoriatic arthritis, and rheumatoid arthritis, the medicinal product is available in the following dosage forms: tablets, injection solution 10 mg/mL in vials for parenteral use, and in prefilled syringes.

Contraindications.

• Hypersensitivity to methotrexate or to any of the excipients.
• Severe, acute or chronic infections (e.g., tuberculosis or HIV).
• Stomatitis, ulceration of the mucous membranes of the oral cavity or gastrointestinal tract.
• Liver disease due to chronic alcohol abuse or other chronic liver diseases (see section "Dosage and administration").
• Hepatic insufficiency (see section "Dosage and administration").
• Impaired renal function (creatinine clearance < 50 mL/min; see section "Dosage and administration").
• Pre-existing hematological disorders (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia, or severe anemia).
• Immunodeficiency.
• Alcohol abuse.
• History of blood disorders.
• Pregnancy, unless there is a life-threatening indication, or breastfeeding (see section "Use in pregnancy or lactation").
• Vaccination with live vaccines during methotrexate therapy.

Special precautions.

Since Methotrexate "Ebewe" contains no preservatives, only a single withdrawal from the ampoule is permitted, and unused solutions must be discarded.

Methotrexate "Ebewe" must not be mixed with other medicinal products in the same infusion bag or vial.

Handling of the product must follow the safety procedures for cytotoxic agents. Precautions must be taken to prevent contact of methotrexate solutions with skin or mucous membranes. Protective gloves and goggles should be worn. If the product does come into contact with skin or mucous membranes, the affected area should be immediately rinsed with copious amounts of water.

To relieve transient burning sensations, a soothing hand cream may be used. In case of risk of absorption of a large amount of methotrexate, regardless of the route of absorption, treatment with leucovorin is required.

Pregnant healthcare workers must not handle this product.

Any residual product and all equipment and materials used in the preparation and administration of the infusion solution must be disposed of according to approved procedures for disposal of cytotoxic waste.

In outpatient settings, residual product must not be poured into drains or discarded with household waste.

Interaction with other medicinal products and other forms of interaction.

The use of nitrous oxide ("laughing gas") may enhance the effect of methotrexate on folate metabolism, resulting in severe and unpredictable bone marrow suppression, stomatitis, and neurotoxicity following intrathecal administration. To reduce the intensity of these effects, calcium folinate must be administered; concomitant use of methotrexate should be avoided.

L-asparaginase has an antagonistic effect on methotrexate when administered concomitantly.

Disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs) should not be used before or during high-dose methotrexate therapy. Concomitant use of certain NSAIDs with high-dose methotrexate has led to elevated and prolonged serum methotrexate levels, sometimes resulting in fatal outcomes due to severe hematological (bone marrow suppression and aplastic anemia) and gastrointestinal toxicity.

Studies have shown that NSAIDs, including salicylic acid, reduce tubular secretion of methotrexate and may increase its toxicity due to elevated methotrexate levels. Therefore, NSAIDs and low-dose methotrexate should be used with caution. Concomitant use of NSAIDs is not recommended in the presence of risk factors such as impaired renal function (even borderline cases).

The potential for increased methotrexate toxicity has not been fully studied with concomitant use of DMARDs (e.g., gold salts, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine); therefore, toxic effects cannot be ruled out.

Proton pump inhibitors (PPIs). Concomitant use of methotrexate and proton pump inhibitors (e.g., omeprazole, pantoprazole, or lansoprazole) may reduce or delay renal clearance of methotrexate, leading to indirectly increased plasma concentrations. Concomitant use of PPIs with high-dose methotrexate should be avoided if possible. These drugs should be used cautiously in patients with renal insufficiency.

The risk of hepatotoxic effects of methotrexate increases with regular consumption of alcohol or concomitant use of other hepatotoxic drugs, such as azathioprine, leflunomide, retinoids, and sulfasalazine. Patients receiving other hepatotoxic drugs should be closely monitored. Alcohol consumption should be avoided during methotrexate therapy.

Drugs such as amidopyrine derivatives, para-aminobenzoic acid, barbiturates, doxorubicin, oral contraceptives, phenylbutazone, phenytoin, probenecid, salicylates, sulfonamides, tetracyclines, tranquilizers, sulfonylureas, penicillins, pristinamycin, and chloramphenicol may displace methotrexate from albumin binding sites in plasma, increasing its bioavailability (indirect dose increase) and thereby enhancing methotrexate toxicity. Close monitoring of patients is required when these drugs are used concomitantly with methotrexate.

Drugs such as para-aminobenzoic acid, NSAIDs, probenecid, salicylates, sulfonamides, and other weak organic acids may reduce tubular secretion and subsequently increase methotrexate toxicity, especially at low doses. Close monitoring is required when these agents are used concomitantly with methotrexate.

Penicillins and sulfonamides may, in rare cases, reduce renal clearance of methotrexate, leading to increased serum concentrations and enhanced toxicity to the hematopoietic system and gastrointestinal tract.

Cyprofl oxacin also reduces tubular secretion in the kidneys; therefore, methotrexate should be used with this antibiotic under close supervision.

Oral antibiotics. Oral antibiotics (e.g., tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics) may affect enterohepatic circulation by inhibiting intestinal flora or suppressing bacterial metabolism.

Drugs adversely affecting bone marrow. When used concomitantly with drugs that may cause bone marrow toxicity (e.g., amidopyrine derivatives, chloramphenicol, phenytoin, pyrimethamine, sulfonamides, trimethoprim/sulfamethoxazole, cytostatics), the possibility of more pronounced hematological disorders (in rare cases, acute pancytopenia) should be considered.

Drugs causing folate deficiency. Concomitant therapy with drugs causing folate deficiency (e.g., sulfonamides, trimethoprim/sulfamethoxazole) may enhance methotrexate toxicity. Particular caution is required in patients with pre-existing folate deficiency. Conversely, concomitant administration of folic acid or vitamin preparations containing folic acid or its derivatives may reduce the efficacy of methotrexate therapy.

Although the effect of methotrexate may be potentiated when used concomitantly with sulfasalazine due to sulfasalazine-induced inhibition of folate synthesis (potentially increasing the frequency of adverse effects), such effects have been observed only rarely in several clinical studies.

Methotrexate may reduce the clearance of theophylline. Therefore, theophylline levels should be monitored during concomitant use with methotrexate.

Caffeine- and theophylline-containing beverages. During methotrexate therapy, excessive consumption of beverages containing caffeine (coffee, caffeinated soft drinks, black tea) and theophylline should be avoided, as the efficacy of methotrexate may be reduced due to interactions between methotrexate and methylxanthines at adenosine receptors.

Concomitant use of methotrexate and leflunomide may increase the risk of pancytopenia.

Concomitant use of methotrexate and mercaptopurine may lead to increased plasma levels of mercaptopurine. Therefore, such concomitant use may require dose adjustment.

Bone marrow suppression and reduced folate concentrations have been reported with concomitant use of triamterene and methotrexate.

During radiotherapy administered concurrently with methotrexate, there may be an increased risk of soft tissue and bone necrosis. Cholestyramine may enhance extra-renal elimination of methotrexate by interfering with enterohepatic circulation.

Special monitoring is required when concentrated red blood cells are administered concomitantly. Patients receiving blood transfusions within 24 hours after methotrexate infusion may experience increased toxicity due to prolonged high serum methotrexate concentrations.

In rare cases, corticosteroids have been associated with disseminated herpes zoster in patients with herpes zoster or postherpetic neuralgia when used concomitantly with methotrexate.

High doses of calcium folinate may negatively affect the efficacy of intrathecally administered methotrexate.

Anesthetic agents based on nitrous oxide may enhance the effect of methotrexate on folate metabolism, resulting in unpredictable, severe bone marrow suppression and stomatitis. Calcium folinate administration is required to reduce the intensity of these effects.

Pyrimethamine or co-trimoxazole in combination with methotrexate may cause pancytopenia, likely due to additional inhibition of dihydrofolate reductase by these substances and methotrexate.

The risk of hepatotoxic effects of methotrexate increases with alcohol abuse or concomitant use of other hepatotoxic drugs.

Treatment with methotrexate in patients taking hematotoxic drugs (e.g., metamizole) increases the risk of severe hematotoxic effects.

Pharmacokinetic interactions between methotrexate and anticonvulsants (reduced methotrexate blood concentration) and 5-fluorouracil (increased half-life of 5-fluorouracil) should be considered.

When used concomitantly with other antirheumatic drugs (e.g., gold salts, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine), methotrexate toxicity is generally not increased.

When used concomitantly with other cytostatics, methotrexate clearance may be reduced.

Decreased plasma levels of phenytoin have been observed in patients with acute lymphoblastic leukemia during induction therapy, which, in addition to prednisone, vincristine, and 6-mercaptopurine, also included high-dose methotrexate with calcium folinate as protective therapy.

Administration of procarbazine during high-dose methotrexate therapy increases the risk of renal dysfunction.

Concomitant therapy with intravenous cytarabine and intrathecal methotrexate may increase the risk of severe neurological adverse effects such as headache, paralysis, coma, and stroke-like episodes.

Increased nephrotoxicity may occur when high-dose methotrexate is combined with potentially nephrotoxic drugs (e.g., cisplatin).

Since methotrexate affects the immune system, it may alter the response to vaccination and affect test results (immunological procedures to assess immune response). Vaccination with live vaccines should not be performed during methotrexate therapy.

Methotrexate may enhance the effects of oral anticoagulants of the coumarin type (acenocoumarol, phenprocoumon), leading to prolonged prothrombin time due to reduced degradation of coumarin derivatives.

Concomitant administration of levetiracetam and methotrexate has been reported to reduce methotrexate clearance, leading to increased or prolonged blood concentrations to potentially toxic levels. Methotrexate and levetiracetam levels should be closely monitored in patients receiving concomitant therapy with these two drugs.

Amoxicillin

Penicillins may reduce methotrexate excretion, potentially increasing its toxicity.

Special precautions for use.

Treatment with methotrexate should be carried out under the supervision of an experienced oncologist.

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

Discontinuation of methotrexate does not always lead to complete regression of adverse effects.

A mandatory condition for methotrexate treatment is the determination of methotrexate levels in blood serum.

In patients with pathological fluid accumulation in body cavities ("third space"), such as ascites or pleural effusion, the plasma half-life of methotrexate is prolonged.

Pleural effusion or ascites must be eliminated prior to initiating methotrexate therapy. Drainage of pleural exudate or ascites should be performed before starting methotrexate treatment. If this is not possible, methotrexate therapy should not be initiated.

Blood and lymphatic system

Methotrexate may suppress hematopoiesis, causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia.

When treating malignant diseases, methotrexate therapy should continue only if the potential benefit outweighs the risk of severe myelosuppression. Initial signs of these life-threatening complications may include fever, sore throat, oral mucosal ulcers, influenza-like symptoms, severe fatigue, and nasal or skin bleeding. Megaloblastic anemia has been observed in elderly patients during prolonged therapy.

Methotrexate should not be used in patients with peptic ulcer disease or ulcerative colitis (see section "Contraindications").

After treatment with drugs exhibiting cumulative myelotoxicity or after radiotherapy affecting bone marrow function, impaired bone marrow function should be considered, particularly increased bone marrow sensitivity to methotrexate therapy, resulting in enhanced suppression of the hematopoietic system. During prolonged methotrexate therapy, bone marrow biopsy is necessary.

In acute lymphoblastic leukemia, methotrexate may cause pain in the left upper quadrant of the abdomen (inflammation of the spleen capsule due to destruction of leukemic cells).

Liver function

Since methotrexate exerts hepatotoxic effects, other hepatotoxic drugs should not be prescribed during methotrexate treatment unless absolutely necessary. Alcohol consumption should also be avoided or significantly limited.

Methotrexate may cause acute hepatitis and chronic, potentially fatal, liver toxicity (fibrosis, cirrhosis), usually only after prolonged use. Persistent elevation of liver enzyme levels is frequently observed, which is usually transient and asymptomatic and does not necessarily predict subsequent liver disease.

Methotrexate may reactivate hepatitis B infection or its complications, or exacerbate hepatitis C, potentially leading to fatal outcomes in some cases. Some cases of hepatitis B reactivation have been reported after discontinuation of methotrexate. Therefore, patients with a history of hepatitis B or C should undergo clinical and laboratory evaluations to determine the appropriateness of methotrexate therapy.

Particular caution is required when treating patients with inactive chronic infections (such as herpes zoster, tuberculosis, hepatitis B or C) due to the risk of their reactivation.

Special caution is needed when treating patients with insulin-dependent diabetes mellitus, as isolated cases of liver cirrhosis have been reported during methotrexate therapy without prior elevation of transaminase activity.

Kidney function

Due to reduced methotrexate excretion, treatment of patients with impaired kidney function should be conducted with increased caution and at lower doses (see section "Dosage and administration").

During methotrexate therapy, kidney function may deteriorate, accompanied by increased levels of certain laboratory parameters (serum creatinine, urea, and uric acid), potentially leading to acute renal failure with oliguria/anuria. This is likely due to precipitation of methotrexate and/or its metabolites in renal tubules.

Conditions leading to dehydration, such as vomiting, diarrhea, or stomatitis, may potentiate methotrexate toxicity by increasing the concentration of the active substance. In such cases, supportive therapy should be administered, and methotrexate treatment should be discontinued until symptoms resolve.

Gastrointestinal disorders

Conditions causing dehydration, such as vomiting, diarrhea, or stomatitis, may increase methotrexate toxicity due to elevated drug concentration. In such cases, further therapy should be temporarily interrupted until these symptoms resolve. It is crucial to identify patients with potentially elevated methotrexate concentrations within 48 hours after administration, as otherwise methotrexate toxicity may become irreversible. Diarrhea and ulcerative stomatitis may be manifestations of toxic effects and require temporary discontinuation of further therapy; otherwise, hemorrhagic enteritis and fatal outcomes due to intestinal wall perforation may occur.

If vomiting with blood, black stools, or blood in the stool occurs, further therapy should be discontinued.

Nervous system

Leukoencephalopathy has been observed in patients receiving intravenous methotrexate who had previously undergone cranial radiotherapy.

Chronic leukoencephalopathy has also been observed in patients receiving repeated high-dose methotrexate therapy with calcium folinate without prior cranial radiotherapy.

Data indicate that combined cranial irradiation and intrathecal methotrexate administration increases the frequency of leukoencephalopathy development (see also section "Adverse reactions").

After intrathecal methotrexate administration, patients should be monitored for signs of neurotoxicity (nervous system disorders), such as meningitis, transient or permanent paralysis, or encephalopathy.

Severe neurological adverse effects, ranging from headache to paralysis, coma, and stroke, have been reported in adolescents and young patients receiving methotrexate in combination with cytarabine.

During high-dose methotrexate therapy, a transient acute neurological syndrome may occur, manifesting, in particular, as behavioral abnormalities, focal sensorimotor symptoms (including temporary blindness), and abnormal reflexes. The exact cause has not been established.

Lung function

Methotrexate should be used with great caution when treating patients with impaired lung function.

Pulmonary complications, pleural effusion, alveolitis, or pneumonitis with symptoms such as dry non-productive cough, fever, malaise, cough, chest pain, dyspnea, hypoxemia, and radiologically detected infiltrates or nonspecific pneumonia occurring during methotrexate therapy may indicate potentially dangerous and possibly fatal lung injury. Methotrexate-induced lung diseases are not always fully reversible. Methotrexate-induced lung diseases, such as pneumonitis, may begin suddenly at any stage of therapy, do not always resolve completely, and have been observed with all therapeutic doses of methotrexate (including low doses of 7.5 mg/week). Additionally, pulmonary alveolar hemorrhage has been reported during methotrexate use for rheumatological and similar indications. This phenomenon may also be associated with vasculitis and other concomitant diseases. Rapid diagnostic tests should be considered to confirm the diagnosis in suspected cases of pulmonary alveolar hemorrhage.

Skin toxicity

Severe, sometimes fatal, skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) have been reported after single or prolonged use of methotrexate.

Psoriatic lesions may worsen after UV exposure during concomitant methotrexate therapy. During methotrexate therapy, there is a risk of radiation dermatitis and sunburn (recurrence of adverse effects of radiotherapy).

Immune system

Opportunistic infections, including Pneumocystis pneumonia, which may lead to fatal outcomes, are possible during methotrexate therapy. In patients with symptoms of pulmonary dysfunction, Pneumocystis pneumonia should be considered.

Since methotrexate affects the immune system, it may alter the response to vaccination and affect the results of immunological tests. Live vaccines should not be administered during methotrexate therapy.

Particular caution is required when treating patients with progressive infections with methotrexate. Methotrexate is contraindicated in patients with evident or laboratory-confirmed immunodeficiency syndromes. Additionally, methotrexate should be used cautiously in patients with infections caused by varicella or herpes zoster.

Neoplasms

In patients with rapidly growing tumors, methotrexate, like other cytostatic agents, may induce tumor lysis syndrome. Appropriate supportive therapy may prevent or reduce the manifestations of these complications.

Methotrexate may increase the risk of developing neoplasms (predominantly lymphomas). Malignant lymphomas may develop even in patients receiving low-dose methotrexate. In such cases, the drug should be discontinued. If spontaneous regression of lymphoma does not occur, cytotoxic therapy should be initiated.

Musculoskeletal and connective tissue disorders

The risk of soft tissue or bone necrosis is increased when radiotherapy is administered concurrently with methotrexate.

Folic acid preparations

Folic acid deficiency may increase methotrexate toxicity (see section "Interaction with other medicinal products and other forms of interaction").

Vitamin supplements and other products containing folic acid, folinic acid, or their derivatives may reduce methotrexate toxicity (gastrointestinal symptoms, stomatitis, alopecia, and elevated liver enzyme activity).

Before taking folic acid-containing medicinal products, vitamin B12 levels should be checked, as folic acid use may mask vitamin B12 deficiency, especially in individuals over 50 years of age.

Recommended examinations and preventive measures

Patients receiving methotrexate should be closely monitored to promptly detect toxic effects.

Before starting methotrexate therapy or continuing therapy after interruption, a blood test with determination of leukocyte formula and platelet count, liver enzyme levels, bilirubin, serum albumin, hepatitis testing (A, B, C), chest X-ray, and renal function tests should be performed. If clinically indicated, tests to exclude tuberculosis and hepatitis should be prescribed. In suspected lung disease (e.g., interstitial pneumonia), lung function tests should be performed, especially if previous test results are available.

Depending on the dosage or treatment protocol used, regular monitoring of methotrexate levels in blood serum is necessary, particularly during and after high-dose methotrexate therapy (see also section "Overdose"). Dose adjustment and protective therapy can significantly reduce toxicity and potential mortality associated with methotrexate treatment. Patients with pleural effusion, ascites, dehydration, decreased urine pH, gastrointestinal obstruction, previous cisplatin therapy, or impaired kidney function are at increased risk of elevated or slowly decreasing methotrexate levels in blood serum. These patients should be closely monitored.

In some patients, delayed methotrexate elimination may occur without the above-mentioned causes. It is important to monitor methotrexate concentration within 48 hours after administration, as its increase may lead to irreversible methotrexate toxicity.

When methotrexate is administered at doses exceeding 100 mg/m² BSA, protective therapy with calcium folinate is required. Depending on the methotrexate dose and duration of infusion, different doses of calcium folinate should be used to protect normal cells from methotrexate toxicity.

Appropriate calcium folinate protective therapy should be initiated within 42–48 hours after methotrexate administration. Therefore, methotrexate levels should be monitored at least at 24, 48, and 72 hours, and, if necessary, monitoring should continue to determine the duration of calcium folinate protective therapy.

During methotrexate therapy, complete blood count with differential blood analysis, including platelet and leukocyte counts (daily or weekly), should be performed.

Before starting combination therapy, including high-dose methotrexate, leukocyte and platelet counts should exceed the minimum values specified in the corresponding treatment protocol (leukocytes: 1000–1500/μL, platelets: 50,000–100,000/μL).

The maximum decrease in circulating leukocytes, neutrophil granulocytes, and platelets usually occurs 5–13 days after intravenous methotrexate administration (the "rebound" phenomenon occurs 14–28 days later). Sometimes two peaks of leukocyte and neutrophil granulocyte reduction are observed, the first at 4–7 days and the second at 12–21 days, followed by the rebound phenomenon.

Renal and liver function tests and urine analysis should be performed regularly.

Transient elevation of transaminase levels (up to 2–3 times above the upper limit of normal) has been reported in some patients. If liver enzyme activity remains persistently elevated, methotrexate doses should be reduced or therapy discontinued.

Enzyme activity tests do not reliably predict morphological changes due to hepatotoxic effects; thus, even with normal transaminase levels, fibrosis may only be detected by histological analysis, or, less frequently, liver cirrhosis.

Serum creatinine, urea, and electrolyte levels should be monitored, especially when high-dose methotrexate is used, on days 2 and 3, to detect any possible impairment of methotrexate excretion at an early stage.

If signs of impaired kidney function are present (e.g., severe adverse effects from previous methotrexate therapy or urinary tract obstruction), creatinine clearance should be determined. High-dose methotrexate therapy should only be performed if creatinine levels are within normal limits.

If creatinine levels increase, the dose should be reduced. If serum creatinine concentration rises above 2 mg/dL, further methotrexate therapy should not be administered. Patients with possible kidney function impairment (e.g., elderly patients) should be closely monitored. This is particularly important when concomitant therapy includes drugs that reduce methotrexate excretion, adversely affect the kidneys (e.g., nonsteroidal anti-inflammatory drugs), or affect the hematopoietic system.

During methotrexate infusion, urine output and urine pH should be monitored. To reduce nephrotoxicity and prevent renal failure during high-dose methotrexate therapy, sufficient intravenous fluid should be administered, and urine should be alkalinized (urine pH ≥ 7).

Oral cavity and throat examinations should be performed daily to detect mucosal changes.

Careful monitoring of the patient's condition is required in cases of prior intensive radiotherapy, worsening general condition, and in adolescents or elderly patients.

Monitoring should be more frequent at the beginning of therapy, during dose adjustments, or in cases of increased risk of elevated methotrexate levels (e.g., dehydration, impaired kidney function, additional concomitant medications, or increased number of concomitant medications such as nonsteroidal anti-inflammatory drugs).

Use in children

When using methotrexate in children and adolescents, caution should be exercised, and appropriate pediatric-specific treatment protocols should be followed. In children with acute lymphoblastic leukemia, severe neurotoxicity may occur after treatment with moderately high doses (1 g/m² BSA) of methotrexate. It is often considered generalized or focal epileptic seizures. In symptomatic patients, diagnostic imaging typically reveals leukoencephalopathy and/or microangiopathic calcification.

Use in elderly patients

Particular caution is required when treating elderly patients. Patients should be regularly monitored for early signs of toxicity. The clinical pharmacology of methotrexate in elderly patients has not been fully studied. Methotrexate dosage should be adjusted based on kidney and liver function. The dose should be reduced due to advanced age. Partially modified protocols have been developed for elderly patients (aged 55 years and older), for example, for the treatment of acute lymphoblastic leukemia.

Reproductive function

Oligospermia, menstrual cycle disturbances, and amenorrhea have been reported during and shortly after methotrexate therapy, potentially leading to impaired fertility due to disturbances in oogenesis and spermatogenesis during treatment. These effects are reversible after discontinuation of the drug.

Teratogenicity – reproductive risk

Methotrexate causes embryotoxicity, miscarriage, and congenital abnormalities in humans. Therefore, physicians must inform women of reproductive age about the potential impact on reproductive function, miscarriage, and fetal congenital abnormalities (see section "Adverse reactions"). Women of reproductive age must use effective contraception during therapy and for six months after completion of methotrexate therapy.

Use in men

Methotrexate may exhibit genotoxicity. Therefore, men must use effective contraception during therapy and for six months after completion of methotrexate therapy. Since methotrexate may lead to serious and potentially irreversible impairment of spermatogenesis, men should consider sperm cryopreservation before starting therapy (see section "Use during pregnancy or breastfeeding").

Infusion solutions with methotrexate concentrations of 0.1 mg/mL or 3 mg/mL, prepared by diluting Methotrexate "Ebewe" with 0.9% sodium chloride solution, 5% glucose solution, 10% glucose solution, or Ringer's lactate solution, are physically and chemically stable for at least 24 hours when stored protected from light at 5 ± 3°C or room temperature (20–25°C).

From a microbiological standpoint, the infusion solution should be administered immediately after preparation.

This medicinal product contains less than 1 mmol of sodium (23 mg) per vial, i.e., essentially sodium-free.

Progressive multifocal leukoencephalopathy

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients using methotrexate, primarily in combination with other immunosuppressive agents. PML may have fatal outcomes. This should be considered in differential diagnosis in immunodeficient patients with worsening or new neurological symptoms.

Use during pregnancy or breastfeeding.

Women of reproductive age / contraception in women

Women should not become pregnant during methotrexate therapy. Effective contraception must be used during therapy and for at least 6 months after completion of methotrexate therapy (see section "Special precautions for use"). Before starting therapy, women of reproductive age must be informed about the risk of negative effects of methotrexate on the fetus and pregnancy must be excluded using appropriate methods, such as a pregnancy test. During therapy, pregnancy tests should be performed as clinically needed (e.g., after any contraception interruption). Women of reproductive age should be counseled regarding prevention and planning of pregnancy. Couples should consult their physician regarding the serious risks to the fetus if pregnancy occurs during therapy.

Contraception in men

There are no data on methotrexate content in semen. Genotoxicity of methotrexate has been demonstrated in animal studies; therefore, the risk of genotoxic effects on spermatozoa cannot be completely excluded. Limited clinical data do not indicate an increased risk of congenital abnormalities or miscarriage after exposure to low doses of methotrexate (less than 30 mg per week). Data are insufficient to assess the risk of congenital abnormalities or miscarriage after exposure to higher doses.

As a precaution, sexually active male patients or their partners are advised to use reliable contraception during male patient therapy and for at least 3 months after completion of methotrexate therapy. Men should not be sperm donors during therapy and for 3 months after discontinuation of methotrexate.

Pregnancy

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

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

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

• Spontaneous miscarriages were recorded in 42.5% of pregnant women using low-dose methotrexate (less than 30 mg per week), compared to 22.5% in patients using other medications.
• Significant congenital defects occurred in 6.6% of live-born children whose mothers used low-dose methotrexate (less than 30 mg per week) during pregnancy, compared to approximately 4% of live-born children whose mothers used other medications.

Insufficient data are available on methotrexate use during pregnancy at doses exceeding 30 mg per week, but a higher rate of spontaneous miscarriages and congenital malformations is expected. Normal pregnancies have been reported after discontinuation of methotrexate before conception.

For oncological indications, methotrexate should not be administered during pregnancy, particularly during the first trimester. In each individual case, the benefit of treatment must be weighed against the potential risk to the fetus. If the drug is used during pregnancy or if a patient undergoing methotrexate therapy becomes pregnant, she must be informed about the risk of negative effects of methotrexate on the fetus.

Breastfeeding

Since methotrexate is excreted in breast milk and may cause toxic effects on breastfed infants, methotrexate is contraindicated during breastfeeding (see section "Contraindications"). If methotrexate use during breastfeeding is necessary, breastfeeding must be discontinued before starting therapy.

Reproductive function

Methotrexate affects spermatogenesis and oogenesis and may reduce fertility. Oligospermia, menstrual cycle disturbances, and amenorrhea have been reported in humans. In most cases, these effects are reversible after discontinuation of therapy.

For women planning pregnancy and receiving methotrexate for oncological indications, referral to genetic counseling centers is recommended, preferably before starting therapy, and men should consider sperm cryopreservation before therapy initiation, as high-dose methotrexate may be genotoxic (see section "Special precautions for use").

Ability to affect reaction speed when driving or operating machinery.

During methotrexate therapy, adverse effects on the central nervous system such as fatigue and confusion may occur. Methotrexate "Ebewe" has a weak or moderate adverse effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Warning

Dosage should be adjusted according to body surface area when methotrexate is used for the treatment of tumors. Cases of intoxication with fatal outcomes have been reported following administration of incorrectly calculated doses. Medical personnel and patients must be fully informed about the toxic effects.

The dose of methotrexate as part of polychemotherapy for malignant tumors or hematologic cancers depends on the indication and is individually determined based on assessment of the patient's general condition and blood parameters. Doses used in standard methotrexate therapy, low-dose methotrexate therapy (single dose below 100 mg/m²), and high-dose methotrexate therapy (single dose above 1000 mg/m²) depend on the respective dosing regimen.

Therefore, the dosage recommendations below should be considered only as guidelines. Current therapeutic protocols will be provided to the treating physician upon request.

Standard methotrexate therapy, calcium folinate rescue not required:

15–20 mg/m² (i.v.); twice weekly; 30–50 mg/m² (i.v.); once weekly; 15 mg/m²/day (i.v., i.m.); 5 days. Repeat cycle every 2–3 weeks.

Moderate high-dose methotrexate therapy:

50–150 mg/m² (i.v. injection); calcium folinate rescue not required. Repeat cycle every 2–3 weeks.

240 mg/m² (i.v. infusion over 24 hours); calcium folinate rescue required. Repeat cycle every 4–7 days.

0.5–1.0 g/m² (i.v. infusion over 36–42 hours); calcium folinate rescue required. Repeat cycle every 2–3 weeks.

High-dose methotrexate therapy – calcium folinate rescue required:

1–12 g/m² (i.v., over 1–6 hours). Repeat cycle every 1–3 weeks.

Systemic (intravenous and intramuscular) administration of methotrexate

Methotrexate therapy in low dose (single dose less than 100 mg/m² BSA) and moderately high dose (single dose of 100–1000 mg/m² BSA).

Malignant trophoblastic tumors (benign gestational trophoblastic tumors, choriocarcinoma)

Low-risk group patients: monotherapy at a dose of 0.4 mg/kg body weight (BW) intramuscularly on days 1 to 5, with therapy resumed after a 7-day break, or at a dose of 0.25–1 mg/kg BW intramuscularly on days 1, 3, 5, and 7, with therapy resumed after a 7-day break. Within 24 hours after such therapy, treatment with calcium folinate should be initiated.

High-risk group patients: 300 mg/m² BSA intravenously as part of combination therapy.

Breast cancer: 40 mg/m² BSA methotrexate intravenously on days 1 and 8 in combination with cyclophosphamide and fluorouracil according to the CMF regimen (cyclophosphamide, methotrexate, 5-fluorouracil).

Head and neck cancer: methotrexate dose of 40–60 mg/m² BSA intravenously once weekly as monotherapy.

Non-Hodgkin's lymphoma: single doses of methotrexate 120 mg/m² BSA as part of combination therapy.

Acute lymphoblastic leukemia: for maintenance of remission within comprehensive treatment protocols: single dose of 20 to 40 mg/m² BSA methotrexate.

High-dose methotrexate therapy (single dose exceeding 1000 mg/m² BSA):

Non-Hodgkin's lymphoma predominantly localized in the central nervous system (CNS). There is no single established treatment regimen and dosing for non-Hodgkin's lymphoma predominantly localized in the CNS. Studies have shown that intravenous administration of methotrexate at doses of at least 1500–4000 mg/m² BSA was effective as a single dose over several cycles, either as monotherapy or in combination with radiotherapy and/or intrathecal administration of methotrexate with other chemotherapeutic agents.

Acute lymphoblastic leukemia. Acute lymphoblastic leukemia in adults: single doses of methotrexate 1500 mg/m² BSA as part of combination therapy.

Acute lymphoblastic leukemia in children and adolescents: usual single doses range from 1000–5000 mg/m² BSA as part of combination therapy.

Intrathecal administration of methotrexate

Intrathecal administration of methotrexate has been effective for prophylaxis and treatment of carcinomatous meningitis or for treatment of primary CNS lymphoma.

When administered intrathecally, methotrexate should be dosed according to age, as cerebrospinal fluid (CSF) volume correlates more closely with age-dependent brain volume than with body surface area.

Children ≤ 3 months of age: 3 mg methotrexate intrathecally.

Children 4–11 months of age: 6 mg methotrexate intrathecally.

Children 1 year of age: 8 mg methotrexate intrathecally.

Children 2 years of age: 10 mg methotrexate intrathecally.

Children 3–8 years of age: 12 mg methotrexate intrathecally.

Patients aged 8 years and older: 12 mg up to a maximum of 15 mg methotrexate intrathecally.

The timing, frequency, and duration of intrathecal methotrexate injections are determined by the treating physician, taking into account specific treatment protocols and each individual clinical situation.

Warning: methotrexate-containing products and/or solvents containing preservatives must not be used for intrathecal administration or for high-dose therapy!

Treatment of patients with impaired renal function.

Methotrexate should be used with caution in patients with impaired renal function. The dose should be adjusted as follows:

Creatinine clearance (mL/min)	% of standard dose
> 80	Full dose
80	75
60	63
50	56
< 50	Contraindicated

Treatment of patients with hepatic impairment.
Methotrexate "Ebewe" should be administered with caution and only if absolutely necessary to patients with significant hepatic dysfunction (current or in medical history, especially if caused by alcohol abuse). Methotrexate must not be used when bilirubin levels exceed 85.5 µmol/L.

Treatment of elderly patients (aged over 65 years).
Since hepatic and renal functions decline with age, and folate reserves are reduced, dose reduction may be advisable for elderly patients.

Patients with third space fluid accumulation (pleural effusion, ascites).
In patients with third space fluid accumulation, the elimination half-life of methotrexate may be prolonged up to four times compared to normal duration. Therefore, dose reduction or even discontinuation of methotrexate administration may be required.

Administration method

For intravenous, intramuscular, intra-arterial, intrathecal, and intraventricular use after dilution.

Methotrexate "Ebewe" concentrate for infusion solution, 100 mg/mL, must be diluted with standard infusion solutions prior to administration, according to the treatment regimen and duration of infusion. The concentrate should be diluted with glucose solution or physiological saline. The drug is generally administered at a concentration of 1–2%.

Such methotrexate solutions remain stable at 25°C (room temperature) for 24 hours, regardless of whether they are stored protected from light or not. For longer infusion durations, the infusion bottle should be replaced.

Preparations containing methotrexate and/or solvents containing preservatives must not be administered intrathecally in high doses!

A mandatory condition for treatment with this drug is the determination of serum methotrexate levels.

Treatment with methotrexate at doses of 100 mg/m² BSA or higher, administered as single doses, must be followed by administration of calcium folinate as an emergency rescue agent.

Doses exceeding 100 mg/m² are usually administered as intravenous infusions. Part of the dose may be given intravenously as an initial bolus injection.

The total duration of therapy is determined by the physician.

Children.

Methotrexate should be used in children and adolescents with particular caution and in accordance with appropriate treatment protocols.

Overdose.

Post-marketing experience with methotrexate indicates that cases of overdose have occurred following both oral and parenteral (intravenous, intramuscular, or intrathecal) administration. Cases of overdose have also been reported due to accidental daily oral intake of methotrexate instead of once weekly (either as a total dose or as several separate doses).

Symptoms of overdose.
After oral or intravenous administration, symptoms are predominantly related to bone marrow suppression and gastrointestinal toxicity. These include leukopenia, thrombocytopenia, anemia, pancytopenia, neutropenia, mucositis, stomatitis, ulceration of oral mucosa, nausea, vomiting, gastrointestinal ulceration, and gastrointestinal bleeding. In some patients, signs of overdose may be absent. Fatal outcomes have been reported due to sepsis, septic shock, renal failure, and aplastic anemia.

Following intrathecal overdose, symptoms are typically related to the central nervous system (CNS), including headache, nausea, vomiting, seizures or convulsions, and acute toxic encephalopathy. In some cases, no symptoms were observed. In other cases, intrathecal overdose resulted in fatal outcomes, including brain herniation, increased cerebrospinal fluid pressure, and acute toxic encephalopathy.

Overdose prevention.
When methotrexate is administered at doses exceeding 100 mg/m² BSA, treatment must be accompanied by administration of calcium folinate.

Treatment in case of overdose.
The specific antidote for methotrexate is calcium folinate. It neutralizes the adverse toxic effects of methotrexate.

Treatment of intoxication symptoms after low-dose methotrexate administration (single dose < 100 mg/m² BSA), which can be explained by tetrahydrofolic acid deficiency.

6–12 mg of calcium folinate should be administered immediately intravenously or intramuscularly, followed by repeated administration of the same dose several times (at least 4 times) at 3–6 hour intervals. For more detailed information on intensive calcium folinate therapy in cases of delayed methotrexate elimination during treatment with moderately high and high doses, refer to specialized literature.

The longer the time interval between methotrexate and calcium folinate administration, the lower the efficacy of calcium folinate. Optimal dosage and duration of calcium folinate administration should be determined by monitoring serum methotrexate levels.

In cases of significant overdose, hydration and urinary alkalization are required to prevent precipitation of methotrexate and/or its metabolites in renal tubules. If intoxication is due to markedly delayed elimination (monitor serum methotrexate levels!), for example, due to acute renal failure, hemodialysis and/or hemoperfusion should be performed. Effective methotrexate clearance can be achieved through intensive intermittent hemodialysis using high-flux dialyzers. Standard hemodialysis and peritoneal dialysis do not enhance methotrexate elimination.

Accidental overdose following intrathecal administration may require intensive systemic interventions: systemic, non-intrathecal! administration of high-dose calcium folinate, alkaline diuresis, rapid cerebrospinal fluid drainage, and ventriculolumbar perfusion.

Adverse Reactions

The frequency and severity of adverse reactions generally depend on the dose, route of administration, and duration of methotrexate therapy. Since severe adverse reactions may occur even at low doses and at any stage of treatment, regular and frequent physician monitoring is required. Most adverse reactions are reversible if detected early. However, some of the serious adverse reactions listed below may, in very rare cases, lead to sudden fatal outcomes.

If adverse reactions occur, the dose should be reduced, or if necessary, treatment should be discontinued and appropriate measures taken (see section "Overdose"). If methotrexate therapy is resumed, it should be continued with caution, following careful assessment of the necessity for continued treatment and heightened vigilance for possible recurrence of toxic effects.

Myelosuppression and mucositis are generally dose-limiting toxic effects. Their severity depends on the dose, route, and duration of methotrexate administration. Mucositis typically occurs approximately 3–7 days after methotrexate administration, while leukopenia and thrombocytopenia occur 5–13 days after administration. Myelosuppression and mucositis usually resolve within 14 days in patients with intact elimination mechanisms.

The most frequently reported adverse reactions include thrombocytopenia, leukopenia, stomatitis, abdominal pain, anorexia, nausea and vomiting, inflammation and ulceration of the mucous membranes of the oral cavity and pharynx (particularly within the first 24–48 hours after methotrexate administration), elevated liver enzymes and bilirubin levels, decreased creatinine clearance, fatigue, and malaise. Oral mucosal ulceration is usually the first clinical sign of toxicity.

Frequency categories are defined as follows: very common (> 1/10), common (> 1/100, < 1/10), uncommon (> 1/1000, < 1/100), rare (> 1/10000, < 1/1000), very rare (< 1/10000), frequency not known (cannot be estimated from available data).

Infections and infestations:
common – herpes zoster;
uncommon – opportunistic infections, which may be fatal;
rare – sepsis (including fatal outcomes);
very rare – nocardiosis, histoplasmosis, cryptococcal meningitis, herpes simplex virus-induced hepatitis, disseminated herpes simplex virus infection, cytomegalovirus infections (including pneumonia), Pneumocystis jirovecii pneumonia;
frequency not known – pneumonia, reactivation of hepatitis B, exacerbation of hepatitis C.

Benign, malignant and unspecified neoplasms (including cysts and polyps):
uncommon – malignant neoplasms;
very rare – tumor lysis syndrome.

Blood and lymphatic system disorders:
very common – leukopenia, thrombocytopenia;
common – anemia, pancytopenia, myelosuppression, agranulocytosis;
rare – megaloblastic anemia;
very rare – aplastic anemia, eosinophilia, neutropenia, lymphadenopathy (partially reversible), lymphoproliferative disorders (partially reversible).

Immune system disorders:
uncommon – allergic reactions, anaphylactic shock, urticaria, immunosuppression;
very rare – hypogammaglobulinemia.

Metabolism and nutrition disorders:
uncommon – diabetes mellitus.

Psychiatric disorders:
uncommon – depression;
rare – mood swings, transient sensory disturbances.

Nervous system disorders:
very common – headache, dizziness;
common – fatigue, somnolence, paresthesia;
uncommon – seizures, encephalopathy/leukoencephalopathy (with parenteral administration), hemiparesis, confusion;
rare – paresis, speech disorders including dysarthria and aphasia, myelopathy (after intrathecal administration);
very rare – unusual cranial sensory perception, myasthenia, limb pain, taste disturbances, acute aseptic meningitis with meningeal signs;
frequency not known – neurotoxicity, arachnoiditis, paraplegia, stupor, ataxia, dementia, increased cerebrospinal fluid pressure after intrathecal administration.

Intravenous administration of methotrexate may also lead to acute encephalitis and acute encephalopathy with fatal outcome.

Eye disorders:
common – conjunctivitis;
rare – visual disturbances (blurred vision, visual clouding), severe dysopia of unknown etiology;
very rare – periorbital edema, blepharitis, lacrimation, photophobia, transient blindness, vision loss.

Cardiac disorders:
very rare – pericarditis, exudative pericarditis, pericardial tamponade.

Vascular disorders:
uncommon – vasculitis, allergic vasculitis;
rare – arterial hypotension, thromboembolic events (including arterial thrombosis, cerebral vessel thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein thrombosis, and pulmonary embolism).

Respiratory, thoracic and mediastinal disorders:
very common – cough;
common – pulmonary complications based on interstitial pneumonitis, alveolitis, which may be fatal (see section "Special precautions");
uncommon – pulmonary fibrosis, pleuritis;
rare – pharyngitis, respiratory arrest, pulmonary embolism;
very rare – chronic obstructive interstitial lung disease, asthma-like reactions with cough, dyspnea, and pathological pulmonary function test results, Pneumocystis pneumonia;
frequency not known – chest pain, hypoxia, pulmonary alveolar hemorrhage (reported with methotrexate use in rheumatic and related indications).

Gastrointestinal disorders:
very common – stomatitis, abdominal pain, anorexia, nausea, vomiting, diarrhea (particularly within the first 24–48 hours after methotrexate administration);
uncommon – gastrointestinal ulcers and bleeding, pancreatitis;
rare – enteritis, gingivitis, melena;
very rare – hematemesis;
frequency not known – non-infectious peritonitis, toxic megacolon, colonic perforation, glossitis.

Hepatobiliary disorders:
very common – increased liver enzyme activity (ALT (GPT), AST (GOT)), alkaline phosphatase, and bilirubin levels;
uncommon – hepatotoxicity, fatty liver changes, chronic liver fibrosis and cirrhosis, decreased serum albumin;
rare – acute hepatitis;
very rare – reactivation of chronic hepatitis, acute liver necrosis, acute liver disease, liver failure.

Skin and subcutaneous tissue disorders:
very common – alopecia;
common – exanthema, erythema, pruritus, photosensitivity, skin ulceration;
uncommon – severe toxic manifestations: herpes-like skin rash, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell's syndrome), urticaria, increased skin pigmentation, nodulosis, painful psoriatic erosions, impaired wound healing;
rare – acne, skin ulcers, bruising, erythema, painful psoriatic erosions, increased nail pigmentation, onycholysis, increased rheumatoid nodules;
very rare – furunculosis, telangiectasia, acute paronychia;
frequency not known – skin reactions associated with eosinophilia and systemic symptoms (DRESS), dermatitis.

Musculoskeletal and connective tissue disorders:
uncommon – arthralgia/myalgia, osteoporosis;
rare – stress fracture;
frequency not known – osteonecrosis of the jaw (secondary to lymphoproliferative disorders), muscle spasms.

Renal and urinary disorders:
very common – decreased creatinine clearance;
uncommon – severe nephropathy, renal failure, ulcerative cystitis, micturition disorders, dysuria, oliguria, anuria;
rare – hyperuricemia, increased serum urea and creatinine, azotemia;
very rare – hematuria, proteinuria.

Pregnancy, puerperium and perinatal conditions:
uncommon – congenital malformations;
rare – abortion;
very rare – fetal death.

Reproductive system and breast disorders:
uncommon – vaginal ulcers and inflammation;
rare – transient oligospermia;
very rare – impaired oogenesis/spermatogenesis, impotence, infertility, loss of libido, vaginal discharge, menstrual cycle disturbances, cycle disorders, gynecomastia;
frequency not known – erectile dysfunction.

General disorders and administration site conditions:
very common – exhaustion, malaise;
uncommon – pyrexia; with intramuscular administration of methotrexate, local adverse reactions (burning sensation) or tissue damage (formation of sterile abscess, destruction of fatty tissue) at the injection site may occur;
very rare – chills.

Adverse reactions with intrathecal administration of methotrexate

CNS toxicity, which may occur after intrathecal administration of methotrexate, may manifest in various ways:

• Acute chemical arachnoiditis (inflammation of the arachnoid membrane), presenting with headache, dorsalgia, nuchal rigidity, and meningismus;
• Subacute myelopathy, characterized by, for example, paraparesis/paraplegia (involving one or more spinal nerve roots);
• Chronic leukoencephalopathy, presenting with confusion, irritability, somnolence, ataxia, dementia, seizures, and coma. This CNS toxicity may progress and lead to fatal outcome.

There is evidence that concomitant cranial irradiation and intrathecal methotrexate administration increases the frequency of leukoencephalopathy. After intrathecal administration of methotrexate, patients should be carefully monitored for possible signs of neurotoxicity (meningeal irritation, transient or permanent paralysis, encephalopathy).

Intrathecal and intravenous administration of methotrexate may also lead to acute encephalitis and acute encephalopathy with fatal outcome.

Cases have been reported of patients with CNS periventricular lymphoma who developed brain herniation after intrathecal methotrexate administration.

Adverse reactions with intramuscular administration of methotrexate

With intramuscular administration of methotrexate, local adverse reactions (burning sensation) or tissue damage (formation of sterile abscess, destruction of fatty tissue) may occur at the injection site.

Shelf life

3 years for the medicinal product in the original packaging.

Storage conditions

Store in the original packaging at a temperature not exceeding 25 °C.

Keep out of the reach of children.

Incompatibilities

The product is incompatible with strong oxidizing agents and acids. Mixing methotrexate solutions with chlorpromazine hydrochloride, droperidol, idarubicin, metoclopramide hydrochloride, heparin, prednisolone sodium phosphate, or promethazine hydrochloride may result in precipitation or clouding of the solution. The ready-to-use infusion solution should generally be used within 24 hours after preparation. In addition, incompatibility with other substances (e.g., bleomycin) may occur during prolonged storage.

Packaging

5 ml (500 mg), 10 ml (1000 mg), or 50 ml (5000 mg) in a vial; 1 vial per cardboard box.

Prescription status

Prescription only.

Manufacturer

(Responsible for batch release)

EBEWE Pharma Ges.m.b.H. Nfg. KG

or

FAREVA Unterach GmbH

Manufacturer's address and location of operations

Mondzeilestraße 11, 4866 Unterach am Attersee, Austria