Methotrexate "ebewe"

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

Composition:

Active substance: methotrexate;

1 ml of solution contains 10 mg of methotrexate;

Excipients: sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Solution for injection.

Main physico-chemical properties: clear yellow solution.

Pharmacotherapeutic group.

Antineoplastic agents. Antimetabolites. Structural analogues of folic acid.

ATC code: L01BA01.

Pharmacological properties.

Pharmacodynamics.

Antirheumatic agent for the treatment of chronic inflammatory rheumatic diseases and polyarticular forms of juvenile idiopathic arthritis.

Methotrexate is a folic acid antagonist and, as an antimetabolite, belongs to the class of cytotoxic substances. It acts by competitively inhibiting the enzyme dihydrofolate reductase, thereby suppressing DNA synthesis. To date, there is no clear evidence as to whether the efficacy of methotrexate in the treatment of psoriasis, psoriatic arthritis, and chronic polyarthritis is related to its anti-inflammatory or immunosuppressive effect, or how extracellular adenosine concentrations contribute to these effects.

Pharmacokinetics.

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

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

Elimination occurs primarily in unchanged form, mainly via the kidneys through glomerular filtration and active tubular secretion in the proximal tubules.

Approximately 5–20% of methotrexate and 1–5% of 7-hydroxymethotrexate are excreted in bile. A pronounced enterohepatic circulation is observed.

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

Clinical characteristics.

Indications.

Methotrexate "Ebewe" is indicated for the treatment of:

• severe active rheumatoid arthritis in adults;
• severe active polyarticular juvenile idiopathic arthritis in patients who have had an inadequate response to nonsteroidal anti-inflammatory drugs (NSAIDs);
• severe generalized psoriasis, particularly plaque-type, and psoriatic arthritis in adult patients when conventional therapies have been insufficiently effective.

Contraindications.

• Hypersensitivity to methotrexate or to any of the excipients of the medicinal product.
• 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 blood 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 during pregnancy or lactation").
• Vaccination with live vaccines during methotrexate therapy.

Special safety precautions.

When handling the medicinal product, standard procedures for cytotoxic substances must be followed. Precautions should be taken to prevent contact of methotrexate solutions with skin or mucous membranes. If contact occurs, the affected area should be immediately rinsed thoroughly with large amounts of water. A soothing hand cream may be used to relieve transient burning sensations. In cases where there is a risk of significant methotrexate absorption, regardless of the route of exposure, treatment with leucovorin is required. Pregnant healthcare workers must not handle this medicinal product.

In outpatient settings, residual medicinal product must not be disposed of via sewage systems or 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 such effects, calcium folinate should be administered; concomitant use of methotrexate should be avoided.

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

• Disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs)* should not be used before or during high-dose methotrexate therapy. Concurrent 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).

Increased methotrexate toxicity has not been fully studied when used concomitantly with DMARDs (e.g., gold salts, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine); therefore, the occurrence of toxic effects cannot be ruled out.

Proton pump inhibitors. Concurrent 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 proton pump inhibitors with high-dose methotrexate should be avoided whenever possible. These drugs should be used cautiously in patients with renal impairment.

The risk of methotrexate-induced hepatotoxicity increases with regular alcohol consumption or concomitant use of other hepatotoxic agents, 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 serum albumin binding sites, thereby increasing its bioavailability (indirect dose increase) and enhancing its toxicity. Therefore, careful monitoring of patients is required when these agents are used concomitantly with methotrexate.

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

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

• Ciprofloxacin* also reduces renal tubular secretion; 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 bacterial metabolism.

Agents 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.

Agents causing folate deficiency. The toxic effects of methotrexate may be enhanced when used concomitantly with agents causing folate deficiency (e.g., sulfonamides, trimethoprim/sulfamethoxazole). Particular caution is also 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's inhibition of folate synthesis (potentially increasing the frequency of adverse effects), such effects have been observed only in isolated cases during several clinical studies.

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

Beverages containing caffeine and theophylline. 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 potential 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 radiation therapy in patients receiving methotrexate, there may be an increased risk of soft tissue and bone necrosis. Cholestyramine may enhance extrarenal elimination of methotrexate by interfering with enterohepatic circulation.

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

In isolated cases, corticosteroids have caused disseminated herpes zoster or postherpetic neuralgia in patients with herpes zoster during concomitant methotrexate therapy.

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 such effects.

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

The risk of methotrexate-induced hepatotoxicity increases with alcohol abuse or concomitant use of other hepatotoxic agents.

When treating patients receiving hematotoxic agents (e.g., metamizole) with methotrexate, the risk of severe hematotoxic effects of methotrexate increases.

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

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

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

Reduced plasma phenytoin levels 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 agents (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 an increased 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 of methotrexate to potentially toxic levels. Methotrexate and levetiracetam levels should be closely monitored in patients receiving concomitant therapy with these two agents.

Amoxicillin

Penicillins may reduce methotrexate excretion, potentially increasing its toxicity.

Special precautions for use.

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

During methotrexate therapy, patients must be closely monitored 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 intake does not always lead to complete regression of adverse effects.

A mandatory condition for methotrexate treatment is 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 elimination half-life of methotrexate from plasma is prolonged.

Removal of pleural effusion or ascites is required before initiating methotrexate therapy. Drainage of pleural exudate or ascites must be performed prior to 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 be continued 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 long-term 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 radiation therapy affecting bone marrow function, impaired bone marrow function should be considered, particularly increased sensitivity of the bone marrow to methotrexate therapy, resulting in enhanced suppression of the hematopoietic system. Bone marrow biopsy is required during prolonged methotrexate therapy.

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

Liver function

Since methotrexate exerts hepatotoxic effects, other hepatotoxic drugs should not be prescribed during 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), although usually only after prolonged use. Persistent elevation of liver enzymes is frequently observed, which is usually transient and asymptomatic and does not necessarily predict subsequent liver disease.

Methotrexate may cause reactivation or complications of hepatitis B infection, or exacerbation of hepatitis C with fatal outcomes in some cases. Some cases of hepatitis B reactivation occurred 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 their potential reactivation.

Special caution is needed when treating patients with insulin-dependent diabetes mellitus, as isolated cases of liver cirrhosis development 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), which may lead 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, and stomatitis, may potentiate methotrexate toxicity due to elevated active substance levels. 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, and 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 very important 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 outcome due to intestinal wall perforation may occur.

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

Nervous system

Leukoencephalopathy has been observed in patients who received intravenous methotrexate following cranial radiation therapy.

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

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, e.g., meningitis, transient or permanent paralysis, or encephalopathy).

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

Transient acute neurological syndrome has been observed during high-dose methotrexate therapy, which may manifest, 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 in treating patients with impaired lung function.

Pulmonary complications, pleural effusion, alveolitis, or pneumonitis with symptoms such as dry non-productive cough, fever, malaise, chest pain, dyspnea, hypoxemia, and radiographic findings of infiltrate or nonspecific pneumonia occurring during methotrexate therapy may indicate potentially dangerous and possibly fatal involvement. Lung diseases caused by methotrexate 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 (including low doses, e.g., 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. Results of rapid tests should be considered when suspecting pulmonary alveolar hemorrhage to confirm diagnosis.

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 sunburns (recurrence of adverse effects of radiation therapy).

Immune system

Opportunistic infections, including Pneumocystis pneumonia, which may be fatal, may occur during methotrexate therapy. If a patient presents symptoms of impaired pulmonary function, Pneumocystis pneumonia should be considered.

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

Particular caution is required when treating patients with progressive infections. Methotrexate is contraindicated in patients with immunodeficiency syndromes, whether apparent or confirmed by laboratory tests. 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 drugs, may induce tumor lysis syndrome. Appropriate supportive medication therapy may prevent or reduce the manifestations of these complications.

Methotrexate may increase the risk of developing neoplasms (predominantly lymphomas). Malignant lymphomas may develop 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 radiation therapy is performed concurrently with methotrexate administration.

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 carefully monitored to allow immediate detection of toxic effects.

Before starting methotrexate therapy or resuming therapy after interruption, complete blood count with differential leukocyte count and platelet count, liver enzyme levels, bilirubin, serum albumin, hepatitis screening (A, B, C), chest X-ray, and renal function tests should be performed. If clinically indicated, tests to rule out tuberculosis and hepatitis should be prescribed. If lung disease is suspected (e.g., interstitial pneumonia), lung function tests should be performed, especially if previous test results are available.

Depending on dosage or treatment protocol, regular monitoring of methotrexate levels in serum is required, 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, low urine pH, gastrointestinal obstruction, prior cisplatin therapy, or impaired kidney function have an increased risk of elevated or slowly decreasing methotrexate levels in serum. These patients should be closely monitored.

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

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

Appropriate protective therapy with calcium folinate 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), must be performed.

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

Maximum reduction in circulating leukocytes, neutrophil granulocytes, and platelets typically occurs 5–13 days after intravenous methotrexate administration (rebound phenomenon occurs at 14–28 days). Sometimes two nadirs in leukocyte and neutrophil granulocyte counts are observed, the first at 4–7 days and the second at 12–21 days, followed by 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 treatment 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 examination, or, less frequently, liver cirrhosis may be present.

Serum creatinine, urea, and electrolyte levels should be monitored, especially when using high-dose methotrexate, 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 range.

If serum 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) must be carefully monitored. This is particularly important when concomitant therapy includes drugs that reduce methotrexate excretion, adversely affect kidneys (especially 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 fluids should be administered and urine alkalinized (urine pH ≥ 7).

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

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

More frequent monitoring is required at the beginning of treatment, during dose adjustments, or in cases of increased risk of elevated methotrexate levels (e.g., dehydration, impaired kidney function, additional concomitant drugs, or increased number of concomitant drugs such as nonsteroidal anti-inflammatory agents).

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 seizure. In symptomatic patients, diagnostic imaging typically shows 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. Dose reduction should be considered due to advanced age. Partially modified protocols have been developed for elderly patients (aged 55 years and older), for example, for treatment of acute lymphoblastic leukemia.

Reproductive function

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

Teratogenicity – reproductive risk

Methotrexate causes embryotoxicity, miscarriages, and congenital abnormalities in humans. Therefore, physicians must warn women of reproductive age about possible effects on reproductive function, miscarriages, and fetal congenital malformations (see section "Adverse reactions"). Women of reproductive age must use effective contraception during treatment and for six months after completion of methotrexate therapy.

Use in men

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

Solutions for infusion 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 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, predominantly 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 must not become pregnant during methotrexate therapy. Effective contraception must be used during treatment and for at least six months after completion of methotrexate therapy (see section "Special precautions for use"). Before initiating treatment, 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 treatment, 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 about the serious risks to the fetus if pregnancy occurs during treatment.

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 malformations or miscarriage after exposure to low doses of methotrexate (less than 30 mg per week) in patients. Data are insufficient to assess the risk of congenital malformations or miscarriage after exposure to higher doses.

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

Pregnancy

Use of methotrexate for non-oncological indications during pregnancy is contraindicated (see section "Contraindications"). If a patient becomes pregnant during methotrexate therapy or within six months after completion of treatment, 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, miscarriages, and/or congenital abnormalities (e.g., craniofacial, cardiovascular, central nervous system, and limb developmental defects).

Methotrexate is a potent human teratogen. Exposure during pregnancy increases the risk of spontaneous miscarriages, 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 drugs.
• 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 drugs.

There is insufficient data on use of methotrexate 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 use of the drug 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 treated with methotrexate for oncological indications, consultation at genetic counseling centers is recommended, preferably before starting therapy, and men should consider sperm cryopreservation before starting therapy, as high-dose methotrexate may be genotoxic (see section "Special precautions for use").

Ability to affect reaction speed when driving vehicles or operating machinery.

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

Method of administration and dosing.

Treatment of patients with rheumatoid arthritis and psoriasis.

Treatment with Methotrexate "Ebewe" should be carried out under the supervision of a rheumatologist or dermatologist, as well as an internist. The drug is administered subcutaneously, intramuscularly, or intravenously.

Doses for adults with rheumatoid arthritis

The recommended initial dose is 7.5 mg of methotrexate once weekly administered subcutaneously, intramuscularly, or intravenously.

Therapeutic effect usually becomes apparent after 4–6 weeks of therapy. If there is no sign of improvement, as well as no signs of toxic effects after 6–8 weeks of treatment, the dose may be gradually increased by 2.5 mg per week. The usual optimal weekly dose ranges from 7.5 to 15 mg. The maximum weekly dose of 25 mg should not be exceeded. If no therapeutic effect is observed after 8 weeks of treatment at the maximum dose, methotrexate should be discontinued. Once the desired therapeutic effect is achieved, treatment should continue at the lowest possible effective maintenance dose. The optimal duration of methotrexate therapy has not yet been established; however, preliminary data indicate that the initial response can be maintained for at least 2 years with ongoing maintenance therapy. After discontinuation of methotrexate treatment, disease symptoms may return within 3–6 weeks.

Doses for patients with psoriasis and psoriatic arthritis.

A trial parenteral administration of 5–10 mg of methotrexate once weekly prior to starting therapy is recommended to detect any idiosyncratic adverse effects. The recommended initial dose is 7.5 mg of methotrexate once weekly administered subcutaneously, intramuscularly, or intravenously. The dose may be gradually increased, but the maximum weekly dose of 30 mg of methotrexate should not be exceeded. Therapeutic effect usually appears approximately 2–6 weeks after initiation of therapy. Once the desired therapeutic effect is achieved, treatment should continue at the lowest possible effective maintenance dose.

Dosing for children under 16 years of age with polyarticular forms of juvenile idiopathic arthritis.

The recommended dose is 10–15 mg/m² body surface area per week. If the response is inadequate, the weekly dose may be increased up to 20 mg/m² body surface area per week.

In juvenile idiopathic arthritis, the drug should be administered only intramuscularly, as there is insufficient data on subcutaneous or intravenous administration in children.

Duration and method of administration.

Methotrexate "Ebewe" in pre-filled syringes is suitable for patient self-administration. In such cases, physician instruction is recommended.

Step-by-step instructions for subcutaneous injections

To avoid any injuries, used syringes should be disposed of after covering the used needle.

The physician determines the overall duration of treatment.

When switching from oral to parenteral administration, a dose reduction may be necessary due to different bioavailability of methotrexate after oral administration.

Supplementation with folic acid may be considered according to current therapeutic guidelines.

Treatment of patients with impaired renal function.

Methotrexate "Ebewe" should be administered with caution to patients with impaired renal function. The dose should be adjusted according to creatinine clearance (if clearance > 50 mL/min, no dose reduction is required; if clearance is 20–50 mL/min, reduce dose by 50%; if clearance < 20 mL/min, methotrexate should not be administered).

Treatment of patients with impaired hepatic function.

Methotrexate "Ebewe" should be administered with extreme caution (if absolutely necessary) to patients with significant hepatic impairment (current or in history, especially due to alcohol abuse). Methotrexate must not be used if bilirubin levels exceed 85.5 µmol/L.

Treatment of elderly patients.

Since liver and kidney function deteriorate with age and folate reserves are reduced, dose reduction may be advisable for elderly patients.

Children.

Dosage recommendations for use in children are provided in the section "Dosage and administration".

Overdose.

Post-marketing experience with methotrexate indicates that cases of overdose have occurred following both oral and 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 individual 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.

In cases of overdose following intrathecal administration, symptoms are typically related to the central nervous system (CNS), including headache, nausea and vomiting, seizures or convulsions, and acute toxic encephalopathy. In some cases, no symptoms were observed. In other cases, intrathecal overdose was fatal; reports include brain herniation and increased cerebrospinal fluid pressure, as well as acute toxic encephalopathy.

Prevention of overdose. When methotrexate is administered at doses exceeding 100 mg/m² BSA, treatment should 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 (single dose <100 mg/m² BSA), which can be explained by tetrahydrofolic acid deficiency.

6–12 mg of calcium folinate should be administered intravenously or intramuscularly immediately, 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 or high doses, refer to specialized literature.

The longer the time interval between methotrexate and calcium folinate administration, the lower the effectiveness of calcium folinate. To determine the optimal dose and duration of calcium folinate administration, serum methotrexate levels should be monitored.

In cases of significant overdose, hydration and urinary alkalinization are required to prevent precipitation of methotrexate and/or its metabolites in renal tubules. If intoxication is caused by very slow elimination (monitor serum methotrexate levels!), e.g., 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. Conventional 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 monitoring by a physician is required. Most adverse reactions are reversible if detected early. However, some of the serious adverse reactions listed below may very rarely lead to sudden fatal outcomes.

If adverse reactions occur, the dose should be reduced, or if necessary, depending on the severity and intensity, 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 of treatment and increased 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 develops 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 throat (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 (> 1/1,000, < 1/100), rare (> 1/10,000, < 1/1,000), very rare (< 1/10,000), 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 mycosis, herpes simplex virus-induced hepatitis, disseminated herpes simplex virus infection, cytomegalovirus infections (including pneumonia), Pneumocystis jirovecii pneumonia. Frequency not known: pneumonia, hepatitis B reactivation, hepatitis C exacerbation.

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 – paralysis, 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 diplopia of unknown etiology; very rare – periorbital edema, blepharitis, lacrimation, photophobia, transient blindness, vision loss.

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

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 for use"); 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 for 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; uncommon – hepatotoxicity, fatty liver changes, chronic liver fibrosis, cirrhosis, decreased serum albumin; rare – acute hepatitis; very rare – recurrence 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 ulcers; 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 – disturbances of 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 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 meningism;
• Subacute myelopathy, characterized, for example, by 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 methotrexate administration, 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 periventricular CNS 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 damage (formation of sterile abscess, destruction of fatty tissue) may occur at the injection site.

Shelf life. 2 years.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

As compatibility studies have not been conducted, this medicinal product must not be mixed with other medicinal products.

Packaging.

0.75 mL (7.5 mg), 1 mL (10 mg), 1.5 mL (15 mg), 2 mL (20 mg) in a pre-filled syringe. 1 or 5 pre-filled syringes in a cardboard box together with a sterile injection needle and swabs.

Prescription category.

Prescription only.

Manufacturer.

(Responsible for batch release)

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

or

FREWA Unterach GmbH

Manufacturer's address and place of business.

Mondzeestrasse 11, 4866 Unterach am Attersee, Austria

INSTRUCTIONS

for medical use of the medicinal product

METHOTREXATE "EBEWE"

(METHOTREXATE "EBEWE")

Composition:

Active ingredient: methotrexate;

1 ml of solution contains 10 mg of methotrexate;

Excipients: sodium chloride, sodium hydroxide, water for injections.

Pharmaceutical form. Injection solution.

Main physicochemical properties: clear yellow solution.

Pharmacotherapeutic group.

Antineoplastic agents. Antimetabolites. Structural analogues of folic acid.

ATC code: L01B A01.

Pharmacological properties.

Pharmacodynamics.

Methotrexate is a folic acid antagonist 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 the proliferation rate of malignant tissues is faster than normal, methotrexate can disrupt their growth without causing irreversible damage to healthy tissues.

The mechanism of action of methotrexate in rheumatoid arthritis has not been fully established, but it may affect immune functions.

In psoriasis, the rate of epithelial cell replication in the skin is much higher than normal. This difference in proliferation rate provides the rationale for using methotrexate to control the psoriatic process.

Pharmacokinetics.

Approximately 50% of methotrexate is protein-bound in plasma. After distribution, methotrexate accumulates primarily 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 minimal amounts of methotrexate penetrate into the cerebrospinal fluid. The terminal half-life of methotrexate varies widely (3–17 hours), averaging 6–7 hours. In patients with a third space (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 primary metabolite of methotrexate is 7-hydroxymethotrexate.

Methotrexate is excreted predominantly 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", 10 mg/ml solution for injection, 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 stage 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.

Additionally, Methotrexate "Ebewe", 10 mg/ml solution for injection, is indicated for the following conditions:

• Treatment of rheumatoid arthritis.
• Treatment of psoriasis, particularly extensive psoriasis, generalized pustular psoriasis, psoriatic arthritis, or psoriatic nail lesions.

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 "Method of administration and dosage").
• Hepatic insufficiency (see section "Method of administration and dosage").
• Impaired renal function (creatinine clearance < 50 ml/min; see section "Method of administration and dosage").
• 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 during pregnancy or breastfeeding").
• Vaccination with live vaccines during methotrexate treatment.

Special precautions.

When handling the drug, standard procedures for cytotoxic substances must be observed. Precautions (use of protective gloves and goggles) must be taken to prevent contact of methotrexate solutions with skin or mucous membranes. If the drug does come into contact with skin or mucous membranes, the affected area should be immediately rinsed with copious amounts of water. A soothing hand cream may be used to relieve transient burning sensations. In cases where there is a risk of significant absorption of methotrexate, regardless of the route of absorption, treatment with leucovorin is required. Pregnant healthcare workers must not handle this drug.

Any unused drug residue and all instruments and materials used in the preparation and administration of the infusion solution must be disposed of according to approved procedures for cytotoxic waste disposal.

In outpatient settings, any unused drug residue 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; concurrent 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 values).

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, the occurrence of toxic effects cannot be excluded.

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 whenever possible. These drugs should be used with caution 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, thereby increasing its bioavailability (indirect dose increase) and enhancing its toxicity. Close monitoring of patients is therefore 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 thereby increase methotrexate toxicity, especially at low doses. Close monitoring is also required when these drugs are used concomitantly with methotrexate.

Penicillins and sulfonamides may, in isolated cases, reduce renal clearance of methotrexate, leading to increased serum concentrations and enhanced toxicity on 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 with adverse effects on bone marrow. When used concomitantly with drugs that may cause adverse effects on bone marrow (e.g., aminopyrine 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 that cause folate deficiency (e.g., sulfonamides, trimethoprim/sulfamethoxazole) may enhance the toxic effects of methotrexate. Particular caution is also 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 methotrexate effects 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 in isolated cases during several clinical studies.

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

Caffeine- and theophylline-containing beverages. During methotrexate therapy, excessive consumption of beverages containing caffeine (coffee, caffeinated soft drinks, black tea) or 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 adjustments.

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

During radiotherapy in patients receiving 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 recirculation.

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

In isolated cases, corticosteroids have been associated with disseminated shingles or postherpetic neuralgia in patients with shingles 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 agents and methotrexate.

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

The risk of severe hematotoxic effects of methotrexate is increased in patients receiving hematotoxic drugs (e.g., metamizole).

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 enhanced.

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

Reduced 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 impaired renal function.

Concomitant therapy with cytarabine administered intravenously and methotrexate administered intrathecally 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 and prolonged blood concentrations of methotrexate 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.

Methotrexate therapy should be administered under the supervision of an experienced oncologist.

Patients receiving methotrexate must be under close monitoring to allow timely detection of signs of potential toxicity and adverse effects. 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 resolution of adverse effects.

Monitoring serum methotrexate levels is mandatory during methotrexate therapy.

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

Pleural effusion or ascites must be resolved prior to initiating methotrexate therapy. Drainage should be performed before starting methotrexate treatment if pleural effusion or ascites is present. If this is not feasible, methotrexate therapy should not be initiated.

Blood and lymphatic system

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

During treatment of neoplastic diseases, methotrexate therapy should be continued only if the potential benefit outweighs the risk of severe myelosuppression. Early 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 long-term therapy.

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

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

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

Liver function

Since methotrexate has hepatotoxic effects, hepatotoxic drugs should not be prescribed during methotrexate therapy unless clearly necessary. Alcohol consumption should also be avoided or significantly limited.

Methotrexate may cause acute hepatitis and chronic, potentially fatal, liver toxicity (fibrosis, cirrhosis), although usually only after prolonged use. Persistent elevation of liver enzymes 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 with 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 potential for reactivation.

Special caution is needed when treating patients with insulin-dependent diabetes mellitus, as there have been reports of individual cases of liver cirrhosis developing 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 reduced 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 due to increased active substance levels. 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, and 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 is observed, 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, e.g., meningitis, transient or permanent paralysis, or encephalopathy).

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

During high-dose methotrexate therapy, a transient acute neurological syndrome has been observed, which may manifest 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 in 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 non-specific pneumonia occurring during methotrexate therapy may indicate potentially dangerous and possibly fatal involvement. 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, e.g., 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 test results should be considered when suspecting pulmonary alveolar hemorrhage to confirm the diagnosis.

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 plasmacytosis pneumonia, which may lead to fatal outcomes, are possible during methotrexate therapy. If a patient presents symptoms of pulmonary dysfunction, plasmacytosis pneumonia should be considered.

Since methotrexate affects the immune system, it may alter response to vaccination and affect 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 immunodeficiency syndromes, whether apparent or confirmed by laboratory tests. 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 drugs, may induce tumor lysis syndrome. Appropriate supportive medication 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 lymphoma regression 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.

Prior to initiating methotrexate therapy or resuming therapy after interruption, a blood test including leukocyte formula and platelet count, liver enzyme levels, bilirubin, serum albumin, hepatitis screening (A, B, C), chest X-ray, and kidney function tests should be performed. If clinically indicated, tests to exclude tuberculosis and hepatitis should be ordered. If lung disease is suspected (e.g., interstitial pneumonia), lung function tests should be conducted, especially if previous test results are available.

Depending on dosage or treatment protocol, regular monitoring of serum methotrexate levels is necessary, particularly during and after high-dose methotrexate therapy (see also section "Overdose"). Dose adjustment and protective therapy can significantly reduce methotrexate toxicity and potential mortality. Patients with pleural effusion, ascites, dehydration, low urine pH, gastrointestinal obstruction, prior cisplatin therapy, or impaired kidney function are at increased risk of elevated or slowly decreasing serum methotrexate levels. Such patients require close monitoring.

In some patients, methotrexate elimination may be delayed without the above-mentioned causes. Monitoring methotrexate concentration within 48 hours after administration is crucial, as elevated levels may lead to irreversible methotrexate toxicity.

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

Protective therapy with calcium folinate 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 monitoring should continue as needed 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.

Prior to initiating 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 typically occurs 5–13 days after intravenous methotrexate administration (rebound phenomenon observed at 14–28 days). Sometimes two nadirs in leukocyte and neutrophil granulocyte counts are recorded, the first at 4–7 days and the second at 12–21 days, followed by a rebound phenomenon.

Regular kidney and liver function tests, as well as urine analysis, should be performed.

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 during high-dose methotrexate therapy, on days 2 and 3, to detect any potential impairment in 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. Close monitoring of patients with potential kidney function impairment (e.g., elderly patients) is essential. This is particularly important when concomitant therapy includes drugs that reduce methotrexate excretion, adversely affect the kidneys (e.g., non-steroidal 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 alkalinized (urine pH ≥ 7).

Oral and throat examination 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.

More frequent monitoring is recommended 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 drugs, or increased number of concomitant drugs such as non-steroidal anti-inflammatory drugs).

Use in children

When administering methotrexate to 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 as generalized or focal epileptic seizure. In symptomatic patients, diagnostic imaging typically reveals leukoencephalopathy and/or microangiopathic calcification.

Use in elderly patients

Particular caution is required when treating elderly patients. Regular monitoring for early signs of toxicity is necessary. The clinical pharmacology of methotrexate in elderly patients has not been fully studied. Methotrexate dosage should be adjusted according to kidney and liver function. Dose reduction should be considered 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, miscarriages, and congenital abnormalities in humans. Therefore, physicians must warn women of reproductive age about the potential impact on reproductive function, miscarriages, and congenital fetal malformations (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 cause serious and potentially irreversible impairment of spermatogenesis, men should consider sperm cryopreservation prior to starting therapy (see section "Use during pregnancy or breastfeeding").

Infusion solutions containing methotrexate at 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 sodium (23 mg) per vial, i.e., essentially "sodium-free."

Progressive multifocal leukoencephalopathy

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving methotrexate, primarily in combination with other immunosuppressive drugs. PML may have fatal outcomes. This should be considered in differential diagnosis in immunocompromised 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 six months after completion of methotrexate therapy (see section "Special precautions for use"). Before initiating 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 levels 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 malformations or miscarriage after exposure to low doses of methotrexate (less than 30 mg per week). Data are insufficient to assess the risk of congenital malformations 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 three months after completion of methotrexate therapy. Men should not be sperm donors during therapy and for three months after discontinuation of methotrexate.

Pregnancy

Use of methotrexate for non-oncological indications during pregnancy is contraindicated (see section "Contraindications"). If a patient becomes pregnant during methotrexate therapy or within six 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 reported, including fetal death, miscarriages, and/or congenital anomalies (e.g., craniofacial, cardiovascular, central nervous system, and limb developmental defects).

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

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

Insufficient data are available on the use of methotrexate 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 prior to 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 use of the drug 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, consultation with genetic counseling centers is recommended, preferably before starting therapy, and men should consider sperm cryopreservation prior to therapy, 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 slight or moderate adverse effect on the ability to drive or operate machinery.

Method of Administration and Dosage

Warning

The dose 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. Healthcare professionals 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 after assessment of the patient's general condition and blood parameters. Doses used in standard methotrexate regimens, low-dose methotrexate regimens (single dose below 100 mg/m²), and high-dose regimens (single dose above 1000 mg/m²) depend on the specific dosing protocol.

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, leucovorin (calcium folinate) rescue not required:

15–20 mg/m² (IV); twice weekly;
30–50 mg/m² (IV); once weekly;
15 mg/m²/day (IV, IM); for 5 days. Repeat course after 2–3 weeks.

Methotrexate therapy in moderately high doses:

50–150 mg/m² (IV injection); leucovorin rescue not required. Repeat course after 2–3 weeks.
240 mg/m² (IV infusion over 24 hours); leucovorin rescue required. Repeat course after 4–7 days.
0.5–1.0 g/m² (IV infusion over 36–42 hours); leucovorin rescue required. Repeat course after 2–3 weeks.

High-dose methotrexate therapy – leucovorin rescue required:

1–12 g/m² (IV, over 1–6 hours). Repeat course after 1–3 weeks.

Systemic (intravenous and intramuscular) administration of methotrexate

Methotrexate therapy in low (single dose <100 mg/m² BSA) and moderately high doses (single dose 100–1000 mg/m² BSA).

Malignant trophoblastic tumors (benign gestational trophoblastic tumors, choriocarcinoma)

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

High-risk patients: 300 mg/m² BSA methotrexate 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 20–40 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 and dosing regimen 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 is effective as a single dose administered 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 the prevention and treatment of carcinomatous meningitis or for the 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 ≥8 years of age: 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 according to specific treatment protocols and individual clinical circumstances.

Warning: methotrexate-containing products and/or solvents containing preservatives must not be used intrathecally or in high doses!

Treatment of patients with impaired renal function.

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

Dosage in autoimmune diseases

Important warning regarding ebetrexate (methotrexate) dosage:

Methotrexate for the treatment of rheumatic or skin diseases must be administered only once weekly. Dosing errors with methotrexate can lead to serious adverse effects, including fatal outcomes.

Methotrexate should be prescribed only by physicians experienced in the use of chemotherapeutic agents. Methotrexate is administered once weekly.

It is recommended to designate a specific day of the week as the so-called "injection day."

Regular medical check-ups are required.

Dosage for patients with rheumatoid arthritis

To detect specific adverse effects, administration of a parenteral test dose one week prior to starting therapy is recommended.

The recommended initial dose is 7.5 mg of methotrexate administered once weekly by subcutaneous, intramuscular, or intravenous route. Depending on the individual disease course and patient condition, the dose may be gradually increased by 2.5 mg per week. The weekly dose should not exceed 25 mg. Doses exceeding 20 mg/week may be associated with a significant increase in bone marrow suppression-related toxicity.

Therapeutic response may be expected approximately within 4–8 weeks.

After achieving the desired therapeutic effect, the dose should be gradually reduced to the lowest possible effective maintenance dose.

Dosage for children and adolescents with juvenile idiopathic arthritis (JIA):

The recommended dose is 10–15 mg/m² body surface area per week.

In severe cases, the weekly dose may be higher, up to 20 mg/m² body surface area per week. With such high-dose therapy, more frequent patient monitoring is required. Since data on intravenous administration of the drug in children and adolescents are limited, subcutaneous and intramuscular injections are recommended for this patient group.

Patients with JIA should always consult a rheumatologist specialized in treating children and adolescents.

Use in children under 3 years of age is not recommended due to insufficient data on efficacy and safety in this patient group.

Dosage for patients with severe forms of psoriasis and psoriatic arthritis

It is recommended to administer a test dose of 5–10 mg parenterally one week before starting therapy, with monitoring for characteristic adverse effects. The recommended initial dose is 7.5 mg of methotrexate administered once weekly by subcutaneous, intramuscular, or intravenous route.

The dose may be gradually increased; typically, the maximum weekly dose is 25 mg of methotrexate.

Doses exceeding 20 mg per week may lead to a significant increase in bone marrow suppression-related toxicity.

Therapeutic response is usually expected within approximately 2–6 weeks.

After achieving the desired therapeutic effect, the dose should be gradually reduced to the lowest possible effective maintenance dose. The dose may be increased as needed, provided it does not exceed the maximum recommended dose of 25 mg per week. In some exceptional cases, a higher dose may be clinically justified, but should not exceed a maximum weekly dose of 30 mg of methotrexate, as toxicity increases significantly beyond this level.

Treatment of patients with impaired liver function. Methotrexate "Ebewe" should be used with caution and only if absolutely necessary in patients with significant liver dysfunction (current or in history, particularly alcohol-related). Methotrexate must not be used if bilirubin levels exceed 85.5 µmol/L.

Treatment of elderly patients (over 65 years of age). Since liver and kidney function decline with age and folate reserves are reduced, dose reduction may be appropriate for elderly patients.

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

Administration method

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

The medicinal product 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 infusion duration. 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 stored protected from light or not. For longer infusion durations, the infusion bottle should be replaced.

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

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

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

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

The total duration of therapy is determined by the physician.

Children.

In children and adolescents, methotrexate should be used with particular caution and in accordance with appropriate treatment protocols.

Overdose.

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

Symptoms of overdose. After oral or intravenous administration, symptoms are predominantly related to bone marrow and gastrointestinal system suppression. Symptoms include leukopenia, thrombocytopenia, anemia, pancytopenia, neutropenia, mucositis, stomatitis, ulcerative lesions of oral mucosa, nausea, vomiting, ulcerative gastrointestinal tract lesions, 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 usually related to the central nervous system (CNS), including headache, nausea and vomiting, seizures or convulsions, and acute toxic encephalopathy. In some cases, no symptoms were observed. In other cases, intrathecal overdose resulted in fatal outcomes; cerebral herniation and increased cerebrospinal fluid pressure have been reported, as well as acute toxic encephalopathy.

Prevention of overdose. When administering methotrexate 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 toxic side 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 amount 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 interval between methotrexate and calcium folinate administration, the lower the effectiveness of calcium folinate. Serum methotrexate levels should be monitored to determine the optimal dose and duration of calcium folinate administration.

In cases of significant overdose, hydration and urinary alkalinization are required to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. If intoxication is due to very slow elimination (monitor serum methotrexate levels!), for example, in acute renal failure, hemodialysis and/or hemoperfusion should be performed. Effective methotrexate clearance can be achieved through intensive intermittent hemodialysis using high-flux dialyzers. Conventional 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 depending on the severity and intensity, 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.

Myelosuppression and mucositis are generally dose-limiting toxic effects. Their severity depends on the dose, route, and duration of methotrexate administration. Mucositis typically develops 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 commonly 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 levels of liver enzymes and bilirubin, 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, hepatitis due to herpes simplex virus, 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), and lymphoproliferative disorders (partially reversible).

Immune system disorders: uncommon – allergic reactions, anaphylactic shock, hypersensitivity, 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, clouding of vision), 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 abnormal pulmonary function test results, Pneumocystis pneumonia; frequency not known – chest pain, hypoxia, pulmonary alveolar hemorrhage (reported with methotrexate use in rheumatological 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 activity of liver enzymes (ALT (GPT), AST (GOT)), alkaline phosphatase, and bilirubin; 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 ulcers; uncommon – severe toxic skin reactions: 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 fetal abnormalities; rare – abortion; very rare – fatal outcome for the fetus.

Reproductive system and breast disorders: uncommon – vaginal ulcers and inflammation; rare – transient oligospermia; very rare – disturbances of oogenesis/spermatogenesis, impotence, infertility, loss of libido, vaginal discharge, menstrual cycle disorders, cycle disturbances, 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

Central nervous system (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 vomiting;
• 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.

Evidence indicates 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 periventricular CNS lymphoma who developed cerebral 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

In the original packaging – 3 years.

Storage conditions

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

Keep out of the reach of children.

Incompatibilities

Incompatibility is known with strong oxidizing agents and acids. Precipitation or clouding of the solution may occur when methotrexate solutions are mixed with chlorpromazine hydrochloride, droperidol, idarubicin, metoclopramide hydrochloride, heparin, prednisolone sodium phosphate, or promethazine hydrochloride.

This medicinal product must not be mixed with other medicinal products.

Packaging

1 ml (10 mg), 5 ml (50 mg) in a vial; 1 vial in a cardboard box with instructions for medical use.

Prescription category

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