Methotrexate-teva

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

Composition:

Active substance: methotrexate;

1 ml of solution contains 25 mg of methotrexate;

Excipients: sodium hydroxide, sodium chloride, sodium hydroxide solution, diluted hydrochloric acid, water for injections.

Pharmaceutical form. Solution for injection.

Main physicochemical properties: a clear yellow solution practically free from visible particles.

Pharmacotherapeutic group.

Antineoplastic agents. Antimetabolites. Structural analogues of folic acid.

ATC code L01B A01.

Pharmacological properties.

Pharmacodynamics.

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

Pharmacokinetics.

Absorption. Following parenteral administration, methotrexate is usually completely absorbed. Peak plasma concentrations are reached within 30–60 minutes after intramuscular injection.

Distribution. After intravenous administration, the apparent volume of distribution is approximately 0.18 L/kg (18% of body weight) and at steady state is approximately 0.4–0.8 L/kg (40–80% of body weight).

Methotrexate slowly penetrates into interstitial fluids such as pleural effusion and ascites, with plasma concentrations stabilizing within 6 hours. Methotrexate competes with reduced folates for active transport across cell membranes. At serum concentrations above 100 μmol, passive diffusion becomes the primary route for achieving effective intracellular concentrations. Approximately 50% of methotrexate in blood serum is protein-bound. Methotrexate does not cross the blood-brain barrier in therapeutic concentrations following oral or parenteral administration. However, high concentrations in cerebrospinal fluid can be achieved with intrathecal administration.

Metabolism. After absorption, methotrexate is metabolized in the liver and intracellularly to polyglutamated forms, which can be converted back to methotrexate by hydrolase enzymes. These polyglutamates act as inhibitors of dihydrofolate reductase and thymidylate synthetase. Small amounts of methotrexate polyglutamates may persist in tissues for prolonged periods. The retention and prolonged effect of these active metabolites vary among different cells, tissues, and tumors. At usual doses, a minor portion may be metabolized in the liver to 7-hydroxymethotrexate. Accumulation of this inactive metabolite may become significant during high-dose therapy. The aqueous solubility of 7-hydroxymethotrexate is 3 to 5 times lower than that of the parent compound. The elimination half-life of methotrexate is approximately 3–10 hours in patients treated for psoriasis and with low-dose therapy for neoplasms (less than 30 mg/m²). In patients receiving high-dose methotrexate, the elimination half-life ranges from 8 to 15 hours.

Excretion. Elimination occurs primarily via renal excretion and depends on dose and route of administration. Within 24 hours after intravenous administration, 44–100% of the administered dose is excreted unchanged in urine. Ten percent or less of the dose is excreted in bile. Enterohepatic recirculation of methotrexate has been demonstrated. Renal excretion occurs via glomerular filtration and active tubular secretion. Nonlinear elimination due to reabsorption during renal tubular reabsorption has been observed in psoriatic patients receiving doses of 7.5–30 mg. Impaired renal function, as well as concomitant use of drugs undergoing tubular secretion (such as weak organic acids), can significantly increase serum methotrexate concentrations. A correlation exists between methotrexate clearance and endogenous creatinine clearance. Methotrexate clearance varies considerably and typically decreases at high doses. Delayed clearance has been shown to be one of the most important factors responsible for methotrexate toxicity. Methotrexate toxicity in normal tissues is more dependent on the duration of exposure than on the peak concentration achieved. If a patient experiences delayed elimination due to impaired renal function, sequestration into third-space fluid, or another cause, serum methotrexate concentrations may remain elevated for prolonged periods.

The risk of toxicity following high-dose administration or delayed elimination is reduced by administering calcium folinate during the late elimination phase of methotrexate from plasma. Regarding methotrexate solubility in the kidneys, the risk of precipitation is higher at urine pH < 7 during high-dose therapy. Therefore, hydration and urinary alkalinization are recommended when administering high-dose methotrexate to prevent nephrotoxicity. Therapeutic drug monitoring of serum methotrexate concentrations may be useful in patients at increased risk of methotrexate toxicity and when correction of toxic effects with calcium folinate is required.

Clinical Characteristics.

Indications.

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

Contraindications.

Hypersensitivity to the components of the drug, pregnancy (when used for non-oncological indications) or breastfeeding, poor nutritional status, significant impairment of liver function (bilirubin level > 85.5 μmol/L), significant renal dysfunction (creatinine clearance < 20 mL/min), hematopoietic system disorders (particularly bone marrow hypoplasia, leukopenia, thrombocytopenia, or severe anemia), alcohol abuse, pulmonary toxicity caused by methotrexate, severe acute or chronic infections (e.g., tuberculosis or AIDS), immunodeficiency syndrome (when used in patients with psoriasis or rheumatoid arthritis), stomatitis, ulcers of the oral or gastrointestinal mucosa, vaccination with live vaccines during methotrexate therapy.

Special Safety Precautions.

When handling the drug, standard procedures for managing cytotoxic substances must be followed. Solution preparation must be performed under strict aseptic conditions using personal protective equipment (wearing protective gloves, mask, protective goggles, and protective clothing) 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 large amounts of water. Pregnant healthcare workers must not handle the drug.

Preparation of methotrexate solution, like any cytostatic medicinal product, should be carried out in a room with vertical ventilation. The drug should be administered while wearing protective gloves. Disposal must take into account the cytotoxic nature of the drug.

Interaction with Other Medicinal Products and Other Forms of Interaction.

Methotrexate should be used cautiously in combination with potentially hepatotoxic substances (such as alcohol, leflunomide, azathioprine, sulfasalazine, metamizole).

When methotrexate is used in combination with leflunomide, the frequency of pancytopenia and hepatotoxic effects increases. Combined treatment with methotrexate and retinoids, such as acitretin or etretinate, increases the risk of hepatotoxicity.

The risk of hepatotoxic effects of methotrexate increases with regular alcohol consumption.

Oral antibiotics (including tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics, so-called intestinal antiseptics) may reduce methotrexate absorption or affect enterohepatic circulation due to inhibition of intestinal flora or suppression of bacterial metabolism.

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

Probenecid, weak organic acids (e.g., loop diuretics) and pyrazoles (phenylbutazone) may slow methotrexate elimination (by reducing tubular secretion of methotrexate), resulting in increased serum concentration and enhanced hematological toxicity. The risk of toxic effects also increases with combined use of low-dose methotrexate and nonsteroidal anti-inflammatory drugs (NSAIDs) or salicylates. The potential toxicity of methotrexate is particularly increased when NSAIDs and diuretics are used concurrently. In rheumatology, methotrexate at low doses is usually combined with NSAIDs. Close monitoring of the patient is required when these drugs are used concomitantly.

Protein-bound methotrexate may be displaced by salicylates, nonsteroidal anti-inflammatory drugs (e.g., phenylbutazone), sulfonamides, hypoglycemic agents, diuretics, phenytoin, barbiturates, tranquilizers, oral contraceptives, tetracyclines, chloramphenicol, amidopyrine derivatives, p-aminobenzoic acid, doxorubicin, bleomycin, cyclophosphamide, aminoglycosides, allopurinol, vincristine, hydrocortisone, prednisone, asparaginase, and cytarabine. This leads to an increased level of unbound methotrexate in plasma. Elevated concentrations of unbound methotrexate in plasma may intensify toxic hematological effects.

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

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

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

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

When used in combination with other cytostatic agents, pharmacodynamic interactions may occur, resulting in increased therapeutic activity and enhanced toxicity.

In patients undergoing radiation therapy, interactions with radioactive substances are possible.

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

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

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

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

Methotrexate may reduce the clearance of theophylline.

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

Methotrexate increases plasma levels of mercaptopurines. Therefore, dose adjustments may be necessary when using this combination.

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

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

Concomitant use of methotrexate and proton pump inhibitors (e.g., omeprazole, pantoprazole) may result in interactions. Omeprazole may reduce renal clearance of methotrexate, while pantoprazole may inhibit renal elimination of the metabolite 7-hydroxymethotrexate, potentially leading to myalgia and tremor.

When used in combination with sulfasalazine, effects may be potentiated due to sulfasalazine-induced suppression of folic acid synthesis (resulting in increased frequency of adverse effects).

Pharmacokinetic interactions between methotrexate and flucloxacillin, anticonvulsants, and 5-fluorouracil should be considered.

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

Anesthetic agents based on nitrous oxide may enhance the effect of methotrexate on folate metabolism, resulting in unpredictable, severe bone marrow suppression, stomatitis, and, in case of intrathecal administration, severe and unpredictable neurotoxicity. Although this effect can be mitigated by calcium folinate administration, concomitant use of nitrous oxide and methotrexate should be avoided.

Cholestyramine may enhance extra-renal elimination of methotrexate by interfering with enterohepatic circulation.

During radiation therapy in patients receiving methotrexate, an increased risk of soft tissue and bone necrosis is possible.

Special precautions for use.

Methotrexate therapy must be administered under the supervision of a qualified oncologist experienced in the use of antineoplastic chemotherapeutic agents.

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

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

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

Recommended investigations and precautions

Before initiating methotrexate therapy or continuing treatment after an interruption, the following should be performed: blood analysis including white blood cell differential and platelet count, liver enzyme levels, bilirubin, serum albumin, chest X-ray, and renal function tests. If clinically indicated, tests should be conducted to exclude tuberculosis and hepatitis.

During methotrexate therapy (weekly during the first 2 weeks, every 2 weeks during the following month, then, depending on white blood cell count and patient stability, at least once a month for the next 6 months and no less frequently than every 3 months thereafter; dose increases may require more frequent monitoring), the following evaluations are recommended: oral and pharyngeal examination to detect mucosal changes; complete blood count with white blood cell differential and leukocyte count; platelet count and hematocrit; urinalysis and renal function tests; liver enzyme activity assessment; periodic chest X-ray is recommended.

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

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

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

For psoriasis treatment, the following monitoring is recommended: monthly blood tests, and liver and kidney function tests every 1–3 months. Monitoring is usually more frequent when therapy is directed at neoplastic conditions. At the beginning of treatment, after dose adjustments, or during periods of increased risk of methotrexate accumulation in blood (e.g., during dehydration), monitoring should be intensified.

When methotrexate is used for oncological indications, particular attention should be paid to signs of liver damage. Persistent deterioration in liver function test results immediately prior to drug administration and/or decreased serum albumin levels may indicate severe hepatotoxicity and require further evaluation. Methotrexate therapy should not be initiated or should be suspended in case of any abnormalities in liver function tests or liver biopsy. Usually, test results normalize within 2 weeks, after which treatment may be resumed at the physician’s discretion. Signs of liver fibrosis or cirrhosis require discontinuation of therapy. The relationship between liver function test abnormalities and fibrosis or cirrhosis has not been established. Further studies are needed to determine whether serial liver biochemical tests or type III collagen propeptide tests are sufficient for early detection of hepatotoxic effects. Such assessments should be individualized, considering the absence or presence of patient risk factors such as past alcohol abuse, persistent elevation of liver enzymes, history of liver disease, familial hereditary liver disorders, diabetes, obesity, prior treatment with hepatotoxic drugs or exposure to hepatotoxic chemicals, prolonged methotrexate therapy, or cumulative doses of 1.5 g or more. In case of persistent elevation of liver enzyme activity, dose reduction or discontinuation of further therapy should be considered. Transient increases in transaminase levels (up to 2–3 times the upper limit of normal) have been reported in some patients. Persistent elevation of liver enzyme activity requires dose reduction or discontinuation of methotrexate therapy.

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. Close monitoring of liver enzyme levels is particularly important in patients receiving concomitant therapy with other hepatotoxic and hematotoxic agents (e.g., leflunomide).

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

Methotrexate should be used with caution in patients with myelosuppression, impaired renal function, infections, peptic ulcer, non-specific ulcerative colitis, ulcerative stomatitis, diarrhea, poor general condition, children, and elderly patients.

Methotrexate may cause kidney damage and lead to renal failure. Nephrotoxicity is primarily due to precipitation of methotrexate and 7-hydroxymethotrexate in renal tubules. Regular monitoring of renal function (including urine alkalinity) and measurement of serum methotrexate levels are recommended. In cases of nephrotoxicity, methotrexate therapy should be discontinued.

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

In suspected methotrexate-induced lung disease, pulmonary function tests should be performed, particularly if baseline values are known. Fatal cases of acute or chronic interstitial pneumonitis, often accompanied by eosinophilia, have been reported. Lung disease associated with methotrexate use at doses exceeding 7.5 mg per week may occur at any stage of treatment and can be life-threatening. This condition is not always fully reversible and may not respond to treatment. Symptoms of lung disease or nonspecific pneumonitis (dyspnea, cough (especially dry and non-productive), fever, hypoxemia, and infiltrates on chest X-ray) developing during methotrexate therapy (including intrathecal administration) may indicate potentially severe damage and require immediate discontinuation of therapy and thorough patient evaluation (including chest X-ray) to exclude infection. These symptoms should be monitored at every patient visit. In treating methotrexate-induced pneumonitis, corticosteroid therapy may be required immediately after discontinuation of methotrexate. Reinitiation of methotrexate therapy after lung toxicity is contraindicated.

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

During methotrexate therapy, opportunistic infections, including plasma cell pneumonia, which may be fatal, are possible. Plasma cell pneumonia should be considered in patients presenting with symptoms of impaired lung function.

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

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

When used for non-oncological indications, subcutaneous administration of methotrexate is well tolerated locally. Only mild local skin reactions have been observed, which decreased during therapy.

Data on carcinogenic risk with methotrexate use in patients with rheumatoid arthritis are limited. Cases of malignant lymphomas have been reported in patients receiving low-dose methotrexate. Sometimes they resolved after methotrexate discontinuation without the need for cytotoxic agents. In such cases, methotrexate therapy should be discontinued first. If remission does not occur, appropriate therapy should be initiated.

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

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

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

If symptoms of gastrointestinal toxicity (diarrhea, ulcerative stomatitis) appear, methotrexate therapy should be suspended, as continued treatment may lead to life-threatening complications such as hemorrhagic enteritis and intestinal perforation. In case of vomiting, diarrhea, or stomatitis that may lead to dehydration, methotrexate therapy should be discontinued until the patient's condition normalizes.

In case of hematemesis, black stools, or blood in stools, further therapy should be discontinued.

The drug should be used with caution or not used at all in patients with existing hematopoietic disorders. In psoriasis treatment, methotrexate should be immediately discontinued in case of significant reduction in blood cell counts. Methotrexate therapy in cancer patients may be continued only if the potential benefit outweighs the risk of severe myelosuppression. Myelosuppression may also occur after intrathecal methotrexate administration. Patients with profound granulocytopenia and fever require immediate evaluation and usually parenteral broad-spectrum antibiotics.

Patients with psoriasis and rheumatoid arthritis should be informed that methotrexate should be taken once a week, as daily use may cause acute toxic reactions.

Despite lower methotrexate doses typically used in psoriasis and rheumatoid arthritis treatment compared to antineoplastic therapy, intoxication and fatal outcomes are possible. Patients must be fully informed about the risks associated with methotrexate therapy and the need to promptly report any signs of toxicity.

For psoriasis treatment, methotrexate use should be limited to severe, disabling, treatment-resistant psoriasis, when other therapies are insufficient, and only after biopsy confirmation and/or dermatologist consultation.

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

Cases of encephalopathy/leukoencephalopathy have been reported in oncology patients receiving methotrexate, and its occurrence cannot be excluded in non-oncology patients. Complete recovery after methotrexate discontinuation is not always observed. Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients receiving methotrexate, usually in combination with other immunosuppressive agents. PML may be fatal and should be considered in the differential diagnosis of immunosuppressed patients with new or worsening neurological symptoms.

High-dose therapy. During high-dose treatment, folinic acid should be administered concurrently. Serum methotrexate concentrations are an appropriate indicator of how long folinic acid therapy should continue. Residual methotrexate levels should be assessed 48 hours after the start of methotrexate infusion. If residual methotrexate level is < 0.5 µmol/L, additional folinic acid administration is not necessary.

Fertility. Oligospermia, menstrual cycle disturbances, and amenorrhea have been reported during and for some time after methotrexate therapy. The drug's effect on spermatogenesis and oogenesis may lead to impaired fertility during treatment. These effects are reversible after therapy discontinuation.

Teratogenicity. Methotrexate has embryotoxic and teratogenic effects and may cause abortion. Therefore, women of reproductive age must be informed about possible effects on fertility, pregnancy loss, and congenital malformations (see section "Use during pregnancy or breastfeeding"). When methotrexate is used for non-oncological indications, pregnancy must be excluded before starting treatment. Effective contraception must be used during treatment and for at least 6 months after methotrexate therapy ends in sexually mature women.

Excipients.

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

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 treatment and for at least 6 months after methotrexate therapy ends. Women of reproductive age must be informed about the risk of methotrexate's adverse effects on the fetus before starting treatment, and pregnancy must be excluded by appropriate methods, such as a pregnancy test. Pregnancy tests should be performed during treatment as clinically needed (e.g., after any contraception interruption).

Contraception in men

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

As a precautionary measure, sexually active male patients or their partners are recommended to use reliable contraception during treatment and for at least 3 months after methotrexate therapy ends. Men should not be sperm donors during treatment or for 3 months after methotrexate discontinuation.

Pregnancy

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

Animal studies have shown reproductive toxicity of methotrexate, especially in the first trimester. Teratogenic effects of methotrexate have been demonstrated, with reports of fetal death, miscarriages, and/or congenital anomalies (e.g., craniofacial, cardiovascular, central nervous system, and limb malformations).

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

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

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

Normal pregnancies have been reported after discontinuation of methotrexate before conception.

For oncological indications, methotrexate should not be administered during pregnancy, especially 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 methotrexate's adverse effects on the fetus.

Breastfeeding

Methotrexate is excreted in breast milk. Due to the possibility of serious adverse reactions in infants, methotrexate is contraindicated during breastfeeding. Breastfeeding must be discontinued during treatment with this medicinal product.

Fertility

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

For oncological indications, women planning pregnancy are advised to consult genetic counseling centers, preferably before starting therapy, and men should consider sperm cryopreservation before therapy initiation due to the potential genotoxicity of methotrexate.

Ability to influence reaction speed when driving or operating machinery.

Due to the possibility of fatigue, somnolence, dizziness, visual disturbances, paresis, and hemiparesis, methotrexate may have a mild to moderate adverse effect on the ability to drive or operate machinery. Patients should be informed about the need for caution when starting methotrexate therapy, and if such effects occur, potentially hazardous activities such as driving or operating machinery should be avoided.

Method of Administration and Dosage.

Doses and duration of treatment are established individually, depending on the chemotherapy regimen, indications, and drug tolerance. Treatment should be administered by a physician experienced in the use of methotrexate and who understands the risks associated with methotrexate therapy.

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

Trophoblastic tumors. For patients without metastases or with trophoblastic tumors not representing a high risk, the daily dose is 15–30 mg intramuscularly for 5 consecutive days. Such courses, if necessary, should be repeated 3–5 times with an interval of 1 or more weeks.

For patients at high risk of developing trophoblastic tumors, combination therapy is often prescribed, including 300 mg/m² of methotrexate followed by folic acid.

Therapeutic efficacy is assessed by serum chorionic gonadotropin concentration levels.

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

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

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

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

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

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

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

Mycosis fungoides. Methotrexate should be administered intramuscularly at a dose of 50 mg once weekly or 25 mg twice weekly.

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

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

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

Rheumatoid arthritis. When methotrexate is administered intravenously or intramuscularly, the initial dose for adult patients is 10 mg weekly. If necessary, this dose may be gradually increased by 2.5 mg weekly up to a maximum dose of 25 mg. When increasing the dose further, one interval regimen—approximately every 6 weeks—should be maintained. One week prior to starting methotrexate therapy, a test dose of 5–10 mg should be administered parenterally to detect any idiosyncratic reactions in the patient.

In most patients, improvement is observed within 4–6 weeks. The clinical effect of therapy is achieved after 6 months, after which dose adjustments may be necessary to maintain optimal clinical outcomes.

After discontinuation of therapy, relapse of rheumatoid arthritis may occur.

When treating psoriasis and rheumatoid arthritis, methotrexate should be administered only once weekly. Dosing errors in methotrexate administration may lead to serious adverse reactions, including fatal outcomes. This section of the medical instructions should be carefully read.

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

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

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

Dose adjustment.

If leukocyte or platelet counts decrease on the first day of therapy, methotrexate dosage in standard therapy with a dose of 40 mg/m² should be adjusted according to the scheme below based on the lowest parameter value.

% of normal dose	Leukocyte count, mm³	Platelet count, mm³
100	> 3500	> 125000
50	2500–3500	75000–125000
0	< 2500	< 75000

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

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

Special patient groups

Patients with renal impairment

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

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

Patients with impaired liver function

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

Patients with pathological fluid accumulation

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

Elderly patients

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

Children

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

Overdose

Symptoms of overdose include increased severity of one or more adverse reactions. Toxic effects are more pronounced in patients receiving prolonged therapy.

Predominant symptoms are related to bone marrow suppression and gastrointestinal toxicity.

Symptoms include leukopenia, thrombocytopenia, anemia, pancytopenia, neutropenia, bone marrow suppression, mucositis, stomatitis, ulcerative lesions of the oral mucosa, nausea, vomiting, ulcerative gastrointestinal tract lesions, and gastrointestinal bleeding. In some patients, signs of overdose may be absent. There have been reports of fatal outcomes due to sepsis, septic shock, renal failure, and aplastic anemia.

The specific antidote for methotrexate is calcium folinate.

In case of accidental overdose, calcium folinate should be administered intravenously or intramuscularly at a dose equal to or higher than the methotrexate dose, no later than 1 hour after methotrexate administration. Subsequent doses of calcium folinate should be administered until serum methotrexate concentration falls below 10⁻⁷ mol/L.

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

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

Adverse Reactions

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

The most significant adverse effects associated with methotrexate therapy are hematopoietic system suppression and gastrointestinal adverse reactions. The most commonly reported adverse reactions include ulcerative stomatitis, leukopenia, nausea, and gastrointestinal disturbances. Other frequently observed adverse reactions include general malaise, unusual fatigue, chills and feverish sensations, dizziness, and decreased resistance to infections.

Due to the presence of underlying malignancies, concomitant treatments, and pre-existing conditions, it is often difficult to determine the extent to which certain adverse reactions are related to this medicinal product.

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

Benign and malignant neoplasms, unspecified neoplasms (including cysts and polyps): lymphoma, lymphoproliferative disorders (isolated cases of lymphoma and other lymphoproliferative disorders, some of which resolved after discontinuation of methotrexate therapy), tumor lysis syndrome.

Blood and lymphatic system disorders: anemia, leukopenia and/or thrombocytopenia, pancytopenia, agranulocytosis, bone marrow suppression, megaloblastic anemia, aplastic anemia, neutropenia, lymphadenopathy, lymphoproliferative disorders (partially reversible), eosinophilia, hematopoietic dysfunction. Initial signs of these potentially life-threatening reactions may include: fever, sore throat, oral mucosal ulcers, influenza-like syndrome, exhaustion, nosebleeds, and skin hemorrhages. If there is a significant reduction in blood cell counts, further therapy with methotrexate should be discontinued immediately.

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

Metabolism and nutrition disorders: diabetes mellitus.

Psychiatric disorders: mood disturbances, depression, confusion, insomnia.

Nervous system disorders: headache, vertigo-type dizziness, somnolence, fatigue, unusual sensations in the cranial area, severe visual disturbances, apathy, confusion, depression, mood changes, transient cognitive disorders, speech disorders (including dysarthria, aphasia), sensory disturbances, hemiparesis, paralysis, seizures, leukoencephalopathy/encephalopathy, pain, muscle asthenia, paresthesia/hypesthesia, altered taste sensation (metallic taste), meningeal signs (paralysis, vomiting), acute aseptic meningitis;
with intravenous administration: leukoencephalopathy observed in patients with osteosarcoma and in patients who received craniospinal radiotherapy; acute neurological syndromes (abnormal behavior, focal sensorimotor disturbances, and abnormal reflexes) observed in patients receiving high-dose methotrexate;
with intrathecal administration: chemical arachnoiditis (with symptoms such as headache, back pain, nuchal rigidity, fever); paralysis, usually temporary, paraplegia affecting one or more spinal nerves, leukoencephalopathy (accompanied by confusion, agitation, somnolence, ataxia, dementia, and sometimes severe seizures); myelopathy.

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

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

Respiratory, thoracic and mediastinal disorders: interstitial alveolitis/pneumonitis (often with eosinophilia) with pulmonary complications and associated fatalities (independent of dose and duration of methotrexate therapy): typical symptoms may include general illness, dry irritating cough, dyspnea which may progress to dyspnea at rest, chest pain, tachypnea (if such complications are suspected, methotrexate therapy should be discontinued immediately and infectious causes (including pneumonia) excluded); pulmonary fibrosis, dyspnea, pleuritis, alveolitis, acute pulmonary edema, epistaxis, pleural effusion, pharyngitis, apnea, bronchial asthma, asthma-like reactions with cough, dyspnea, impaired pulmonary function test results; infections, including pneumonia, interstitial plasmacytic pneumonia caused by Pneumocystis carinii, and other lung infections, chronic obstructive pulmonary disease, syndrome characterized by pleural pain and pleural thickening. Cases of pulmonary alveolar hemorrhage have been reported during methotrexate use for rheumatological and related indications.

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

Hepatobiliary disorders: marked elevation of liver transaminases (ALT, AST), increased alkaline phosphatase and bilirubin levels, hepatotoxicity, fibrosis and cirrhosis of the liver (frequent despite regular monitoring and normal liver enzyme values), diabetic metabolism, hepatic steatosis, fatty liver degeneration, acute hepatitis, recurrence of chronic hepatitis, acute liver degeneration, herpes hepatitis, liver failure, liver atrophy, liver necrosis.

Skin and subcutaneous tissue disorders: exanthema, erythema, erythematous rashes, pruritus, urticaria, ulcers, increased photosensitivity, hyperpigmentation, abnormal pigmentation, hair loss, alopecia, ecchymoses, telangiectasia, acne, toxic epidermal necrolysis (Lyell’s syndrome), Stevens-Johnson syndrome, sudden onset psoriasis, erythema multiforme, sudden increase in number of rheumatoid nodules in patients with rheumatoid arthritis, herpes zoster, painful psoriatic plaque lesions, vasculitis, herpes-like skin rashes, impaired wound healing, appearance of psoriatic plaques, petechiae, ulcer formation in psoriasis patients, increased nail pigmentation, acute paronychia, furunculosis, nocardial, histoplasma, and cryptococcal mycosis, disseminated herpes simplex, allergic vasculitis, hidradenitis, skin desquamation/exfoliative dermatitis.

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

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

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

General disorders and administration site conditions: local tissue damage (formation of sterile abscess, lipodystrophy) at the injection site following intramuscular or subcutaneous administration, burning sensation at injection site, necrosis, mucositis, increased fatigue, chills, malaise, fever, edema, impaired wound healing, sudden death.

Investigations: elevated liver enzyme levels, decreased serum albumin levels.

Injury, poisoning and procedural complications: radiation recall dermatitis, recurrence of symptoms in areas of previous radiation or sun burns.

Shelf life. 2 years.

Storage conditions.

Store at temperatures not exceeding 25 °C in a place inaccessible to children.

Incompatibility.

Methotrexate must not be mixed with other medicinal products.

Packaging.

2 ml solution in a vial; 1 vial per carton.

Prescription category. Prescription only.

Manufacturer.

Farmahem B.V.

Manufacturer’s address and place of business.

Svensweg 5, 2031 GA Haarlem, the Netherlands.