Methotrexate "ebewe"

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT METHOTREXATE "EBEWE" METHOTREXAT "EBEWE"

Composition:

Active substance: methotrexate;

1 tablet contains 2.5 mg or 5 mg or 10 mg of methotrexate;

Excipients: lactose monohydrate; corn starch; microcrystalline cellulose; colloidal anhydrous silicon dioxide; magnesium stearate.

Pharmaceutical form. Tablets.

Main physicochemical properties:

Methotrexate "Ebewe" 2.5 mg: round, flat tablets with bevelled edges, light yellow in colour, with possible specks ranging from yellow to orange or whitish specks;

Methotrexate "Ebewe" 5 mg: round, biconvex tablets, light yellow in colour, with a score line on one side, with possible specks ranging from yellow to orange or whitish specks;

Methotrexate "Ebewe" 10 mg: capsule-shaped, biconvex tablets, light yellow in colour, with a score line on one side, with possible specks ranging from yellow to orange or whitish specks.

Pharmacotherapeutic group.

Immunosuppressants, other immunosuppressants. ATC Code: L04AX03.

Antineoplastic agents. Antimetabolites. Structural analogues of folic acid.

ATC Code: L01BA01.

Pharmacological properties.

Pharmacodynamics.

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

The mechanism of action of methotrexate in rheumatoid arthritis is not fully understood, but it may affect immune functions. Further investigation of the effects of methotrexate on the immune system is needed in relation to the immunopathogenesis of rheumatoid arthritis.

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

Pharmacokinetics.

Following oral administration, Methotrexate "Ebewe" is rapidly absorbed. After a dose of 2 × 2.5 mg, the maximum plasma concentration of methotrexate is reached within 0.83 hours and averages 170 ng/mL.

Approximately 50% of methotrexate is bound to plasma proteins. After distribution, methotrexate accumulates predominantly in the liver, kidneys, and spleen in the form of polyglutamates, which can be retained for weeks or even months. When administered in low doses, only minimal amounts of methotrexate penetrate into the cerebrospinal fluid. The terminal elimination half-life of methotrexate ranges from 3 to 17 hours, averaging 6–7 hours. In patients with a third space compartment (e.g., 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 tubular 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 not known whether hepatic dysfunction affects the elimination of methotrexate.

Clinical characteristics.

Indications.

Antirheumatic therapy. Active rheumatoid arthritis in adult patients for whom treatment with disease-modifying antirheumatic drugs (DMARDs) is indicated.

Treatment of psoriasis. Severe and extensive forms of vulgar psoriasis, particularly plaque-type, in adult patients when conventional therapy (e.g., phototherapy, PUVA therapy, or retinoids) has been ineffective.

As a cytostatic agent. Maintenance therapy for acute lymphoblastic leukemia.

Contraindications.

• Hypersensitivity to methotrexate or any of the excipients.
• Severe, acute, or chronic infections (e.g., tuberculosis or HIV).
• Stomatitis, oral or gastrointestinal ulcers.
• Liver disease associated with chronic alcohol abuse, and significant impairment of liver function (bilirubin level > 85.5 µmol/L).
• Hepatic failure.
• Impaired renal function (creatinine clearance < 50 mL/min).
• Pre-existing hematological disorders (e.g., bone marrow hypoplasia, leukopenia, thrombocytopenia, or severe anemia).
• Immunodeficiency.
• Alcohol abuse.
• History of blood disorders.
• Pregnancy or breastfeeding.
• Vaccination with live vaccines during methotrexate treatment.

Interaction with other medicinal products and other forms of interaction.

Alcohol, hepatotoxic, and hematotoxic agents

The risk of hepatotoxic effects of methotrexate increases with regular alcohol consumption or concomitant use of other hepatotoxic agents. Alcohol intake should be avoided during methotrexate therapy. Particular caution is required when treating patients receiving other hepatotoxic and hematotoxic agents (e.g., leflunomide, metamizole) with methotrexate. Concomitant use of additional hematotoxic drugs increases the likelihood of severe hematotoxic adverse reactions to methotrexate. Concomitant administration of metamizole and methotrexate may enhance the hematotoxic effects of methotrexate, especially in elderly patients. Therefore, concomitant use of these agents should be avoided.

Combination therapy with methotrexate and retinoids, such as acitretin or etretinate, increases the risk of hepatotoxicity.

Combination therapy with methotrexate and leflunomide increases the incidence of pancytopenia and hepatotoxic effects.

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.

Antibiotics

Antibiotics such as penicillins, glycopeptides, sulfonamides, ciprofloxacin, and cephalothin may, in isolated cases, reduce renal clearance of methotrexate, leading to increased plasma concentrations and enhanced toxicity to the hematopoietic system and gastrointestinal tract.

Probenecid, weak organic acids, pyrazoles, and nonsteroidal anti-inflammatory drugs (NSAIDs)

Probenecid, weak organic acids (e.g., loop diuretics), and pyrazoles (phenylbutazone) may delay methotrexate excretion, increasing its plasma concentration and enhancing hematological toxicity. The risk of toxic effects also increases with concomitant use of low-dose methotrexate and NSAIDs or salicylates. Caution is advised when administering NSAIDs and methotrexate within 24 hours after methotrexate administration, as methotrexate plasma levels may rise, increasing drug toxicity.

Animal studies have shown that NSAIDs, including salicylic acid, reduce tubular secretion of methotrexate and thereby enhance its toxic effects. However, clinical studies using NSAIDs and salicylic acid as concomitant therapy in patients with rheumatoid arthritis did not show an increased incidence of adverse reactions. These agents may be continued as part of combination therapy for rheumatoid arthritis alongside methotrexate, but only under close medical supervision.

Caution is required when using NSAIDs and methotrexate concomitantly, as serious adverse events such as sudden severe bone marrow suppression, aplastic anemia, and gastrointestinal toxicity, and even isolated fatal cases, have been reported.

Agents acting adversely on bone marrow

When co-administering agents that may cause adverse effects on bone marrow (e.g., sulfonamides, trimethoprim/sulfamethoxazole, chloramphenicol, pyrimethamine), the possibility of more pronounced hematological disturbances should be considered.

Agents causing folate deficiency

Concomitant therapy with agents that induce folate deficiency (e.g., sulfonamides, trimethoprim/sulfamethoxazole) may enhance methotrexate toxicity. Particular caution is also required in patients with pre-existing folate deficiency. Conversely, concomitant intake of folic acid-containing supplements or vitamins may interfere with methotrexate's action.

Other antirheumatic agents

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

Sulfasalazine

Although sulfasalazine may potentiate methotrexate effects by inhibiting folate synthesis (potentially increasing the frequency of adverse effects), such effects were observed only in isolated cases during several clinical trials.

Proton pump inhibitors

Concomitant use of methotrexate and proton pump inhibitors (e.g., omeprazole or pantoprazole) may result in interaction. Omeprazole may reduce renal clearance of methotrexate, and pantoprazole may inhibit renal elimination of the metabolite 7-hydroxymethotrexate, which in one case was associated with myalgia and tremor.

Pharmacokinetic interactions between methotrexate and flucloxacillin (reduced area under the pharmacokinetic curve for methotrexate), anticonvulsants (reduced methotrexate blood concentration), and 5-fluorouracil (prolonged half-life of 5-fluorouracil) should be considered. After concomitant administration of methotrexate with oxacillin and omeprazole, marked increases in methotrexate plasma concentration were observed in isolated cases. Interactions between leflunomide and methotrexate (leading to liver cirrhosis, musculoskeletal infections, and thrombocytopenia) have been reported. Methotrexate should be used cautiously in combination with immunomodulators during orthopedic surgery, when susceptibility to infection is increased. Concomitant use of mercaptopurine and methotrexate may increase mercaptopurine bioavailability, likely due to slowed metabolism of mercaptopurine.

Concomitant administration of methotrexate and theophylline may reduce theophylline clearance. Plasma theophylline levels should be monitored regularly.

Salicylates, phenylbutazone, phenytoin, barbiturates, tranquilizers, oral contraceptives, tetracyclines, amidopyrine derivatives, sulfonamides, and para-aminobenzoic acid displace methotrexate from serum albumin binding, thereby increasing its bioavailability (indirect dose increase).

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.

Cholestyramine may enhance non-renal elimination of methotrexate by interfering with enterohepatic circulation. Radiation therapy during methotrexate treatment may increase the risk of soft tissue and bone necrosis.

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

Vitamin complexes and oral iron supplements containing folic acid may alter the body's response to methotrexate therapy.

Beverages containing caffeine and theophylline

Excessive consumption of beverages containing caffeine or theophylline (coffee, caffeinated soft drinks, black tea) should be avoided during methotrexate therapy, as this may reduce methotrexate efficacy due to interaction with adenosine receptors.

Cytarabine

Severe neurotoxic reactions ranging from headache to paralysis, coma, and stroke-like episodes have been observed primarily in children and adolescents receiving methotrexate in combination with cytarabine.

Concomitant use of L-asparaginase inhibits the action of methotrexate.

In isolated cases, corticosteroids have led to generalized herpes zoster in patients with herpes zoster or postherpetic neuralgia receiving concomitant methotrexate.

Concomitant use of mercaptopurine and methotrexate may increase mercaptopurine plasma concentration, likely due to slowed mercaptopurine metabolism.

Thus, concomitant use may require dose adjustment.

Pyrimethamine or co-trimoxazole, when used in combination with methotrexate, may cause pancytopenia, likely due to additional inhibition of dihydrofolate reductase by these agents and methotrexate (see above for sulfonamide-methotrexate interactions).

Patients receiving retinoids, such as etretinate, concomitantly with methotrexate should be closely monitored for early signs of potentially increased hepatotoxicity.

Cyprofl oxacin

Reduces tubular secretion; caution is advised when using this drug concomitantly with methotrexate.

Amiodarone has caused skin ulceration in patients receiving methotrexate for psoriasis treatment.

In some patients with psoriasis treated with methotrexate in combination with PUVA therapy, skin cancer has been reported.

Cholestyramine may increase non-renal elimination of methotrexate by interrupting enterohepatic circulation.

Caution is advised when using packed red blood cells concomitantly with methotrexate due to increased toxicity resulting from prolonged high methotrexate plasma concentrations.

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.

Bone marrow suppression and reduced folate levels have been observed with concomitant use of triamterene and methotrexate.

Methotrexate

Penicillins may reduce methotrexate excretion, potentially increasing its toxicity.

Special precautions for use.

Methotrexate therapy should be administered under the supervision of qualified oncologists, dermatologists, or rheumatologists experienced in the use of chemotherapeutic agents and familiar with the potential risks associated with methotrexate.

Methotrexate should be taken once weekly. The prescription should clearly indicate the day of administration. Patients must be informed about the importance of adhering strictly to the once-weekly dosing schedule.

Toxicity

Close monitoring of patients is required during methotrexate therapy to detect early signs of possible toxic effects and adverse reactions. Due to the risk of severe or even fatal toxic reactions, patients should be thoroughly informed about potential complications and recommended precautionary measures.

However, doses exceeding 20 mg/week may be associated with significantly increased toxicity, particularly bone marrow suppression.

Discontinuation of methotrexate does not always result in complete resolution of adverse effects.

A mandatory requirement for methotrexate therapy is the determination of serum methotrexate levels.

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

If possible, fluid accumulation should be removed via puncture prior to initiating methotrexate therapy.

Blood and lymphatic system

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

Initial signs of these life-threatening complications may include fever, sore throat, oral mucosal ulceration, influenza-like symptoms, severe fatigue, epistaxis, and skin hemorrhages.

In the treatment of neoplastic diseases, methotrexate therapy should be continued only if the potential benefit outweighs the risk of severe myelosuppression.

In particular, megaloblastic anemia has been observed during prolonged treatment in elderly patients.

Methotrexate should not be used in the presence of gastrointestinal ulcers or ulcerative colitis (see section "Contraindications").

After therapy with drugs that enhance myelotoxic effects, or after radiation, including to the bone marrow, the bone marrow reserve may be reduced. In the context of methotrexate therapy, this may lead to increased bone marrow sensitivity and suppression of its hematopoietic function. Bone marrow biopsy is necessary during long-term methotrexate therapy.

Concomitant use of methotrexate with radiation therapy may increase the risk of soft tissue necrosis.

Musculoskeletal and connective tissue disorders

During radiation therapy in patients receiving methotrexate, there may be an increased risk of soft tissue and bone necrosis.

Transient acute neurological syndromes have been observed during high-dose methotrexate therapy, which may manifest as behavioral abnormalities, focal sensorimotor symptoms (including temporary blindness), and abnormal reflexes. The exact cause has not been established.

Serious neurological adverse effects, ranging from headache to paralysis, coma, and stroke-like episodes, have been reported primarily in children and adolescents receiving methotrexate in combination with cytarabine.

Particular caution is required when nonsteroidal anti-inflammatory drugs (NSAIDs) are used concomitantly with methotrexate. Serious adverse reactions, including fatal cases such as severe and unpredictable bone marrow suppression, aplastic anemia, and gastrointestinal toxicity, have been reported, especially after high-dose methotrexate administration.

Liver function

Since methotrexate has hepatotoxic effects, other hepatotoxic drugs should not be prescribed during methotrexate therapy unless clearly necessary. Alcohol consumption should also be avoided or significantly limited. Particular attention should be paid to monitoring liver enzyme levels in patients receiving concomitant therapy with other hepatotoxic and hematotoxic agents (e.g., leflunomide).

Methotrexate may cause acute hepatitis and chronic, potentially fatal, hepatotoxicity (fibrosis, cirrhosis), although usually only after prolonged use. Persistent elevation of liver enzymes has frequently been observed. These elevations are usually transient and asymptomatic and do not necessarily precede further liver disease.

Chronic toxicity typically manifests after prolonged administration (usually after two years or more) and cumulative doses of at least 1.5 g. Studies in patients with psoriasis have shown a correlation between hepatotoxicity and total cumulative dose, with increased risk associated with alcohol abuse, obesity, diabetes, and advanced age. Liver biopsies performed after long-term methotrexate therapy often reveal histological changes. Cases of fibrosis and cirrhosis have also been reported.

Methotrexate use may lead to reactivation of hepatitis B or exacerbation of hepatitis C, which in some cases have been fatal. Cases of hepatitis B reactivation have been reported even after discontinuation of methotrexate therapy. 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 in treating patients with inactive chronic infections (e.g., herpes zoster, tuberculosis) due to the potential for reactivation.

Special caution is required in treating patients with insulin-dependent diabetes mellitus, as cirrhosis of the liver without prior elevation of transaminases may develop during methotrexate therapy in individual cases.

Kidney function

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

During methotrexate therapy, kidney function may deteriorate, with increases in 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 its metabolites in renal tubules.

Conditions leading to dehydration, such as vomiting, diarrhea, or stomatitis, may increase toxicity due to elevated levels of the active substance. In such cases, supportive therapy should be administered, and methotrexate treatment should be suspended until symptoms resolve.

Gastrointestinal disorders

If ulcerative stomatitis or diarrhea, hematemesis, black stools, or blood in feces occur, therapy should be discontinued, as hemorrhagic enteritis may develop, and fatal cases due to intestinal perforation have been reported.

Nervous system

Chronic leukoencephalopathy has also been observed in patients receiving repeated high-dose methotrexate therapy with calcium folinate without prior cranial irradiation. Cases of leukoencephalopathy have also been reported in patients taking methotrexate orally.

Lung function

Particular caution is required when treating patients with impaired lung function.

Pulmonary complications, pleural effusion, alveolitis, or pneumonitis with symptoms such as dry non-productive cough, fever, malaise, cough, chest pain, dyspnea, hypoxemia, and radiologically detected infiltrates or nonspecific pneumonia occurring during methotrexate therapy may indicate potentially dangerous and possibly fatal involvement. Lung biopsies have shown various findings (e.g., interstitial edema, mononuclear infiltrates, or necrotizing granuloma). In case of suspicion of these complications, methotrexate therapy must be immediately discontinued, and a thorough evaluation should be performed to exclude infections, tumors, etc. Methotrexate-induced lung diseases may occur acutely at any time during therapy; they are not always fully reversible and have been reported with doses as low as 7.5 mg/week.

Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur, and fatal outcomes have been reported. Symptoms typically include dyspnea, cough (especially dry, non-productive cough), chest pain, and fever; these should be monitored at every follow-up visit.

Patients should be informed about the risk of developing pneumonitis and advised to seek immediate medical attention if persistent cough or dyspnea occurs.

Additionally, pulmonary alveolar hemorrhage has been reported during methotrexate use for rheumatological and related indications. This phenomenon may also be associated with vasculitis and other comorbid conditions. Rapid diagnostic evaluation should be considered in case of suspected pulmonary alveolar hemorrhage to confirm the diagnosis.

Opportunistic infections, including Pneumocystis jirovecii pneumonia, may occur during methotrexate use and can be fatal. If a patient presents with pulmonary symptoms, Pneumocystis jirovecii pneumonia should be considered.

Skin and subcutaneous tissue disorders

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.

Photosensitization

Photosensitization, manifesting as a sunburn-like reaction, has been observed in some patients 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 to prevent exposure to intense sunlight.

Radiation-induced dermatitis and sunburns may recur during methotrexate therapy (so-called "memory reactions").

Psoriatic lesions may be exacerbated by UV radiation when methotrexate is used concomitantly.

Immune system

Cytostatic agents may increase the risk of infection following live vaccinations. Cytostatics can reduce antibody production after influenza vaccination. Since methotrexate affects the immune system, it may alter the response to vaccination and affect the results of immunological tests. Vaccinations administered during methotrexate therapy may be ineffective. 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 evident or laboratory-confirmed immunodeficiency syndromes. Additionally, methotrexate should be used cautiously in patients with infections such as varicella or herpes zoster.

Neoplasms

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

Malignant lymphoma may develop in patients receiving low-dose methotrexate; in such cases, methotrexate therapy should be discontinued. If spontaneous regression of lymphoma does not occur, cytotoxic therapy should be initiated.

Folic acid supplements

Folic acid deficiency may increase methotrexate toxicity.

Administration of folic acid or folinic acid may reduce methotrexate toxicity (gastrointestinal symptoms, stomatitis, alopecia, and elevated liver enzyme activity).

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

Methotrexate should be prescribed with great caution (if absolutely necessary) in patients with significant liver function impairment (current or in history, particularly due to alcohol abuse).

Fertility and reproductive function

Fertility

It has been reported that methotrexate may negatively affect reproductive function, causing oligospermia, menstrual cycle disturbances, and amenorrhea during and for a short period after therapy. Additionally, methotrexate causes embryotoxicity, miscarriages, and congenital abnormalities. Therefore, physicians should inform patients of reproductive age about all potential risks associated with the drug.

Teratogenicity – risk of reproductive toxicity

Methotrexate causes embryotoxicity, miscarriages, and congenital abnormalities in humans. Therefore, physicians must inform women of reproductive age about the potential effects on reproductive function, miscarriages, and congenital malformations. Pregnancy must be ruled out before initiating methotrexate therapy. Women of reproductive age must use effective contraception during therapy and for at least six months after discontinuation of methotrexate.

Reliable contraception is recommended during treatment of male patients and for at least 6 months after discontinuation of methotrexate. Since methotrexate may lead to serious and potentially irreversible impairment of spermatogenesis, men should consider sperm cryopreservation before starting therapy.

Recommended investigations and precautions

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

Before initiating methotrexate therapy or resuming therapy after interruption, a blood test including white blood cell count and platelet count, liver enzymes (ALT, AST, ALP), bilirubin, serum albumin, kidney function tests, and chest X-ray should be performed. If clinically indicated, tests to exclude tuberculosis and hepatitis (A, B, C) should be conducted.

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

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

During therapy (at least once monthly during the first 6 months, then at least once every 3 months), the following evaluations should be performed:

Oral and throat examination to detect mucosal changes.

Blood test including white blood cell count and platelet count (daily or weekly).

Even at standard therapeutic doses, methotrexate may suddenly suppress hematopoiesis. In case of significant decrease in leukocyte or platelet counts, methotrexate therapy should be immediately discontinued, and symptomatic supportive therapy initiated. Patients should be instructed to report any signs or symptoms suggesting infection immediately. Leukocyte and platelet counts should be closely monitored during concomitant therapy with hematotoxic agents (e.g., leflunomide).

Liver function tests. Particular attention should be paid to signs of liver damage. Methotrexate therapy should not be initiated or should be suspended in case of any abnormalities in liver function tests or liver biopsy.

Typically, values normalize within two weeks, after which therapy may be resumed at the physician's discretion.

Liver function tests. Additional investigations should be conducted to determine whether hepatotoxicity can be detected with sufficient accuracy using liver function tests from a series of biochemical blood analyses or by measuring serum type III collagen propeptide levels. This analysis helps differentiate patients without risk factors from those with risk factors, including prior alcohol abuse; persistent elevation of liver enzymes; history of liver disease or family history of hereditary liver disorders; diabetes, obesity; prior exposure to hepatotoxic drugs or chemicals; prolonged methotrexate therapy; or cumulative dose of 1.5 g or more.

Monitoring of liver enzymes in serum.

Transient elevation of transaminases (up to 2–3 times the upper limit of normal) has been reported in 13–20% of patients. Such elevations usually do not require dose adjustment. However, persistent elevation of liver enzymes and/or decreased serum albumin may indicate severe hepatotoxicity.

In case of persistent elevation of liver enzymes, dose reduction or discontinuation of methotrexate may be necessary. In any case, methotrexate should be discontinued in patients with persistent liver function impairment. Liver enzyme tests do not reliably predict liver damage detectable by morphological methods; thus, fibrosis may be identified only by histological analysis, or rarely, cirrhosis, even with normal transaminase levels. In case of persistent elevation of liver enzymes, dose reduction or additional treatment breaks should be considered.

Kidney function tests and urine analysis. Since methotrexate is primarily excreted in urine, patients with impaired kidney function may have elevated methotrexate levels in blood, leading to severe adverse reactions. Patients at risk of kidney function impairment (e.g., elderly patients) should be closely monitored. Monitoring of creatinine, urea, and electrolyte levels on days 2 and 3 is recommended to detect any possible impairment in methotrexate elimination at an early stage. This is particularly important during concomitant therapy with drugs that reduce methotrexate excretion, have adverse effects on kidneys (e.g., NSAIDs), or affect hematopoiesis. Dehydration may also potentiate methotrexate toxicity. Procedures to alkalinize urine and increase diuresis are recommended.

If signs of impaired kidney function are present (e.g., severe adverse effects from prior methotrexate therapy or urinary tract obstruction), creatinine clearance should be determined. If creatinine levels increase, the dose should be reduced. Methotrexate therapy should not be administered if serum creatinine exceeds 2 mg/dL. Elderly patients with severe kidney impairment require frequent medical evaluations, especially if taking additional drugs that negatively affect methotrexate elimination, cause kidney damage (e.g., NSAIDs), or may lead to hematopoietic disorders.

Concomitant use of NSAIDs is not recommended in patients with risk factors such as impaired kidney function, including mild impairment.

It is important to monitor potential elevated drug levels within 48 hours after administration, as otherwise irreversible methotrexate toxicity may occur.

Respiratory system evaluation. Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may develop; fatal cases have also been reported. Typical symptoms to monitor at each follow-up visit include dyspnea, cough (especially dry, non-productive cough), and fever. Patients should be informed about the risk of pneumonitis and advised to seek immediate medical attention if persistent cough or dyspnea occurs. In patients with symptoms of lung involvement, methotrexate use should be discontinued and a thorough evaluation (including chest fluoroscopy) performed to exclude infection. In case of suspected methotrexate-induced lung disease, corticosteroid therapy should be initiated without resuming methotrexate. Pulmonary symptoms require rapid diagnosis and discontinuation of methotrexate. Pneumonitis may occur at any dose.

Acute or chronic interstitial pneumonitis, often associated with eosinophilia and pleural effusion, may occur at any stage of therapy, including with low doses. This condition is not always fully reversible. Fatal cases have been reported. Patients should be fully informed about the risk of developing pneumonia and should seek immediate medical attention if persistent cough or dyspnea occurs.

Additionally, pulmonary alveolar hemorrhage has been reported during methotrexate use for rheumatological and related indications. This hemorrhage may also be associated with vasculitis and other comorbid conditions. Rapid diagnostic evaluation is necessary in case of suspected pulmonary alveolar hemorrhage to confirm the diagnosis.

Potentially fatal opportunistic infections, including Pneumocystis jirovecii pneumonia, may occur during methotrexate therapy. In patients with symptoms of impaired lung function, Pneumocystis jirovecii pneumonia should be considered.

Since methotrexate affects the immune system, it may alter the response to vaccination and affect the results of immunological tests. Particular caution is required in treating patients with inactive chronic infections (e.g., herpes zoster, tuberculosis, hepatitis B or C) due to the potential for reactivation. Live vaccines should not be administered during methotrexate therapy.

Liver biopsy

The benefit of liver biopsy for monitoring hepatotoxicity in rheumatological and dermatological indications has not been confirmed.

Liver biopsy should be performed during long-term methotrexate therapy for severe forms of psoriasis, including psoriatic arthritis, due to the risk of hepatotoxicity. This is necessary because fibrosis or cirrhosis may be present even when liver function tests are within normal limits. These changes can often be detected only by biopsy.

Patients without risk factors. According to current medical knowledge, liver biopsy is not necessary until cumulative dose reaches 1.0–1.5 g.

Patients with risk factors. Risk factors primarily include: history of alcohol abuse; persistent elevation of liver enzymes; history of hepatopathy, including chronic hepatitis B or C; hereditary hepatopathy in family history; and secondarily (with possible lower significance): diabetes; obesity; treatment with hepatotoxic or chemotherapeutic agents.

Liver biopsy

Since a small percentage of patients discontinue treatment for various reasons within 2–4 months, the first biopsy may be performed after the initial phase. Biopsy should be performed when long-term therapy is anticipated. Repeat liver biopsies are recommended after reaching a cumulative dose of 1.0–1.5 g.

Liver biopsy is not necessary in the following cases: elderly patients; patients with acute illnesses; patients in whom liver biopsy is contraindicated (e.g., cardiac disorders, coagulation abnormalities); patients with limited life expectancy.

If liver biopsy results show only minor changes (I, II, IIIa on the Roenigk scale), methotrexate therapy may continue with careful patient monitoring. Methotrexate should be discontinued in patients with elevated liver tests who decline biopsy or in patients whose biopsy confirms moderate or severe changes (IIIb or IV on the Roenigk scale).

Methotrexate should be discontinued in cases of moderate fibrosis or cirrhosis; repeat biopsy is recommended after 6 months in cases of mild fibrosis. Less severe findings before therapy initiation, such as fatty acid content changes or mild portal inflammation, are relatively common. Although these minor changes are generally not a contraindication to starting or continuing methotrexate therapy, the drug should be used cautiously.

Encephalopathy/leukoencephalopathy has been reported in oncology patients receiving methotrexate, and its occurrence cannot be excluded in patients treated for non-oncological indications.

Diarrhea and ulcerative stomatitis may be signs of toxicity and require discontinuation of therapy due to the risk of hemorrhagic enteritis and fatal outcomes from intestinal perforation.

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

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

During methotrexate therapy, radiation-induced dermatitis and sunburns may recur (remission of side effects). Psoriasis symptoms may worsen during UV irradiation when methotrexate is used concomitantly.

In acute lymphoblastic leukemia, methotrexate may cause left-sided epigastric pain (inflammation of the spleen capsule due to leukemic cell lysis).

Methotrexate "Ebewe" tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medication.

Methotrexate should be used with great caution in patients with myelosuppression, impaired kidney function, peptic ulcer, ulcerative colitis, ulcerative stomatitis, diarrhea, poor general condition, and in young children and elderly patients.

In the presence of pleural effusion or ascites, drainage should be performed before initiating methotrexate therapy. If this is not possible, methotrexate therapy should not be administered.

Conditions leading to dehydration, such as vomiting, diarrhea, or stomatitis, may increase methotrexate toxicity due to elevated drug levels. In such cases, methotrexate use should be discontinued until symptoms resolve.

Methotrexate should be taken with particular caution in patients with insulin-dependent diabetes mellitus and impaired lung function.

Individual cases of liver cirrhosis development during methotrexate therapy without prior elevation of transaminase activity have been reported.

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

Calcium folinate rescue therapy (emergency treatment) should be administered after methotrexate therapy, starting at a dose of 100 mg/m² body surface area. Depending on methotrexate dose and infusion duration, different doses of calcium folinate are required to protect normal cells from methotrexate toxicity.

Appropriate emergency calcium folinate therapy should be initiated within 42–48 hours after methotrexate administration. Therefore, methotrexate concentration should be monitored at 24, 48, and 72 hours, and monitoring continued as necessary to determine the duration of emergency calcium folinate therapy.

For psoriasis and psoriatic arthritis treatment, methotrexate concentration should be monitored weekly during the first two weeks, every two weeks during the following month, then at least once monthly depending on leukocyte count and patient stability.

Use in elderly patients

Particular caution is required when treating elderly patients. They should be regularly monitored for early signs of toxicity. The clinical pharmacology of methotrexate in elderly patients has not been fully studied. Methotrexate dose 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 acute lymphoblastic leukemia treatment.

Progressive multifocal leukoencephalopathy

Cases of progressive multifocal leukoencephalopathy (PML) have been reported in patients using methotrexate, primarily in combination with other immunosuppressive agents. PML may have fatal outcomes. This should be considered in differential diagnosis in 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 6 months after discontinuation of methotrexate. Before initiating therapy, women of reproductive age must be informed about the risk of methotrexate's adverse effects on the fetus, and pregnancy must be excluded by appropriate methods, such as a pregnancy test. Pregnancy tests should be performed during therapy as clinically needed (e.g., after any contraception failure). Women of reproductive age should receive counseling on pregnancy prevention and planning.

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

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

Pregnancy

Methotrexate use for non-oncological indications during pregnancy is contraindicated. If a patient becomes pregnant during methotrexate therapy or within 6 months after discontinuation, 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 demonstrated reproductive toxicity of methotrexate, particularly in the first trimester of pregnancy. Teratogenic effects of methotrexate have been demonstrated, with reports of fetal death, miscarriages, and/or congenital abnormalities (e.g., craniofacial, cardiovascular, central nervous system, and limb malformations).

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

• Spontaneous abortions were reported in 42.5% of pregnant women using low-dose methotrexate (less than 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 (less than 30 mg/week) during pregnancy, compared to approximately 4% of live-born children whose mothers used other drugs.

Insufficient data are available on methotrexate use during pregnancy at doses exceeding 30 mg/week, but a higher rate of spontaneous abortions and congenital malformations is expected.

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

Breastfeeding

Since methotrexate is excreted in breast milk and may cause toxic effects on breastfed infants, methotrexate is contraindicated during breastfeeding. If methotrexate use during breastfeeding is necessary, breastfeeding must be discontinued before initiating therapy.

Reproductive function

Since methotrexate is a genotoxic substance, all women planning pregnancy are recommended to consult genetic counseling centers, preferably before starting therapy.

Men should consider sperm cryopreservation before starting therapy.

Methotrexate negatively affects spermatogenesis and oogenesis and may lead to impaired fertility. Oligospermia, menstrual cycle disturbances, and amenorrhea have been reported in individuals during and for some time after therapy. In most cases, these symptoms were reversible after discontinuation of therapy.

Ability to affect reaction speed when driving or operating machinery.

Methotrexate has a weak or moderate adverse effect on the ability to drive or operate machinery. During methotrexate therapy, adverse effects from the central nervous system such as fatigue, confusion, and somnolence may occur; the ability to drive or operate machinery may be impaired in individual cases. These disturbances are more pronounced when combined with alcohol.

Administration and Dosage.

Treatment with Methotrexate "Ebewe" must be carried out under the supervision of an oncologist, dermatologist, rheumatologist, or internist. The physician must have experience in treating patients with methotrexate and be aware of the risks associated with this therapy. Rheumatoid and Dermatological Conditions

Important Warnings Regarding Methotrexate Dosing:

For the treatment of rheumatoid or skin disorders, methotrexate should be administered once weekly only. Incorrect dosing may result in severe adverse effects or even fatal outcomes.

The medication should be taken once a week.

The prescribing physician must indicate the day of administration on the prescription. Patients must be informed that methotrexate should be taken only once a week. It is advisable to establish a fixed day of the week for methotrexate administration.

Methotrexate "Ebewe" should be taken 1 hour before or 2 hours after a meal.

Doses for Rheumatoid Arthritis and Psoriasis

Psoriasis. The recommended initial dose for adults is 7.5 mg once weekly; alternatively, the planned weekly dose may be divided into three doses administered within 24 hours (with 12-hour intervals).

Rheumatoid Arthritis. The initial dose for adults is 7.5 mg once weekly orally. A therapeutic effect is usually observed within 6 weeks, with further improvement over the following 12 weeks or longer. If there is no therapeutic response and no signs of toxicity after 6–8 weeks of treatment, the weekly dose may be gradually increased by 2.5 mg. The oral dose may be divided into three doses taken at 12-hour intervals once weekly. Weekly oral administration typically consists of 2–3 divided doses taken approximately 12 hours apart, with no medication administered on other days of the week (e.g., methotrexate is taken Monday morning, Monday evening, Tuesday morning, then no methotrexate until the following week).

The weekly dose may also be taken as a single dose on an empty stomach. Food should be consumed after taking the medication.

The usual optimal dose ranges from 7.5 to 15 mg and should not exceed 20 mg per week. Doses exceeding 20 mg/week are associated with a significant increase in toxicity, particularly bone marrow suppression. If the oral dose is ineffective, parenteral administration should be considered. Methotrexate is administered intramuscularly or subcutaneously. This route is recommended for patients with poor absorption of oral methotrexate or those who poorly tolerate the oral form.

Supplemental folic acid 5 mg twice weekly (excluding the day of methotrexate administration) is recommended.

A therapeutic effect is typically observed after 4–8 weeks of treatment.

If no therapeutic effect is observed after 8 weeks of treatment at the maximum dose, methotrexate should be discontinued. Once a therapeutic response is achieved, the maintenance dose should be reduced to the lowest effective level. The optimal duration of methotrexate treatment has not yet been established, but preliminary data suggest that the initial effect may be maintained for at least 2 years with maintenance dosing. After discontinuation of methotrexate, disease symptoms may reappear within 3–6 weeks.

As a cytostatic agent.

Methotrexate may be administered orally at doses up to 30 mg/m²; higher doses must be given parenterally.

Treatment of Patients with Renal Impairment

Methotrexate "Ebewe" must be prescribed with caution in patients with impaired renal function. Doses should be adjusted according to creatinine clearance.

Treatment of patients with hepatic impairment

Methotrexate "Ebewe" should be administered with great caution (if absolutely necessary) to patients with significant hepatic dysfunction (present or in the history, particularly if caused by alcohol abuse). Methotrexate must not be used when bilirubin levels exceed 85.5 µmol/L.

Treatment of elderly patients

Since hepatic and renal function decline with age, and folate reserves are reduced, dose reduction may be advisable for elderly patients. In addition, careful monitoring of patients is required to detect early signs of toxicity.

Patients with third space fluid accumulation (pleural effusion, ascites):

In patients with third space fluid accumulation, the elimination half-life of methotrexate may be prolonged up to four times the normal duration; therefore, dose reduction or, in some cases, discontinuation of methotrexate administration may be necessary.

Method of administration:

For oral use.

Tablets should be swallowed whole with sufficient liquid (water, not milk products).

The physician determines the total duration of treatment.

Children.

The drug may be used in children with acute lymphoblastic leukemia (as maintenance therapy). It is not recommended for use in children under 3 years of age, as there is insufficient information on efficacy and safety of the drug in this patient group.

Overdose.

Post-marketing experience with methotrexate indicates that cases of overdose have been reported following both oral and intravenous or intramuscular administration.

Cases of overdose have occurred due to accidental daily administration of the weekly methotrexate dose, sometimes resulting in fatalities. The most commonly reported symptoms are predominantly related to bone marrow suppression. Symptoms include leukopenia, thrombocytopenia, anemia, pancytopenia, neutropenia, bone marrow suppression, mucosal inflammation, stomatitis, oral ulceration, nausea, vomiting, gastrointestinal ulceration and hemorrhage. In some patients, symptoms of overdose were absent.

Fatal cases have been reported due to sepsis, septic shock, renal failure, and aplastic anemia. Cases of overdose, sometimes with fatal outcomes, have also been reported following accidental daily oral intake of methotrexate instead of once weekly. Symptoms observed in such cases were mostly hematological or gastrointestinal reactions.

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

In case of accidental overdose, calcium folinate should be administered intravenously or intramuscularly at a dose equal to or exceeding the methotrexate dose, no later than one hour after methotrexate administration. Subsequently, additional doses of calcium folinate should be administered until the serum methotrexate concentration falls below 10^-7 mol/L. In cases of leukocyte count reduction following low-dose methotrexate administration (e.g., 6–12 mg), intravenous or intramuscular calcium folinate therapy should be initiated as soon as possible, followed by multiple administrations (at least 4 times) at the same doses at intervals of 3–6 hours. In cases of significant overdose, hydration and urinary alkalinization may be required to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Conventional hemodialysis and peritoneal dialysis do not enhance methotrexate elimination. Effective clearance of methotrexate can be achieved with high-flux intermittent hemodialysis using high-flux dialyzers.

In patients with rheumatoid arthritis, polyarticular forms of juvenile idiopathic arthritis, psoriatic arthritis, or psoriasis, administration of folic acid or folinic acid may reduce methotrexate toxicity (gastrointestinal symptoms, oral mucosal inflammation, hair loss, and elevated liver enzymes), see section 4.5. Prior to initiating folic acid products, monitoring of vitamin B12 levels is recommended, as folic acid may mask vitamin B12 deficiency, particularly in adults over 50 years of age.

Adverse Reactions.

The frequency and severity of adverse reactions depend on the dose, route of administration, and duration of treatment with Methotrexate "Ebewe". Since severe adverse reactions may occur even at low doses and at any stage of therapy, careful medical monitoring is required.

Most adverse reactions are reversible if detected early. However, in very rare cases, some of the serious adverse reactions listed below may lead to sudden fatal outcomes.

If adverse reactions occur, the dose should be reduced, or if necessary, therapy 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 with caution, provided that a careful assessment of the necessity of therapy and increased vigilance for possible recurrence of toxic effects is maintained.

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

The most commonly reported adverse reactions include thrombocytopenia, leukopenia, headache, dizziness, cough, anorexia, diarrhea, abdominal pain, nausea, 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 levels of liver enzymes and bilirubin, decreased creatinine clearance, fatigue, and malaise.

Ulceration of the oral mucosa is usually the first clinical sign of toxicity.

When assessing adverse effects, their frequency is categorized as follows:

Very common: ≥ 1/10; common: ≥1/100, <1/10; uncommon: ≥1/1000, <1/100; rare: ≥1/10,000, <1/1000; very rare: <1/10,000; frequency not known (cannot be estimated based on available data).

Infections and infestations

Common: herpes zoster; uncommon: opportunistic infections, which may be fatal; rare: sepsis (including fatal outcomes); very rare: hepatitis due to herpes simplex virus, cryptococcal mycosis, histoplasmosis, cytomegalovirus infections (including pneumonia), disseminated herpes simplex virus infection, nocardiosis, Pneumocystis jirovecii-induced pneumonia*; frequency not known: pneumonia, reactivation of hepatitis B, exacerbation of hepatitis C.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Uncommon: malignant lymphoma*.

Blood and lymphatic system disorders*

Very common: thrombocytopenia, leukopenia; common: anemia, pancytopenia, bone marrow suppression, agranulocytosis; rare: megaloblastic anemia; very rare: aplastic anemia, eosinophilia, neutropenia, lymphadenopathy (partially reversible), and lymphoproliferative disorders (partially reversible).

Immune system disorders

Uncommon: allergic reactions up to anaphylactic shock, immunosuppression; very rare: hypogammaglobulinemia.

Metabolism and nutrition disorders

Uncommon: diabetes mellitus.

Psychiatric disorders

Uncommon: depression; rare: mood swings, sometimes insomnia, transient perception disturbances.

Nervous system disorders

Very common: headache, dizziness; common: somnolence, paresthesia; uncommon: hemiparesis, confusion; rare: paralysis, speech disorders including dysarthria and aphasia, leukoencephalopathy; very rare: muscle fatigue and limb pain, taste disturbances (metallic taste), acute aseptic meningitis (paralysis, vomiting), cranial nerve disorder syndrome; frequency not known: neurotoxicity, arachnoiditis, paraplegia, stupor, ataxia, dementia, increased cerebrospinal fluid pressure.

Eye disorders

Common: conjunctivitis; rare: visual disturbances (partially severe), severe retinal vein thrombosis; 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).

Respiratory, thoracic and mediastinal disorders*

Very common: cough; common: pulmonary complications due to interstitial alveolitis/pneumonitis, which may be fatal (regardless of dose or duration of methotrexate treatment); uncommon: pulmonary fibrosis, pleural effusion; rare: pharyngitis, respiratory arrest, pulmonary embolism; very rare: chronic obstructive lung disease, asthma-like reactions with cough, dyspnea, and pathological pulmonary function test results; frequency not known: chest pain, hypoxia, epistaxis, pulmonary alveolar hemorrhage.

Gastrointestinal disorders*

Very common: loss of appetite, diarrhea (particularly within the first 24–48 hours after methotrexate administration), abdominal pain, nausea, vomiting, inflammation and ulceration of the mucous membranes of the oral cavity and throat (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, AST), alkaline phosphatase, and bilirubin; uncommon: hepatotoxicity, fatty liver changes, chronic liver fibrosis and cirrhosis, decreased serum albumin; rare: acute hepatitis; very rare: acute liver necrosis, acute liver disease, liver failure (also see information on liver biopsy in section "Special warnings and precautions for use").

Skin and subcutaneous tissue disorders*

Very common: alopecia; common: exanthema, erythema, pruritus, 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, photosensitivity reactions; rare: acne, petechiae, ecchymosis, erythema multiforme, erythematous skin rashes, increased nail pigmentation, onycholysis; very rare: furunculosis, telangiectasia, acute paronychia; frequency not known: skin reactions with eosinophilia and systemic symptoms (DRESS), dermatitis, hidradenitis.

Musculoskeletal and connective tissue disorders

Uncommon: arthralgia, myalgia, and osteoporosis; rare: stress fracture; frequency not known: osteonecrosis, osteonecrosis of the jaw (secondary to lymphoproliferative disorders).

Renal and urinary disorders*

Very common: decreased creatinine clearance; uncommon: nephropathy, renal failure, ulcerative cystitis (with hematuria), urinary disorders, dysuria, oliguria, anuria; rare: hyperuricemia, increased serum urea and creatinine, azotemia; very rare: hematuria, proteinuria.

Pregnancy, puerperium and perinatal conditions

Uncommon: congenital malformations in the fetus; rare: abortion; very rare: fetal death.

Reproductive system and breast disorders

Uncommon: vaginal ulcers and inflammation; rare: transient oligospermia; very rare: disturbances in oogenesis/spermatogenesis*, infertility*, menstrual cycle disturbances, loss of libido, impotence, vaginal discharge, gynecomastia; frequency not known: erectile dysfunction.

General disorders and administration site conditions

Very common: exhaustion, malaise; uncommon: fever*; very rare: chills.

*For information on serious adverse reactions, see section "Special warnings and precautions for use".

In rare cases, severe progressive bone marrow suppression, agranulocytosis, aplastic anemia, lymphadenopathy, lymphoproliferative disorders (partially reversible), eosinophilia, and neutropenia have been reported. The initial signs of life-threatening complications may include: fever, sore throat, oral mucosal ulceration, flu-like symptoms, severe fatigue, epistaxis, and skin hemorrhages. Methotrexate administration should be immediately discontinued in case of significant reduction in red blood cell count.

Other adverse reactions: vertigo, convulsions, leukopathy, pathological changes in pulmonary function tests, pulmonary complications due to interstitial alveolitis, pneumonitis, and fatal cases (symptoms may include: malaise, breathing difficulties progressing to dyspnea at rest, chest pain), chronic obstructive pulmonary disease, hematemesis, increased bilirubin, AST, ALT, alkaline phosphatase, hematuria, severe skin toxic reactions, impaired wound healing.

Shelf life.

3 years.

Storage conditions.

No special storage conditions required.

Keep out of reach and sight of children.

Packaging.

2.5 mg tablets: 10 tablets per blister; 5 or 10 blisters per cardboard box.

5 mg tablets: 10 tablets per blister; 2 or 5 blisters per cardboard box.

10 mg tablets: 10 tablets per blister; 1 or 5 blisters per cardboard box.

Prescription status.

Prescription only.

Manufacturer.

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

Haupt Pharma Amareg GmbH.

or:

Salutas Pharma GmbH.

Haupt Pharma Amareg GmbH.

Manufacturer's address and location of its operations.

Mondseestrasse 11, 4866 Unterach am Attersee, Austria.

Donaustaufer Str. 378, 93055, Regensburg, Germany.

or:

Otto-von-Guericke-Allee 1, 39179, Barleben, Germany.

Donaustaufer Str. 378, 93055, Regensburg, Germany.