Instructions for Methotrexate Ebeve tablets 5 mg container No. 50
Composition
active ingredient: methotrexate;
1 tablet contains 2.5 mg, or 5 mg, or 10 mg of methotrexate;
Excipients: lactose monohydrate; corn starch; microcrystalline cellulose; colloidal anhydrous silica; magnesium stearate.
Dosage form
Pills.
Basic physicochemical properties.
Methotrexate "Ebeve" 2.5 mg: round flat tablets with beveled edges, light yellow in color, with inclusions from yellow to orange or whitish inclusions allowed;
Methotrexate "Ebeve" 5 mg: round biconvex tablets of light yellow color with a score line on one side, the presence of yellow to orange or whitish inclusions is allowed;
Methotrexate "Ebeve" 10 mg: capsule-shaped, biconvex tablets of light yellow color with a score line on one side, the presence of yellow to orange or whitish inclusions is allowed.
Pharmacotherapeutic group
Antineoplastic agents. Antimetabolites. Structural analogues of folic acid.
ATX code L01B A01.
Pharmacological properties
Pharmacodynamics.
Methotrexate is a folic acid derivative belonging to the class of cytotoxic agents known as 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. Actively proliferating tissues, such as malignant tumors, bone marrow, fetal cells, oral and intestinal mucosa, and bladder cells, are usually more sensitive to methotrexate. Since malignant tissues proliferate more rapidly than normal, methotrexate can disrupt their development without causing irreversible damage to healthy tissues.
The mechanism of action of methotrexate in rheumatoid arthritis is unknown, but it may affect immune function. Further study of the effects of methotrexate on the immune system in relation to rheumatoid immunopathogenesis is needed.
In psoriasis, the rate of replication of epithelial cells in the skin is significantly higher than normal. This difference in proliferation rate is the basis for the use of methotrexate to control the psoriatic process.
Pharmacokinetics.
Methotrexate "Ebewe" is rapidly absorbed when administered orally. After taking a dose of 2 ´ 2.5 mg, the maximum concentration of methotrexate in the blood serum is reached after 0.83 hours and averages 170 ng/ml.
About 50% of methotrexate is bound to plasma proteins. After distribution, methotrexate accumulates mainly in the liver, kidneys and spleen in the form of polyglutamates, which can persist for weeks and months. When used in low doses, minimal amounts of methotrexate penetrate the cerebrospinal fluid. The terminal half-life of methotrexate varies from 3 to 17 hours and averages 6-7 hours. In patients with a third distribution chamber (pleural effusion, ascites), the half-life of methotrexate can be up to 4 times longer.
Approximately 10% of the administered dose is metabolized in the liver. The main metabolite of methotrexate is 7-hydroxymethotrexate.
Methotrexate is excreted mainly unchanged by the kidneys (by glomerular filtration and active secretion in the proximal tubules).
Approximately 5-20% of methotrexate and 1-5% of 7-hydroxymethotrexate are excreted in the bile. There is significant enterohepatic recirculation of methotrexate.
In patients with impaired renal function, methotrexate is eliminated much more slowly. It is not known whether impaired hepatic function affects the elimination of methotrexate.
Indication
Antirheumatic therapy. Active rheumatoid arthritis in adult patients who are eligible for treatment with disease-modifying antirheumatic drugs (DMARDs).
Treatment of psoriasis. Severe and widespread forms of psoriasis vulgaris, especially plaque type, in adult patients when traditional therapy, such as phototherapy, PUVA therapy and retinoids, is ineffective.
As a cytostatic drug. Supportive therapy for acute lymphoblastic leukemia.
Contraindication
Hypersensitivity to methotrexate or to any of the other ingredients of the drug.
· Significant liver dysfunction (bilirubin level > 85.5 μmol/l).
· Alcohol abuse.
· Renal impairment (creatinine clearance < 20 ml/min).
· Existing disorders of the hematopoietic system (including bone marrow hypoplasia, leukopenia, thrombocytopenia or severe anemia).
Immunodeficiency.
Severe, acute or chronic infections (e.g. tuberculosis or HIV).
· Ulcers of the mouth or gastrointestinal tract.
· Pregnancy and breastfeeding.
· Vaccination with live vaccines during treatment with methotrexate.
Interaction with other medicinal products and other forms of interactions
The risk of hepatotoxicity of methotrexate increases with regular alcohol consumption or concomitant use of other hepatotoxic drugs. Alcohol consumption should be avoided during methotrexate treatment. Particular caution is required when treating patients with methotrexate who are taking other hepatotoxic and hematotoxic drugs (e.g. leflunomide, metamizole). Combined treatment with methotrexate and retinoids, such as acitretin or etretinate, increases the risk of hepatotoxicity.
With combined therapy with methotrexate and leflunomide, the incidence of pancytopenia and hepatotoxic effects increases.
Oral antibiotics
Oral antibiotics (including tetracyclines, chloramphenicol, and non-absorbable broad-spectrum antibiotics) may affect enterohepatic circulation by inhibiting the intestinal microflora or suppressing bacterial metabolism.
Antibiotics
Antibiotics such as penicillins, glycopeptides, sulfonamides, ciprofloxacin and cephalothin may, in isolated cases, reduce the renal clearance of methotrexate, which may result in an increase in its serum concentration and an increase in toxic effects on the hematopoietic system and the digestive tract.
Probenecid, weak organic acids, pyrazoles and nonsteroidal anti-inflammatory drugs
Probenecid, weak organic acids (e.g. loop diuretics) and pyrazoles (phenylbutazone) may slow the elimination of methotrexate, which may increase its serum concentration and increase hematological toxicity. The risk of toxic effects is also increased when methotrexate is used in combination with low doses of nonsteroidal anti-inflammatory drugs or salicylates. Caution should be exercised when taking nonsteroidal anti-inflammatory drugs and methotrexate within 24 hours of taking the drug, when the plasma level of methotrexate may increase and cause increased toxicity of the drug.
Animal studies have shown that nonsteroidal anti-inflammatory drugs (NSAIDs), including salicylic acid, cause a decrease in the tubular secretion of methotrexate and, accordingly, increase its toxic effects. However, in clinical studies in which NSAIDs and salicylic acid were used as concomitant therapy for the treatment of patients with rheumatoid arthritis, no increase in the frequency of adverse reactions was noted. The mentioned drugs can be continued to be used as part of the complex therapy of rheumatoid arthritis simultaneously with methotrexate, but only under careful medical supervision.
Drugs that adversely affect the bone marrow
With concomitant therapy with drugs that may cause side effects on the bone marrow (e.g. sulfonamide, trimethoprim/sulfamethoxazole, chloramphenicol, pyrimethamine), the possibility of developing more pronounced hematological disorders should be taken into account.
Drugs that cause folate deficiency
Concomitant treatment with drugs that cause folate deficiency (e.g. sulfonamides, trimethoprim/sulfamethoxazole) may increase the toxicity of methotrexate. Special caution is also required when treating patients with existing folic acid deficiency. On the other hand, concomitant administration of drugs containing folic acid or vitamins may impair the effect of methotrexate.
Other antirheumatic drugs
When combined with other antirheumatic drugs (e.g. gold salts, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine), the toxic effect of methotrexate is usually not enhanced.
Sulfasalazine
Although the effect of methotrexate may be potentiated when used in combination with sulfasalazine due to inhibition of folic acid synthesis by sulfasalazine (which may result in an increased incidence of side effects), such effects were observed only in isolated cases in several clinical studies.
Proton pump inhibitors
When methotrexate is used concomitantly with proton pump inhibitors (e.g. omeprazole or pantoprazole), an interaction is possible. Omeprazole may reduce the renal clearance of methotrexate, and pantoprazole may inhibit the renal elimination of the metabolite 7-hydroxymethotrexate, which in one case was accompanied by the development of myalgia and tremor.
Concomitant use of methotrexate and theophylline may reduce theophylline clearance. Regular determination of theophylline plasma levels should be ensured.
Salicylates, phenylbutazone, phenytoin, barbiturates, tranquilizers, oral contraceptives, tetracyclines, amidopyrine derivatives, sulfonamides, and para-aminobenzoic acid replace methotrexate in the process of binding to serum albumin, resulting in increased bioavailability (mediated dose increase).
Nitrous oxide-based anesthetics may enhance the effect of methotrexate on the metabolic transformation of folic acid, resulting in unpredictable, severe bone marrow depression and stomatitis. Calcium folinate should be administered to reduce the intensity of these effects.
Copestyramine may enhance the extrarenal excretion of methotrexate by interfering with the enterohepatic circulation. When undergoing radiotherapy while the patient is receiving methotrexate, the risk of soft tissue and bone necrosis may increase.
In case of simultaneous use with other cytostatics, the clearance of methotrexate may decrease.
Vitamin complexes and oral iron preparations containing folic acid may alter the body's response to methotrexate therapy.
Due to its possible effect on the immune system, methotrexate may alter the response to vaccination and the results of studies (immunological procedures to determine the immune response). Concomitant vaccination with live vaccines should not be carried out during methotrexate therapy.
Beverages containing caffeine and theophylline
Excessive consumption of beverages containing caffeine or theophylline (coffee, cold caffeinated drinks, black tea) should be avoided during treatment with methotrexate, as this may reduce the effectiveness of methotrexate due to the interaction of methotrexate and methyxanthine adenosine receptors.
Application features
Treatment with methotrexate should be supervised by qualified oncologists, dermatologists or rheumatologists who have experience in the use of anticancer chemotherapeutic agents.
Methotrexate should be taken once a week. The prescription should state the day of administration.
During methotrexate therapy, patients should be closely monitored for signs of possible toxicity and side effects. Given the risk of severe or even fatal toxic reactions, patients should be thoroughly informed about possible complications and recommended precautions. However, doses exceeding 20 mg/week may be associated with a significant increase in toxicity, especially bone marrow suppression.
Methotrexate has been reported to have adverse effects on reproductive function, causing oligospermia, menstrual irregularities, and amenorrhea during therapy and for a short period after its discontinuation. In addition, methotrexate has been shown to cause embryotoxicity, miscarriage, and intrauterine malformations. Accordingly, physicians should advise patients of reproductive age of all possible risks associated with the drug.
Recommended studies and precautions
Before starting treatment with methotrexate or when continuing therapy after a break, a blood test should be performed to determine the leukocyte formula and platelet count, liver enzymes, bilirubin, serum albumin and kidney function tests, as well as a chest X-ray. If clinically indicated, tests should be performed to exclude tuberculosis and hepatitis.
During therapy (during the first 6 months - at least once a month, subsequently - at least once every 3 months) the following studies should be performed:
Examination of the oral cavity and throat to detect changes in the mucous membranes.
Blood test with determination of leukocyte formula and platelet count. Even when used in normal therapeutic doses, methotrexate can cause sudden suppression of the hematopoietic system. In the event of a significant decrease in the number of leukocytes or platelets, methotrexate treatment should be discontinued immediately and symptomatic supportive therapy should be prescribed. Patients should be instructed to immediately report any signs and symptoms indicating the development of infection to their doctor. In case of concomitant therapy with hematotoxic drugs (e.g. leflunomide), the number of leukocytes and platelets in the blood should be carefully monitored.
Liver function tests. Particular attention should be paid to detecting signs of liver damage. Methotrexate treatment should not be initiated or should be discontinued in the event of any abnormalities in liver function tests or liver biopsy.
Liver function tests. Further studies are needed to determine whether liver function tests from a blood chemistry panel or by measuring the level of collagen type III propeptide can detect hepatotoxicity with sufficient accuracy. Such tests would differentiate patients without any risk factors from those with risk factors, including those who abused alcohol before starting treatment; those with persistently elevated liver enzymes; those with a history of liver disease or a family history of hereditary liver disease; those with diabetes mellitus, obesity; those who had previous exposure to hepatotoxic drugs or chemicals, those who were on long-term methotrexate treatment, or those who received a total dose of 1.5 g or more.
Control of liver enzymes in blood serum.
Transient elevations of transaminases (up to 2-3 times the upper limit of normal) have been reported in some patients. In the event of persistent elevations of liver enzymes, methotrexate should be reduced or treatment discontinued.
Since methotrexate has a toxic effect on the liver, during treatment with the drug, other hepatotoxic drugs should not be prescribed unless clearly necessary. It is also necessary to avoid or significantly limit alcohol consumption. Liver enzyme levels should be monitored particularly carefully in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular leflunomide).
Liver biopsy. There is insufficient evidence to support liver biopsy for monitoring hepatotoxicity in patients with rheumatic diseases. In the case of longer-term treatment of severe psoriasis with methotrexate, liver biopsy should be performed due to the possibility of hepatotoxicity. Patients at normal and increased risk of hepatotoxicity should be distinguished.
Patients without risk factors: According to current medical knowledge, liver biopsy is not necessary until a cumulative dose of 1.0-1.5 g is reached.
Patients with risk factors. Risk factors include, first and foremost, a history of alcohol abuse; persistent elevation of liver enzymes; history of hepatopathy, including chronic hepatitis B or C; family history of hereditary hepatopathy; and secondarily (possibly of lesser importance): diabetes mellitus; obesity; treatment with hepatotoxic drugs or chemotherapy. In such patients, a liver biopsy is recommended during or immediately after the start of methotrexate treatment. Since a small percentage of patients discontinue treatment for various reasons within 2-4 months, the first biopsy may be performed after the first phase. Biopsy should be performed when long-term treatment is envisaged. 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 for whom liver biopsy is contraindicated (such as cardiac disorders, changes in blood coagulation parameters); patients with a short life expectancy.
Regular examinations may be necessary: at the beginning of treatment; when the dose is increased; when there is a high risk of increased methotrexate blood levels (e.g. dehydration, impaired liver function, additional or increased doses of concomitant medications such as non-steroidal anti-inflammatory drugs (NSAIDs)).
Renal function tests and urine tests. Since methotrexate is excreted mainly in the urine, patients with impaired renal function may experience increased methotrexate blood concentrations, which may result in severe adverse reactions. Patients with possible impaired renal function (e.g. elderly patients) should be carefully monitored. This is particularly important in the case of concomitant therapy with drugs that reduce methotrexate excretion, have an adverse effect on the kidneys (in particular non-steroidal anti-inflammatory drugs) or on the hematopoietic system. Dehydration may also potentiate the toxic effect of methotrexate. It is recommended to carry out procedures to alkalinize the urine and increase diuresis.
Since methotrexate affects the immune system, it may alter the response to vaccination and affect the results of immunological tests. Particular caution is required when treating patients with inactive chronic infections (such as herpes zoster, tuberculosis, hepatitis B or C) because of their possible activation. Vaccination with live vaccines should not be carried out during treatment with methotrexate.
Malignant lymphoma may develop in patients receiving low-dose methotrexate; in such cases, methotrexate treatment should be discontinued. If the lymphoma does not regress spontaneously, cytotoxic therapy should be initiated.
Pleural effusions and ascites should be eliminated before starting methotrexate treatment.
Diarrhea and ulcerative stomatitis may be signs of toxicity and require discontinuation of treatment due to the risk of hemorrhagic enteritis and fatal cases due to intestinal perforation.
Vitamin preparations and other products containing folic acid, folinic acid or their derivatives may reduce the effectiveness of methotrexate.
Use in children under 3 years of age is not recommended due to the lack of sufficient data on the efficacy and safety of the drug in this category of patients.
During treatment with methotrexate, recurrence of radiation-induced dermatitis and sunburn (remission of side effects) is possible. During UV irradiation with simultaneous use of methotrexate, psoriasis manifestations may be exacerbated.
Methotrexate Ebewe tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Methotrexate should be used with great caution in the treatment of patients with myelosuppression, renal impairment, peptic ulcer, ulcerative colitis, ulcerative stomatitis, diarrhea, poor general condition, as well as in the treatment of young children and the elderly.
If pleural effusion or ascites is present, drainage should be performed before starting methotrexate treatment. If this is not possible, methotrexate therapy should not be administered.
If symptoms of gastrointestinal toxicity occur (usually stomatitis develops first), methotrexate treatment should be discontinued, as continued therapy may lead to hemorrhagic enteritis and intestinal perforation, which are life-threatening. Conditions leading to dehydration, such as vomiting, diarrhea, stomatitis, may increase methotrexate toxicity by increasing the drug levels in the body. In these cases, methotrexate should be discontinued until symptoms resolve.
In patients with pathological fluid accumulation in body cavities ("third space") such as ascites and pleural effusion, the half-life of methotrexate from blood plasma is longer.
Methotrexate should be used with extreme caution in patients with insulin-dependent diabetes mellitus and impaired lung function.
Use during pregnancy or breastfeeding
The use of methotrexate during pregnancy is contraindicated. Studies have shown that methotrexate is teratogenic (the drug caused fetal death and/or congenital malformations, especially when used in the first trimester of pregnancy), so it should not be used during pregnancy. When using the drug in a limited group of pregnant women (42), an increased frequency (1:14) of malformations (cranial, cardiovascular and distal) was noted. In the case of discontinuation of methotrexate before conception, no cases of deviations from the normal course of pregnancy were recorded. Before starting therapy with the drug, the possibility of pregnancy in women of reproductive age should be definitely excluded by using appropriate measures (such as pregnancy tests).
Patients of reproductive age (both women and men) and their partners should use effective contraception during treatment and for at least 6 months after the end of therapy with Methotrexate "Ebewe". If the patient or the partner of a man treated with methotrexate nevertheless becomes pregnant, it is necessary to consult specialists regarding the risk of adverse effects of methotrexate on the fetus. Given the possible genotoxic effect of methotrexate, all women who wish to become pregnant are recommended to seek advice from genetic specialists if possible before treatment with the drug, and men - to consult specialists regarding the possibility of sperm conservation before starting therapy.
Since methotrexate passes into breast milk and may have toxic effects on infants, treatment with the drug is contraindicated during breastfeeding. If necessary, breastfeeding should be discontinued before starting therapy.
Ability to influence reaction speed when driving vehicles or other mechanisms
Methotrexate has a mild to moderate adverse effect on the ability to drive and use machines. During treatment with methotrexate, CNS side effects such as fatigue, confusion, drowsiness may occur; the ability to drive and use machines may be impaired in isolated cases. These impairments are more pronounced when combined with alcohol.
Method of administration and doses
Treatment with Methotrexate "Ebeve" should be carried out under the supervision of an oncologist, dermatologist or rheumatologist, as well as a therapist. The drug should be taken once a week.
The prescribing physician may indicate on the prescription the day the medication is to be taken.
Swallow the tablets without chewing, 1 hour before or 1.5-2 hours after meals.
Dosages for rheumatoid arthritis and psoriasis
Psoriasis: The recommended starting dose for adults is 2.5 mg three times a week at 12-hour intervals or 7.5 mg once a week.
Rheumatoid arthritis. The initial dose for adults is 7.5 mg per week once. Usually, the therapeutic effect is achieved within 6 weeks, with further improvement in the patient's condition over the next 12 weeks or more. In the absence of a therapeutic effect and signs of toxicity after 6-8 weeks of treatment, the weekly dose of the drug can be gradually increased by 2.5 mg.
The usual optimal dose is in the range of 7.5 to 15 mg and should not exceed 20 mg per week. In the absence of a therapeutic effect after 8 weeks of treatment with the maximum dose, methotrexate is discontinued. When a therapeutic effect is achieved, the maintenance dose of the drug should be reduced to the lowest possible level. The optimal duration of treatment with methotrexate has not yet been established, but preliminary data indicate that the initial effect is maintained for at least 2 years when using maintenance doses. After stopping treatment with the drug, symptoms of the disease may reappear after 3-6 weeks.
As a cytostatic drug.
Methotrexate can be administered orally at doses up to 30 mg/m2; higher doses must be administered parenterally.
Treatment of patients with renal impairment
Methotrexate "Ebewe" should be administered with caution to patients with impaired renal function. Doses should be adjusted depending on creatinine clearance (with clearance > 50 ml/min there is no need to reduce the dose, with clearance 20-50 ml/min the dose should be reduced by 50%, and with clearance < 20 ml/min methotrexate should not be administered).
Treatment of patients with liver dysfunction
Methotrexate "Ebewe" should be administered with great caution (unless absolutely necessary) to patients with significant liver dysfunction (current or history, especially caused by alcohol abuse). Methotrexate should not be used if bilirubin levels are > 85.5 μmol/l.
Treatment of elderly patients
Since liver and kidney function decline with age, and folate reserves decrease, it may be appropriate to reduce doses for elderly patients.
Children.
The drug is used in children with acute lymphocytic leukemia (as maintenance therapy). It is not recommended for use in children under 3 years of age, as there is insufficient information on the efficacy and safety of the drug in this group of patients.
Overdose
Symptoms of overdose. Symptoms associated with suppression of the hematopoietic system are mainly observed. Symptoms include leukocytopenia, thrombocytopenia, anemia, pancytopenia, neutropenia, bone marrow depression, inflammation of the mucous membranes, stomatitis, oral ulceration, nausea, vomiting, ulceration and bleeding in the gastrointestinal tract. In some patients, symptoms of overdose were absent.
Fatalities have been reported due to sepsis, septic shock, renal failure and aplastic anaemia. Overdose, sometimes fatal, has also been reported when oral methotrexate was mistakenly administered daily instead of once weekly. The symptoms reported in these cases were mostly haematological or gastrointestinal reactions.
Treatment of overdose. The specific antidote for methotrexate is calcium folinate. It neutralizes the toxic side effects of methotrexate.
In case of accidental overdose of calcium folinate, a dose equal to or greater than the dose of methotrexate should be administered intravenously or intramuscularly no later than one hour after the administration of methotrexate. Then several more doses of calcium folinate should be administered until the serum concentration of methotrexate is below 10–7 mol. If the leukocyte count decreases with low doses of methotrexate, e.g. 6-12 mg, intravenous or intramuscular calcium folinate therapy should be started as soon as possible, followed by repeated administration of the drug (at least 4 times) in the same doses at intervals of 3-6 hours. In case of significant overdose, it may be necessary to hydrate the body and alkalinize the urine to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Conventional hemodialysis and peritoneal dialysis do not improve methotrexate elimination. Intensive intermittent hemodialysis using high-flux dialyzers can provide effective clearance of methotrexate.
Adverse reactions
The most serious side effects of methotrexate treatment are hematopoietic suppression and gastrointestinal adverse reactions. In most cases, adverse reactions are reversible if detected early. If they occur, the dose of the drug should be reduced or therapy should be discontinued and appropriate measures should be taken. Re-introduction of methotrexate therapy should be undertaken with caution, after careful assessment of the need for such treatment and with increased monitoring due to possible recurrence of toxicity.
From the side of the cardiovascular system
Pericardial effusion, pericardial tamponade, pericarditis.
Blood and lymphatic system disorders
Bone marrow depression (manifested mainly as leukopenia, although thrombocytopenia, anemia, or combinations thereof may occur); pancytopenia, megaloblastic anemia.
Severe progressive bone marrow depression, agranulocytosis, aplastic anemia have been reported in isolated cases. Lymphadenopathy, lymphoproliferative disorders (partially reversible), eosinophilia and neutropenia. The first signs of life-threatening complications may be: fever, sore throat, oral mucosal ulcers, flu-like symptoms, severe fatigue, epistaxis and skin hemorrhages. Methotrexate should be discontinued immediately if the number of red blood cells decreases significantly.
From the nervous system
Drowsiness, headache, fatigue. During therapy with low doses of methotrexate, minor transient disturbances of cognitive functions and unusual sensations in the skull area are possible.
In some cases, visual disturbances, pain, myasthenia or paresthesia in the extremities, taste changes (metallic taste in the mouth), epileptic seizures, acute aseptic meningitis accompanied by paralysis, and vomiting have been noted.
From the organs of vision
Blurred vision, eye irritation, conjunctivitis, retinopathy.
Respiratory, thoracic and mediastinal disorders
Chronic interstitial pneumonitis (symptoms suggestive of potentially serious lung damage in interstitial pneumonitis: dry non-productive cough, shortness of breath, fever). Acute pulmonary edema has been reported following oral and intrathecal administration of methotrexate.
Epistaxis, alveolitis, pleural effusion have been reported. Pulmonary fibrosis, pneumocystis pneumonia, dyspnea, bronchial asthma, pharyngitis, apnea; asthma-like reactions accompanied by cough have been reported in some cases.
There have been isolated reports of a syndrome characterized by pleural pain and pleural thickening (with high-dose methotrexate treatment).
From the digestive tract
Loss of appetite, nausea, vomiting, abdominal pain, inflammation and ulceration of the mouth and throat (especially during the first 24-48 hours after the use of methotrexate). Stomatitis, dyspepsia. Diarrhea has been observed (especially during the first 24-48 hours after the use of methotrexate). Ulcers of the digestive tract and bleeding. In isolated cases, enteritis, melena, gingivitis have been noted. The effect of methotrexate on the intestinal mucosa may cause the development of malabsorption syndrome or toxic megacolon.
Renal and urinary disorders
Inflammation and ulcers of the bladder, impaired renal function, impaired urination. Cases of renal failure, oliguria, anuria, electrolyte imbalance, azotemia have been reported. In isolated cases, proteinuria has been noted.
Skin and subcutaneous tissue disorders
Exanthema, erythema, pruritus. Photosensitivity, alopecia, herpes zoster, vasculitis, herpetiform skin eruptions, urticaria, hair loss, impaired wound healing, increased rheumatic nodules, Stevens-Johnson syndrome and epidermal necrolysis (Lyell's syndrome), and tenderness of psoriatic lesions have been observed. Psoriatic lesions may be exacerbated by ultraviolet irradiation during methotrexate therapy. Cases of increased skin and nail pigmentation, acne, skin hemorrhages, ecchymosis, erythema multiforme, and erythematous skin eruptions have been reported. There have been isolated reports of acute paronychia, furuncles, and erythematous skin eruptions.
