Instructions for Methotrexate Ebeve tablets 10 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.
Main 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
Immunosuppressants, other immunosuppressants. ATX code L04A X03.
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, has failed.
As a cytostatic drug. Supportive therapy for acute lymphoblastic leukemia.
Contraindication
Hypersensitivity to methotrexate or to any other component of the drug.
Severe, acute or chronic infections (such as tuberculosis or HIV).
Stomatitis, ulcers of the oral cavity or gastrointestinal tract.
Liver disease associated with chronic alcohol abuse and significant liver dysfunction (bilirubin level > 85.5 μmol/L).
Liver failure.
Renal impairment (creatinine clearance < 50 ml/min).
Existing disorders of the hematopoietic system (including bone marrow hypoplasia, leukopenia, thrombocytopenia, or severe anemia).
Immunodeficiency.
Alcohol abuse.
History of blood system disorders.
Pregnancy or breastfeeding.
Vaccination with live vaccines during methotrexate treatment.
Interaction with other medicinal products and other types 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 (NSAIDs)
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 NSAIDs or salicylates. Caution should be exercised when NSAIDs and methotrexate are administered within 24 hours of administration, when plasma levels of methotrexate may increase and lead to increased toxicity.
Animal studies have shown that 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.
Caution is required when NSAIDs and methotrexate are used concomitantly, as serious adverse events such as sudden severe bone marrow suppression, aplastic anemia, and gastrointestinal toxicity, and even individual fatalities, have been reported with concomitant use of NSAIDs.
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
Pharmacokinetic interactions between methotrexate and flucloxacillin (decreased area under the pharmacokinetic curve for methotrexate), anticonvulsants (decreased blood methotrexate concentration) and 5-fluorouracil (increased half-life of 5-fluorouracil) should be considered. After the use of methotrexate together with oxacillin and omeprazole, a significant increase in serum methotrexate concentrations has been observed in isolated cases. Interactions between leflunomide and methotrexate (with development of liver cirrhosis, musculoskeletal infections and decreased platelet count) have been reported. Methotrexate should be used with caution in combination with immunomodulators during orthopedic surgery, when susceptibility to infection is increased. Concomitant use of mercaptopurine and methotrexate may increase the bioavailability of mercaptopurine, presumably by slowing the metabolism of mercaptopurine.
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. Radiation therapy during the period of methotrexate administration may increase the risk of soft tissue and bone necrosis.
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.
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.
Cytarabine
Cases of severe neurotic disorders ranging from headache to paralysis, coma and stroke-like episodes have been observed mainly in children and adolescents during treatment with methotrexate in combination with cytarabine.
When used concomitantly with methotrexate, L-asparaginase blocks the action of the latter.
In isolated cases, corticosteroids have resulted in generalized herpes zoster in patients with herpes zoster or postherpetic neuralgia and concomitant methotrexate.
Concomitant use of mercaptopurine and methotrexate may increase the concentration of mercaptopurine in the blood plasma, presumably due to a slowdown in the metabolism of mercaptopurine.
Therefore, concomitant use may require dose adjustment.
Pyrimethamine or co-trimoxazole used in combination with methotrexate may cause pancytopenia, presumably due to additive inhibition of dihydrofolic acid reductase by these agents and methotrexate (see above for interactions between sulfonamides and methotrexate).
Patients receiving concomitant retinoids, such as etretinate, and methotrexate should be closely monitored for signs of possible increased hepatic toxicity.
Ciprofloxacin
Reduces tubular secretion; caution should be exercised when using this drug with methotrexate.
Amiodarone has caused skin ulcers in patients receiving methotrexate for the treatment of psoriasis.
Skin cancer has been reported in some patients with psoriasis who have received methotrexate treatment in combination with PUVA therapy.
Cholestyramine may increase the non-renal excretion of methotrexate by inhibiting enterohepatic circulation.
Caution should be exercised when using red blood cell mass and methotrexate simultaneously due to increased toxic effects due to prolonged high serum concentrations of methotrexate.
Concomitant administration of levetiracetam and methotrexate has been reported to reduce the clearance of methotrexate, leading to increased/prolonged blood concentrations of this drug to potentially toxic levels. Methotrexate and levetiracetam levels should be carefully monitored in patients receiving concomitant therapy with these two drugs.
Bone marrow suppression and decreased folate levels have been reported with concomitant use of triamterene and methotrexate.
Methotrexate
Penicillins may reduce the excretion of methotrexate, which may lead to a potential increase in toxicity.
Application features
Treatment with methotrexate should be supervised by qualified oncologists, dermatologists or rheumatologists who are experienced in the use of chemotherapeutic agents and familiar with the possible risks of methotrexate use.
Methotrexate should be taken once a week. The prescription should state the day of administration. The patient should be warned about the importance of adhering to the once-a-week dosing schedule.
Toxicity
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 informed in detail about possible complications and recommended precautions.
However, doses exceeding 20 mg/week may be associated with a significant increase in toxicity, particularly bone marrow suppression.
Discontinuation of methotrexate does not always lead to complete regression of adverse effects.
A mandatory condition for methotrexate treatment is the determination of methotrexate levels in blood serum.
In patients with pathological fluid accumulation in body cavities ("third space") such as ascites and pleural effusion, the plasma half-life of methotrexate is longer and may lead to unexpected toxicity.
If possible, fluid accumulation should be removed by puncture before starting methotrexate therapy.
Blood and lymphatic system
Methotrexate may suppress hematopoiesis, thus causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia and/or thrombocytopenia.
The first signs of these life-threatening complications may include: fever, sore throat, mouth ulcers, flu-like symptoms, severe exhaustion, nosebleeds, and skin hemorrhages.
In the treatment of neoplastic diseases, methotrexate therapy should be continued only if the possible benefit outweighs the risk of severe myelosuppression.
In particular, megaloblastic anemia has been observed with prolonged use 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, as well as after irradiation, including bone marrow, the bone marrow reserve decreases. Against the background of methotrexate therapy, this can lead to increased sensitivity of the bone marrow and suppression of its hematopoietic function. During long-term therapy with methotrexate, a bone marrow biopsy is necessary.
When used concomitantly with radiation therapy, methotrexate may increase the risk of soft tissue necrosis.
Musculoskeletal and connective tissue disorders
When undergoing radiotherapy while the patient is receiving methotrexate, there may be an increased risk of soft tissue and bone necrosis.
A transient acute neurological syndrome has been observed during high-dose methotrexate therapy, which may manifest itself, in particular, through behavioral abnormalities, local sensorimotor symptoms (including temporary blindness) and abnormal reflexes. The exact cause has not been established.
Cases of serious neurological side effects ranging from headache to paralysis, coma and stroke episodes have been observed mainly in children and adolescents receiving methotrexate in combination with cytarabine.
Special caution is required when NSAIDs are administered concomitantly with methotrexate. Serious adverse reactions, including fatalities, such as severe and unexpected bone marrow depression, aplastic anemia, and gastrointestinal toxicity, have been reported, especially after high doses of methotrexate.
Liver function
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).
Methotrexate can cause acute hepatitis and chronic, potentially fatal liver toxicity (fibrosis, cirrhosis), but usually only after prolonged use. Persistent elevations of liver enzymes have been frequently observed. These are usually transient and asymptomatic and do not indicate further liver disease.
Methotrexate may cause reactivation of hepatitis B or exacerbation of hepatitis C, which in some cases have been fatal. Cases of reactivation of hepatitis B have been reported after discontinuation of methotrexate therapy. Therefore, patients with a history of hepatitis B or C should undergo clinical and laboratory examinations to determine the appropriateness of methotrexate therapy.
Particular caution is required when treating patients with inactive, chronic infections (such as herpes zoster, tuberculosis) due to their possible activation.
Particular caution should be exercised when treating patients with insulin-dependent diabetes mellitus with methotrexate, since during treatment with methotrexate, in some cases, cirrhosis of the liver may develop without a temporary increase in transaminase levels.
Kidney function
Due to the delayed elimination of methotrexate, patients with impaired renal function should be treated with caution and at low doses (see section "Method of administration and dosage").
During treatment with methotrexate, renal function may deteriorate with an increase in certain laboratory parameters (serum creatinine, urea and uric acid levels), which may lead to acute renal failure with oliguria/anuria. This is probably due to precipitation of methotrexate and its metabolites in the renal tubules.
Conditions leading to dehydration, such as vomiting, diarrhea, stomatitis, may increase toxicity due to increased levels of the active substance. In these cases, supportive therapy should be provided and methotrexate treatment should be suspended until symptoms resolve.
Gastrointestinal disorders
In the event of ulcerative stomatitis or diarrhea, hematemesis, black stools or blood in the stool, therapy should be discontinued, as hemorrhagic enteritis and fatalities due to intestinal perforation may occur.
Nervous system
Chronic leukoencephalopathy has also been observed in patients who were re-treated with high-dose methotrexate with calcium folinate without prior cranial radiotherapy. Cases of leukoencephalopathy have also been reported in patients receiving oral methotrexate.
Lung function
Special caution is required when treating patients with impaired pulmonary function.
Pulmonary complications, pleural effusion, alveolitis or pneumonitis with symptoms such as dry, non-productive cough, fever, malaise, cough, chest pain, dyspnoea, hypoxaemia and infiltrates on chest X-ray or non-specific pneumonia occurring during methotrexate treatment may indicate a potentially dangerous and possibly fatal lesion. Lung biopsies have shown variable findings (e.g. interstitial oedema, mononuclear infiltrates or necrotising granuloma). If these complications are suspected, methotrexate treatment should be discontinued immediately and a careful examination should be carried out to exclude infections, tumours, etc. Methotrexate-induced lung diseases may occur acutely at any time during therapy; they are not always fully reversible and have been observed with a dose of 7.5 mg/week.
Acute or chronic interstitial pneumonitis, often associated with blood eosinophilia, may occur, and fatalities have been reported. Symptoms typically include dyspnea, cough (especially dry, nonproductive cough), chest pain, and fever; patients should be monitored for these at each follow-up visit.
Patients should be informed of the risk of pneumonitis and advised to seek immediate medical attention if persistent cough or shortness of breath occurs.
In addition, pulmonary alveolar hemorrhage has been reported in patients receiving methotrexate in rheumatologic and related indications. This phenomenon may also be associated with vasculitis and other comorbidities. Rapid investigations should be considered in suspected pulmonary alveolar hemorrhage to confirm the diagnosis.
Opportunistic infections, including pneumocystis pneumonia, may occur with methotrexate and may be fatal. If a patient presents with pulmonary symptoms, the possibility of pneumocystis 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.
Immune system
Particular caution is required when treating patients with progressive infections with methotrexate. Methotrexate is contraindicated in patients with immunodeficiency syndromes that are evident or confirmed by laboratory tests. In addition, methotrexate should be used with caution in patients with infections such as varicella and herpes zoster.
Neoplasm
In patients with rapidly growing tumors, methotrexate, like other cytostatic drugs, can cause tumor lysis syndrome. Appropriate supportive drug therapy can prevent or reduce the manifestations of these complications.
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.
Folic acid supplements
Folic acid deficiency may increase the toxicity of methotrexate.
Taking folic acid or folinic acid may reduce the toxicity of methotrexate (gastrointestinal symptoms, stomatitis, alopecia, and increased liver enzyme activity).
It is recommended to check vitamin B12 levels before taking medications containing folic acid, as folate use may mask vitamin B12 deficiency, especially in people over 50 years of age.
Methotrexate should be administered with great caution (unless absolutely necessary) to patients with significant liver dysfunction (present or history, especially caused by alcohol abuse).
Fertility and reproductive function
Fertility
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.
Teratogenicity – risk of reproductive toxicity
Methotrexate causes embryotoxicity, miscarriages and intrauterine abnormalities in humans. Therefore, the physician should warn women of childbearing potential about the possible effects on reproductive function, miscarriages and congenital malformations. Before starting treatment with methotrexate, it is necessary to confirm the absence of pregnancy. Women of childbearing potential should use effective contraceptive measures during treatment and for six months after the end of methotrexate therapy.
It is recommended that male patients use reliable contraception during treatment and for at least 6 months after the end of methotrexate therapy. Since methotrexate can cause serious and potentially irreversible impairment of spermatogenesis, men should consider cryopreservation of sperm before starting therapy.
Recommended studies and precautions
Patients taking methotrexate should be carefully monitored for immediate detection of toxic effects.
Before starting methotrexate treatment or when continuing therapy after a break, it is necessary to perform a blood test with the determination of the leukocyte formula and platelet count, liver enzyme levels ((ALT, AST, LF)), bilirubin, serum albumin and kidney function indicators, as well as a chest X-ray examination. If clinically indicated, tests should be prescribed to exclude tuberculosis and hepatitis (A, B, C).
Depending on the dosage or treatment protocol used, regular monitoring of serum methotrexate levels is necessary, particularly during and after high-dose methotrexate therapy. Adjustment of the methotrexate dose and maintenance therapy can significantly reduce the toxicity and potential mortality associated with methotrexate therapy. Patients with pleural effusion, ascites, gastrointestinal obstruction, previous cisplatin therapy, dehydration, decreased urine pH, or renal impairment are at increased risk of increased or only slowly decreased methotrexate levels. These patients should be closely monitored.
Some patients may also experience delayed methotrexate elimination for reasons not listed above. It is important to monitor methotrexate levels for 48 hours after administration, as any increase in methotrexate levels may lead to irreversible toxicity.
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.
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 of infection to their physician. 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.
Usually, the indicators normalize within two weeks, after which treatment can be continued at the doctor's discretion.
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 with previous exposure to hepatotoxic drugs or chemicals, those with long-term treatment with methotrexate, 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 13-20% of patients. Such elevations usually do not require a change in dosage regimen. However, persistent elevations of liver enzymes and/or decreases in serum albumin may indicate severe hepatotoxicity.
In case of persistent elevation of liver enzymes, a reduction in the dose of methotrexate or its withdrawal may be necessary. In any case, methotrexate should be discontinued in patients with persistent liver dysfunction. Enzyme assays do not reliably predict the development of liver damage that can be detected by morphological means, i.e. even with normal transaminase levels, the presence of fibrosis can only be determined by histological analysis, or, more rarely, the presence of cirrhosis. In case of persistent elevation of liver enzymes, a reduction in the dose or additional interruptions in the course of therapy should be considered.
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. It is recommended to monitor creatinine, urea and electrolyte levels on days 2 and 3 to detect any possible impairment of methotrexate excretion at an early stage. 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 NSAIDs) 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.
If there are signs of impaired renal function (e.g. severe adverse effects of previous methotrexate therapy or urinary obstruction), creatinine clearance should be determined. If creatinine levels increase, the dose should be reduced. Methotrexate therapy should not be administered if serum creatinine levels exceed 2 mg/dl. Patients with severe renal impairment (e.g. elderly patients) should be monitored frequently. This is particularly true if additional medicinal products are being taken that may adversely affect the elimination of methotrexate, cause renal damage (e.g. non-steroidal anti-inflammatory drugs) or may lead to impaired hematopoiesis.
In the presence of risk factors such as renal impairment, including mild renal impairment, concomitant use of nonsteroidal anti-inflammatory drugs is not recommended.
It is important to check for potential elevated levels of the active substance within 48 hours after taking the drug, otherwise irreversible methotrexate toxicity may occur.
Respiratory system research
