Instructions Methotrexate Ebeve solution for injection 50 mg vial 5 ml No. 1
Composition
active ingredient: methotrexate;
1 ml of solution contains 10 mg of methotrexate;
excipients: sodium chloride, sodium hydroxide, water for injections.
Dosage form
Solution for injection.
Main physicochemical properties: clear yellow solution.
Pharmacotherapeutic group
Antineoplastic agents. Antimetabolites. Structural analogues of folic acid.
ATX code L01B A01.
Pharmacological properties
Pharmacodynamics.
Methotrexate is a folic acid antagonist and belongs to the class of cytotoxic agents of the antimetabolite class. It acts during the S phase of the cell cycle and competitively inhibits the enzyme dihydrofolate reductase, thus preventing the reduction of dihydrofolate to tetrahydrofolate, which is necessary 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 the rate of 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 has not been definitively established; it may affect immune function.
In psoriasis, the rate of replication of epithelial cells in the skin is much higher than normal. This difference in proliferation rate is the basis for the use of methotrexate to control the psoriatic process.
Pharmacokinetics.
Approximately 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 widely (3-17 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
The drug Methotrexate "Ebeve", solution for injection 10 mg/ml is used to treat adults and children aged 3 years and older.
The drug Methotrexate "Ebeve" in low (single dose < 100 mg/m2 body surface area [BSA]) and medium-high doses (single dose 100‒1000 mg/m2 [BSA]) is intended for the treatment of the following oncological diseases:
malignant trophoblastic tumors (benign gestational trophoblastic disease, choriocarcinoma):
as monochemotherapy for low-risk women;
in combination with other cytostatic agents for women at high risk;
breast cancer:
in combination with other cytostatic agents for adjuvant therapy after tumor resection or mastectomy and for palliative treatment at a late stage;
Head and neck cancer:
for palliative monotherapy at the stage of metastasis or in case of relapse;
non-Hodgkin lymphoma:
for the treatment of intermediate or high-grade non-Hodgkin lymphoma in combination with other cytostatic agents;
acute lymphoblastic leukemia:
as part of complex therapy protocols in combination with other cytostatic agents, for maintenance therapy during the period of remission and for the prevention and treatment of carcinomatous meningitis.
The drug Methotrexate "Ebeve" in high doses (single dose >1000 mg/m2 BSA) is intended for the treatment of the following oncological diseases:
non-Hodgkin lymphoma, which is mainly localized in the central nervous system, before radiation therapy;
acute lymphoblastic leukemia;
prevention and therapy of carcinomatous meningitis.
Also, Methotrexate "Ebeve", solution for injection 10 mg/ml is indicated for the following diseases:
Treatment of rheumatoid arthritis.
Treatment of psoriasis, especially widespread psoriasis, widespread pustular psoriasis, psoriatic arthritis or psoriatic nail lesions.
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 mucous membrane of the oral cavity or digestive tract.
Liver disease due to chronic alcohol abuse or other chronic liver diseases (see section "Method of administration and dosage").
Hepatic failure (See section "Method of administration and dosage").
Existing disorders of the hematopoietic system (including bone marrow hypoplasia, leukopenia, thrombocytopenia, or severe anemia).
Immunodeficiency.
Alcohol abuse.
History of blood system disorders.
Pregnancy, unless absolutely necessary, or breastfeeding (see section "Use during pregnancy or breastfeeding").
Vaccination with live vaccines during methotrexate treatment.
Special safety precautions
When handling the drug, it is necessary to follow the rules for handling cytotoxic substances. It is necessary to take measures (use protective gloves and glasses) to prevent methotrexate solutions from getting on the skin and mucous membranes. If the drug does get on the skin or mucous membranes, the affected area should be washed immediately with plenty of water. To eliminate the temporary burning sensation, you can use an emollient hand cream. If there is a threat of absorption of a large amount of methotrexate, regardless of the absorption route, treatment with leucovorin is necessary. Pregnant medical workers should not work with the drug.
Residual drug and all instruments and materials used for preparation of infusion solution and administration of the drug should be disposed of in accordance with an approved procedure for the disposal of cytotoxic waste.
In the case of outpatient use, do not pour the drug residues into the sewer or throw them away with other waste.
Interaction with other medicinal products and other types of interactions
The use of nitrous oxide ("laughing gas") may enhance the effect of methotrexate on the metabolic transformation of folic acid, resulting in severe and unpredictable bone marrow suppression, stomatitis, and neurotoxicity with intrathecal administration. To reduce the intensity of such phenomena, calcium folinate administration is necessary; concomitant use of methotrexate should be avoided.
L-asparaginase has an antagonistic effect on methotrexate when administered concomitantly.
Disease-modifying antirheumatic drugs (DMARDs) and nonsteroidal anti-inflammatory drugs (NSAIDs) should not be used before or during treatment with high-dose methotrexate. Concomitant use of certain NSAIDs and high-dose methotrexate has resulted in elevated and persistent serum levels of methotrexate, sometimes resulting in fatal outcomes as a result of severe hematological (bone marrow depression and aplastic anemia) and gastrointestinal toxicity.
Studies have shown that NSAIDs, including salicylic acid, have been shown to reduce the tubular secretion of methotrexate and may increase toxicity due to increased methotrexate levels. Therefore, NSAIDs and methotrexate at low doses should be used with caution. In the presence of risk factors such as impaired renal function (even in cases of borderline values), concomitant use of NSAIDs is not recommended.
Increased toxicity of methotrexate has not been studied when used concomitantly with HMARDs (e.g. gold salts, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine), therefore the occurrence of toxic effects should not be excluded.
Proton pump inhibitors. Concomitant use of methotrexate and proton pump inhibitors (e.g. omeprazole, pantoprazole or lansoprazole) may result in a reduction or delay in the renal clearance of methotrexate and a corresponding indirect increase in plasma concentrations. Concomitant use of proton pump inhibitors with high doses of methotrexate should be avoided if possible. These drugs should be used with caution in patients with renal insufficiency.
The risk of hepatotoxicity of methotrexate increases with regular alcohol consumption or concomitant use of other hepatotoxic drugs, such as azathioprine, leflunomide, retinoids, and sulfasalazine. Patients taking other hepatotoxic drugs should be carefully monitored. Alcohol consumption should be avoided during methotrexate treatment.
By displacing methotrexate from serum albumin binding, drugs such as amidopyrine derivatives, para-aminobenzoic acid, barbiturates, doxorubicin, oral contraceptives, phenylbutazone, phenytoin, probenecid, salicylates, sulfonamides, tetracyclines, tranquilizers, sulfonylureas, penicillins, pristinamycin and chloramphenicol may increase the bioavailability of methotrexate (indirect dose increase), resulting in increased methotrexate toxicity. Therefore, careful monitoring of patients is also necessary when these drugs are used concomitantly with methotrexate.
Drugs such as para-aminobenzoic acid, NSAIDs, probenecid, salicylates, sulfonamides and other weak organic acids may cause a decrease in tubular secretion with a subsequent increase in methotrexate toxicity, especially at low doses. Therefore, careful monitoring of patients is also necessary when these drugs are used concomitantly with methotrexate.
Ciprofloxacin also reduces tubular secretion in the kidneys, so the use of methotrexate with this antibiotic should be under close supervision.
Oral antibiotics: Oral antibiotics (including tetracyclines, chloramphenicol, and nonabsorbable broad-spectrum antibiotics) may affect enterohepatic circulation by inhibiting the intestinal microflora or suppressing bacterial metabolism.
Drugs that adversely affect the bone marrow. In case of concomitant therapy with drugs that may cause side effects on the bone marrow (e.g. aminopyridine derivatives, chloramphenicol, phenytoin, pyrimethamine, sulfonamides, trimethoprim/sulfamethoxazole, cytostatics), the possibility of developing more pronounced hematological disorders (in isolated cases - acute pancytopenia) should be taken into account.
Drugs that cause folate deficiency. With concomitant therapy with drugs that cause folate deficiency (e.g. sulfonamides, trimethoprim/sulfamethoxazole), the toxic effect of methotrexate may be enhanced. Particular caution is also required when treating patients with an existing folic acid deficiency in the body. Conversely, concomitant administration of folic acid, as well as vitamin preparations containing folic acid or its derivatives, may reduce the effectiveness of methotrexate therapy.
Although the effect of methotrexate may be potentiated when combined 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.
Methotrexate may reduce theophylline clearance. Therefore, theophylline levels should be monitored during concomitant use of methotrexate.
Beverages containing caffeine and theophylline. During treatment with methotrexate, excessive consumption of beverages containing caffeine (coffee, sweet drinks containing caffeine, black tea) and theophylline should be avoided, as the effectiveness of methotrexate may be reduced due to the interaction between methotrexate and methylxanthines at adenosine receptors.
Concomitant use of methotrexate and leflunomide may increase the risk of pancytopenia.
Concomitant use of methotrexate and mercaptopurine may lead to increased plasma levels of mercaptopurine. Therefore, such concomitant use may require dosage adjustment.
Bone marrow suppression and decreased folate concentrations have been reported with concomitant use of triamterene and methotrexate.
When radiotherapy is performed while the patient is receiving methotrexate, the risk of soft tissue and bone necrosis may be increased. Cholestyramine may enhance the extrarenal excretion of methotrexate by interfering with the enterohepatic circulation.
Special patient monitoring is required when red blood cell concentrate is administered concomitantly. Patients who receive blood transfusions within 24 hours of methotrexate infusions may experience increased toxicity due to prolonged high serum concentrations of methotrexate.
In isolated cases, corticosteroids have caused disseminated zoster in patients with herpes zoster or postherpetic neuralgia when used concomitantly with methotrexate.
High doses of calcium folinate may negatively affect the efficacy of intrathecally administered methotrexate.
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.
Pyrimethamine or co-trimoxazole in combination with methotrexate may cause pancytopenia, presumably due to additive inhibition of dihydrofolic acid reductase by these agents and methotrexate.
The risk of hepatotoxic effects of methotrexate increases in case of alcohol abuse or concomitant use of other hepatotoxic drugs.
When treating patients with methotrexate who are taking hematotoxic drugs (e.g. metamizole), the risk of developing severe hematotoxic effects of methotrexate increases.
It is necessary to take into account the pharmacokinetic interaction between methotrexate and anticonvulsants (the concentration of methotrexate in the blood decreases) and 5-fluorouracil (the half-life of 5-fluorouracil increases).
When combined with other antirheumatic drugs (e.g. gold salts, penicillamine, hydroxychloroquine, sulfasalazine, azathioprine, cyclosporine), the toxic effect of methotrexate is usually not enhanced.
In case of simultaneous use with other cytostatics, the clearance of methotrexate may decrease.
A decrease in phenytoin plasma levels has been observed in patients with acute lymphoblastic leukemia during induction therapy, which, in addition to prednisone, vincristine, and 6-mercaptopurine, also included high-dose methotrexate with calcium folinate as maintenance therapy.
Concomitant therapy with intravenous cytarabine and intrathecal methotrexate may increase the risk of severe neurological side effects such as headache, paralysis, coma, and stroke episodes.
Increased nephrotoxicity may occur when high doses of methotrexate are combined with potentially nephrotoxic drugs (such as cisplatin).
Since methotrexate affects the immune system, it may alter the response to vaccination and affect the results of tests (immunological procedures to assess the immune response). Vaccination with live vaccines should not be carried out during treatment with methotrexate.
Methotrexate may enhance the effects of oral coumarin-type anticoagulants (acenocoumarol, phenprocoumon), leading to an increase in prothrombin time due to a decrease in the breakdown of coumarin derivatives.
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 closely monitored in patients receiving concomitant therapy with these two drugs.
Amoxicillin
Penicillins may reduce the excretion of methotrexate, which may lead to a potential increase in toxicity.
Application features
Treatment with methotrexate should be carried out under the supervision of an experienced oncologist.
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.
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 or pleural effusion, the plasma half-life of methotrexate is increased.
Pleural effusion or ascites should be drained before starting methotrexate therapy. If pleural effusion or ascites is present, drainage should be performed before starting methotrexate therapy. If this is not possible, methotrexate therapy should not be administered.
Blood and lymphatic system
Methotrexate may suppress hematopoiesis, causing anemia, aplastic anemia, pancytopenia, leukopenia, neutropenia, and/or thrombocytopenia.
In the treatment of neoplastic diseases, methotrexate therapy should be continued only if the potential benefit outweighs the risk of severe myelosuppression. The first signs of these life-threatening complications may be: fever, sore throat, oral mucosal ulcers, flu-like symptoms, severe exhaustion, nasal and skin bleeding. Megaloblastic anemia has been observed in elderly patients during long-term therapy.
Methotrexate should not be used in the presence of peptic ulcer disease or ulcerative colitis (see section "Contraindications").
After treatment with drugs with cumulative myelotoxicity or after radiation therapy that has affected bone marrow function, bone marrow dysfunction should be considered, namely increased sensitivity of the bone marrow to methotrexate therapy with increased suppression of the hematopoietic system. During long-term therapy with methotrexate, a bone marrow biopsy is necessary.
In the case of acute lymphoblastic leukemia, methotrexate can cause pain in the left upper abdomen (inflammation of the splenic capsule due to destruction of leukemia cells).
Liver function
Since methotrexate is toxic to the liver, other hepatotoxic drugs should not be prescribed during treatment with the drug unless clearly necessary. Alcohol consumption should also be avoided or significantly limited.
Methotrexate can cause acute hepatitis and chronic, potentially fatal, liver toxicity (fibrosis, cirrhosis), but usually only after prolonged use. Persistent elevations of liver enzymes are common, which are usually transient and asymptomatic and do not indicate further liver disease.
Methotrexate may cause reactivation of hepatitis B infection or its complications, or exacerbation of hepatitis C, with fatal outcome in some cases. Some cases of hepatitis B reactivation have been observed after discontinuation of methotrexate. 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, hepatitis B or C) due to their possible activation.
Particular caution is required when treating patients with insulin-dependent diabetes mellitus, as there are reports of isolated cases of liver cirrhosis during methotrexate therapy without a prior increase in transaminase activity.
Due to reduced excretion of methotrexate, patients with impaired renal function should be treated with increased caution and at low doses (see section "Method of administration and dosage").
During treatment with methotrexate, renal function may deteriorate, accompanied by 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/or its metabolites in the renal tubules.
Disorders leading to dehydration, such as vomiting, diarrhea, stomatitis, may potentiate the toxic effects of methotrexate due to increased levels of the active substance. In these cases, supportive therapy should be provided and methotrexate treatment should be discontinued until symptoms resolve.
Gastrointestinal disorders
Disorders that cause dehydration, such as vomiting, diarrhea, stomatitis, may increase the toxic effect of methotrexate due to an increase in its concentration. In such cases, further therapy should be temporarily interrupted until such symptoms resolve. It is very important to identify patients with a possible increase in methotrexate concentration within 48 hours after administration, since otherwise the toxic effect of methotrexate may be irreversible. Diarrhea and ulcerative stomatitis may be manifestations of toxic effects and require temporary discontinuation of further therapy, otherwise hemorrhagic enteritis and fatal outcome due to perforation of the intestinal wall are possible.
In case of vomiting with blood, black stools or the presence of blood in the stools, further therapy should be discontinued.
Nervous system
Leukoencephalopathy has been observed following intravenous methotrexate administration in patients undergoing cranial radiotherapy.
Chronic leukoencephalopathy has also been observed in patients who were re-treated with high-dose methotrexate with calcium folinate without prior cranial radiotherapy.
There is evidence that the combined use of cranial irradiation simultaneously with intrathecal administration of methotrexate increases the incidence of leukoencephalopathy (see also section "Adverse reactions").
After intrathecal administration of methotrexate, patients should be monitored for signs of neurotoxicity (nervous system disorders, such as meningitis, transient or permanent paralysis, or encephalopathy).
Cases of severe neurological side effects ranging from headache to paralysis, coma and stroke have been observed in adolescents and young patients receiving methotrexate in combination with cytarabine.
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.
Lung function
Methotrexate should be used with great caution in 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 treatment with methotrexate may indicate a potentially dangerous and possibly fatal condition. Pulmonary disorders caused by methotrexate are not always completely reversible. Pulmonary disorders caused by methotrexate, such as pneumonitis, may occur suddenly and at any stage of therapy, are not always completely reversible and have been observed with methotrexate at all therapeutic doses (including the low dose of 7.5 mg/week). In addition, pulmonary alveolar hemorrhage has been reported in patients receiving methotrexate in rheumatological and similar indications. This phenomenon may also be associated with vasculitis and other concomitant diseases. Rapid test results should be considered when pulmonary alveolar hemorrhage is suspected to confirm the diagnosis.
Toxic effect on the skin.
Severe, sometimes fatal, skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis (Lyell's syndrome) have been reported after single or prolonged use of methotrexate.
Psoriatic lesions may worsen after UV irradiation with concomitant methotrexate therapy. During methotrexate therapy, there is a risk of radiation dermatitis and sunburn (relapse of side effects of radiotherapy).
Immune system
Opportunistic infections, including plasma cell pneumonia, which can be fatal, may occur during methotrexate therapy. Plasma cell pneumonia should be considered in patients presenting with symptoms of pulmonary dysfunction.
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 that cause 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.
Methotrexate may increase the risk of developing neoplasms (mainly lymphomas). Malignant lymphomas may also develop in patients receiving methotrexate at low doses. In such cases, the drug should be discontinued. If spontaneous regression of the lymphoma is not observed, therapy with cytotoxic drugs should be prescribed.
Musculoskeletal and connective tissue disorders
In the case of radiation therapy while taking methotrexate, the risk of soft tissue or bone necrosis increases.
Folic acid preparations
Folic acid deficiency may increase the toxicity of methotrexate (see section "Interaction with other medicinal products and other types of interactions").
Vitamin preparations and other products containing folic acid, folinic acid or their derivatives 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.
Recommended research 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, bilirubin, serum albumin, hepatitis (A, B, C) analysis, as well as a chest X-ray and renal function tests. If clinically indicated, prescribe tests to exclude tuberculosis and hepatitis. In case of suspected lung disease (e.g. interstitial pneumonia), lung function should be checked, especially if the results of previous tests are available.
Depending on the dosage or treatment protocol used, regular monitoring of serum methotrexate levels is necessary, particularly during and after high-dose methotrexate therapy (see also section “Overdose”). Adjustment of the methotrexate dose and protective therapy can significantly reduce the toxicity and potential mortality associated with methotrexate therapy. Patients with pleural effusion, ascites, dehydration, decreased urine pH, gastrointestinal obstruction, previous cisplatin therapy, or patients with impaired renal function are at increased risk of increased or slow decline in serum 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 increased levels may lead to irreversible methotrexate toxicity.
When methotrexate is administered at a dose of more than 100 mg/m2 of BBT, protective calcium folinate therapy should be administered. Depending on the methotrexate dose and the duration of infusion, different doses of calcium folinate should be used to protect normal cells from the toxic effects of methotrexate.
Adequate calcium folinate prophylaxis should be initiated within 42–48 hours after methotrexate administration. Methotrexate levels should therefore be monitored at least 24, 48 and 72 hours later and, if necessary, continued to be monitored to determine the duration of calcium folinate prophylaxis.
During methotrexate therapy, a complete blood count with differential blood count, including platelet and leukocyte counts, should be performed (daily or weekly).
Before starting combination therapy, including high-dose methotrexate, the white blood cell and platelet counts should be above the minimum values specified in the relevant treatment protocol (white blood cells: 1000 to 1500/μl, platelets: 50,000 to 100,000/μl).
The maximum decrease in circulating leukocytes, neutrophils, and platelets is usually observed 5–13 days after intravenous methotrexate administration (the rebound phenomenon is observed after 14–28 days). Sometimes two maximum decreases in leukocytes and neutrophils are recorded, the first after 4–7 days, and the second after 12–21 days, with a subsequent rebound phenomenon.
Renal and liver function tests, as well as urinalysis, should be performed regularly.
Enzyme activity tests do not reliably predict morphological changes due to hepatotoxic effects, i.e., even with normal transaminase levels, the presence of fibrosis can only be determined by histological analysis, or, less commonly, the presence of cirrhosis.
Creatinine, urea and electrolyte levels should be monitored, especially when using high doses of methotrexate, on days 2 and 3 to detect any possible impairment of methotrexate excretion at an early stage.
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. High-dose methotrexate treatment should only be initiated if creatinine levels are within the normal range.
If creatinine levels increase, the dose should be reduced. In the event of an increase in serum creatinine to a level of more than 2 mg/ml, further methotrexate therapy should not be carried out. It is necessary to carefully monitor the condition of patients in whom renal function may be impaired (e.g. elderly patients). This is especially 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.
During methotrexate infusion, urine output and urine pH should be monitored. To reduce renal toxicity and prevent the development of renal failure during treatment with high doses of methotrexate, sufficient intravenous fluids should be administered and urine alkalinized (urine pH ≥ 7).
The mouth and throat should be examined daily to detect changes in the mucous membranes.
Careful monitoring of the patient's condition should be carried out in case of previous intensive radiotherapy, deterioration of the general condition, as well as in adolescents or elderly patients.
More frequent monitoring should be performed at the beginning of treatment, during dose adjustments, or in cases of increased risk of increased methotrexate levels (e.g. dehydration, renal impairment, additional concomitant medications or an increase in the number of concomitant medications such as nonsteroidal anti-inflammatory drugs).
Use in children
Methotrexate should be used with caution in children and adolescents and appropriate treatment protocols specifically designed for children should be used. Severe neurotoxicity may occur in children with acute lymphoblastic leukemia after treatment with moderately high doses (1 g/m2 BBT) of methotrexate. This is often seen as a generalized or focal seizure. In symptomatic patients, leukoencephalopathy and/or microangiopathic calcifications have usually been observed on diagnostic imaging.
Use in elderly patients
Special care is required when treating elderly patients. Patients should be monitored regularly for early signs of toxicity. The clinical pharmacology of methotrexate in elderly patients has not been fully studied. The dose of methotrexate should be adjusted depending on the state of renal and hepatic function. The dose should be reduced taking into account advanced age. Partially modified protocols have been developed for elderly patients (aged 55 years and older), e.g. for the treatment of
