Methotrexate
Patients should be clearly informed that the drug should not be used daily, but once a week
.
Patients receiving Methotrexate therapy should be closely monitored to ensure that signs of potential toxicity and adverse reactions are identified and assessed promptly.
Methotrexate should only be prescribed by a medical specialist with sufficient knowledge and experience in antimetabolic therapy.
Due to the possible development of severe or even fatal adverse reactions, patients should be fully informed by their physician about the possible risks and recommended safety measures.
The use of the drug in children under 3 years of age is not recommended due to insufficient data on the effectiveness and safety of treatment in this group of patients.
Recommended examinations and safety measures
Before starting or resuming treatment with methotrexate
a detailed clinical blood test must be performed with a count of blood cells, including determination of the platelet count; biochemical blood test with determination of liver enzyme activity, bilirubin concentration, serum albumin; chest x-ray, kidney function test. If necessary, diagnostic measures are taken to assess the activity of tuberculosis infection and viral hepatitis.
During treatment (at least once a month in the first six months of treatment
,
then - at least once every three months)
it is necessary to carry out the studies described below.
If the dose of methotrexate is increased, the frequency of examinations should be increased.
1. Examination of the oral mucosa and pharynx to assess the condition of the mucous membrane (stomatitis, pharyngitis).
2. Detailed clinical blood test with counting of blood cells, including determination of platelet count. Suppression of hematopoiesis caused by methotrexate can occur suddenly, including when the drug is used in small doses. In any case of a significant decrease in the number of leukocytes or platelets, it is necessary to immediately interrupt treatment with methotrexate and carry out adequate supportive therapy. Patients should be advised to report any signs and symptoms of possible infections.
Patients concomitantly using drugs that inhibit hematopoiesis (for example, leflunomide) should be carefully monitored with monitoring of blood counts, including platelet counts.
3. Liver function tests: Particular attention should be paid to identifying possible toxic effects on the liver. Treatment should not be started or should be interrupted if, during appropriate examinations or liver biopsy, abnormal liver function is detected that was present before the start of treatment or developed during treatment. Typically, disorders that develop during treatment return to normal within two weeks after interruption of methotrexate therapy, after which, at the discretion of the attending physician, treatment can be resumed.
When methotrexate is used for rheumatological indications, there is no obvious need for liver biopsy to monitor liver toxicity.
The advisability of performing a liver biopsy in patients with psoriasis is associated with the issue of the effectiveness of routine chemical analyzes of liver parameters or studies of type III collagen propeptide for identifying and assessing hepatotoxicity. Appropriate assessment should be carried out individually for each case, differentiating patients depending on the presence or absence of risk factors, such as a history of excessive alcohol consumption, persistent elevation of liver enzymes, history of liver disease, hereditary predisposition to liver disease, diabetes mellitus, obesity, history of use of hepatotoxic drugs or drugs that affect hematopoiesis, long-term previous use of methotrexate, or use of methotrexate in a cumulative dose of 1.5 g or more.
Control of “liver” enzymes in the blood serum: in 13 - 20% of patients, a transient 2-3-fold excess of normal transaminase values was reported. In the case of a persistent increase in liver enzyme activity, dose reduction or discontinuation of treatment should be considered.
Due to the possible toxic effects of the drug on the liver, patients during treatment with methotrexate, unless clearly necessary, should refrain from the simultaneous use of other hepatotoxic drugs; Alcohol consumption should also be avoided or at least significantly reduced.
In patients using other hepatotoxic drugs or drugs that inhibit hematopoiesis (for example, leflunomide), the activity of liver enzymes should be carefully monitored.
4. It is necessary to monitor kidney function by performing functional tests and urine analysis.
Since methotrexate is excreted primarily by the kidneys, in the case of insufficient renal function, an increase in the plasma concentration of methotrexate should be expected, which can lead to severe unwanted side effects.
In cases of possible decline in renal function (for example, in elderly patients), control examinations should be performed more frequently. This also applies to cases of simultaneous administration of drugs that affect the elimination of methotrexate, drugs that can lead to kidney damage (for example, NSAIDs), or drugs that can affect hematopoiesis.
Dehydration may also increase the toxicity of methotrexate.
5.Examination of the respiratory system: special attention should be paid to symptoms of deterioration of lung function, if necessary, appropriate tests should be carried out. Symptoms of respiratory system damage (especially dry nonproductive cough), nonspecific pneumonitis that occur during methotrexate therapy may indicate a potentially dangerous disease and require interruption of treatment and immediate thorough examination to make a diagnosis. Acute or chronic interstitial pneumonitis may develop, often accompanied by eosinophilia; associated deaths have been reported. Clinical symptoms of methotrexate-induced lung injury are varied, but typical signs are fever, cough, difficulty breathing, and hypoxemia. An X-ray examination of the chest is necessary to exclude the presence of infiltrates or infection.
In case of lung disease, rapid diagnosis and discontinuation of treatment are necessary.
The development of respiratory diseases caused by the use of methotrexate is possible at any dose of the drug used.
If the dose of methotrexate is increased, the frequency of examinations should be increased!
Methotrexate affects the immune system and, as a result, may impair the response to vaccination and affect the results of immunological tests. Particular caution is required when using the drug in patients with chronic infectious diseases outside of periods of exacerbation ( Herpes zoster
, tuberculosis, hepatitis B or C) due to the possibility of exacerbation of the disease.
Refusal from immunization is required.
Malignant lymphomas may occur in patients using low doses of methotrexate; in these cases, treatment should be discontinued. In the absence of signs of spontaneous regression of lymphoma, cytotoxic therapy is necessary. Rare cases of acute megaloblastic pancytopenia have been reported when folic acid antagonists (such as trimethoprim/sulfamethoxazole) were co-administered with methotrexate.
The use of methotrexate increases the likelihood of developing dermatitis and skin burns under the influence of solar irradiation and UV irradiation.
In patients with psoriasis, an exacerbation of the disease may occur as a result of UV irradiation during treatment with methotrexate (photosensitivity reaction).
In patients with an additional volume of distribution (presence of pleural effusion, ascites), the elimination of methotrexate is slowed down. In such patients, particularly careful monitoring of toxicity, dose reduction, and in some cases, discontinuation of methotrexate treatment is required. Before starting therapy with Methotrexate, effusion from the pleural or abdominal cavity should be drained.
If diarrhea and ulcerative stomatitis occur, methotrexate therapy must be interrupted, since in such cases the development of hemorrhagic enteritis and death as a result of interstitial perforation are possible.
Vitamin supplements and other products containing folic acid, folinic acid or their derivatives may reduce the effectiveness of methotrexate.
In patients with psoriasis, methotrexate should be used only in cases of severe, persistent, disabling forms of the disease that are difficult to treat with other treatment regimens, and only after confirmation of the diagnosis by biopsy and/or after consultation with a dermatologist.
The drug contains less than 1 mmol of sodium per dose, i.e. practically free of sodium, which is important for patients on a sodium diet.
Before prescribing the drug, women need to make sure that they are not pregnant, since methotrexate is embryotoxic and can cause abortions and fetal defects. Methotrexate affects spermatogenesis and oogenesis, which may lead to decreased fertility during treatment. These effects are reversible after discontinuation of therapy.
Patients of childbearing potential of both sexes should use reliable contraception during treatment with methotrexate and for at least 6 months after its completion.
Patients of childbearing potential and their partners should be properly informed of the possible risks to fertility and pregnancy associated with the use of methotrexate.
METHOTREXATE EBEVE solution for injection. 10 mg/ml syringe 0.75 ml
special instructions
Methotrexate can only be prescribed by an oncologist with experience in antineoplastic chemotherapy.
Taking into account the risk of severe toxic reactions, including death, the doctor is obliged to inform the patient in detail about the possible risk and the necessary safety measures. If a significant amount of fluid in the pleural cavities or ascites is detected in a patient, the fluid should be evacuated by drainage before starting methotrexate therapy or the use of methotrexate should be discontinued.
The appearance of symptoms of toxic damage to the digestive system, the earliest of which is stomatitis, requires temporary cessation of methotrexate therapy due to the high risk of developing hemorrhagic enteritis and intestinal perforation with a fatal outcome if therapy is continued.
During treatment with methotrexate, patients should be closely monitored in order to promptly identify signs of possible toxicity and adverse effects. Given the risk of severe or even fatal toxic reactions, patients should be thoroughly informed about possible complications and recommended precautions.
Before starting treatment with methotrexate or when resuming therapy after a break, it is necessary to conduct a clinical blood test with counting the leukocyte formula and platelet count, assess the activity of liver enzymes, the concentration of bilirubin, serum albumin, as well as a chest x-ray and renal function tests. If there are clinical indications, studies are prescribed to exclude tuberculosis and hepatitis.
During treatment with methotrexate (monthly in the first 6 months and at least every 3 months thereafter, with increasing doses it is advisable to increase the frequency of examinations) the following studies are carried out:
1. Examination of the mouth and throat to identify changes in the mucous membranes.
2. Blood test to determine the leukocyte formula and platelet count. Even when used in normal therapeutic doses, methotrexate can suddenly cause depression of the hematopoietic system. If there is a significant decrease in the number of leukocytes or platelets, treatment with methotrexate is stopped immediately and symptomatic supportive therapy is prescribed. Patients should be instructed to immediately report any signs and symptoms indicating an infection to their physician. During concomitant therapy with hematotoxic drugs (for example, leflunomide), it is necessary to carefully monitor the number of leukocytes and platelets in the blood.
3. Functional liver tests. Particular attention should be paid to identifying signs of liver damage. Treatment with methotrexate should not be started or should be suspended if there is any abnormality in the results of liver function tests or liver biopsy. Typically, the indicators return to normal within two weeks, after which treatment can be resumed according to the doctor’s decision. When using methotrexate for rheumatological indications, there is no reason to perform a liver biopsy to monitor the hepatotoxic effect of the drug. When treating patients with psoriasis, it is necessary to evaluate the advisability of performing a liver biopsy before or during treatment with methotrexate, based on current scientific recommendations. This assessment should differentiate between patients without risk factors and patients at risk (for example, patients with a history of alcohol abuse, persistently elevated liver enzymes, a history of liver disease, a family history of hereditary liver disease, patients with diabetes mellitus, obese patients, and previously have taken hepatotoxic drugs or been exposed to hepatotoxic chemicals). In case of persistent increase in liver enzyme activity, it is necessary to reduce the dose or discontinue treatment with methotrexate.
Since methotrexate has a toxic effect on the liver, other hepatotoxic drugs should not be prescribed during treatment with the drug unless clearly necessary. You should also avoid or greatly reduce your alcohol consumption. Liver enzyme activity should be especially closely monitored in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular, leflunomide).
4. Renal function tests and urine examination. Since methotrexate is excreted primarily by the kidneys, patients with impaired renal function may experience increased concentrations of methotrexate in the blood, which may result in severe adverse reactions. It is necessary to carefully monitor the condition of patients who may have impaired renal function (for example, elderly patients). This is especially important in the case of concomitant therapy with drugs that reduce the excretion of methotrexate, have an adverse effect on the kidneys (in particular, NSAIDs) or on the hematopoietic system. Dehydration may also potentiate the toxic effects of methotrexate.
5. Study of the respiratory system. It is necessary to closely monitor symptoms of possible development of pulmonary function disorders and, if necessary, order a pulmonary function test. Pulmonary diseases require rapid diagnosis and discontinuation of methotrexate. The appearance of corresponding symptoms (especially a dry, nonproductive cough) or the development of nonspecific pneumonitis during treatment with methotrexate may indicate a potential danger of lung damage. In such cases, methotrexate is discontinued and the patient is carefully examined. Although the clinical presentation may vary, the typical patient with methotrexate-induced pulmonary disease exhibits fever, cough with dyspnea, hypoxemia, and pulmonary infiltrates on x-ray. In the differential diagnosis, infectious diseases should be excluded. Lung damage can occur during treatment with methotrexate at any dose.
6. Because methotrexate affects the immune system, it may alter the response to vaccinations 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) due to their possible activation. During treatment with methotrexate, vaccination with live vaccines should not be performed.
It is recommended that methotrexate treatment be interrupted one week before surgery and restarted one or two weeks after surgery. When body temperature rises (more than 38°C), the elimination of methotrexate slows down significantly.
Methotrexate may increase the risk of developing neoplasms (mainly lymphomas). Malignant lymphomas can also develop in patients receiving low-dose methotrexate. In such cases, the drug is discontinued. If spontaneous regression of lymphoma is not observed, therapy with cytotoxic drugs is prescribed.
Before starting treatment with Methotrexate-Ebeve, pregnancy must be excluded. Methotrexate has an embryotoxic effect, promotes abortion and the formation of fetal development abnormalities. Methotrexate therapy is accompanied by inhibition of spermatogenesis and oogenesis, which can lead to decreased fertility. After discontinuation of methotrexate therapy, these effects spontaneously regress. During methotrexate therapy and for 6 months after its completion, patients are advised to use contraception. Patients of reproductive age, as well as their partners, should be informed about the possible effects of methotrexate on reproduction and development.
The life-threatening consequences of intrathecal administration of methotrexate are well known, so in each individual case it is necessary to assess the balance of risk and expected benefit from therapy. When the first signs of serious side effects appear, the drug is discontinued.
During high-dose therapy, precipitation of methotrexate or its metabolites in the renal tubules may occur. In such cases, to prevent this complication, it is recommended to carry out infusion therapy and alkalization of urine until a pH of 6.5-7.0 is achieved through oral or intravenous administration of sodium bicarbonate (5 tablets of 625 mg every 3 hours) or acetazolamide (500 mg orally 4 times a day) .
Methotrexate-Ebewe does not contain preservatives, therefore only a single withdrawal of the drug from the container is allowed, and unused solutions must be disposed of. Solutions for infusion with a methotrexate concentration of 0.1 mg/ml or 3 mg/ml, prepared by diluting Methotrexate-Ebewe with 0.9% sodium chloride solution, 5% glucose solution, 10% glucose solution, and lactated Ringer's solution, are physically and chemically stable for at least 24 hours if stored away from light, at 5±3°C or room temperature (20-25°C). From a microbiological point of view, the solution for infusion should be administered immediately after preparation. Methotrexate-Ebeve should not be mixed with other medications in the same infusion bag or vial. When manipulating methotrexate solutions, it is necessary to follow the rules for handling cytotoxic substances. Pregnant healthcare workers should not work with the drug.
Measures should be taken to prevent methotrexate solutions from coming into contact with the skin and mucous membranes. If the drug does get on the skin or mucous membranes, the affected area is immediately washed with plenty of water.
Residues of the drug and all instruments and materials used to prepare Methotrexate-Ebewe infusion solutions should be disposed of in accordance with standard hospital cytotoxic waste disposal procedures, taking into account applicable hazardous waste disposal regulations.
