Nosological classification (ICD-10)
- C34 Malignant neoplasm of bronchus and lung
- C40-C41 Malignant neoplasms of bones and articular cartilage
- C49 Malignant neoplasm of other types of connective and soft tissues
- C50 Malignant neoplasms of the breast
- C56 Malignant neoplasm of the ovary
- C58 Malignant neoplasm of the placenta
- C62 Testicular malignancy
- C69.2 Malignant neoplasm of the retina
- C81 Hodgkin's disease [lymphogranulomatosis]
- C91.0 Acute lymphoblastic leukemia
- L40 Psoriasis
- O01 Hydatidiform skid
Directions for use and doses
Inside, before meals, without chewing, with water; IM, IV (bolus, infusion), IV, intrathecal (subarachnoid). Doses are selected individually, depending on the disease, general condition and blood picture of the patient. Doses above 100 mg/m2 of body surface are administered only intravenously (the solution or concentrate is pre-diluted with a 5% glucose solution to a level of 10 mg (500-1000 ml) and under the protection of calcium folinate. Intrathecal - 0.2-0.5 mg /kg (8-12 mg/m2) every 2-3 days; after the disappearance (or reduction) of symptoms, the interval between injections increases to 1 week, then to 1 month; prophylactically - every 6-8 weeks. For psoriasis, psoriatic arthritis , autoimmune diseases - 10-25 mg orally, weekly (it is also possible to administer intravenously or intramuscularly at the same dose); initial dose - 2.5-5 mg, then the dose is increased to 7.5-25 mg/week (no more than 30 mg/week).
Methotrexate-Ebeve, 1 piece, 1 ml, 10 mg/ml, solution for injection
The drug Methotrexate-Ebeve is a cytotoxic drug, so care must be taken when handling it. The drug should be prescribed by a doctor who has experience in the use of methotrexate and is familiar with its properties and characteristics of action. Before prescribing methotrexate, you should ensure that it is possible to determine the plasma concentration of the drug.
Taking into account the possibility of developing severe toxic reactions, including death, the doctor is obliged to inform the patient in detail about the possible risk and the necessary precautions.
Methotrexate, especially in medium and high doses, should be used only in patients with potentially life-threatening malignancies. Cases of fatal toxicity have been described during drug therapy. Discontinuation of methotrexate does not always lead to complete resolution of adverse events.
The safety and potential benefits of high-dose methotrexate used outside its approved indications have not been established.
During treatment with Methotrexate-Ebeve, patients should be closely monitored in order to promptly identify signs of possible toxicity and adverse effects. When using the drug for non-oncological indications, the patient should pay special attention to the fact that the drug is not taken daily, but once a week.
Before starting treatment with Methotrexate-Ebeve 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” transaminases, the concentration of bilirubin, albumin in the blood plasma, the concentration of uric acid in the blood plasma, and renal function ( blood urea nitrogen, creatinine clearance and/or plasma creatinine), as well as chest x-ray. If there are clinical indications, studies are prescribed to exclude tuberculosis and viral hepatitis.
Prescribing high doses of methotrexate is possible only if the concentration of creatinine in the blood plasma is normal. If an increase in creatinine concentration is noted, the dose of the drug should be reduced; if the creatinine concentration increases by more than 2 mg/dL, the drug should not be used.
Leukopenia and thrombocytopenia, as a rule, develop within 4 to 14 days from the moment of methotrexate administration. Sometimes the development of a second leukopenic phase is observed, developing in a period of 12 to 21 days.
In elderly patients, the development of megaloblastic anemia has been described during prolonged therapy with methotrexate.
During treatment with Methotrexate-Ebeve (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 oral cavity and pharynx 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 suppression of hematopoiesis. In case of a significant decrease in the number of leukocytes or platelets, treatment with Methotrexate-Ebeve is immediately stopped and symptomatic maintenance therapy is prescribed.
Patients should be instructed to immediately report any signs and symptoms indicating an infection to their physician. With concomitant or previous therapy with hematotoxic drugs (for example, leflunomide), radiation therapy, it is necessary to carefully monitor the number of leukocytes and platelets in the blood. If necessary, it is advisable to perform a bone marrow biopsy.
3. Functional liver tests. Long-term use of methotrexate may result in the development of acute hepatitis and chronic hepatotoxicity (liver fibrosis and cirrhosis). Particular attention should be paid to identifying signs of liver damage. Treatment with Methotrxat-Ebeve should not be started or should be suspended if abnormal liver function tests or liver biopsy are detected. During drug therapy, a 2-3-fold transient increase in the activity of “liver” transaminases is possible, usually
asymptomatic. As a rule, this is not a reason to change the treatment regimen; usually the indicators normalize within two weeks, after which treatment can be resumed according to the doctor’s decision. However, if a persistent increase in the activity of “liver” transaminases is detected, it is necessary to reduce the dose or discontinue treatment with Methotrexate-Ebeve. Since the drug Methotrexate-Ebeve has a toxic effect on the liver, during treatment with the drug you should not use other hepatotoxic drugs unless clearly necessary. Ethanol consumption should also be avoided or greatly reduced. The activity of liver enzymes should be especially carefully monitored in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular, leflunomide).
In case of long-term treatment, especially severe forms of psoriasis, including psoriatic arthritis, due to the possible hepatotoxic effect of methotrexate, given that fibrotic and/or cirrhotic changes can develop against the background of normal liver tests, a liver biopsy is necessary in the following cases:
1. In patients without risk factors, liver biopsy is not indicated until the total cumulative dose of 1.0-1.5 g is reached.
2. Against the background of the presence of risk factors such as alcohol abuse, a persistent increase in the activity of “liver” transamises, chronic viral hepatitis, a family history of liver disease, as well as for patients with less significant risk factors such as diabetes mellitus, obesity, anamnestic data on exposure to hepatotoxic drugs/chemicals, a liver biopsy should be performed 2-4 months after the start of treatment. After reaching a total cumulative dose of 1.0-1.5 g, a repeat liver biopsy is recommended.
Liver biopsy is not indicated in elderly patients; in patients with active acute diseases (for example, respiratory system); in patients with contraindications to liver biopsy (for example, unstable hemodynamics, changes in coagulogram parameters); in patients with a poor prognosis for life expectancy.
If liver biopsy reveals only mild changes (grade I, II or IIIa on the Roenigk scale), continued methotrexate therapy is possible, subject to careful monitoring of the patient's condition. The drug should be discontinued if moderate or severe changes are detected (grades IIIb and IV on the Roenigk scale), or if a liver biopsy is refused in a patient who has a persistent increase in the activity of “liver” transaminases. If moderate fibrosis or cirrhosis of the liver is detected, methotrexate should be discontinued; in case of minimal fibrosis, a repeat liver biopsy is recommended after 6 months. Changes such as fatty liver or mild inflammation of the portal veins are a fairly common finding on liver biopsy in patients receiving methotrexate. Although the detection of such changes is usually not a reason to make a decision about the inappropriateness or discontinuation of methotrexate therapy, caution should be exercised when treating such patients.
4. Renal function tests and urine examination. Since Methotrexate-Ebeve is excreted primarily by the kidneys, patients with impaired renal function may experience increased plasma concentrations of methotrexate, 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, non-steroidal anti-inflammatory drugs (NSAIDs)) or on the hematopoietic system. Cases of severe side effects have been described in patients taking NSAIDs during therapy with methotrexate (especially in high doses), including cases of severe suppression of bone marrow hematopoiesis, aplastic anemia, gastrointestinal damage and death.
5. Examination of the respiratory system. It is necessary to closely monitor symptoms of possible development of pulmonary function disorders and, if necessary, prescribe appropriate tests to monitor pulmonary function. The appearance of corresponding symptoms (especially a dry, nonproductive cough) or the development of nonspecific pneumonitis during treatment with Methotrexate-Ebeve may indicate a potential danger of lung damage. In such cases, the drug Methotrexate-Ebeve should be discontinued and the patient should be carefully examined. Although the clinical presentation may vary, typical cases of respiratory symptoms associated with Methotrexate-Ebeve include fever, cough with dyspnea, hypoxemia, and pulmonary infiltrates on x-ray. Lung damage caused by the use of methotrexate can occur regardless of how long the drug has been used or the doses used (cases of lung damage have been described when using methotrexate in low doses, including 7.5 mg/week). In differential diagnosis, the infectious nature of the disease should be excluded. During methotrexate therapy, the development of potentially dangerous (even fatal) opportunistic infections, including Pyeumocystis pneumonia, is possible. If respiratory symptoms develop in a patient receiving methotrexate, pneumonia caused by Pneumocystis carinii should be excluded.
If the dose of the drug is increased, the frequency of examinations should be increased.
Due to the immunosuppressive effect of methotrexate, it is necessary to avoid immunization (unless approved by a physician) during treatment with the drug and for 3 to 12 months after stopping the drug; Family members living with the patient should refuse immunization with oral polio vaccine (the patient should avoid contact with people who have received the polio vaccine or wear a protective mask covering the nose and mouth).
If stomatitis or diarrhea, hemoptysis, melena or the appearance of blood in the stool are observed during methotrexate therapy, the drug must be discontinued immediately due to the high risk of developing potentially fatal complications, such as hemorrhagic enteritis and perforation of the intestinal wall.
Symptoms such as fever, sore throat, flu-like symptoms, ulceration of the oral mucosa, severe general weakness, hemoptysis, hemorrhagic rash may be harbingers of the development of life-threatening complications.
If a patient is diagnosed with conditions leading to the accumulation of a significant amount of fluid in the body cavities (hydrothorax, ascites), given the prolongation of the half-life of the drug in such patients, therapy with Methotrxat-Ebeve should be carried out with caution; before starting therapy with the drug, the fluid should be evacuated by drainage, or stop using the drug.
Particular caution should be observed when treating patients with insulin-dependent diabetes mellitus, since cases of the development of liver cirrhosis without a previous increase in the activity of “liver” transaminases have been described.
Like other cytotoxic drugs, methotrexate can cause the development of tumor lysis syndrome in patients with rapidly growing malignant neoplasms. To prevent the development of this complication, it is necessary to take appropriate supportive therapy measures. The use of methotrexate in combination with radiation therapy may lead to an increased risk of developing soft tissue necrosis or osteonecrosis.
The condition of patients with previous radiation therapy, as well as impaired general condition, should be especially carefully monitored.
Dehydration can also potentiate the toxic effect of Methotrexate-Ebeve, therefore, if conditions develop that can lead to dehydration (severe vomiting, diarrhea), methotrexate therapy should be interrupted until these conditions resolve.
Cases of the development of leukoencephalopathy have been described in patients receiving therapy with high doses of methotrexate, including orally, in combination with calcium folinate (without previous radiation therapy to the head area). When using methotrexate for acute lymphocytic leukemia, pain in the left epigastric region may occur due to the development of an inflammatory process in the spleen capsule against the background of the breakdown of tumor cells.
It is recommended to interrupt treatment with Methotrexate-Ebeve one week before surgery and resume one or two weeks after surgery. Particular caution should be exercised when using methotrexate in patients with active infections. The use of methotrexate in patients with immunodeficiency syndrome is contraindicated.
When body temperature rises (more than 38°C), the elimination of methotrexate slows down significantly.
The drug Methotrexate-Ebeve may increase the risk of developing neoplasms (mainly lymphomas). Malignant lymphomas can also develop in patients receiving Methotrexate-Ebeve in low doses. In such cases, the drug should be discontinued. If spontaneous regression of lymphoma is not observed, therapy with other cytotoxic drugs is prescribed.
Before starting treatment with Methotrexate-Ebeve, pregnancy must be excluded. The drug Methotrexate-Ebeve has an embryotoxic effect, promotes termination of pregnancy and the formation of fetal development abnormalities. Therapy with Methotrexate-Ebeve is accompanied by inhibition of spermatogenesis and oogenesis, which can lead to decreased fertility. After discontinuation of drug therapy, these effects spontaneously regress. During therapy with Methotrexate-Ebeve and for six 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 effect of Methotrexate-Ebeve on reproduction and fetal development. Men of reproductive age should be warned about the risks; fatherhood is not recommended during treatment and for 6 months after discontinuation of the drug. Since irreversible infertility may develop during treatment, men should consider cryopreserving sperm in a bank before starting treatment.
The use of methotrexate increases the likelihood of developing dermatitis and skin burns under the influence of solar and ultraviolet irradiation (UV). Do not expose unprotected skin to sunlight for too long or overuse a UV lamp (photosensitization reaction is possible). In patients with psoriasis, exacerbation of the disease may occur due to UV radiation during treatment with methotrexate.
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 (5 tablets of 625 mg every 3 hours) or intravenous administration of sodium bicarbonate or acetazolamide (500 mg orally four times per day). During therapy with methotrexate, exacerbation of chronic viral hepatitis (reactivation of the hepatitis B or C virus) is possible. Cases of reactivation of the hepatitis B virus after discontinuation of methotrexate have also been described. If it is necessary to prescribe the drug to a patient with a history of viral hepatitis, a thorough clinical and laboratory examination should be performed.
The presence of pleural effusion, ascites, gastrointestinal obstruction, concomitant cisplatin therapy, dehydration, impaired liver function, or decreased urine pH slows down the elimination of methotrexate, which may result in an increase in the concentration of the drug in the blood plasma. It is extremely important to detect the accumulation of the drug in the body during the first 48 hours, since irreversible consequences of drug toxicity may develop. Particular caution should be exercised when using the drug in elderly patients; their condition should be monitored more often than in younger patients to identify early signs of therapy toxicity. When treating pediatric patients, pediatric treatment protocols should be followed.
Pediatric patients with acute lymphoblastic leukemia may develop severe neurotoxicity when using medium (1 g/m2) doses of methotrexate, which most often manifests clinically as a generalized or partial epileptic seizure. The development of leukoencephalopathy and/or microangiopathic calcifications during instrumental studies in such patients has been described.
When using high doses of methotrexate, the development of transient acute neurological symptoms has been described, which can manifest themselves, including changes in behavior, local disturbances in the sensory organs (including short-term blindness) and the motor system, and impaired reflexes. The exact reasons for the development of these adverse reactions are unknown. When using methotrexate at a dose higher than 100 mg/m2, it is necessary to use “rescue therapy” with calcium folinate 42-48 hours after administration of methotrexate. The dose of calcium folinate is determined depending on the size of the dose of methotrexate used and the duration of its infusion. Methotrexate concentrations should be determined after 24, 48 and 72 hours and, if necessary, over a long period of time, to determine the optimal duration of calcium folinate therapy. The use of methotrexate together with red blood cell infusion (within 24 hours) requires careful monitoring of the patient's condition, as the plasma concentration of the drug may increase.
Special precautions when disposing of unused drugs
Residues and all instruments and materials used to prepare Methotrexate-Ebeve infusion solutions must be disposed of in accordance with standard hospital cytotoxic waste disposal procedures, taking into account applicable hazardous waste disposal regulations.
