The drug Methotrexate-Ebweze is a cytotoxic drug, so care must be taken when handling it. The drug should be appointed by a doctor who has experience with methotrexate and is familiar with its properties and the characteristics of the action. Before the appointment of methotrexate, you should make sure that you can determine the plasma concentration of the drug.
Taking into account the possibility of developing severe toxic reactions, including fatalities, the doctor must inform the patient in detail about the possible risk and necessary precautions. Methotrexate, especially in moderate to high doses, should be used only in patients with potentially life-threatening malignant tumors. Cases of fatal manifestations of toxicity against the background of drug therapy are described. The abolition of methotrexate does not always lead to a complete resolution of undesirable phenomena.
The safety and potential benefits of using high doses of methotrexate outside the approved indications are not established.
During treatment with the drug Methotrexate-Ebwe, patients should be carefully monitored in order to identify signs of possible toxic effects and adverse effects in a timely manner. When using the drug for non-oncological indications, it is necessary to pay special attention to the patient that the drug is not taken every day, but once a week.
Before starting treatment with Methotrexate-Ebwe or with the resumption of therapy after a break, it is necessary to conduct a clinical blood test with counting the leukocyte formula and the number of platelets, assess the activity of "hepatic" transaminases, the concentration of bilirubin, albumin of blood plasma,the concentration of uric acid in the blood plasma, the function of the kidneys (urea nitrogen, creatinine clearance and / or plasma creatinine), as well as radiographic examination of the chest. In the presence of clinical indications, studies are prescribed to exclude tuberculosis and viral hepatitis.
The appointment of high doses of methotrexate is possible only in the case of a normal concentration of creatinine in the blood plasma. If there is an increase in creatinine concentration, the dose of the drug should be reduced, if the creatinine concentration is increased by more than 2 mg / dL, the drug should not be used.
Leukopenia and thrombocytopenia, as a rule, develop in a period of 4 to 14 days after the administration of methotrexate. Sometimes there is a development of the second leukopenic phase, which develops in a period of 12 to 21 days.
In elderly patients, the development of megaloblastic anemia is described against the background of prolonged therapy with methotrexate.
In the process of treatment with the drug Methotrexate-Ebwe (monthly in the first 6 months and at least every 3 months thereafter, with increasing doses it is advisable to increase the frequency of the examinations), the following studies are carried out:
1.Examination of the oral cavity and pharynx to detect changes in the mucous membranes.
2. A blood test with the definition of the leukocyte formula and the number of platelets. Even when used in conventional therapeutic doses methotrexate can suddenly cause oppression of hematopoiesis. In the case of a significant decrease in the number of white blood cells or platelets, treatment with Methotrexate-Ebene immediately stop and prescribe symptomatic maintenance therapy.
Patients should be instructed to immediately inform the doctor of any signs and symptoms that indicate the development of the infection. With concomitant or previously conducted therapy with hematotoxic drugs (eg leflunomide), radiation therapy should be closely monitored for the number of leukocytes and platelets in the blood. If necessary, it is advisable to perform a bone marrow biopsy.
3. Functional liver tests.
Against the background of prolonged use of methotrexate, the development of acute hepatitis and the phenomena of chronic hepatotoxicity (fibrosis and cirrhosis of the liver) is possible. Particular attention should be given to identifying signs of liver damage.Treatment with Methotrexate-Ebwee should not be initiated or should be discontinued if abnormalities in the results of functional liver tests or liver biopsy are detected. Against the background of drug therapy, a 2-3-fold transient increase in the activity of "liver" transaminases, as a rule, is asymptomatic. As a rule, this is not an excuse for changing the treatment regimen, usually the indicators are normalized within two weeks, after which the treatment can be resumed by the doctor's decision. However, in case of a persistent increase in the activity of "hepatic" transaminases, a dose reduction or withdrawal of treatment with the drug Methotrexate-Ebweze is necessary. Since the drug Methotrexate-Ebwee has a toxic effect on the liver, during the treatment with the drug should not without the obvious need to use other hepatotoxic drugs. Also, ethanol consumption should be avoided or greatly reduced. Particularly closely monitor the activity of "hepatic" enzymes followed in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular, leflunomide).
In the case of prolonged treatment, especially severe forms of psoriasis, including psoriatic arthritis, due to possible hepatotoxic effects of methotrexate, given that fibrotic and / or cirrhotic changes can develop against a background of normal hepatic samples, liver biopsy is necessary in the following cases:
1. In patients without risk factors, a liver biopsy is not shown before a total cumulative dose of 1.0-1.5 g is achieved.
2. Against the background of the presence of such risk factors as alcohol abuse, persistent increase in the activity of "liver" transaminases, chronic viral hepatitis, a family history of liver disease, and also for patients with less significant risk factors, such as diabetes, obesity, anamnestic data exposure to hepatotoxic drugs / chemicals, liver biopsy should be performed 2 to 4 months after the start of treatment. After reaching a total cumulative dose of 1.0-1.5 g, repeated liver biopsy is recommended.
A 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 an unfavorable prognosis for life expectancy.
If only small changes (degree I, II or IIIa on the Roenigk scale) are detected with liver biopsy, methotrexate therapy may be continued, provided that the patient's condition is carefully monitored. The drug should be withdrawn in case of moderate or severe changes (IIIb and IV degree on the Roenigk scale), or in case of refusal of a liver biopsy of a patient who has a persistent increase in the activity of "liver" transaminases. If mild fibrosis or liver cirrhosis is detected methotrexate should be abolished, in the case of minimal fibrosis, repeated liver biopsy is recommended after 6 months. Changes such as fatty liver disease or mild inflammation of portal veins are a fairly common finding in liver biopsy in patients receiving methotrexate. Although the identification of such changes, as a rule,is not the reason for deciding whether it is inexpedient or canceling methotrexate therapy, caution should be exercised in the treatment of such patients.
4. Functional renal tests and urinalysis. Since the drug Methotrexate-Ebewe was excreted mainly by the kidneys, in patients with impaired renal function there may be an increase in the concentration of methotrexate in the blood plasma, which can lead to serious adverse reactions. It is necessary to carefully monitor the condition of patients who may have impaired renal function (eg, elderly patients). This is especially important in the case of concomitant therapy with drugs that reduce the excretion of methotrexate, which have an adverse effect on the kidneys (in particular, nonsteroidal anti-inflammatory drugs (NSAIDs)) or on the hematopoiesis system. The cases of severe adverse effects in patients taking NSAIDs against methotrexate therapy (especially in high doses) are described, including cases of development of severe oppression of bone marrow hematopoiesis, aplastic anemia, gastrointestinal lesions and death.
5. Examination of the respiratory system.
It is necessary to closely monitor the symptoms of possible development of pulmonary function disorders and, if necessary, assign appropriate studies to monitor lung function. The appearance of the corresponding symptomatology (especially dry, unproductive cough) during the treatment with Methotrexate-Ebweze or the development of nonspecific pneumonitis may indicate a potential lung injury. In such cases, Megotrexate-Ebweve should be withdrawn and a thorough examination of the patient should be carried out. Although the clinical picture may vary, in typical cases where the symptoms from the respiratory system are caused by the use of the drug Methotrexate-Ebwee, there is an increase in body temperature, cough with shortness of breath, hypoxemia, and pulmonary infiltrates on X-rays. Lung damage caused by the use of methotrexate may occur regardless of the prescription of the drug, the dosages used (cases of lung injury with low-dose methotrexate, including 7.5 mg / week) have been described. In differential diagnosis, the infectious nature of the disease should be excluded.On the background of methotrexate therapy, the development of potentially dangerous (up to fatal outcome) opportunistic infections, including pneumocis pneumonia, is possible. In the case of development of symptoms from the respiratory system, the patient receiving methotrexate, pneumonia due to Pneumocystis carinii should be excluded.
In the case of increasing the dose of the drug, the frequency of the examinations should be increased.
Due to the immunosuppressive effect of methotrexate, it is necessary to refuse immunization (if it is not approved by the doctor) during treatment with the drug and in the interval from 3 to 12 months after completion of the drug intake; family members of the patient living with it should opt out of immunization with oral polio vaccine (the patient should avoid contact with people who have received a polio vaccine, or wear a face mask covering the nose and mouth).
If the symptoms of stomatitis or diarrhea, hemoptysis, melena or the appearance of blood impurities in the stool are noted against the background of methotrexate therapy, the drug should be immediately discontinued because of the high risk of 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, pronounced general weakness, hemoptysis, hemorrhagic rash may be harbingers of life-threatening complications.
If the patient experiences conditions that lead to the accumulation of a significant amount of fluid in the body cavities (hydrothorax, ascites), taking into account the elongation of the half-life of the drug in such patients, therapy with Methotrexate-Ebweave should be carried out with caution, before starting therapy with the drug, the liquid should be evacuated by drainage, or refuse to use the drug.
Particular care should be taken when treating patients with insulin-dependent diabetes mellitus, since cases of liver cirrhosis have been reported without a previous increase in the activity of "liver" transaminases.
Like other cytotoxic drugs, methotrexate can cause the development of tumor lysis syndrome in patients with intensively growing malignancies. To prevent the development of this complication, appropriate measures of maintenance therapy should be taken.The use of methotrexate in combination with radiotherapy can lead to an increased risk of soft tissue necrosis or osteonecrosis.
It is necessary to closely monitor the condition of patients with previous radiation therapy, as well as the disturbed general condition.
Dehydration can also potentiate the toxic effect of the drug Methotrexate-Ebwe, therefore, in the development of conditions that can lead to the development of dehydration (severe vomiting, diarrhea), methotrexate therapy should be discontinued until these conditions are resolved.
The cases of development of leukoencephalopathy in patients receiving high-dose methotrexate therapy, including oral, in combination with calcium folinate (without previous radiation therapy on the head area) are described. When methotrexate is used for acute lymphatic leukemia, pain in the left epigastric region can occur, due to the development of the inflammatory process in the spleen capsule against the background of the disintegration of tumor cells.
It is recommended to discontinue treatment with Methotrexate-Ebweave one week before surgery and resume one or two weeks after surgery.Special care should be taken with methotrexate in patients with active infections. The use of methotrexate in patients with immunodeficiency syndrome is contraindicated.
With an increase in body temperature (more than 38 ° C), the elimination of methotrexate significantly slows down.
The drug Methotrexate-Ebwee can increase the risk of developing neoplasms (mainly lymphomas). Malignant lymphomas can also develop in patients receiving the drug Methotrexate-Ebweve in low doses. In such cases, the drug should be discontinued. If spontaneous regression of lymphoma is not observed, prescribe therapy with other cytotoxic drugs.
Before starting treatment with the drug Methotrexate-Ebeva, pregnancy should be excluded. The drug Methotrexate-Ebwee has an embryotoxic effect, promotes the termination of pregnancy and the formation of fetal development abnormalities. Therapy with the drug Methotrexate-Ebwee is accompanied by oppression of spermatogenesis and ovogenesis, which can lead to a decrease in fertility. After the abolition of drug therapy, these effects spontaneously regress.During the period of therapy with the drug Methotrexate-Ebwe, and for six months after its completion, patients are advised to use contraceptive measures. Patients of reproductive age, as well as their partners, should be informed about the possible effect of the drug Methotrexate-Ebene on reproductive and fetal development. Men of reproductive age should be warned about the risks, paternity is not recommended during treatment and within 6 months after the drug is discontinued. Since in the process of treatment possible the development of irreversible infertility, men should consider the possibility of cryo-preservation of sperm in the bank before the treatment.
The use of methotrexate increases the likelihood of dermatitis and skin burns caused by sun and ultraviolet radiation (UV). Do not expose unprotected skin to prolonged sun exposure or abuse the UV lamp (a photosensitization reaction is possible). In patients with psoriasis, an exacerbation of the disease may occur on the background of UV irradiation during treatment with methotrexate.
When therapy with high doses, precipitation of methotrexate or its metabolites in the renal tubules may occur. In such cases, as a prophylaxis of this complication, it is recommended to perform infusion therapy and alkalinization of urine to achieve a pH of 6.5-7.0 by oral (5 tablets of 625 mg every 3 hours) or intravenous sodium bicarbonate or acetazolamide (500 mg orally four times per day). On the background of methotrexate therapy, exacerbation of chronic viral hepatitis (reactivation of the hepatitis B or C virus) is possible. Also, cases of reactivation of the hepatitis B virus after the withdrawal of methotrexate are described. If it is necessary to prescribe the drug to a patient with an anamnesis of viral hepatitis, a thorough clinical and laboratory examination should be carried out.
The presence of pleural effusion, ascites, abnormalities of the gastrointestinal tract, concomitant cisplatin therapy, dehydration, impaired liver function or a decrease in urine pH slows the excretion of methotrexate, resulting in an increase in the concentration of the drug in the blood plasma. It is extremely important to identify cumulation of the drug in the body during the first 48 hours, since it is possible to develop irreversible effects of toxicity of the drug.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 toxicity of therapy. Pediatric treatment protocols should be used in the treatment of pediatric patients.
In pediatric patients with acute lymphoblastic leukemia, a marked neurotoxicity may develop with the use of averages (1 g /m2 ) doses of methotrexate, which is most often manifested clinically as a generalized or partial epileptic seizure. The development of leukoencephalopathy and / or microangiopathic calcification in the course of instrumental studies in such patients is described. When high doses of methotrexate are used, the development of transient acute neurologic symptoms is described, which can be manifested, among other things, by behavioral changes, local impaired sensory organs (including short-term blindness) and motor system, reflex reflexes. The exact reasons for the development of these unwanted reactions are unknown.When methotrexate is used at a dose of more than 100 mg / m, the use of calcium salvage therapy for folate must be taken 42-48 hours after the administration of methotrexate. The dose of calcium folinata is determined depending on the amount of applied dose of methotrexate, the duration of its infusion. The concentration of methotrexate should be determined after 24, 48 and 72 hours and, if necessary, for a long time, to determine the optimal duration of calcium folate therapy. The use of methotrexate together with the infusion of erythrocyte mass (within 24 hours) requires careful monitoring of the patient's condition, since it is possible to increase the plasma concentration of the drug.