METHOTREXATE EBEVE solution for injection. 10 mg/ml vial. 5 ml
Directions for use and doses
Methotrexate is included in many chemotherapy treatment regimens, and therefore, when choosing the route of administration, regimen and doses in each individual case, one should be guided by data from specialized literature.
The drug Megotrexate-Ebewe in the dosage form of an injection solution can be administered intramuscularly, subcutaneously, intravenously, intraarterially or intrathecally. Doses of the drug over 100 mg/m2 are administered only intravenously! The solution is pre-diluted with 5% dextrose solution. When using high doses of the drug (above 100 mg/m2), subsequent administration of calcium folinate is mandatory.
Methotrexate for the treatment of rheumatic diseases or skin diseases should only be used once a week! Improper use of methotrexate can lead to serious adverse effects, including death. The following dosage regimens are used:
Trophoblastic tumors:
15-30 mg intramuscularly, daily for 5 days at intervals of one or more weeks (depending on signs of toxicity). Or 50 mg once every 5 days with an interval of at least 1 month. Courses of treatment are usually repeated 3 to 5 times up to a total dose of 300-400 mg.
Solid tumors:
in combination with other antitumor drugs
drugs 30-40 mg/m2 intravenously once a week. Leukemia and lymphoma:
200-500 mg/m2 by intravenous infusion once every 2-4 weeks.
Neuroleukemia:
12 mg/m2 intrathecally over 15-30 seconds 1 or 2 times a week.
When treating children, the dose is selected depending on the age of the child: children under 1 year of age are prescribed 6 mg, children under 1 year of age - 8 mg, children under 2 years of age - 10 mg, children aged 3 years and older - 12 mg. Before administration, a volume of cerebrospinal fluid approximately equal to the volume of the drug to be administered should be removed. For intrathecal administration, methotrexate is diluted to a concentration of 1 mg/ml in 0.9% isotonic sodium chloride solution. It should be administered intrathecally with caution. Exceeding the recommended dose for intrathecal administration significantly increases the risk of severe toxicity.
Caution: Do not administer calcium folinate intrathecally!
Mycosis fungoides:
intramuscularly 50 mg once a week or 25 mg 2 times a week per day for several weeks or months. Dose reduction or discontinuation of the drug is determined by the patient's response and hematological parameters.
Dermatomyositis:
adults 7.5-15 mg per week, children 2.5-7.5 mg per week. Subsequently, the dose is reduced until the lowest effective dose is reached and used for a long time, for months, in combination with a maintenance dose of glucocorticosteroids.
Systemic lupus erythematosus:
adults 15 mg per week, children 7.5-10 mg/m2. The course of treatment is 6-8 weeks, then a maintenance dose is used for many months.
Psoriasis and psoriatic arthritis:
a week before the start of treatment, it is recommended to administer a test dose of 5-10 mg of methotrexate parenterally to identify an intolerance reaction.
The recommended starting dose is 7.5 mg methotrexate once a week intramuscularly, intravenously or subcutaneously. The dose should be gradually increased, with the maximum dose not exceeding 30 mg of methotrexate per week. Response to treatment usually occurs 2-6 weeks after starting the drug. When the optimal clinical effect is achieved, dose reduction begins until the lowest effective dose is achieved.
Rheumatoid arthritis:
The initial dose is usually 7.5 mg once a week, which is administered simultaneously intravenously, intramuscularly or subcutaneously. To achieve optimal effect, the weekly dose can be gradually increased (2.5 mg per week), but it should not exceed 20 mg. When optimal clinical effect is achieved (usually 4-8 weeks after initiation of therapy), dose reduction should begin to achieve the lowest effective maintenance dose.
The optimal duration of therapy has not been established; in each specific case, the duration of therapy is determined by the doctor. Juvenile chronic arthritis:
in children under 16 years of age at a dose of 10-20 mg/m2 once a week. Typically, an effective dose is 10-15 mg/m2 per week. Initially, the drug is used in half the dose. If well tolerated, use the full dose after a week. In children and adolescents, if parenteral administration of the drug is necessary, due to the fact that the available data on the safety of intravenous administration are limited, the subcutaneous or intramuscular route of administration should be used. Due to limited data on the effectiveness and safety of methotrexate in children under 3 years of age, it is not recommended to use the drug in this group of patients. When using methotrexate in children as immunosuppressive therapy (psoriasis, rheumatoid arthritis, juvenile chronic arthritis, dermatomyositis and systemic lupus erythematosus), the benefit/risk ratio of use should be carefully considered.
Method of use of the syringe (pre-filled): Subcutaneous.
The injection needle included in the package is intended only for subcutaneous administration of Methotrexate-Ebeve.
The pre-filled syringe is equipped with a special automatic needle protection system.
Select a site to administer the drug. For subcutaneous application, choose a location where you can reach a 2-3 cm fold of skin, usually in the abdomen or thighs, as shown in the picture. If someone helps you, it is possible to give an injection in the forearm. If the intended injection site is the abdominal area, then it is necessary to retreat at least 3 fingers' width from the navel. It is recommended to alternate sides (left, right) of injections, as well as choose different locations on the thighs or abdomen.
Do not inject the drug subcutaneously near scars, bruises, red or swollen areas, or close to the groin. To minimize bruising, it is recommended to avoid injecting into skin where a network of small blood vessels is visible on the surface. Remove the inner package containing the prefilled syringe and needle. Open the inner package by pulling the cut corner. Remove the syringe.
Remove the gray rubber cap from the syringe without touching the opened inside of the syringe. Place the syringe back into the inner packaging without worrying about the yellow solution running out. Make sure that the integrity of the security label is not damaged. Remove the cap, attach the needle without removing the protective cover from it, and secure the needle to the syringe. Before using the syringe, the intended injection site should be pre-disinfected.
Pull the cap (strictly at a right angle) to remove it. Do not touch the protective cover of the needle.
Using two fingers, form a fold of skin and quickly insert the needle completely into the skin (at an angle of about 90 degrees) until the protective mechanism is completely retracted. Slowly inject the contents of the syringe under the skin. Gently pull out the needle, after which it will automatically retract into the syringe.
If you notice blood at the injection site after removing the needle, apply a cotton swab to the injection site until the blood or medication is absorbed. Minor bleeding or leakage of the drug will soon stop. If necessary, apply a bandage. Do not rub the injection site.
If the skin at the injection site turns yellow, do not worry, within one or two days the drug will be absorbed and the skin color will return to normal. This may occur due to improper subcutaneous injection or insufficient needle length. Patients with impaired renal function require dose adjustment depending on creatinine clearance (with a creatinine clearance of 30-50 ml/min, the dose is reduced by 50%; with a creatinine clearance of less than 30 ml/min, the use of methotrexate is contraindicated).
In patients with impaired liver function, Methotrexate-Ebeve is used with caution. Methotrexate should not be used if the plasma bilirubin concentration is more than 5 mg/dL (85.5 µmol/L). Elderly patients (over 65 years of age) may need to reduce the dose of methotrexate because liver and kidney function deteriorates with age, as well as a decrease in folate levels in the body.
Methotrexate-Ebeve Solution, syringe, 1 piece, 2 ml, 20 mg, for injection
Side effect
According to WHO, adverse effects are classified according to their frequency as follows: very common (≥ .1/10), common (≥ .1/100 to less than 1/10), uncommon (≥ .1/1000 to less 1/100), rare (from ≥ .1/10,000 to less than 1/1000), very rare (less than 1/10,000). frequency unknown - based on available data, it was not possible to determine the frequency of occurrence. From the hematopoietic system: often - suppression of bone marrow function (leukopenia, thrombocytopenia, anemia). infrequently - pancytopenia. very rarely - severe progressive depression of bone marrow function, agranulocytosis. frequency unknown - megaloblastic anemia. From the central nervous system: often - drowsiness, headache, fatigue. infrequently - depression, confusion, mood changes. rarely - when using methotrexate in low doses - transient slight impairment of cognitive functions, unusual sensations in the cranial area. very rarely - pain, myasthenia gravis or paresthesia in the extremities, perversion of taste (metallic taste in the mouth), epileptic seizures, meningism, paralysis, insomnia. From the senses: often - visual impairment. uncommon - eye irritation. rarely - conjunctivitis. From the respiratory system: often - chronic interstitial pneumonitis (symptoms indicating potentially serious damage to the lungs with interstitial pneumonitis: dry, unproductive cough, shortening of breathing, increased body temperature). infrequently - alveolitis, pleural effusion. rarely - pulmonary fibrosis, Pneumocystis pneumonia, bronchial asthma. very rarely - pleural pain and thickening of the pleura (when treated with methotrexate in high doses), acute pulmonary edema. From the digestive system: very often - stomatitis, nausea, inflammation of the mucous membranes, loss of appetite, dyspepsia, anorexia, a significant increase in the activity of liver transaminases. often - diarrhea, ulceration of the oral mucosa. infrequently - enteritis, vomiting, liver cirrhosis, liver fibrosis, liver steatosis. rarely - ulceration of the gastrointestinal mucosa. very rarely - malabsorption syndrome, toxic megacolon. From the urinary system: infrequently - inflammation and ulceration of the bladder, impaired renal function, urinary disorders. rarely - renal failure, oliguria, anuria, electrolyte imbalance. From the skin: often - exanthema, erythema, itching. uncommon - photosensitivity, alopecia, herpes zoster, vasculitis, skin rashes herpetiformis, urticaria. rarely - increased pigmentation. very rarely - Stevens-Johnson syndrome, epidermal necrolysis (Lyell's syndrome). When exposed to ultraviolet radiation, increased psoriatic skin lesions, increased pigmentation of nails, acute paronychia, furunculosis and hidradenitis. From the musculoskeletal system: infrequently - arthralgia, myalgia, osteoporosis. From the cardiovascular system: often - vasculitis, bleeding of various locations. infrequently - effusion into the pericardial cavity. rarely - cardiac tamponade, nosebleeds. From the immune system: very often - decreased resistance to infections, pharyngitis. infrequently - hypogammaglobulinemia. rarely - sepsis. very rarely - anaphylactic reactions, increased number of rheumatoid nodules. From the reproductive system: infrequently - ulceration and inflammation of the vagina. very rarely - loss of libido, impotence, oligospermia, menstrual disorders, vaginal discharge. Other: often - chills, malaise, fever, necrosis. rarely - deterioration of wound healing. With intramuscular injection - a burning sensation or tissue damage (formation of a sterile abscess, destruction of adipose tissue) at the injection site. very rarely - benign, malignant and nonspecific neoplasms (including cysts and polyps), lymphomas, which in some cases regress after discontinuation of methotrexate. frequency unknown - diabetes, other metabolic disorders, sudden death. Adverse reactions with intrathecal methotrexate Acute: chemical arachnoiditis, manifested by headache, back or shoulder pain, stiffness of the muscles in the back of the neck and fever. Subacute: paresis (usually transient), paraplegia, impaired cerebellar function. Chronic: leukoencephalopathy, manifested by irritability, confusion, ataxia, muscle plasticity, sometimes convulsions, dementia, drowsiness, coma, in rare cases with death. When combining radiation therapy to the cranial area and intrathecal administration of methotrexate, the incidence of leukoencephalopathy increases.
Methotrexate-Ebewe
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 reactions. 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 taken not daily, but once a week. Because of the potential for serious (and potentially fatal) toxic reactions, methotrexate should only be used in patients with severe, persistent and disabling psoriasis that is not responsive to other treatments. Patients receiving methotrexate treatment should be closely monitored so that signs of possible toxic effects or adverse reactions can be identified and assessed with minimal delay. 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. Before combination therapy, including treatment with methotrexate in high doses, the number of leukocytes and platelets should be higher than the minimum values specified in the treatment protocol (white blood cell count from 1000 to 1500 / μl, platelet count from 50,000 to 10,0000 / μl). The lowest levels of circulating leukocytes, neutrophils and platelets are usually observed between 5 and 13 days after IV methotrexate administration (with a recovery period of 14 to 28 days). The number of leukocytes and neutrophils can sometimes decrease twice: the first time after 4-7 days, and the second time the minimum values are observed after 12-21 days, followed by recovery. In elderly patients, the development of megaloblastic anemia has been described during prolonged therapy with methotrexate. During treatment with Methotrexate-Ebeve (monthly for the first 6 months and at least every 3 months thereafter, as doses increase, 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. During treatment with methotrexate, you should constantly (with a frequency of daily to once a week) monitor your general blood count, including leukocyte count and platelet count. 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 Methotrexate-Ebeve should not be started or should be suspended if abnormal results of liver function tests or liver biopsy are detected. During drug therapy, 13–20% of patients experience a 2–3-fold transient increase in the activity of “liver” transaminases, most often 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, liver biopsy is necessary in the following cases: 1. In patients without factors risk until the total cumulative dose of 1.0-1.5 g is reached, liver biopsy is not indicated. 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, 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 may be 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 the 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. Monitoring of creatinine, urea and electrolyte levels is recommended on days 2 and 3, especially during treatment with high-dose methotrexate, for early diagnosis of imminent abnormal excretion of methotrexate. If there are signs of renal impairment (for example, severe adverse reactions to previous methotrexate therapy or urinary tract obstruction), creatinine clearance should be determined. Treatment with high-dose methotrexate should only be carried out if the creatinine level is within the standard range. If creatinine levels are elevated, the dose should be reduced; Treatment with methotrexate should not be carried out if serum creatinine concentrations are above 2 mg/dl. At borderline levels of renal function (for example, in elderly patients), monitoring should be careful. 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 adverse reactions 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. During methotrexate infusion, urine output and pH should also be monitored. To reduce renal toxicity and to prevent renal failure during treatment with high-dose methotrexate, adequate intravenous fluid support and urine alkalinization (pH ≥7) are absolutely necessary. Treatment with methotrexate may worsen renal function with increases in certain laboratory parameters (creatinine, urea, serum uric acid), which may lead to acute renal failure with oliguria/anuria. This is likely due to precipitation of methotrexate and its metabolites in the renal tubules. 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 caused by Methotrexate-Ebeve include fever, general malaise, chest pain, cough with shortness of breath, hypoxemia, and pulmonary infiltrates on x-ray. Lung biopsy showed various changes (eg, interstitial edema, mononuclear infiltrates, or granuloma without caseating necrosis). 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 addition, intra-alveolar hemorrhage has been reported with the use of methotrexate for rheumatologic and related indications. This adverse reaction may also be associated with vasculitis and other concomitant diseases. If intra-alveolar hemorrhage is suspected, urgent examination should be considered to confirm the diagnosis. 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 Pneumocystis pneumonia, is possible. If respiratory symptoms develop in a patient receiving methotrexate, pneumonia caused by Pneumocystis jirovecii 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). Also, due to the possible effect of methotrexate on the immune system, the results of assessing the effectiveness of vaccines and tests (immunological procedures for recording an immune response) may be distorted. 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 Methotrexate-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. With an increase in body temperature (more than 38 ° C), the elimination of methotrexate is significantly slowed down. The drug Metotrexate Ebev can increase the risk of neoplasms (mainly lymph). It was not often reported about the development of malignant lymphomas in patients receiving the drug Metotrex-Ebeva in low doses. In such cases, the drug should be canceled. If the lymphoma is not observed spontaneous regression, appropriate therapy is prescribed. The increased frequency of lymph occurred during treatment with methotrexate could not be determined in a later study. The use of high dose for the treatment of neoplasms outside approved indications is studied; Therapeutic benefit is not proved. Prior to the start of treatment with Metretexate Ebev, pregnancy must be excluded. The drug Metotrexate Ebev has an embryotoxic effect, helps terminate pregnancy and the formation of anomalies of fetal development. Therapy with Metotrexate Ebev is accompanied by inhibition of spermatogenesis and ovogenes, which can lead to a decrease in fertility. After canceling therapy with the drug, these effects spontaneously regress. During the period of therapy with the drug Metotrex-Ebeva and for six months after its completion, patients are recommended to use contraceptive measures. Patients of reproductive age should be informed, as well as their partners about the possible effect of the drug of Metotorsat-Ebeva on reproductivity and the development of the fetus. Men of reproductive age should be warned of existing risks, paternity is not recommended during treatment and within 6 months after the cancellation of the drug. Since in the process of treatment it is possible to develop irreversible infertility, men should consider the possibility of cryoponservation of sperm before starting treatment. The occurrence of severe, sometimes deadly skin reactions, such as Stevens-Johnson and toxic epidermal necrolysis (Layella syndrome), after a single or prolonged use of methotrexate. Against the background of the use of methotrexate, the likelihood of developing dermatitis and burns of the skin under the influence of solar and ultraviolet irradiation (UV) increases. Unprotected skin should not be subjected to too long solar irradiation or abuse a UV-exposure lamp (a response of photosensitization is possible). In patients with psoriasis, an exacerbation of the disease is possible against the background of UV exposure during treatment with methotrexate. With high doses, the precipitation of methotrexate or its metabolites in renal tubules is possible. In such cases, it is recommended that infusion therapy and snatching urine are recommended as the prevention of this complication to 6.5-7.0 pH with the oral (5 tablets of 625 mg every 3 hours) or intravenous introduction of sodium bicarbonate or acetazolamide (500 mg orally four times per day). Against the background of therapy of methotrexate, an exacerbation of chronic viral hepatitis (reactivation of the hepatitis B or C) virus is possible with a possible fatal outcome. Cases of reactivation of the hepatitis B virus after the abolition of methotrexate are also 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 carried out. Based on the results of these examinations, treatment with methotrexate can be recognized as inappropriate for some patients. In addition, in the presence of such inactive chronic infections as governing herpes or tuberculosis, caution should be observed due to their possible activation. The presence of pleural effusion, ascite, gastrointestinal tract disorders, accompanying therapy with cisplatin, dehydration, impaired liver function or pH reduction of urine slows down the excretion of methotrexate, as a result of which an increase in the concentration of the drug in blood plasma is possible. It is extremely important to identify the cumulation of the drug in the body during the first 48 hours, since it is possible to develop irreversible consequences of the toxicity of the drug. Particular caution should be taken when using the drug in elderly patients, their condition should be controlled more often than in patients of a younger age, to detect early signs of therapy toxicity. In the treatment of patients in children's age, pediatric medical protocols should be guided. In pediatric patients with acute lymphoblastic leukemia, the development of pronounced neurotoxicity is possible against the background of the use of medium (1 g/m2) doses of methotrexate, which is most often manifested clinically as a generalized or partial epileptic seizure. The development of leakoencephalopathy and/or microangiopathic calcinates during instrumental studies in such patients is described. When using high doses of methotrexate, the development of transient acute neurological symptoms is described, which can manifest, including changes in behavior, local impaired senses (including short -term blindness) and the motor system, violation of reflexes. The exact reasons for the development of these undesirable reactions are unknown. When using methotrexate at a dose above 100 mg/m2, it is necessary to use the “salvation therapy” of calcium with a folinate 42-48 hours after the introduction of methotrexate. The dose of calcium folinate is determined depending on the value of the applied dose of methotrexate, the duration of its infusion. The concentration of methotrexate must be determined after 24, 48 and 72 hours and, if necessary, for a long time, to determine the optimal duration of calcium treatment with folinate. The use of methotrexate together with infusion of the red blood cell (within 24 hours) requires careful monitoring of the patient's condition, since it is possible to increase the plasma concentration of the drug.
