Medicine methotrexate use. Overdose of Methotrexate. Pharmacological group of the substance Methotrexate

Methotrexate is a cytostatic (substances that inhibit the division of body cells, including cancer cells), and has a pronounced immunosuppressive effect.

Indications

Methotrexate injections are prescribed for the following pathologies:

• chorionepithelioma of the uterus;
• trophoblast disease;
• acute lymphoblastic leukemia;
• malignant neoplasms CNS, retina;
• oncology individual parts body (chest, head, neck, genitals) and internal organs;
• malignant granuloma;
• non-Hodgkin's lymphoma;
• osteogenic and soft tissue sarcoma;
• malignant tumor skeleton (Ewing's sarcoma);
• mycosis fungoides (severe stage);
• psoriasis and rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, which occur in severe form (in cases of ineffectiveness of other types of treatment).

Directions for use and doses

Methotrexate injections are given into a muscle, vein, artery and spinal canal.

The dosage in each specific case is selected individually depending on the type of disease, its severity, the condition of the hematopoietic organs, and the chemotherapy regimen.

In case of trophoblast disease, the drug is prescribed intramuscularly for 5 days at a dosage of 15-30 mg, after which take a break for at least 1 week (its duration depends on the severity of toxicity).

The medication can be prescribed 1 injection every 5 days at a dosage of 50 mg with a break of at least 1 month. The course of therapy is usually repeated 3-5 times, up to a total dosage of 300 to 400 mg.

For solid tumors, Methotrexate is prescribed intravenously as a bolus once every 7 days in parallel with other antitumor agents at a dosage of 30 to 40 mg/m2.

With the development of lymphomas and leukemia, the drug is administered in the form intravenous infusions once every 14-28 days, the dosage can vary from 200 to 500 mg/m2.

At malignant diseases CNS is injected under meninges 12 mg/m2 for 15-30 seconds 1-2 times every 7 days.

In pediatrics, the dosage is selected based on the child’s age:

Before giving an injection of Methotrexate, it is necessary to remove a volume of cerebrospinal fluid almost equal to the volume of the drug that is about to be administered.

During development rheumatoid arthritis The drug is started to be administered at a dose of 2.5 mg, with an interval of 12 hours, a course of 3 injections per week. The weekly dosage is gradually increased (to a maximum of 20 mg); as soon as the patient’s condition stabilizes, it begins to be gradually reduced to the minimum effective dosage. The duration of therapy is individual.

For psoriasis, injections are given once a week either intramuscularly or intravenously. The weekly dose can be 10-25 mg. In most cases, the dosage is slowly increased until the optimal dose is reached. clinical picture, after which the dose is gradually reduced to the minimum effective.

In case of mycosis fungoides development, the medicine is administered intramuscularly at a dose of 50 mg per week, the drug can be administered 1-2 times. The duration of therapy can vary from several weeks to several months. The dose is reduced or the injections are canceled completely depending on the patient’s reaction and blood picture.

Contraindications

Methotrexate injections are not prescribed if the patient has:

• individual intolerance;
• alcoholism;
• severe liver and renal failure;
• decrease in leukocytes, platelets, hemoglobin;
• leukemia accompanied by hemorrhage;
• parallel administration of methotrexate in a weekly dosage of at least 15 mg with drugs based on acetylsalicylic acid;
• organ ulcers digestive system in the acute stage;
• concomitant immunotherapy with live vaccines.

The drug should be used with caution in patients with the following pathologies:

• infectious diseases of various etiologies(viral, bacterial, fungal, etc.);
• recently transferred surgical intervention;
• gout;
• stones in the kidneys;
• children's and elderly age;
• chemotherapy and radiotherapy;
• asthenia;
• increased acidity urine (pH<7);
• liver and kidney diseases;
• endocrine disorders (such as diabetes and excess weight);
• dehydration;
• accumulation of large amounts of fluid in the abdominal cavity (ascites);
• erosive and ulcerative diseases of the gastrointestinal tract in remission;
• contact with patients who have a viral infection (herpes, herpes zoster, measles), since there is a risk of developing a severe generalized infection in patients receiving methotrexate treatment.

Prescription of Methotrexate for pregnant and lactating women

Methotrexate injections should not be given to pregnant women, as they can cause fetal death or congenital deformities.

During treatment, breastfeeding is unacceptable; the baby must be switched to formula.

Overdose

You can find out about a drug overdose by determining the level of the active substance in the blood, since no specific symptoms of intoxication are observed.

Therapy consists of immediate administration of an antidote - calcium phosphate.

It is advisable to do this within the first 60 minutes, at a dosage equal to or higher than the dosage of the cytostatic.

The subsequent dosage of the antidote is calculated based on the amount of methotrexate in the body.

A sufficient amount of fluid must be supplied to the body, and the urine pH must be alkaline to avoid precipitation of the active substance and its metabolites in urine.

Side effects

During therapy, the following adverse reactions may occur:

Compound

Each ampoule contains 10 mg of active substance. Sodium chloride and hydroxide and water are used as auxiliary components.

Pharmacology and pharmacokinetics

The active substance stops the formation of DNA and cell division, especially fast-growing cells, which include cells of the bone marrow, malignant neoplasms, embryos, epithelial mucosa, keratinocytes in psoriatic plaques.

In rheumatoid arthritis, the drug relieves the symptoms of inflammation, but the mechanism of action has not been studied.

With intramuscular injections, the maximum concentration of the drug is observed after 30-60 minutes, but with leukemia it can be achieved only 3 hours after the injection.

The active substance does not penetrate the BBB, so the medicine must be injected directly into the spinal canal.

Methotrexate undergoes metabolic reactions in the body. The half-life, depending on the dose, can vary from 6 to 17 hours. During the day, 80-90% of the active substance is excreted in the urine.

With kidney pathology, this time increases.

Terms of purchase and storage

You can purchase the medicine with a doctor's prescription. It should be stored in a dark place where children cannot reach it, at a temperature of 15 to 25 degrees. Shelf life 36 months.

Immunosuppressive, antitumor drug. Actively affects malignant tumor cells. It has a high level of toxicity. Available in pharmacies according to prescription.

Diseases for which methotrexate is used

• Neuroleukemia.
• Penile cancer.
• Trophoblastic tumors.
• Multiple myeloma.
• Myeloblastic leukemia.
• Lymphoblastic leukemia.
• Esophageal carcinoma.
• Bladder cancer.
• Epidermoid cancer of the neck and head.
• Liver cancer.
• Lung cancer.
• Ureteral cancer.
• Mammary cancer.
• Kidney cancer.
• Vulvar cancer.
• Cervical cancer.
• Testicular cancer.
• Ovarian cancer.
• Mycosis fungoides.
• Non-Hodgkin's lymphoma.
• Hodgkin's lymphoma.
• Prostate cancer.
• Rheumatoid arthritis.
• Non-metastatic osteosarcoma.
• Crohn's disease.
• Psoriasis.
• Sézary's syndrome.
• Reiter's syndrome.
• Lichen planus.
• Steroid-dependent bronchial asthma.
• Chronic nonspecific ulcerative colitis.
• Psoriatic arthritis.
• Multiple sclerosis.
• Psoriasis.

Instructions for use of methotrexate

Inside, intramuscularly, intravenously, interactively. Take the tablets whole, without chewing, before meals. When treating with large doses of the drug, it is recommended to take calcium folinate to reduce the toxic effects of methotrexate.

Types of methotrexate

Pills:

• 2.5 mg AB (active substance).

• 5 mg AB.

Solution for injection in ampoules:

• Volume 5 mg.

• Volume 10 mg.

• Volume 20 mg.

• Volume 50 mg.

Methotrexate dosage

The exact dosage varies from person to person. Calculated based on indications, course of the disease, effectiveness of treatment, characteristics of the patient’s body

Inside

The initial dose is 2.5-5 mg. The weekly dose is gradually increased until it reaches 7.5-25 mg. The weekly dose should not exceed 25 mg. As a rule, the weekly dose is divided into 3 doses, between which at least 12 hours should pass. Then there is a break for a week.

Intravenous, intramuscular

Doses are calculated based on the patient's body weight or body surface area. Doses exceeding 100 mg per m2 of area are administered intravenously. To reduce toxic effects, calcium folinate is administered in parallel.

Dosage regimens depending on the treatment regimen:

• The daily dose is 400 mcg per 1 kg of body weight. Intramuscularly, intravenously. Course duration is 4 days.
• Once every 5 days, 400 mcg per 1 kg of body weight. Intramuscularly, intravenously. Course duration is 4 weeks.
• Once a week, 30-40 mg per m2 of body surface area. Intramuscularly, intravenously.
• Take every 2-3 days 0.2-0.5 mg per 1 kg of body weight, or 8-12 mg per m2 of body surface area. When signs of symptoms disappear, the interval is increased to 1 week. After this, gradually up to 1 month. Take no more than 15 mg per m2 of body surface area. Interacal (injection into the tissue surrounding the spinal cord).

Side effects of methotrexate

• Headache.
• Dizziness.
• Encephalopathy.
• Back pain.
• Lethargy, drowsiness.
• Drowsiness.
• Photophobia.
• Tremor.
• Conjunctivitis.
• Cramps.
• Irritability.
• Thrombocytopenia, leukopenia, lymphopenia, neutropenia.
• Hemorrhage.
• Anemia.
• Septicemia.
• Hypotension.
• Pericarditis.
• Thromboembolism.
• Exudative pericarditis.
• Pulmonary fibrosis.
• Interstitial pneumonitis.
• Gastrointestinal bleeding.
• Difficulty swallowing.
• Liver damage.
• Nausea, vomiting.
• Ulcerative stomatitis.
• Anorexia.
• Gingivitis.
• Enteritis.
• Impaired functioning of the kidneys and urinary tract.
• Allergic reaction.
• Stevens-Johnson syndrome.
• Furunculosis. Blistering.
• Skin erythema. Peeling of the skin.
• Telangiectasia.
• Hair loss.
• Ecchymosis.
• Photosensitivity.

Methotrexate contraindications

• Thrombocytopenia, leukopenia.
• Increased sensitivity.
• Anemia.
• Kidney failure.
• Immunodeficiency.
• Liver failure.
• Chicken pox.
• Pregnancy and lactation.
• Leukemia accompanied by hemorrhagic syndrome.
• Ulcerative colitis.
• Spinal cord dysfunction.
• Stomatitis.
• Pleural effusion.

Use with extreme caution:

• Ulcerative lesions of the gastrointestinal tract.
• Ulcers in the mouth.
• Infectious diseases.
• Recovery period after surgery.
• Dehydration.
• Kidney stones.
• Children's, old age.
• Gout.

Methotrexate during pregnancy

During pregnancy, taking the drug is contraindicated. Due to its high toxicity, it can provoke the development of congenital pathologies and lead to fetal death. It is recommended to stop breastfeeding during treatment. It is also advisable to refrain from conceiving a child during treatment with methotrexate to avoid possible complications for the fetus.

Gross formula

Pharmacological group of the substance Methotrexate

Nosological classification (ICD-10)

CAS code

Characteristics of the substance Methotrexate

An antimetabolite of the group of structural analogues of folic acid. Yellow or orange-yellow crystalline powder. Practically insoluble in water and alcohol, hygroscopic and unstable to light. Available in the form of a lyophilized porous mass from yellow to yellow-brown color, soluble in water. Molecular weight 454.45.

Pharmacology

One tablet contains:

active substance: methotrexate (calculated as 100% substance) - 2.50 mg;

Excipients: sucrose (sugar) - 43.97 mg, potato starch - 21.82 mg, talc - 0.68 mg, calcium stearate - 0.34 mg, crospovidone - 0.34 mg, povidone - 0.35 mg. shell composition: sucrose (sugar) - 32.5865 mg, magnesium hydroxycarbonate hydrate - 20.4570 mg, wheat flour - 16.1440 mg, povidone - 0.1660 mg, gelatin - 0.1380 mg, dye azorubine E 122 (carmoisine , acid red dye 2C) - 0.0166 mg, titanium dioxide E 171 - 0.4500 mg, wax - 0.0279 mg, talc - 0.0140 mg.

An antitumor, cytostatic agent of the antimetabolite group, it inhibits dihydrofolate reductase, which is involved in the reduction of dihydrofolic acid to tetrahydrofolic acid (a carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives).

Inhibits DNA synthesis, repair and cellular mitosis. Rapidly proliferating tissues are especially sensitive to the action: cells of malignant tumors, bone marrow, embryonic cells, epithelial cells of the intestinal mucosa, bladder, and oral cavity. Along with antitumor, it has an immunosuppressive effect.

Oral absorption depends on the dose: when taken 30 mg/day m2 absorbed well, average bioavailability is 60%. Absorption is reduced when taken in doses exceeding 80 mg/day m2 .

In children with leukemia, absorption ranges from 23% to 95%. The time to reach maximum concentration (TCmax) is from 40 minutes to 4 hours. Food slows down absorption and reduces Cmax. Communication with plasma proteins is about 50%, mainly with albumin.

Once distributed into tissues, high concentrations of methotrexate in the form of polyglutamates are found in the liver, kidneys and especially the spleen, where they can be retained for several weeks or even months.

When taken in therapeutic doses, it practically does not penetrate the blood-brain barrier. Passes into breast milk.

After oral administration, it is partially metabolized by the intestinal flora, the main part in the liver (regardless of the route of administration) with the formation of a pharmacologically active polyglutamine form, which also inhibits dihydrofolate reductase and thymidine synthesis. Half-life (T1/2) in patients receiving less than 30 mg/day m2 of the drug, in the initial phase is 2-4 hours, and in the final phase (which is long) - 3-10 hours when using small doses and 8-15 hours when using large doses of the drug. In chronic renal failure, both phases of drug elimination can be significantly prolonged.

It is excreted primarily by the kidneys unchanged through glomerular filtration and tubular secretion; up to 10% is excreted with bile (followed by reabsorption in the intestine). The elimination of the drug in patients with impaired renal function, severe ascites or transudate is significantly slowed down. Upon repeated administration, it accumulates in tissues in the form of polyglutamates.

Acute lymphoblastic leukemia and non-Hodgkin's lymphomas;

Trophoblastic tumors;

Mycosis fungoides in advanced stages;

Severe forms of psoriasis;

Rheumatoid arthritis (if other methods of therapy are ineffective).

Methotrexate tablets are used orally. Doses and duration of treatment are determined individually depending on the chemotherapy regimen.

Trophoblastic tumors:

15-30 mg orally daily for 5 days at intervals of one or more weeks (depending on signs of toxicity). Courses of treatment are usually repeated 3 to 5 times.

50 mg once every 5 days with an interval of at least 1 month. A course of treatment requires 300-400 mg.

Acute lymphoblastic leukemia (as part of complex therapy):

3.3 mg/ m2 in combination with prednisolone until remission is achieved, then 15 mg/day m2 2 times a week or 2.5 mg/kg every 14 days.

Non-Hodgkin's lymphoma (as part of complex therapy):

15-20 mg/ m2 for 1 dose 2 times a week;

7.5 mg/ m2 daily for 5 days.

Rheumatoid arthritis:

The starting dose is usually 7.5 mg once a week, taken at once or divided into three doses 12 hours apart. To achieve the optimal effect, the weekly dose can be increased, but it should not exceed 20 mg. When optimal clinical effect is achieved, dose reduction should begin to achieve the lowest effective dose. The optimal duration of therapy is not known. For juvenile chronic arthritis, doses of 10-30 mg/m2/week (0.3-1 mg/kg) are effective for children.

Psoriasis:

Methotrexate therapy is carried out in doses of 10 to 25 mg per week. The dose is usually increased gradually; when the optimal clinical effect is achieved, the dose is reduced until the lowest effective dose is reached.

Mycosis fungoides:

25 mg 2 times a week. Reducing the dose or discontinuing the drug is determined by the patient’s response and hematological parameters.

From the hematopoietic system: anemia (including aplastic), thrombocytopenia, leukopenia, neutropenia, agranulocytosis, eosinophilia, pancytopenia, lymphoproliferative diseases, hypogammaglobulinemia, lymphadenopathy.

From the digestive system: anorexia, nausea, vomiting, stomatitis, gingivitis, pharyngitis, enteritis, erosive and ulcerative lesions and bleeding from the gastrointestinal tract (including melena, hematemesis), hepatotoxicity (acute hepatitis, fibrosis and cirrhosis of the liver, liver failure, hypoalbuminemia, increased activity of liver "transaminases), pancreatitis.

From the nervous system: headache, dizziness, drowsiness, dysarthria, aphasia, hemiparesis, paresis, convulsions; when used in high doses - transient impairment of cognitive functions, emotional lability; unusual cranial sensitivity, encephalopathy (including leukoencephalopathy).

From the side of the organ of vision: conjunctivitis, visual impairment (including transient blindness).

From the cardiovascular system: pericarditis, pericardial effusion, decreased blood pressure (BP), thromboembolism (including arterial thrombosis, cerebral vascular thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolism).

From the respiratory system: rarely - pulmonary fibrosis, respiratory failure, alveolitis, interstitial pneumonitis (including fatal), chronic obstructive pulmonary disease (COPD), symptoms of potentially serious interstitial pneumonia - dry non-productive cough, shortness of breath, fever.

From the genitourinary system: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria, impaired spermato- and oogenesis, transient oligospermia, decreased libido, impotence, dysmenorrhea, vaginal discharge, gynecomastia, infertility, miscarriage, fetal death, fetal development defects.

From the skin: erythematous rash, skin itching, urticaria, photosensitivity, skin pigmentation disorders, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrolysis, ulceration and necrosis of the skin, exfoliative dermatitis. When treating psoriasis - a burning sensation of the skin, painful erosive plaques on the skin.

From the musculoskeletal system: arthralgia, myalgia, osteoporosis, osteonecrosis, fractures.

Neoplasms: lymphoma (including reversible).

General reactions: allergic reactions up to anaphylactic shock, allergic vasculitis, tumor lysis syndrome, soft tissue necrosis, sudden death, life-threatening opportunistic infections (including Pneumocystis pneumonia), cytomegalovirus (CMV) infections (including CMV pneumonia), sepsis (in including fatal), nocardiosis, histoplasmosis, cryptococcosis, infections caused by Herpes zoster and Herpes simplex (including disseminated herpes), diabetes mellitus, excessive sweating.

There are no specific symptoms of methotrexate overdose; it is diagnosed by the concentration of methotrexate in plasma.

Treatment: Administration of a specific antidote - calcium folinate, if possible immediately, preferably within the first hour, in a dose equal to or greater than the dose of methotrexate; subsequent doses are administered as needed, depending on the concentration of methotrexate in the blood serum. To prevent precipitation of methotrexate and/or its metabolites in the renal tubules, the body is hydrated and the urine is alkalinized, which accelerates the excretion of methotrexate. To minimize the risk of nephropathy resulting from the formation of sediment of the drug or its metabolites in the urine, it is necessary to additionally determine the urine pH before each administration and every 6 hours throughout the period of use of calcium folinate as an antidote, until the plasma concentration of methotrexate falls below 0. 05 µmol/l, to ensure a pH above 7.

Increases the anticoagulant activity of coumarin or indanedione derivatives and/or increases the risk of bleeding by reducing the synthesis of a procoagulant factor in the liver and impairing platelet formation.

It increases the concentration of uric acid in the blood, therefore, when treating patients with concomitant hyperuricemia and gout, dose adjustment of anti-gout medications (, sulfinpyrazone) may be required; the use of uricosuric anti-gout drugs may increase the risk of developing nephropathy associated with increased formation of uric acid during treatment with methotrexate (preferably used). Simultaneous administration of salicylates, phenylbutazone, phenytoin, sulfonamides, sulfonylurea derivatives, aminobenzoic acid, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, ), indirect anticoagulants and lipid-lowering drugs () increases toxicity due to the displacement of methotrexate from communication with albumin and/or a decrease in tubular secretion, which in some cases can cause the development of severe toxic effects, sometimes even fatal.

Nonsteroidal anti-inflammatory drugs (NSAIDs) in combination with high doses of methotrexate increase the concentration and slow down the elimination of the latter, which can lead to death from severe hematological and gastrointestinal intoxication. It is recommended to stop taking phenylbutazone 7-12 days before, piroxicam 10 days before, diflunisal and indomethacin 24-48 hours before, ketoprofen and NSAIDs with short T1/2 12-24 hours before methotrexate infusion in moderate and high doses and for at least 12 hours (depending on the concentration of methotrexate in the blood) after its completion. Caution should be exercised when combining NSAIDs with low doses of methotrexate (reduced renal tubular excretion of methotrexate is possible). Medicines that block tubular secretion (for example probenecid) increase the toxicity of methotrexate by reducing its excretion by the kidneys.

Antibiotics that are poorly absorbed in the gastrointestinal tract (tetracyclines) reduce the absorption of methotrexate and disrupt its metabolism due to the suppression of normal intestinal microflora.

Retinoids and other hepatotoxic drugs increase the risk of developing hepatotoxicity.

L-asparaginase reduces the severity of the antitumor effect of methotrexate by inhibiting cell replication.

Anesthesia using dinitrogen oxide can lead to the development of unpredictable severe myelosuppression and stomatitis.

The use of cytarabine 48 hours before or within 10 minutes after the start of methotrexate therapy may cause the development of a synergistic cytotoxic effect (adjustment of the dosage regimen is recommended based on monitoring hematological parameters).

Hematotoxic drugs increase the risk of developing methotrexate hematotoxicity.

Methotrexate reduces the clearance of theophylline.

Oral neomycin may reduce the absorption of methotrexate.

Several patients with psoriasis or mycosis fungoides treated with methotrexate in combination with PUVA therapy (and ultraviolet irradiation (UVR)) have been diagnosed with skin cancer.

Combination with radiation therapy may increase the risk of bone marrow suppression. may reduce the immune response to vaccination with live and inactivated viral vaccines.

Administration of amiodarone to patients receiving methotrexate therapy for psoriasis may cause skin ulceration.

Methotrexate is a cytotoxic drug and must be handled with caution. 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. Due to the possible development of severe and even fatal adverse reactions, patients should be fully informed by their physician about the possible risks and recommended safety measures. Patients receiving methotrexate therapy should be closely monitored to ensure that signs of potential toxicity and adverse reactions are identified and assessed promptly.

Before starting or resuming therapy with methotrexate, a complete general blood count should be performed to determine the level of platelets, a biochemical blood test to determine the values ​​of liver enzymes, bilirubin, serum albumin, a chest X-ray examination, a kidney function test, and, if necessary, tests for tuberculosis and hepatitis.

For timely detection of symptoms of intoxication, it is necessary to monitor the state of peripheral blood (the number of leukocytes and platelets: first every other day, then every 3-5 days during the first month, then once every 7-10 days, during remission - once every 1-2 week), the activity of “liver” transaminases, renal function (urea nitrogen, creatinine clearance and/or serum creatinine), the concentration of uric acid in the blood serum, periodically conduct a chest x-ray, examine the oral mucosa and pharynx for the presence of ulcerations before each application. It is recommended to monitor the state of bone marrow hematopoiesis before treatment, once during the treatment period and at the end of the course.

Methotrexate can potentially lead to the development of symptoms of acute or chronic hepatotoxicity (including fibrosis and cirrhosis of the liver). Chronic hepatotoxicity usually develops after long-term use of methotrexate (usually for 2 or more years) or a total cumulative dose of at least 1.5 g and can lead to an adverse outcome. The hepatotoxic effect may also be due to a burdened, concomitant medical history (alcoholism, obesity, diabetes mellitus) and old age. Due to the toxic effects of the drug on the liver during treatment, you should refrain from prescribing other hepatotoxic drugs to patients unless clearly necessary. Patients taking other hepatotoxic drugs (for example) should be closely monitored.

To objectify liver function, along with biochemical parameters, it is recommended to perform a liver biopsy before or after 2-4 months. after starting treatment; with a total cumulative dose of 1.5 g and after each additional 1-1.5 g. For moderate liver fibrosis or any degree of cirrhosis, methotrexate therapy is discontinued; For mild fibrosis, a repeat biopsy is usually recommended after 6 months. During initial therapy, minor histological changes in the liver (minor portal inflammation and fatty changes) are possible, which is not a reason to refuse or discontinue treatment, but indicates the need for caution when using the drug.

If diarrhea and ulcerative stomatitis develop, methotrexate therapy must be interrupted due to the high risk of developing hemorrhagic enteritis and perforation of the intestinal wall, which can lead to the death of the patient.

Do not expose unprotected skin to too much sunlight or overuse a UV lamp (a photosensitivity reaction is possible).

Due to its effect on the immune system, it may impair the response to vaccination and affect the results of immunological tests. It is necessary to refuse immunization (if it is not approved by a doctor) in the interval from 3 to 12 months after taking the drug; other family members living with the patient should refuse immunization with oral polio vaccine (avoid contact with people who have received the polio vaccine or wear a protective mask covering the nose and mouth). Patients of childbearing potential of both sexes and their partners should use reliable contraception during treatment with methotrexate and after treatment for at least 3 months in men and at least one ovulation cycle in women.

After a course of treatment with high doses of methotrexate, the use of calcium folinate is recommended to reduce its toxicity.

10 tablets in a blister pack made of polyvinyl chloride film and printed varnished aluminum foil.

50 tablets in polymer jars complete with lids.

Each jar, 5 blister packs, along with instructions for use, are placed in a cardboard pack.

In a place protected from light at a temperature not exceeding 25 ° C.

Keep out of the reach of children.