Gross formula

C20H22N8O5

Pharmacological group of the substance Methotrexate

Nosological classification (ICD-10)

CAS code

59-05-2

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

Pharmacological action- antitumor, cytostatic, immunosuppressive.

Inhibits dihydrofolate reductase (DHF), which converts dihydrofolic acid into tetrahydrofolic acid, which is a donor of one-carbon groups in the synthesis of purine nucleotides and thymidylate, necessary for DNA synthesis. In addition, in the cell, methotrexate undergoes polyglutamination with the formation of metabolites that have an inhibitory effect not only on DHF, but also on other folate-dependent enzymes, including thymidylate synthetase, 5-aminoimidazole-4-carboxamidoribonucleotide (AICAR) transamylase.

Suppresses DNA synthesis and repair, cell mitosis, and to a lesser extent affects the synthesis of RNA and protein. It has S-phase specificity, is active against tissues with high cell proliferative activity, and inhibits the growth of malignant tumors. The most sensitive are actively dividing tumor cells, as well as bone marrow, embryo, mucous membranes of the oral cavity, intestines, and bladder.

It has a cytotoxic effect and has teratogenic properties.

Carcinogenicity studies have found that methotrexate causes chromosomal damage in animal somatic cells and human bone marrow cells, but this has not allowed definitive conclusions about the carcinogenicity of the drug.

Methotrexate has been shown to be effective in the treatment of bronchial asthma (steroid-dependent), Crohn's disease, chronic ulcerative colitis, mycosis fungoides (late stages), Reiter's syndrome, reticular erythroderma (Sezary syndrome), psoriatic arthritis, juvenile rheumatoid arthritis, to prevent graft-versus-host reactions. .

After oral administration at a dose of 30 mg/m2 and below, it is quickly and completely absorbed from the gastrointestinal tract (bioavailability about 60%). In children with leukemia, absorption rates range from 23 to 95%. Absorption decreases significantly when the dose exceeds 80 mg/m2 (possibly due to a saturation effect). Cmax is achieved after 1-2 hours with oral administration and after 30-60 minutes with intramuscular administration. Taking with food slows the time required to reach Cmax by approximately 30 minutes, but the level of absorption and bioavailability do not change.

After intravenous administration, it is quickly distributed within a volume equivalent to the total volume of body fluids. The initial volume of distribution is 0.18 l/kg (18% of body weight), the equilibrium volume of distribution is 0.4-0.8 l/kg (40-80% of body weight).

50-60% of methotrexate circulating in the vascular bed is associated with proteins (mainly albumin).

Passes through the BBB when taken orally or parenterally only to a limited extent (dose-dependent); after intrathecal administration, significant quantities enter the systemic circulation. Secreted into breast milk, passes through the placenta (has a teratogenic effect on the fetus).

Metabolized in liver cells and other cells to form polyglutamates (DHF and thymidylate synthetase inhibitors), which can be converted to methotrexate by hydrolases. Partially metabolized by intestinal microflora (after oral administration). A small amount of polyglutaminated derivatives is retained in tissues for a long time. The retention time and duration of action of these active metabolites depends on the cell type, tissue, and tumor type. Slightly metabolized (when taken in normal doses) to 7-hydroxymethotrexate (water solubility is 3-5 times lower than that of methotrexate). Accumulation of this metabolite occurs when taking high doses of methotrexate prescribed for the treatment of osteosarcoma.

The final half-life is dose-dependent and is 3-10 hours with low doses of methotrexate and 8-15 hours with high doses of methotrexate. 80-90% of the intravenous dose is excreted unchanged by the kidneys through glomerular filtration and active tubular secretion within 24 hours, and less than 10% with bile. Methotrexate clearance varies widely and decreases at high doses.

The elimination of the drug in patients with severe ascites or effusion into the pleural fluid is slow.

Use of the substance Methotrexate

Uterine chorionic carcinoma, acute lymphocytic leukemia, central nervous system tumors (leukemoid infiltration of the meninges), breast cancer, head and neck cancer, lung cancer, bladder, stomach; Hodgkin's disease, non-Hodgkin's lymphoma, retinoblastoma, osteosarcoma, Ewing's sarcoma, soft tissue sarcoma; refractory psoriasis (only with an established diagnosis in case of resistance to other types of therapy), rheumatoid arthritis.

Contraindications

Hypersensitivity, immunodeficiency, anemia (including hypo- and aplastic), leukopenia, thrombocytopenia, leukemia with hemorrhagic syndrome, liver or kidney failure.

Restrictions on use

Infectious diseases, ulcers of the oral cavity and gastrointestinal tract, recent surgery, history of gout or kidney stones (risk of hyperuricemia), old age and childhood.

Use during pregnancy and breastfeeding

Contraindicated during pregnancy (may cause fetal death or cause congenital deformities).

Breastfeeding should be stopped during treatment.

Side effects of the substance Methotrexate

From the nervous system and sensory organs: encephalopathy (especially when multiple doses are administered intrathecally, as well as in patients after irradiation of the brain), dizziness, headache, blurred vision, drowsiness, aphasia, back pain, stiffness of the muscles of the back of the neck, convulsions, paralysis, hemiparesis; in some cases - fatigue, weakness, confusion, ataxia, tremor, irritability, coma; conjunctivitis, excessive lacrimation, cataracts, photophobia, cortical blindness (at high doses).

From the cardiovascular system (hematopoiesis, hemostasis): anemia, leukopenia, thrombocytopenia, neutropenia, lymphopenia (especially T-lymphocytes), hypogammaglobulinemia, hemorrhage, septicemia due to leukopenia; rarely - pericarditis, exudative pericarditis, hypotension, thromboembolic changes (arterial thrombosis, cerebral thrombosis, deep vein thrombosis, renal vein thrombosis, thrombophlebitis, pulmonary embolism).

From the respiratory system: rarely - interstitial pneumonitis, pulmonary fibrosis, exacerbation of pulmonary infections.

From the gastrointestinal tract: gingivitis, pharyngitis, ulcerative stomatitis, anorexia, nausea, vomiting, diarrhea, difficulty swallowing, melena, ulceration of the gastrointestinal mucosa, gastrointestinal bleeding, enteritis, liver damage, fibrosis and cirrhosis of the liver (the likelihood is increased in patients receiving continuous or long-term therapy ).

From the genitourinary system: cystitis, nephropathy, azotemia, hematuria, hyperuricemia or severe nephropathy, dysmenorrhea, unstable oligospermia, disruption of the process of oogenesis and spermatogenesis, fetal defects.

From the skin: skin erythema, itching, hair loss (rare), photosensitivity, ecchymosis, acne, furunculosis, peeling, de- or hyperpigmentation of the skin, blistering, folliculitis, telangiectasia, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Allergic reactions: fever, chills, rash, urticaria, anaphylaxis.

Others: immunosuppression, rarely - opportunistic infection (bacterial, viral, fungal, protozoal), osteoporosis, vasculitis.

Interaction

An enhanced and prolonged effect of methotrexate, leading to intoxication, is facilitated by the simultaneous use of NSAIDs, barbiturates, sulfonamides, corticosteroids, tetracyclines, trimethoprim, chloramphenicol, para-aminobenzoic and para-aminohippuric acids, probenecid. Folic acid and its derivatives reduce effectiveness. Strengthens the effect of indirect anticoagulants (coumarin or indanedione derivatives) and increases the risk of bleeding. Penicillin group drugs reduce the renal clearance of methotrexate. With the simultaneous use of methotrexate and asparaginase, the effect of methotrexate may be blocked. Neomycin (oral) may reduce the absorption of methotrexate (oral). Drugs that cause pathological changes in the blood increase leukopenia and/or thrombocytopenia if these drugs have the same effect as methotrexate on bone marrow function. Other drugs that cause bone marrow suppression or radiation therapy potentiate the effect and additively suppress bone marrow function. A synergistic cytotoxic effect with cytarabine is possible when used simultaneously. With the simultaneous use of methotrexate (intrathecal) with acyclovir (parenteral), neurological disorders are possible. In combination with live viral vaccines, it can cause an intensification of the replication process of the vaccine virus, increased side effects of the vaccine and a decrease in the production of antibodies in response to the administration of both live and inactivated vaccines.

Overdose

Symptoms: There are no specific symptoms.

Treatment: immediate administration of calcium folinate to neutralize the myelotoxic effect of methotrexate (orally, intramuscularly or intravenously). The dose of calcium folinate should be at least equal to the dose of methotrexate and should be administered within the first hour; subsequent doses are administered as needed. Increase body hydration and alkalize urine to avoid precipitation of the drug and its metabolites in the urinary tract.

Routes of administration

Inside, parenterally(i.m., i.v., intra-arterial, intrathecal), depending on the indications.

Precautions for the substance Methotrexate

Use under close medical supervision. 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 weeks), liver transaminase activity, kidney function, and periodically perform chest x-rays. Methotrexate therapy is stopped if the number of lymphocytes in the blood is less than 1.5·10 9 /l, the number of neutrophils is less than 0.2·10 9 /l, the number of platelets is less than 75·10 9 /l. An increase in creatinine levels by 50% or more of the initial level requires repeated measurement of creatinine clearance. An increase in bilirubin levels requires intensive detoxification therapy. A bone marrow hematopoiesis study is recommended to be carried out before treatment, once during the treatment period and at the end of the course. The level of methotrexate in plasma is determined immediately after the end of the infusion, as well as after 24, 48 and 72 hours (to identify signs of intoxication, which can be relieved by the administration of calcium folinate).

During treatment in higher and higher doses, it is necessary to monitor the pH of the urine (the reaction should be alkaline on the day of administration and in the next 2-3 days). To do this, a mixture of 40 ml of 4.2% sodium bicarbonate solution and 400-800 ml of isotonic sodium chloride solution is administered intravenously (drip) the day before, on the day of treatment and in the next 2-3 days. Treatment with methotrexate in increased and high doses is combined with increased hydration (up to 2 liters of fluid per day).

Particular attention should be paid to cases of decreased hematopoietic function of the bone marrow caused by the use of radiation therapy, chemotherapy or long-term use of certain drugs (sulfonamides, amidopyrine derivatives, chloramphenicol, indomethacin). In such cases, the general condition usually worsens, which poses the greatest danger to young and elderly patients.

If diarrhea and ulcerative stomatitis develop, methotrexate therapy must be interrupted, otherwise this may lead to the development of hemorrhagic enteritis. If signs of pulmonary toxicity (especially dry cough without sputum) occur, methotrexate treatment is recommended to be discontinued due to the risk of possibly irreversible pulmonary toxicity. Prescribe with caution to patients with impaired liver and/or kidney function (doses reduced).

The use of alcohol and drugs that have hepatotoxicity should be avoided, because their use during treatment with methotrexate increases the risk of liver damage; prolonged exposure to the sun. In combination treatment, each drug should be taken at the prescribed time; If a dose is missed, do not take the drug and do not double the dose.

During the treatment period, vaccination with viral vaccines is not recommended; contact with people who have received the polio vaccine and those with bacterial infections should be avoided. Live viral vaccines should not be used in patients with leukemia in remission for at least 3 months after the last course of chemotherapy. Immunization with oral polio vaccine should be delayed in close contacts of the patient, especially family members.

Signs of bone marrow suppression, unusual bleeding or hemorrhage, black tarry stools, blood in the urine or stool, or pinpoint red spots on the skin require immediate consultation with a doctor.

Active ingredient

Methotrexate

Release form, composition and packaging

50 pcs. - polymer jars (1) - cardboard packs.

Pharmacological action

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.

Pharmacokinetics

Absorption after oral administration depends on the dose: when taken 30 mg/m2, it is well absorbed, the average bioavailability is 60%. Absorption is reduced when taken in doses exceeding 80 mg/m2.

In children with leukemia, absorption ranges from 23% to 95%. The time to reach Cmax is from 40 minutes to 4 hours. Food slows down absorption and reduces Cmax. Protein binding is about 50%, mainly with albumin.

After tissue distribution, high concentrations of methotrexate in the form of polyglutamates are found in the liver, kidneys and especially the spleen, where methotrexate 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. T1/2 in patients receiving less than 30 mg/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 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.

Indications

- 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).

Contraindications

The use of methotrexate is contraindicated during pregnancy and lactation, with pronounced changes in kidney and liver function, with hematological disorders (such as bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia), with the acute stage of infectious diseases, immunodeficiency syndrome, with hypersensitivity to methotrexate or other components of the tablet, for children under 3 years of age.

With caution. With ascites, effusion into the pleural cavity, gastric and duodenal ulcers, ulcerative colitis, dehydration, gout or nephrolithiasis in history, previous radiation therapy or chemotherapy, infectious diseases of a viral, fungal or bacterial nature.

Dosage

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 1 time 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/m 2 in combination with until remission is achieved, then 15 mg/m 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 per dose, 2 times a week;

- 7.5 mg/m2 daily for 5 days.

Rheumatoid arthritis:

The initial dose is usually 7.5 mg once a week, which is taken simultaneously or divided into three doses with an interval of 12 hours. To achieve 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.

Side effects

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, 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.

Overdose

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 is below 0.05 µmol /l, to ensure a pH above 7.

Drug interactions

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.

Increases the concentration of uric acid in the blood, therefore, when treating patients with concomitant hyperuricemia and gout, dose adjustment of medications (allopurinol, colchicine, 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). Concomitant use of salicylates, phenylbutazone, phenytoin, sulfonamides, sulfonylurea derivatives, aminobenzoic acid, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and lipid-lowering drugs (colestyramine) increases toxicity due to the displacement of methotrexate from the connection with / or a decrease in tubular secretion, which in some cases can lead to the development of severe toxic effects, sometimes even fatal.

Non-steroidal 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 half-life 12-24 hours before infusion of methotrexate 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 from the gastrointestinal tract (tetracyclines, chloramphenicol) reduce the absorption of methotrexate and disrupt its metabolism due to suppression of normal intestinal microflora.

Retinoids, azathioprine, sulfasalazine, ethanol 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 (methoxsalen and ultraviolet irradiation (UV)) have been diagnosed with skin cancer.

Combination with radiation therapy may increase the risk of bone marrow suppression. Methotrexate 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.

Special instructions

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), activity of “liver” transaminases, renal function (urea nitrogen, creatinine clearance and/or serum creatinine), concentration of uric acid in the blood serum, periodically perform chest X-ray, examination of the oral mucosa and pharynx for the presence of ulceration 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 may potentially lead to the development of symptoms of acute or chronic hepatotoxicity (including liver fibrosis and cirrhosis). 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 (eg leflunomide) should be closely monitored.

To objectify liver function, along with biochemical parameters, it is recommended to perform a liver biopsy before or 2-4 months after the start of 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, methotrexate may worsen the response to vaccination and affect the results of immunological tests. It is necessary to refuse immunization (unless it is 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

Since methotrexate can have an effect on the central nervous system (fatigue, dizziness), patients taking the drug should refrain from driving vehicles or potentially dangerous machinery.

Pregnancy and lactation

It has a teratogenic effect: it can cause fetal death and congenital deformities. If a woman becomes pregnant during methotrexate therapy, the issue of terminating the pregnancy should be considered due to the risk of side effects on the fetus. Methotrexate is excreted in breast milk; breastfeeding should be discontinued during the entire course of treatment.

Conditions for dispensing from pharmacies

The drug is available with a prescription.

Storage conditions and periods

Store the drug in a place protected from light at a temperature not exceeding 25°C. Keep out of the reach of children.

Shelf life - 3 years. Do not use after the expiration date stated on the package.

Content

The drug is one of the best antitumor agents available on the pharmaceutical market. Therapy with this drug should be carried out under the supervision of a physician and in strict accordance with the instructions for use. Self-use can cause serious consequences.

Composition and release form

Pharmacological action

According to the instructions for use, Methotrexate belongs to the group of drugs of antimetabolites, cytostatics, and is a folic acid antagonist. The medication has an antitumor and immunosuppressive effect. The active substance helps slow down DNA synthesis and repair and cell mitosis. The following are highly sensitive to the drug: bone marrow, mucosal epithelium, tumor tissue, and embryonic cells.

The use of the drug helps to disrupt the growth of malignant tumors without damaging healthy areas of the body. When treating rheumatoid arthritis, Methotrexate relieves pain, swelling, joint stiffness and other signs of the inflammatory process. When treating psoriasis, plaque keratinocytes are affected. The active substance is excreted through the kidneys and bile.

Indications for use

The drug belongs to the group of antitumor drugs. According to the instructions for use, the medication has the following indications:

• lymphoblastic, myeloblastic acute leukemia;
• cancer of the skin, breast, lungs, bladder, kidneys, female and male genital organs, esophagus;
• medulloblastoma, squamous cell carcinoma, retinoblastoma;
• neuroleukemia;
• osteogenic and soft tissue sarcoma, lymphosarcoma;
• psoriasis, severe mycosis fungoides;
• trophoblast tumors;
• rheumatoid, psoriatic arthritis;
• ankylosing spondylitis;
• dermatomyositis;
• systemic lupus erythematosus.

How to take Methotrexate

The instructions for use of the medication indicate that the choice of treatment regimen and dosage regimen should be made by a specialist. The doctor prescribes the required amount of the drug and the frequency of its use, based on the diagnosis and data from the medical literature.

Pills

Methotrexate for rheumatoid arthritis is prescribed orally. According to the instructions for use, the pills should be taken before meals without chewing. It is recommended to take the medicine with water. The initial dose is 7.5 mg 1 time/week. It can be used simultaneously or divided into 3 doses, maintaining an interval of 12 hours. During therapy, the doctor may increase the weekly dose. The maximum allowed amount is 20 mg.

Methotrexate tablets for trophoblastic tumors should be taken at a dose of 15-30 mg for 5 days. Then a break is taken for 1-2 weeks. The course is repeated 3-5 times. The doctor may prescribe 50 mg tablets 1 time/5 days. In this case, an interval of 1 month is required. For a course of therapy, the patient will need 300-400 mg of medication. When treating psoriasis, 10-25 mg/week is prescribed. The dose is increased gradually until the required clinical effect is achieved.

For the treatment of mycosis fungoides, it is recommended to take 25 mg twice a week. The basis for reducing the dose or discontinuing the medication may be hematological parameters and the patient’s response. As part of complex therapy, the instructions for use prescribe the use of Methotrexate for acute lymphoblastic leukemia and non-Hodgkin's lymphoma. The course and dosage regimen is determined by the attending physician.

Ampoules

Methotrexate solution is administered intramuscularly, intravenously, intrathecally, intraarterially. Injections are performed for the following diseases:

• Trophoblastic tumors - 30 mg daily, intramuscularly. The course of treatment is 5 days. A week's break is required. Therapy is carried out until a dose of 400 mg is reached.
• Leukemia, lymphoma - administered intravenously at 200-500 mg/m2 once a month.
• Neuroleukemia – intrathecally, 12 mg/m2 1-2 times/week.
• Psoriasis – administered intramuscularly or intravenously at a dose of 25 mg/week.
• Mycosis fungoides - intramuscularly, 50 mg/7 days once or divided into 2 procedures.

Special instructions

Methotrexate should only be prescribed by an oncologist who has experience administering chemotherapy. The doctor should warn the patient about the likelihood of developing severe adverse reactions leading to impairment of health or death, manifested by toxic lesions. If the patient has an accumulation of fluid inside the pleural or abdominal cavity, it must be removed before starting drug therapy.

If symptoms of stomatitis appear, which are evidence of toxic damage to the gastrointestinal tract, you should stop taking Methotrexate for a while to prevent perforation and intestinal ulceration. Before starting therapy, a clinical, biochemical blood test of the patient, chest x-ray, and a study of kidney function are required. During the treatment process, it is necessary to carry out the following diagnostic measures every month:

• examination of the oral cavity;
• study of liver functionality;
• detailed blood test;
• examination of the respiratory system;
• urine test;
• study of the condition and functioning of the kidneys.

Methotrexate should be discontinued 7 days before the intended surgery; treatment should be resumed 2 weeks after surgery. When prescribing a medication, it should be taken into account that it increases the risk of the formation of malignant lymphomas. Before starting therapy, it is necessary to exclude the patient's pregnancy. Patients of reproductive age are recommended to use contraception during the treatment period, since the drug negatively affects the reproductive system.

When the drug is administered intrathecally, complications that threaten the patient's life may occur. When the first sign of side effects appears, the medication should be stopped immediately. It is forbidden to mix Methotrexate in one bottle with other substances. If the product gets on the mucous membranes or skin, it must be immediately washed off with water. When taking medication, patients need to be careful when performing actions that require quick reactions and increased attention.

During pregnancy

Methotrexate should not be taken during pregnancy and lactation. The medication has an embryotoxic effect and can cause internal organ defects in the fetus. The medicine passes into breast milk in high concentrations that are dangerous to the baby’s health. If a woman needs Methotrexate therapy, breastfeeding should be stopped so as not to harm the baby's health.

Drug interactions

Some medications in combination with Methotrexate have a negative effect on the patient's body. When interacting with other medications, the following effects may occur:

• The toxic effect of the drug on the liver increases if the patient has an alcohol addiction or is simultaneously taking hepatoxic drugs, Leflunamide.
• The absorption of Methotrexate is reduced with the combined use of oral forms of Tetracycline and Chloramphenicol.
• Glycopeptides, ciprofloxacin penicillins, phenylbutazone, loop diuretics increase the concentration of the active substance in the blood, reducing the clearance of the drug in the kidneys.
• The toxicity of Methotrexate increases when combined with non-steroidal anti-inflammatory drugs and salicylates.
• Hematological disorders are aggravated when the drug interacts with sulfonamides, Chloramphenicol, Pyrimethamine.
• Trimethoprim, Sulfamethoxazole, which contribute to folate deficiency, indirect anticoagulants, and lipid-lowering agents can enhance the toxic effect of Methotrexate.
• Clearance of the active substance is reduced when combined with cytostatics.
• The risk of tissue necrosis increases when drug treatment is combined with radiotherapy.
• The medication reduces the immune response to vaccinations; when live vaccines are administered, severe antigenic reactions are possible.
• The risk of neurological complications increases with the simultaneous use of intrathecal Methotrexate and acyclovir.

Side effects of Methotrexate

Drug therapy can provoke pathological reactions from various body systems. The instructions for use indicate the following side effects:

• thrombocytopenia, pancytopenia, anemia, leukopenia, high-grade bone marrow dysfunction;
• drowsiness, frequent mood swings, increased fatigue, depression, headache, insomnia, confusion, leukoencephalopathy, epileptic seizures, paralysis, paresthesia of the limbs, symptoms of meningism, metallic taste in the mouth;
• conjunctivitis, eye irritation;
• development of pneumonitis, alveolitis, pleural effusion, pulmonary fibrosis, bronchial asthma, pharyngitis, pulmonary edema, thickening of the pleural layers;
• the appearance of inflammation and ulcers in the oral cavity, nausea, dyspepsia, stomatitis, diarrhea, cirrhosis and fibrosis of the liver, anorexia, vomiting, increased transaminases, steatosis;
• skin itching, photosensitivity, herpes zoster, alopecia, vasculitis, herpetiform rashes, epidermal necrosis, increased pigmentation of nails, hidradenitis, acute paronychia, furunculosis;
• the appearance of ulcers, inflammation of the bladder, impaired functioning of the kidneys, electrolyte balance, problems with urination, anuria, oliguria;
• osteoporosis, joint and muscle pain;
• bleeding, pericardial effusion, cardiac tamponade;
• decreased immune defense of the body, anaphylactic reactions, increased number of rheumatoid nodules, sepsis;
• inflammation, vaginal ulceration, menstrual irregularities, atypical vaginal discharge, decreased sexual desire, impotence;
• fever, chills, general malaise, decreased wound healing;
• when administered intramuscularly, the formation of polyps, cysts, lymphomas, abscesses, and tissue destruction at the injection site is possible;
• metabolic disorders, diabetes;
• with intrathecal administration: acute arachnoiditis, plegia, paresis, dysfunction of the cerebellum, leukoencephalopathy, death.

Overdose

If the dose of the drug specified in the instructions or recommended by the doctor is exceeded, depression of the hematopoietic system occurs. Calcium folinate is used as an antidote. The substance must be administered in the first hour after taking the medication, its dose must match or exceed the amount of Methotrexate ingested. In case of severe overdose, hydration of the body and alkalization of urine are used. If the amount of the drug is exceeded when administered intrathecally, it is necessary to use an antidote in combination with drainage of cerebrospinal fluid.

Contraindications

• alcoholism;
• severe liver and kidney damage;
• availability of vaccinations with live vaccines;
• HIV infection, tuberculosis and other serious infectious diseases;
• a history of oral and gastrointestinal ulcers;
• taking medications containing acetylsalicylic acid in large doses;
• disorders of the hematopoietic system;
• individual intolerance to the active substance or other components of the drug;
• period of pregnancy and lactation.

In some cases, Methotrexate is prescribed with caution so as not to provoke side effects. The drug should be taken under the supervision of a doctor in the presence of certain pathologies and conditions:

• liver and kidney diseases;
• diabetes mellitus;
• obesity;
• inhibition of bone marrow circulation;
• infections of viral, fungal or bacterial origin;
• pleural and peritoneal effusion;
• dehydration;
• herpes zoster;
• measles, chickenpox;
• strongyloidiasis, amoebiasis;
• gout;
• inflammatory processes, infections of the oral mucosa;
• vomiting, ulcerative colitis, diarrhea, gastrointestinal obstruction;
• asthenia, aciduria;
• prior to treatment with radiation or chemotherapy.

Terms of sale and storage

According to the instructions for use, Methotrexate is a prescription drug. The medication should be stored out of the reach of children, protected from light at a temperature of 15-25 degrees. The shelf life of the medicine is 36 months.

Analogues

Doctors can prescribe medications identical to Methotrexate in composition and action. The main analogues of the drug are:

• Vero-Methotrexate is available in the form of ampoules with an injection solution. The drug has an antitumor effect and is used for malignant neoplasms in organs, trophoblastic disease, severe psoriasis, and rheumatoid arthritis. According to the instructions for use, Vero-Methotrexate is prohibited for use during pregnancy, leukopenia, thrombocytopenia, dysfunction of the liver, kidneys, and immune system. The dose and method of administration of the drug depend on the state of the hematopoietic system, concomitant antitumor therapy, and the stage of the disease. The cost of Vero-Methotrexate is about 120 rubles.
• Metoject is an antitumor, immunosuppressive agent. Dispensed in the form of a solution placed inside special syringes. According to the instructions for use, Metoject is indicated for polyarthritis, severe psoriasis, and juvenile rheumatoid arthritis. The medicine has a wide list of contraindications and side effects, so its use is recommended only when prescribed by a doctor. The solution is administered intramuscularly, subcutaneously or intravenously. The treatment regimen should only be selected by a specialist. You can purchase Methodject for a price starting from 461 rubles.
• Teva methotrexate is an injection solution that has an antitumor effect. According to the instructions for use, the product is used to treat malignant neoplasms, severe forms of psoriasis, and rheumatoid arthritis. Taking the medication is prohibited in case of hypersensitivity to the components, pregnancy, lactation, liver or kidney failure, thrombocytopenia, anemia, neutropenia, leukopenia. The method of use and dosage are determined by the doctor, according to the instructions. The cost of Methotrexate Teva is from 250 rubles.
• Methotab is a tablet whose active ingredient is methotrexate. Instructions for use prescribe taking the pills for rheumatoid arthritis, chronic psoriasis, and acute lymphocytic leukemia. Methotab has an extensive list of contraindications and side effects, and is used only with a doctor's prescription. The drug is taken orally in the dosage prescribed by the doctor and instructions. The cost of Metotab is about 1,400 rubles.

Methodject and Methotrexate - what is the difference

There are no significant differences in the composition and principle of action on the patient’s body. Methodject is dispensed only in the form of a solution intended for intramuscular or intravenous injection. According to reviews from doctors and patients, Methotrexate from the Austrian manufacturer Ebewe has less toxicity. The cost of drugs is approximately the same.

Video

Latin name: Methotrexate
ATX code: L01BA01
Active ingredient: methotrexate
Manufacturer: Ebewe Pharma, Australia
Dispensing from the pharmacy: By prescription
Storage conditions: darkness, coolness
Best before date: 2-3 years.

Methotrexate has antitumor and immunosuppressive properties. Therefore, the medicine is used to treat cancer and malignant tumors.

The product is available in the form of tablets and medicinal solution. The drug can be purchased at a pharmacy only with a prescription.

Composition and release form

Methotrexate is produced in the form of tablets or medicinal solution with varying concentrations of the active ingredient. Thus, tablets containing 2.5 mg of methotrexate have a flat, round shape. The pills are yellow in color; the tablets have red or orange inclusions.

Methotrexate Ebeve tablets 2.5 mg are placed in polypropylene bottles (50 pieces) and cardboard packs. Also, pills can be packaged in blisters of 10 pieces, which are in a cardboard pack. The cost of the medicine is from 203 rubles.

Methotrexate 5 mg tablets have a round, convex shape. Yellow pills with white or orange splashes, separated on one side by a beveled strip. The pills are placed in polypropylene bottles (50 pieces) and cardboard packs. The price of the drug is from 350 rubles.

Methotrexate Ebeve 10 mg is a yellow pill that has a biconvex oblong shape. The tablet has a dividing strip; on one side the edges of the pill are beveled. The cost of the medicine is from 500 rubles.

Regardless of the amount of methotrexate, all tablets have the same auxiliary composition:

• Cornstarch
• E 572
• Polysorb
• Milk sugar.

Methotrexate solution is a colorless liquid with a yellowish tint. In ampoules, Methotrixate can be contained in the form of a yellow-brown lyophilisate, from which a medicinal liquid for injection is prepared.

Methotrixate 10 ml is placed in transparent glass bottles, closed with a rubber stopper, on top of which there is a metal ring. Methotrixate 10 mg is also bottled in darkened glass ampoules.

Solution for injection Methotrexate 15 mg is placed in transparent ampoules, packaged in cardboard packs. Methotrexate 20 mg, 50 g and 1 g is available in vials as a concentrate.

Also, the medicinal solution is placed in clear glass syringes intended for single use. The kit includes 1-2 needles. The syringe containing methotrexate, on the basis of which injections are made, is packaged in a blister, located in a cardboard pack.

Regardless of the amount of medicinal liquid and dosage form, the Methotrexate solution has the same additional composition:

• Injection water
• E 524.

Methotrexate solution for injection costs from 200 rubles. The price of medicinal liquid placed in a syringe is about 1000 rubles.

Pharmacological properties

Methotrexate is a folic acid substitute that belongs to the antimetabolites. The drug has immunosuppressive and antitumor effects, so the use of Methotrexate is justified for sarcoma, thromboplastic formations, lymphoma and cancer.

Methotrexate inhibits dihydrofolate reductase, which reduces the folate derivative to tetrahydrofolate. The latter transports carbon fragments involved in the production of purine bases of their metabolites.

Folate antagonist inhibits DNA production, cell division and repair. Tissues with increased cell proliferation through mitosis are sensitive to the antimetabolite. These are ESCs, cancer cells, epithelial cells of the inner membranes and soft bone tissue. Methotrexate is also an immunosuppressant.

Pharmacokinetics of tablets:

• Resorption from the gastrointestinal tract – high at a dose of 30 mg/m2, low at a dose of 80 mg/m2
• F is 50%
• Tmax – 60-120 minutes
• Interaction with plasma proteins – 50%
• Metabolism - occurs in the liver, partly in the intestines
• T1/2 – initial phase – up to 4 hours, final phase – up to 10-15 hours
• Excretion - excreted unchanged in urine and bile.

Methotrexate tablets almost do not penetrate the placenta, but are absorbed into breast milk.

With leukemia in childhood, resorption is 23-95%. With chronic renal failure and abdominal dropsy, the release of the drug slows down.

With intramuscular administration of Methotrexate, its optimal amount in the blood is achieved within 30-60 minutes, with leukemia - 1-3 hours.

The drug binds 50% to albumin. Metabolism occurs in cells and liver.

The half-life at a dosage of less than 30 mg/m2 takes up to 7 hours, if the amount of the drug is higher - up to 17 hours. In chronic renal failure, methotrexate excretion decreases. Up to 90% of the solution is excreted by the kidneys throughout the day.

Indications and contraindications for use

Methotrexate is used for osteosarcoma, gestational trophoblastic neoplasm, advanced fungal infections, and leukoma of the spinal cord or brain. The drug is also used for lymphoblastic or myeloid leukemia, soft tissue tumors, and non-Hodgkin lymphomas.

Other indications are cancer affecting the genitals, head, mammary gland, kidneys, neck, eyes, integument, gastrointestinal tract and urinary system. Also, solution and tablets are prescribed for severe cases of Bechterov's or Libman's disease, lichen planus, sporadic or rheumatoid arthritis, and lilac disease.

Contraindications:

• Withdrawal syndrome
• Kidney or liver dysfunction
• Lactation
• Gastrointestinal and oral ulcers
• Acute severe chronic infections
• Vaccination using live bacteria
• Pregnancy
• Methotrexate intolerance.

Instructions for use

Methotrexate tablets are taken orally. For leukemia, the dose for adults is 30 mg twice a week. The permissible amount of the drug per day for children is 0.02 g/1 m2.

The duration of therapy is 14 days. Intensive course for adults – 20-25 mg, which is taken for 5 days. After a break of 14-20 days, the treatment is repeated.

For uterine tumors, Methotrexate is taken for five days, 50 mg per day. After 30 days, treatment is repeated. Another therapeutic regimen is up to 30 mg per day for 5 days with interruption of intake for 7-14 days.

Methotrexate Ebewe instructions for use for psoriasis:

• 5 mg once a day or 2.5 mg up to 4 times a day.
• Therapy time is 5-7 days on and 3 days off.

It is noteworthy that during treatment with Methotrexate it is necessary to test the blood three times a week for the content of platelets and leukocytes.

Methotrexate solution is administered intravenously, intramuscularly, or an injection into the spinal canal. Before use, the concentrate is mixed with NaCl solution.

The standard treatment regimen is 30 mg twice a week. Intensive treatment - up to 25 mg every day for 5 days. After 14-20 days, repeated therapy is carried out.

The highest dose per day in childhood is 20 mg/m2. For uterine tumors, administer 50 mg once a day for 5 days. After a 30-day break, treatment is repeated.

In the case of neuroleukemia, an injection of Methotrexate is given into the cavity in the spinal column. Dosage of solution (0.2%) – up to 10 mg/m2 every 3-4 days.

The treatment regimen for psoriasis is 10-25 mg once every 7 days.

When administering high dose Methotrexate, it is important to adjust the pH of the urine.

Side effects, overdose, interactions

After using Methotrexate, the function of the circulatory system may be impaired, which is manifested by anemia, low levels of platelets, neutrophils, leukocytes, and T-lymphocytes. When using the solution, local reactions often occur in the form of rashes, itching, acne, peeling, dermatitis or baldness.

Other side effects of Methotrexate:

• CNS – vertigo, organic brain damage, myalgia, malaise, convulsions, coma, nervousness, headache
• Gastrointestinal tract - pancreatitis, nausea, stool disorder, bleeding, liver dysfunction, ulcer of the digestive organs, vomiting
• Reproductive system – impotence, spermatogenesis disorder, teratogenic effect
• Respiratory organs – pulmonary infections, fibrosing alveolitis, pulmonary fibrosis
• Genitourinary system – kidney dysfunction, bladder inflammation
• Immune system – photophobia, fever, dermatitis bellosa, urticaria, erythema, anaphylactic shock, chills.

Methotrexate can also cause visual disturbances and contribute to the occurrence of immunosuppression, atralgia, osteoporosis, and inflammation of the vascular walls.

In case of overdose, an antidote is used - calcium salt of folinic acid. The drug must be administered in the first 60 minutes in a dosage similar to the amount of previously used Methotrexate. It is equally important to increase urine pH and restore water balance.

• Antibiotics
• Probenacid
• Azathioprine
• Phenytoin
• L-asparaginase
• Cholestyramine
• Aminobenzoic acid
• Sulfonylurea derivatives
• Folic acid
• Dinitrogen oxide
• Indirect anticoagulants
• Phenylbutazone and others.

Analogues

The drug Methotrexate has the following analogues - Metortit and Methoject.

Manufacturer – K.O. Rompharm, Romania

Price– 530 rubles

Description – injection solution is used for severe rheumatoid arthritis, psoriasis, kidney, liver, breast, ovarian, blood, sarcoma cancer

Pros– effectiveness, extensive list of indications

Cons– many undesirable effects, allergic reactions at the injection site.

Manufacturer – Medak GmbH, Germany

Price– about 700 rubles

Description – medicinal solution is indicated for arthritis and psoriasis

Pros– eliminates inflammation and pain, well tolerated

Cons– cost, a lot of side effects.

Formula: C20H22N8O5, chemical name: N-methylamino]benzoyl]-L-glutamic acid (and as disodium salt).
Pharmacological group: antitumor agents/ antimetabolites/ folic acid antagonist.
Pharmacological action: cytostatic, antitumor, immunosuppressive.

Pharmacological properties

Methotrexate inhibits the enzyme dihydrofolate reductase, under the influence of which tetrahydrofolic acid is synthesized from dihydrofolic acid, which, in turn, is a donor of one-carbon groups in the formation of thymidylate and purine nucleotides necessary in DNA synthesis. Also in cells, methotrexate is polyglutaminated, and metabolites are formed that inhibit not only dihydrofolate reductase, but also other folate-dependent enzymes, including 5-aminoimidazole-4-carboxamidoribonucleotide transamylase and thymidylate synthetase. Methotrexate suppresses cell mitosis, DNA repair and synthesis, and has less effect on protein and RNA synthesis. Methotrexate has S-phase specificity, is active against tissues with high cell proliferative activity, and slows the growth of malignant tumors.
The most sensitive to methotrexate are actively dividing tumor cells, as well as the embryo, bone marrow, intestinal mucous membranes, oral cavity, and bladder. Methotrexate has teratogenic properties and has a cytotoxic effect. When conducting carcinogenicity studies, it was discovered that methotrexate leads to chromosomal damage in human bone marrow cells and animal somatic cells, but this information did not allow us to draw definitive conclusions about the presence of carcinogenicity of the drug.
Methotrexate is effective in the treatment of steroid-dependent bronchial asthma, chronic ulcerative colitis, Crohn's disease, Reiter's syndrome, mycosis fungoides (in later stages), psoriatic arthritis, reticular erythroderma, juvenile rheumatoid arthritis, for the prevention of graft-versus-host reactions. When taken orally, 30 mg/m2 or less is completely and quickly absorbed from the gastrointestinal tract (bioavailability is approximately 60%). In children with leukemia, the absorption rate of the drug ranges from 23 to 95%. When the dose is increased to 80 mg/m2, the absorption of methotrexate decreases significantly. The maximum concentration is achieved after 1–2 hours when administered orally and after 0.5–1 hour when administered intravenously. Eating slows down the absorption time by about 0.5 hours, but does not affect the degree of absorption and bioavailability. 50–60% bound to proteins (mainly albumin). It passes through the blood-brain to a limited extent (depending on the dose), enters breast milk and penetrates the placental barrier and has a teratogenic effect on the fetus. In cells (not only the liver) it is metabolized to form polyglutamates, which under the action of hydrolases can be converted into methotrexate. When taken orally, it is partially metabolized by intestinal microflora. A small amount of polyglutaminated derivatives is retained in tissues for a long time. The duration of exposure and retention time of these active metabolites depends on the tissue type, cell type, and tumor type. A small amount of methotrexate is metabolized to 7-hydroxymethotrexate. The accumulation of this metabolite occurs after taking high doses of the drug prescribed for the treatment of osteosarcoma.
The terminal half-life depends on the dose and is 3–10 hours when using low doses and 8–15 hours when using high doses of the drug. 80–90% of an intravenously administered dose of methotrexate is excreted unchanged by the kidneys within 24 hours, and less than 10% is excreted in the bile. The clearance of methotrexate varies widely and decreases when used in high doses. The elimination of methotrexate in patients with pleural effusion or severe ascites is slow.

Indications

Choriocarcinoma of the uterus, tumors of the central nervous system (leukemoid infiltration of the meninges); acute lymphocytic leukemia; breast cancer; neck and head cancer; cancer of the bladder, lungs, stomach; non-Hodgkin's lymphoma; Hodgkin's disease; retinoblastoma; Ewing's sarcoma; osteosarcoma; soft tissue sarcoma; rheumatoid arthritis; refractory psoriasis (only with an accurate diagnosis and resistance to other types of treatment).

Method of administration of methotrexate and dose

Methotrexate is taken orally, administered parenterally (intraarterial, intravenous, intramuscular, intrathecal), depending on the indications. Doses are selected individually depending on the type of tumor, its stage, tolerability and effectiveness of treatment. The doses of methotrexate used in accordance with treatment regimens are divided into low (or usual) (single dose less than 100 mg/m2), medium (single dose 100–1000 mg/m2) and high (single dose more than 1000 mg/m2). Treatment with low doses (without covering with calcium folinate): 2 times a week intravenously 15–20 mg/m2 or once a week intravenously 30–50 mg/m2, or intravenously (intramuscularly) 15 mg/m2 per day for 5 days, repeated after 2–3 weeks.
Medium dose treatment: intravenous 50–150 mg/m2 (without calcium folinate coverage) repeated after 2–3 weeks or 240 mg/m2 (intravenous infusion over 24 hours covered with calcium folinate) repeated after 4–7 days; or 500–1000 mg/m2 (intravenous infusion over 36–42 hours under cover of calcium folinate), repeated after 2–3 weeks.
Treatment with high doses (under the cover of calcium folinate): 1000–1200 mg/m2 (intravenous infusion 1–6 hours) repeated after 1–3 weeks (monitoring of methotrexate blood levels is necessary). 8–12 mg/m2 or 0.2–0.5 mg/kg body weight is administered intrathecally every 2–3 days, the maximum dose is 15 mg/m2; after symptoms decrease, the intervals between courses of treatment are 1 week, in fact 1 month until cerebrospinal fluid levels return to normal; Prophylactic intrathecal administration is indicated every 6–8 weeks.
For severe generalized resistant psoriasis, including psoriatic arthritis and other autoimmune diseases, parenteral methotrexate 10–50 mg is administered at weekly intervals; for resistant rheumatoid arthritis - 5–15 mg intramuscularly once a week, the maximum dose is 25 mg per week. Inside (before meals); The initial dose is 2.5–5 mg, then gradually increase the dose to 7.5–25 mg per week, the maximum total dose per week is 25 mg.
Methotrexate for parenteral administration in the form of lyophilized powder is not suitable for intrathecal administration due to the presence of a preservative.
It is necessary to avoid conception during and after methotrexate therapy (for women - at least one ovulation cycle, for men at least 3 months after therapy). After a course of methotrexate therapy, it is necessary to use calcium folinate to reduce the toxic effects of the drug. It is necessary to follow the rules for the use and disposal of methotrexate. Methotrexate is used only under the close supervision of a physician. For early detection of signs of intoxication, it is necessary to regularly monitor the state of peripheral blood, the activity of liver transaminases, the functional state of the kidneys, and periodically conduct x-ray examinations of the chest organs. Treatment with methotrexate is canceled if the number of lymphocytes in the blood is less than 1.5 109/l, neutrophils - less than 0.2 109/l, platelets less than 75 109/l. An increase in creatinine levels of 50% or more than the initial level requires re-evaluation of creatinine clearance. An increase in bilirubin levels requires intensive detoxification treatment. A bone marrow hematopoiesis study should be carried out before the start of therapy, once during therapy and at the end of the course of therapy. The content of methotrexate in plasma must be determined immediately after the end of administration, as well as after 24 hours, 2 and 3 days. During therapy with increased and high doses, it is necessary to monitor the pH of the urine. Therapy with increased and high doses of methotrexate is combined with enhanced hydration. If ulcerative stomatitis and diarrhea occur, treatment with methotrexate is interrupted. If pulmonary toxicity develops, methotrexate therapy is discontinued due to the possibility of irreversible toxic effects on the lungs. It is necessary to avoid the use of alcohol and drugs that have hepatotoxicity; prolonged exposure to the sun. With combination therapy, each drug must be used at the prescribed time; If a dose is missed, do not take the drug and do not double the dose. During methotrexate therapy, vaccination is not recommended; it is also necessary to avoid contact with patients with bacterial infections, with people who have received the polio vaccine. Live viral vaccines should not be used in patients with leukemia in remission for 3 months after the last course of chemotherapy. The appearance of black tarry stools, unusual hemorrhages or bleeding, signs of bone marrow suppression, pinpoint red spots on the skin, blood in the urine or stool requires urgent consultation with a doctor. It is necessary to try to avoid situations in which the development of bleeding, hemorrhages, and injuries is possible. Ascites, pleural exudates, effusion in the area of ​​surgical wounds can lead to intoxication of the body with methotrexate. In patients with neutropenia, antibiotics should be started empirically if hyperthermia develops.

Contraindications for use

Hypersensitivity, anemia (including hypo- and aplastic), immunodeficiency, leukopenia, leukemia with hemorrhagic syndrome, thrombocytopenia, renal or liver failure.

Restrictions on use

Infectious diseases, recent surgery, ulcers of the gastrointestinal tract and oral cavity, kidney stones or a history of gout (risk of developing hyperuricemia), childhood and old age.

Use during pregnancy and breastfeeding

Methotrexate is contraindicated during pregnancy. Breastfeeding should be stopped during methotrexate therapy.

Side effects of methotrexate

Nervous system and sensory organs: encephalopathy, dizziness, blurred vision, headache, drowsiness, back pain, aphasia, stiff neck, paralysis, convulsions, hemiparesis, fatigue, confusion, weakness, ataxia, irritability, tremor, coma, excessive lacrimation, conjunctivitis , cataract, cortical blindness, photophobia;
circulatory and blood system: anemia, thrombocytopenia, leukopenia, neutropenia, hypogammaglobulinemia, lymphopenia, septicemia due to leukopenia, hemorrhage, pericarditis, hypotension, exudative pericarditis, thromboembolic changes (cerebral thrombosis, arterial thrombosis, deep vein thrombosis, thrombophlebitis, renal vein thrombosis, pulmonary embolism);
digestive system: gingivitis, ulcerative stomatitis, pharyngitis, nausea, anorexia, vomiting, difficulty swallowing, diarrhea, melena, gastrointestinal bleeding, ulceration of the mucous membranes, liver damage, enteritis, cirrhosis and fibrosis of the liver; respiratory system: pulmonary fibrosis, interstitial pneumonitis, exacerbation of pulmonary infections;
genitourinary system: cystitis, azotemia, nephropathy, hematuria, severe nephropathy, hyperuricemia, dysmenorrhea, disturbance of the process of spermatogenesis and oogenesis, unstable oligospermia, fetal defects;
skin: itching, skin erythema, hair loss, photosensitivity, acne, ecchymosis, furunculosis, de- or hyperpigmentation of the skin, peeling, blistering, telangiectasia, folliculitis, Stevens-Johnson syndrome, toxic epidermal necrolysis;
allergic reactions: chills, fever, urticaria, rash, anaphylaxis;
others: immunosuppression, opportunistic infection (viral, bacterial, protozoal, fungal), vasculitis, osteoporosis.

Interaction of methotrexate with other substances

Prolonged and enhanced effects of methotrexate, which leads to intoxication, are facilitated by the combined use of barbiturates, non-steroidal anti-inflammatory drugs, sulfonamides, tetracyclines, corticosteroids, trimethoprim, para-aminohippuric and para-aminobenzoic acids, chloramphenicol, probenecid. Folic acid and its derivatives reduce the effectiveness of methotrexate. Methotrexate enhances the effect of indirect anticoagulants (indanedione or coumarin derivatives) and increases the possibility of bleeding. Penicillins reduce the renal clearance of methotrexate. When methotrexate and asparaginase are used together, the effects of methotrexate may be blocked. The absorption of methotrexate (for oral use) may be reduced by neomycin (for oral use). If any drugs have the same effect on the blood and hematopoietic system as methotrexate, then the inhibition of hematopoiesis increases when used together with methotrexate. It is possible to develop a synergistic cytotoxic effect when combining methotrexate with cytarabine. When intrathecal methotrexate is used together with parenteral acyclovir, the development of neurological disorders is possible. Combining methotrexate with live viral vaccines may result in increased replication of the vaccine virus, decreased antibody production in response to both inactivated and live vaccines, and increased vaccine side effects.

Overdose

There are no specific symptoms in case of an overdose of methotrexate. Immediate administration of calcium folinate is necessary to neutralize the toxic effects of methotrexate on red bone marrow. The dose of calcium folinate should be no less than the dose of methotrexate and is administered within the first hour; the following doses are administered as needed. It is also necessary to increase body hydration and alkalize urine to avoid precipitation of methotrexate and its metabolites in the urinary tract.