What is agitation in medicine? Causes of development, symptoms and treatment methods for agitation

Antitumor drug. Used in the treatment of benign and malignant tumors.

Instructions for use:

Methotrexate is a cytostatic drug from the group of antimetabolites, antagonists folic acid. It has a pronounced immunosuppressive effect even in relatively low doses without noticeable hematological toxicity. Due to this, methotrexate is used more widely than other cytostatics with immunosuppressive activity as an immunosuppressive drug.

Description of the drug Methotrexate is not intended for prescribing treatment without the participation of a physician.

Release form and composition

Pills

Injection

Pharmacological properties

Has antitumor and immunosuppressive effect. Actively dividing cells of malignant tumors, as well as bone marrow, embryo, mucous membranes of the oral cavity, intestines, Bladder.

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). The binding to plasma proteins is about 50%.

Upon admission to therapeutic doses Regardless of the route of administration, it practically does not penetrate the blood-brain barrier (after intrathecal administration in the cerebrospinal fluid high concentrations). Secreted in breast milk, passes through the placenta (has a teratogenic effect on the fetus).

Metabolized predominantly in liver cells to form polyglutamates (DHF and thymidylate synthetase inhibitors), which can be converted to methotrexate by the action of hydrolases.

A small amount of polyglutaminate derivatives is retained in tissues long time. The retention time and duration of action of these active metabolites depends on the cell type, tissue, and tumor type.

Slightly metabolized (with the introduction of normal doses) to 7-hydroxymethotrexate (solubility in water is 3-5 times lower than that of methotrexate). Accumulation of this metabolite occurs upon administration high doses methotrexate, prescribed for the treatment of osteosarcoma.

The half-life in patients receiving less than 30 mg/m2 of the drug in the initial phase is 2-4 hours. The final half-life is dose-dependent and is 3-10 hours with the introduction of low (less than 30 mg/m2) and 8-15 hours with high doses of methotrexate (80 mg/m2 or more).

Excreted primarily by the kidneys glomerular filtration and tubular secretion within 24 hours, less than 10% is excreted in bile. Methotrexate clearance varies widely and decreases at high doses.

Elimination of the drug in patients with severe ascites or effusion in pleural fluid slowly. At reintroduction accumulates in tissues in the form of metabolites. In chronic renal failure, the elimination of the drug can be significantly prolonged.

Indications for use of Methotrexate

lympho- and myeloblastic leukemia;
neuroleukemia;
multiple myeloma;
trophoblastic tumors;
esophageal carcinoma;
squamous cell carcinoma of the head and neck;
bladder cancer;
lung cancer;
liver cancer;
mammary cancer;
kidney cancer;
ureteral cancer;
prostate cancer;
cervical cancer;
vulvar cancer;
ovarian cancer;
testicular cancer;
penile cancer;
Hodgkin and non-Hodgkin lymphomas (including Burkitt lymphoma);
mycosis fungoides (local treatment);
non-metastatic osteosarcoma.

Besides:

rheumatoid arthritis (including Felty's syndrome);
steroid-dependent bronchial asthma;
Crohn's disease;
chronic nonspecific ulcerative colitis;
lichen planus;
psoriasis;
psoriatic arthritis;
Reiter's syndrome;
Sézary syndrome;
multiple sclerosis.

Directions for use and doses

Doses and timing of treatment are set individually, depending on the chemotherapy regimen, indications, treatment regimen, patient “response” and tolerability. Doses are calculated based on body surface area or patient weight.

The doses used in accordance with the treatment regimens are divided:

usual (low) doses ( single dose below 100 mg/m2);
medium (single dose 100-1000 mg/m2);
high (single dose above 1000 mg/m2).

Doses above 100 mg/m2 are administered only intravenously and under the protection of calcium folinate. For intravenous administration the drug is diluted in a 5% dextrose solution to a concentration of 10 mg/ml.

Apply following modes dosing:

Features of application

Conception should be avoided during treatment with methotrexate and after it (men - 3 months after treatment, women - at least one ovulation cycle). After a course of treatment with methotrexate, it is recommended to use calcium folinate to reduce toxic effects high doses of the drug. If diarrhea and ulcerative stomatitis develop, methotrexate therapy should be interrupted and consult a doctor immediately.

Side effects

From the nervous system and sensory organs:

encephalopathy;
dizziness;
headache;
visual impairment;
drowsiness;
aphasia;
back pain;
stiffness of the muscles in the back of the neck;
convulsions;
paralysis;
hemiparesis.

In some cases:

fatigue;
weakness;
confusion;
ataxia;
tremor;
irritability;
coma;
conjunctivitis;
excessive tearing;
cataract;
photophobia;
cortical blindness (at high doses).

From the cardiovascular system:

pericarditis;
exudative pericarditis;
hypotension.

Thromboembolic changes:

arterial thrombosis;
cerebral thrombosis;
deep vein thrombosis;
thrombosis renal vein;
thrombophlebitis;
pulmonary embolism.

From the hematopoietic organs and hemostasis system:

anemia;
leukopenia;
thrombocytopenia;
neutropenia;
lymphopenia (especially T lymphocytes);
hypogamma globulinemia;
hemorrhage;
septicemia due to leukopenia.

From the respiratory system:

interstitial pneumonitis;
pulmonary fibrosis;
exacerbation of pulmonary infections.

From the gastrointestinal tract:

gingivitis;
pharyngitis;
ulcerative stomatitis;
anorexia;
nausea;
vomit;
diarrhea;
difficulty swallowing;
melena;
ulceration of the gastrointestinal mucosa;
gastrointestinal bleeding;
enteritis;
liver damage;
fibrosis and cirrhosis of the liver.

From the genitourinary system:

cystitis;
nephropathy;
azotemia;
hematuria;
hyperuricemia or severe nephropathy;
dysmenorrhea;
unstable oligospermia;
disruption of the process of oogenesis and spermatogenesis;
abnormalities of fetal development.

From the skin:

cutaneous erythema;
hair loss (rare);
photosensitivity;
ecchymosis;
acne-like rash;
furunculosis;
peeling;
de- or hyperpigmentation of the skin;
blistering;
folliculitis;
telangiectasia;
toxic epidermal necrolysis;
Stevens-Johnson syndrome.

Allergic reactions:

fever;
chills;
rash;
hives;
anaphylaxis.

Others:

immunosuppression;
opportunistic infection;
osteoporosis;
vasculitis

Interaction with other drugs

The enhanced and prolonged action 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.

Enhances the effect indirect anticoagulants(coumarin or indanedione derivatives) and increases the risk of bleeding.

Penicillin group drugs reduce renal clearance methotrexate.

At simultaneous use methotrexate and asparaginase may block the action of methotrexate.

Neomycin (oral) may reduce the absorption of methotrexate.

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.

In combination with live viral vaccines, it can cause an intensification of the replication process of the vaccine virus, strengthening side effects vaccines and decreased antibody production in response to administration of both live and inactivated vaccines.

Contraindications

hypersensitivity;
immunodeficiency;
anemia (including hypo- and aplastic);
leukopenia;
thrombocytopenia;
leukemia with hemorrhagic syndrome;
liver or kidney failure;
effusion into the pleural cavity;
ascites;
suppression of bone marrow function;
chicken pox (including recently suffered);
stomatitis;
ulcerative colitis.

Contraindicated during pregnancy (can cause fetal death or cause congenital deformities). During treatment should be stopped breast-feeding.

Overdose

There are no specific symptoms of overdose. In case of intentional or accidental intake of doses exceeding the recommended ones, as well as when obvious symptoms side effects, you should consult a doctor immediately.

Storage conditions and periods

Conditions for dispensing from pharmacies

Dispensed by prescription.

Methotrexate analogues

The following drugs are analogues:

Vero-Methotrexate;
Methotrexate Teva;
Methotab;
Methodject;
Zeksat.

Methotrexate price

You can buy Methotrexate tablets and solution for injections in pharmacies for 169–597 rubles.

Gross formula

C20H22N8O5

Pharmacological group of the substance Methotrexate

Nosological classification (ICD-10)

CAS Code

59-05-2

Characteristics of the substance Methotrexate

Antimetabolite group structural analogues 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

pharmachologic effect- 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, affects RNA and protein synthesis to a lesser extent. Has S-phase specificity, is active against tissues with high cell proliferative activity, inhibits growth malignant neoplasms. 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.

The effectiveness of methotrexate 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 disease.

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.

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 injection into significant quantities enters systemic blood flow. 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 intestinal microflora(after ingestion). 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 (solubility in water 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 meninges), breast cancer, head and neck cancer, lung, bladder, stomach cancer; Hodgkin's disease, non-Hodgkin's lymphoma, retinoblastoma, osteosarcoma, Ewing's sarcoma, soft tissue sarcoma; refractory psoriasis (only with 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, oral and gastrointestinal ulcers, recent surgery, history of gout or kidney stones (risk of hyperuricemia), elderly and childhood.

Use during pregnancy and breastfeeding

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

At the time of treatment should stop breastfeeding.

Side effects of the substance Methotrexate

From the outside nervous system and sense 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 outside of cardio-vascular system(blood formation, 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 outside 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 outside 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 outside 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 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 simultaneous use of methotrexate (intrathecal) with acyclovir (parenteral), neurological disorders. 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: specific symptoms are missing.

Treatment: immediate administration of calcium folinate to neutralize myelo toxic effect 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 hydration of the body, alkalize urine to avoid precipitation of the drug and its metabolites in urinary tract.

Routes of administration

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

Precautions for the substance Methotrexate

Apply under careful medical supervision. For timely detection symptoms of intoxication need to be monitored 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, periodically perform fluoroscopy of organs chest. 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. It is recommended to study bone marrow hematopoiesis 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).

Should be paid Special attention in cases of decreased hematopoietic function of the bone marrow caused by the use of radiation therapy, chemotherapy or long-term use some drugs (sulfonamides, amidopyrine derivatives, chloramphenicol, indomethacin). In such cases it usually worsens general state, 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. At 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 with patients should be avoided bacterial infections. Apply live viral vaccines in patients with leukemia in remission should not be administered 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.

Be careful to avoid accidental cuts sharp objects(safety razor, scissors), avoid activities contact types sports or other situations in which hemorrhage or injury may occur.

Tablets 2.5 mg

- Lyophilisate for the preparation of solution for injection

- Tablets 2.5 mg

- Solution for injection 2.5 or 25 mg/ml

- Concentrate for the preparation of solution for infusion 100 mg/ml

- Injection

Analogs

These are medicines belonging to the same pharmaceutical group that contain different active substances(INN), differ in name, but are used to treat the same diseases.

- Lyophilisate for the preparation of solution for infusion 2 mg

Dosage forms of the drug

Tablets - 2.5 mg
Substance-powder - 0.1-5 kg
Solution for injection - 1 ml

Indications for use of the drug 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.

Release form of the drug Methotrexate

tablets 2.5 mg; bottle (bottle) 100, box (box) 1;
film-coated tablets 2.5 mg; polymer jar (jar) 50, cardboard pack 1;
film-coated tablets 2.5 mg; contour packaging 10, cardboard pack 1,2,3,4,5,6,8,10;
film-coated tablets 2.5 mg; contour packaging 50, cardboard pack 2,3,4,5,6,8,10;

Film-coated tablets 2.5 mg; polymer container 10,20,30,40,50,100 pcs., cardboard pack 1;
tablets, coated film-coated 2.5 mg; contour cell packaging 10, cardboard pack 1,2,3,5;
film-coated tablets 2.5 mg; polymer bottle (bottle) 50, cardboard pack 1;
film-coated tablets 2.5 mg; dark glass jar (jar) 50, cardboard pack 1;

Pharmacodynamics of the drug Methotrexate

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.

Pharmacokinetics of the drug Methotrexate

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 when administered orally and after 30–60 minutes when administered intramuscularly. Taking with food slows the time required to reach Cmax by approximately 30 minutes, but the level of absorption and bioavailability do not change.

Use of the drug Methotrexate during pregnancy

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

At the time of treatment should stop breastfeeding.

Contraindications to the use of Methotrexate

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

Side effects of the drug Methotrexate

From the nervous system and sensory organs: encephalopathy (especially when administered multiple doses 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 (rarely), 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.

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

Method of administration and dosage of the drug Methotrexate

The dose is individualized depending on the type of tumor, stage of the disease, effectiveness of therapy, and tolerability.

The doses used, in accordance with the treatment regimens, are divided into normal (low) doses (single dose below 100 mg/m2), medium (single dose 100–1000 mg/m2) and high (single dose above 1000 mg/m2).

Therapy usual doses(without calcium cover with folinate): IV 15–20 mg/m2 2 times a week or 30–50 mg/m2 once a week, or IM, IV 15 mg/m2 per day for 5 days, repeated every other 2–3 weeks

Medium dose therapy: IV 50–150 mg/m2 (without calcium folinate cover) repeated after 2–3 weeks or 240 mg/m2 (IV infusion over 24 hours covered with calcium folinate) repeated after 4–7 days; or 500–1000 mg/m2 (iv infusion over 36–42 hours under the cover of calcium folinate) repeated after 2–3 weeks.

High-dose therapy (under the cover of calcium folinate): 1000–1200 mg/m2 (iv infusion 1–6 hours) repeated after 1–3 weeks (requires monitoring of serum methotrexate levels).

Intrathecally 0.2–0.5 mg/kg body weight or 8–12 mg/m2 every 2–3 days. The maximum dose for intrathecal administration is 15 mg/m2. After symptoms decrease, the intervals between courses of therapy are a week, then a month, until cerebrospinal fluid levels normalize. Prophylactic intrathecal injections are indicated every 6–8 weeks.

In severe cases of generalized resistant psoriasis, including psoriatic arthritis and other autoimmune diseases, parenteral methotrexate 10-50 mg at weekly intervals. For resistant rheumatoid arthritis - 5–15 mg IM once a week, maximum dose per week - 25 mg.

Inside (before meals). Usually the initial dose is 2.5–5 mg, then the dose is gradually increased to 7.5–25 mg per week, the weekly dose is 10–25 mg, the maximum total dose is 25 mg per week. Typically, 2.5 mg of methotrexate is taken 3 times a week at 12-hour intervals and with a break of a week (Monday - morning and evening, Tuesday - morning, then break until next Monday).

Overdose of Methotrexate

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.

Interactions of Methotrexate with other drugs

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.

Precautions when taking 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 the period of 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 1.5·109/l, the number of neutrophils is less than 0.2·109/l, and the number of platelets is less than 75·109/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. It is recommended to study bone marrow hematopoiesis 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 (dropwise) 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.

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.

Be careful to avoid accidental cuts from sharp objects (safety razor, scissors), and avoid playing contact sports or other situations that may cause bleeding or injury.

Presence of ascites, pleural exudates, effusion in the area surgical wounds promotes the accumulation of methotrexate in tissues and enhances its action, which can lead to intoxication of the body.

Dental interventions should, if possible, be completed before the start of therapy or postponed until the blood picture normalizes (possibly an increased risk of microbial infections, slower healing processes, bleeding gums). During treatment, be careful when using toothbrushes, floss or toothpicks.

In patients with thrombocytopenia that has developed as a result of methotrexate use, it is recommended to observe special measures precautions (limiting the frequency of venipuncture, avoiding intramuscular injections, testing urine, stool and secretions for occult blood; preventing constipation, quitting acetylsalicylic acid etc.), with leukopenia - carefully monitor the development of infections. In patients with neutropenia, when the temperature rises, the use of antibiotics should be started empirically.

Special instructions when taking Methotrexate

Methotrexate for injection in the form of lyophilized powder due to the presence of a preservative is not suitable for intrathecal administration.

Conception should be avoided during and after treatment with methotrexate (men - 3 months after treatment, women - at least one ovulation cycle). After a course of treatment with methotrexate, the use of calcium folinate is recommended to reduce the toxic effects of high doses of the drug.

Should be observed necessary rules use and disposal of the drug.

Storage conditions for the drug Methotrexate

List B.: In a dry place, protected from light, at a temperature of 15–20 °C.

Shelf life of the drug Methotrexate

The drug Methotrexate belongs to the ATX classification:

L Antitumor drugs and immunomodulators

L01 Antineoplastic drugs

L01B Antimetabolites

L01BA Folic acid analogues

Methotrexate – cytostatic agent, belonging to the group of folic acid antagonists. Even in small dosages it leads to an immunosuppressive effect. It was first received in 1940. Currently used as an immune suppressant.

Composition, release form and storage conditions

Methotrexate is available in tablets or as an injection solution for intravenous or intramuscular administration.

The active ingredient is methotrexate. In solutions for injections it is supplemented with methylparaben, propylparaben, and water for injection. The tablets contain cellulose, corn starch, silicon dioxide.

Photo of Methotrexate in ampoules

The medicine must be stored in places where children cannot reach it. Mandatory compliance temperature regime from 15 to 20 degrees. Dispensed according to a doctor's prescription.

Manufacturers

The product is produced by various manufacturers. The differences mainly relate to fillers and stabilizers.

Doctors say that this does not affect the effectiveness, but the side effects on the components may be different.

In Austria, production has been established at Ebewe Pharma. Supplied in tablets, ampoules and concentrate in bottles with different amounts of active ingredient.
In Germany the company Medac GmbH produces ready solution for injection, packaged in disposable syringes.
In Russia The manufacturer is several companies: Valenta Pharmaceuticals, Ozon.

Indications for use

Methotrexate is effective in treating:

trophoblastic tumors,
mycosis fungoides,
rheumatoid arthritis,
psoriasis.

It has been proven to be effective in treating ureteral and aplastic anemia.

Contraindications

Do not take the drug during pregnancy, severe changes in the functioning of the kidneys, liver, or bone marrow hypoplasia.

Since the drug suppresses the immune system, it is not prescribed during acute periods. infectious diseases, as well as in immunodeficiency syndrome. Be careful when peptic ulcers, gout and dehydration.

Also, people who have previously undergone or should be under special supervision.

Mechanism of action

The antitumor drug stimulates the formation of dihydrofolate reductase, which plays a significant role in the reduction of dihydrofolic acid to tetrahydrofolic acid. This leads to inhibition of synthesis and DNA repair.

The mechanism of action of Methotrexate is associated with:

Suppression of LTV formation.
Decreased synthesis of IL-1.
Suppression of the activity of proteolytic enzymes in joints.
Suppression of mononuclear cells and antibody synthesis.

Instructions for use of Methotrexate Ebeve and Teva: dosage

The drug is taken orally or administered intramuscularly. To reduce toxicity in the first case, the drug is used weekly. The dose is calculated based on the patient's weight or body surface area.

Injections

Methotrexate-Ebeve is administered: i.m., i.v., i.v.

For trophoblastic tumors, 15-30 mg for five days. The interval is about one week. Another regimen may be prescribed, when the dose is increased and the interval is about a month.
When prescribed up to 5000 mg/sq. m. Administered by infusion once every 2-4 weeks.
When treating children, age is taken into account. Up to 1 year of age, 6 mg is prescribed, at 12 months - 8 mg, for children over 3 years old - 12 mg.

You may have to remove it before insertion. cerebrospinal fluid in the amount of medication that will be administered.

Pills

The dosage regimen depends on individual indications.

For leukemia as part of complex therapy at 33 mg/sq. m in combination with prednisolone. After the onset of positive dynamics at 15 mg/sq. m once a week or 2.5 mg/kg once every two weeks.
For trophoblastic tumors 15-30 mg every day for five days. The course is repeated 3 to 5 times.
For rheumatoid arthritis Initially, 7.5 mg is taken once a week. The dose may be given in one dose or divided into three doses 12 hours apart. For juvenile chronic arthritis for children, the dose can be up to 1 mg/kg per week.
For psoriasis The dose is increased gradually; when the effect is achieved, it begins to be reduced. For mycosis fungoides, 25 mg is prescribed 2 times a week. When canceling, the patient's reaction and blood counts are taken into account.

For optimal results, tablets are prescribed one hour before a meal or an hour and a half after a meal. It is recommended that when starting treatment the dosage should be in the range of 7.5 to 16 mg. In severe cases, it can be increased immediately.

Side effects

Expressiveness side effects The effects of taking Methotrexate vary from person to person.

From the outside digestive system the development of ulcerative stomatitis, anorexia, and pharyngitis is possible. IN in rare cases diarrhea opens or pancreatitis develops. In exceptional situations, cirrhosis and liver necrosis are possible.
Patients often report feeling tired, sometimes headaches, drowsiness, and convulsions are noted.
From the outside reproductive system a violation is noted menstrual cycle, decreased libido, development of impotence.
Other allergic and dermatological reactions may also occur: chills, skin rash, furunculosis, pigmentation disorder.

The severity of complications depends on many circumstances, including the severity of the disease.

special instructions

Due to the presence of a preservative, the injection product in powder form cannot be administered intrathecally.

You should also avoid conception during and after treatment.

Men should not do this for three months after the end of treatment, women should not do this for at least one ovulation cycle. After treatment, it is recommended to use calcium foliot to reduce toxic effects.

Drug interactions

The effect of Methotrexate is enhanced and its effect is prolonged with the simultaneous use of NSAIDs, barbiturates, corticosteroids, tetracycline and some other drugs.

Folic acid has the opposite effect, reducing the effectiveness of the drug.

Many antibiotics affect enterohepatic circulation due to suppression of bacterial metabolism.

Drugs penicillin group reduce renal clearance.

At concomitant therapy With drugs that affect the bone marrow, the development of more pronounced hematological disorders is often observed.

This drug is used in the fight against cancer, autoimmune diseases, and ectopic pregnancy. It is also used to call medical abortions. The action of methotrexate is aimed at inhibiting folic acid metabolism.

Since the 1950s, this drug began to replace the antifolate aminopterin, which was more toxic. The drug was originally synthesized by Indian biochemist Yellapraghad Subbarow, and clinical development was carried out by American pediatrician Sidney Farber. The drug is included in the List of Essential medicines World Organization health care, list of the most important medicines needed in the mainstream healthcare system.

Methotrexate was originally developed and continues to be used for chemotherapy, either alone or in combination with other agents. It is effective in treating a number of cancer diseases, including breast, head and neck cancer, leukemia, lymphoma, lung cancer, osteosarcoma, bladder cancer and trophoblastic neoplasms.

Autoimmune disorders

Methotrexate is used in therapy autoimmune diseases, including rheumatoid arthritis, juvenile dermatomyositis, psoriasis, psoriatic arthritis, lupus, sarcoidosis, Crohn's disease (although a recent review raised the issue that it is underused in Crohn's disease), eczema and many forms of vasculitis. Although it was originally developed as a chemotherapy drug (using high doses), low doses of methotrexate are generally safe and well tolerated in the treatment of autoimmune diseases. Because of its effectiveness, low doses have now become the first-line treatment for rheumatoid arthritis. Weekly doses are useful for therapy lasting 12–52 weeks, although treatment is discontinued in 16% of cases due to adverse effects. Although methotrexate for autoimmune diseases is taken at lower doses compared to cancer, it is still common unwanted effects such as hair loss, nausea, headaches and skin pigmentation. The use of methotrexate with NSAIDs is safe with adequate monitoring. Not all patients respond to methotrexate treatment, but several studies and reviews have shown that most people taking it for one year experienced less pain, function better, have less joint swelling and pain, and overall disease activity has decreased. as reported by patients and their doctors. X-rays also showed that disease progression slowed or stopped in many patients on methotrexate, and progression stopped completely in almost 30% of patients treated with the drug. People with rheumatoid arthritis treated with methotrexate have a reduced risk of cardiovascular events such as myocardial infarction (heart attacks and strokes). In addition, it was used for multiple sclerosis.

Abortion

Methotrexate is abortive and is used to terminate pregnancy early usually in combination with misoprostol. In addition, it has found use in the treatment of ectopic pregnancy if there is no rupture of the fallopian tubes.

Introduction

Methotrexate can be taken orally or given by injection (intramuscular, intravenous, subcutaneous, or intravenous). spinal canal). Oral doses are taken weekly rather than daily, which helps reduce toxicity. Standard monitoring with full analysis blood, liver functions and creatinine. Creatinine measurements are indicated at least every 2 months.

Video about methotrexate

Side effects of methotrexate

Among the most common side effects hepatotoxicity (liver damage), ulcerative stomatitis, decreased white blood cell count in the blood and thus susceptibility to infection, nausea, abdominal pain, fatigue, fever, dizziness, acute pneumonitis, rarely pulmonary fibrosis and renal failure. Methotrexate is teratogenic (harmful to the fetus) and therefore should not be used during pregnancy.

CNS reactions to methotrexate, especially when administered into the spinal canal, have been reported, including myelopathy and leukoencephalopathy. It has many skin side effects, particularly when administered in high doses.

Although not well understood, possible serious adverse effects of methotrexate include neurological damage and memory loss. Neurotoxicity may result from the drug crossing the blood-brain barrier and damaging neurons in the cerebral cortex. Cancer patients receiving this medication often refer to these effects as "chemobrain" or "chemo fog".

Drug interactions

Penicillins may reduce the elimination of methotrexate and thereby increase the risk of toxicity. Although they can be used together, increased monitoring is recommended. The aminoglycosides neomycin and paromomycin have been found to reduce the absorption of methotrexate in the gastrointestinal tract. Probenecid inhibits the excretion of methotrexate, thereby increasing the risk of toxicity. Retinoids and trimethoprim are known to interact with methotrexate, resulting in additive hepatotoxicity and hematoxicity, respectively. Other immunosuppressants, such as cyclosporine, may potentiate its hematologic effects, thereby leading to potential toxicity. In numerous cases, NSAIDs also interact lethally with methotrexate. Nitrous oxide has also been documented to potentiate the hematologic toxicity of methotrexate. Inhibitors proton pump, including omeprazole and anticonvulsant valproate increases plasma concentrations of methotrexate, as do nephrotoxic agents such as cisplatin, gastrointestinal drugs, cholestyramine and dantrolene. Caffeine may only antagonize the effects of methotrexate on rheumatoid arthritis through adenosine receptor antagonism.

Mechanism of action

Methotrexate is believed to affect cancer and rheumatoid arthritis in two different ways. In the case of cancer, methotrexate competitively inhibits dihydrofolate reductase (DHFR), an enzyme that is involved in the synthesis of tetrahydrofolate. The affinity of methotrexate for DHFR is almost a thousand times higher than that of folic acid. DHFR catalyzes the conversion of dihydrofolate to active tetrahydrofolate. Folic acid is required for new synthesis of the nucleoside thymidine, essential in DNA synthesis. In addition, folic acid is of high importance for the biosynthesis of purine and pyrimidine bases, so the synthesis will be interrupted. Methotrexate therefore inhibits the synthesis of DNA, RNA, thymidylates and proteins.

DHFR inhibition is not considered to be the primary mechanism in the treatment of rheumatoid arthritis, and multiple mechanisms appear to be involved, including:

inhibition of enzymes involved in purine metabolism, which leads to the accumulation of adenosine;
inhibition of T cell activation and inhibition of molecule expression intercellular adhesion via T cells;
selective down-regulation of B cells;
increasing the sensitivity of CD95 activated T cells;
inhibition of methyltransferase activity, and as a result there is deactivation of enzymatic activity associated with the function of the immune system.

Another mechanism is inhibition of the binding of interleukin 1 beta to its cell surface receptor.

Story

In 1947, a group of researchers led by Sidney Farber was able to show that aminopterin, a chemical analogue of folic acid developed by Yellapragade Subbarow of Lederle, could induce remission in pediatric patients with acute lymphoblastic leukemia. The development of folic acid analogues was accelerated by the discovery that folic acid administration worsened leukemia, and that folic acid-deficient diets could conversely produce improvements. The mechanism of action of these effects remained unknown at that time. Development of other folic acid analogues continued, and methotrexate (then known as aminopterin) was proposed as a treatment for leukemia by 1950. Animal studies published in 1956 showed that the therapeutic index of methotrexate was better than aminopterin, resulting in clinical application aminopterin was abandoned in favor of a new drug.

In 1951, Jane S. Wright demonstrated the use of methotrexate in solid tumors, showing remission of breast cancer. Wright's group was the first to demonstrate the drug's use in solid tumors, as opposed to leukemia (bone marrow cancer). Then Ming Chiu Lee's group showed complete remission in women with choriocarcinoma and choriadenomas in 1956, and in 1960 Wright and colleagues demonstrated remission of mycosis fungoides.