Anxious agitation. Frequent feelings of anxiety and excessive arousal are the first signs of agitation

Methotrexate: instructions for use and reviews

Methotrexate is an anticancer drug.

Release form and composition

Dosage form - coated tablets (50 pieces in polymer jars, in a carton box 1 jar).

The active substance is methotrexate, in 1 tablet - 2.5 mg.

Pharmacological properties

Pharmacodynamics

Methotrexate is an antitumor, cytostatic agent belonging to the group of antimetabolites. It inhibits dihydrofolate reductase, which is responsible for the reduction of dihydrofolic acid to tetrahydrofolic acid (the carrier of carbon fragments necessary for the production of purine nucleotides and their derivatives).

Methotrexate slows down cell mitosis and DNA synthesis and repair. Hypersensitivity tissues prone to rapid proliferation exhibit its action: epithelial cells oral mucosa, Bladder, intestines, cells of malignant tumor formations, embryonic cells, bone marrow cells. In addition to antitumor, the drug is also characterized by immunosuppressive action.

Pharmacokinetics

When taken orally, the absorption of methotrexate is determined by the dose: when taking the drug at a dose of 30 mg / m 2, it is well absorbed, and its bioavailability averages 60%.

In pediatric patients diagnosed with leukemia, the absorption of the substance varies from 23% to 95%. The maximum concentration of methotrexate is reached over a period of time ranging from 40 minutes to 4 hours. Its combination with food intake leads to a decrease in the rate of absorption and a decrease in the maximum concentration. The degree of binding to plasma proteins (mainly albumin) reaches approximately 50%.

After distribution in the tissues, methotrexate is found in significant concentrations in the kidneys, liver, and especially the spleen, turning into the form of polyglutamates. In these organs, the drug can accumulate for several weeks and even months.

After oral administration, the drug is partially metabolized with the participation of intestinal flora, mainly in the liver (regardless of the route of administration). This forms a polyglutamine form of methotrexate, which has pharmacological activity and is an inhibitor of dihydrofolate reductase and thymidine synthesis. In patients receiving methotrexate at a dose of less than 30 mg / m 2, the elimination half-life in the initial phase is 2-4 hours, and in the final phase, which is longer, 3-10 hours when using small doses and 8-15 hours - when using large doses of the drug. In patients with chronic renal failure, both phases of methotrexate excretion can be significantly prolonged.

Methotrexate is excreted mainly in the urine unchanged through tubular secretion and glomerular filtration. With bile, up to 10% of the substance is excreted, which is subsequently reabsorbed in the intestine. Removal of methotrexate in patients with renal dysfunction, severe transudate or ascites is significantly slowed down. At reintroduction the drug accumulates in tissues in the form of polyglutamates.

Indications for use

• Trophoblastic neoplasms;
• non-Hodgkin's lymphoma, acute lymphoblastic leukemia;
• Severe form of psoriasis;
• Far advanced stages of mycosis fungoides;
• Rheumatoid arthritis (in the absence of the effect of other treatments).

Contraindications

• Severe impairment of kidney and / or liver function;
• Hematological disorders, including bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia;
• Acute form of infectious diseases;
• immunodeficiency syndrome;
• The period of pregnancy and breastfeeding;
• Age up to 3 years;
• Hypersensitivity to the components of the drug.

According to the instructions, Methotrexate is recommended to be used with caution in patients with peptic ulcer stomach and duodenum, ulcerative colitis, infectious diseases of bacterial, viral or fungal origin, with effusion in pleural cavity, ascites, dehydration, nephrolithiasis or gout in history; against the background of previous radiation or chemotherapy.

Instructions for use Methotrexate: method and dosage

Methotrexate tablets are taken orally.

The doctor prescribes the dose and period of treatment based on clinical indications individually, taking into account the chemotherapy regimen.

• Trophoblastic tumors: 15-30 mg 1 time per day for 5 days. The course of treatment is repeated 3 to 5 times with a break of one or more weeks (taking into account signs of toxicity). In addition, an alternative appointment of 50 mg 1 time in 5 days with a break of 1 month or more is possible, the course involves taking 300-400 mg of the drug;
• Non-Hodgkin's lymphomas (composed of complex therapy): 15-20 mg per 1 m 2 of the patient's body surface 1 time per day 2 times a week or 7.5 mg per 1 m 2 1 time per day for 5 days;
• Acute lymphoblastic leukemia (as part of complex therapy): at the rate of 3.3 mg per 1 m 2 in combination with prednisolone. After achieving remission, the dosage regimen may be 15 mg per 1 m 2 2 times a week or 2.5 mg per 1 kg of the patient's weight every 14 days;
• Psoriasis: 10-25 mg per week, the dose should be increased gradually, after reaching the optimal clinical effect it begins to be reduced to the level of the smallest effective dose;
• Fungal mycosis: initial dose - 25 mg 2 times a week, depending on the patient's response and hematological parameters, the dose is reduced or the drug is discontinued;
• Rheumatoid arthritis: the initial dose is 7.5 mg once a week once or in 3 doses with an interval of 12 hours. In order to achieve the optimal clinical effect, an increase in the weekly dose to 20 mg is allowed. After achieving the desired result, the dose is recommended to be gradually reduced to the level of the lowest effective dose. The duration of therapy is determined individually. For children with juvenile chronic arthritis, the dose is determined at the rate of 10-30 mg per 1 m 2 of the child's body surface once a week or 0.3-1 mg per 1 kg of weight.

Side effects

• Hematopoietic system: thrombocytopenia, anemia (including aplastic), leukopenia, agranulocytosis, neutropenia, eosinophilia, lymphoproliferative diseases, lymphadenopathy, pancytopenia, hypogammaglobulinemia;
• Cardiovascular system: pericardial effusion, pericarditis, decreased blood pressure, thromboembolism (thrombosis cerebral vessels, arterial thrombosis, deep vein thrombosis, thrombophlebitis, retinal vein thrombosis, pulmonary embolism);
• Digestive system: nausea, vomiting, anorexia, stomatitis, pharyngitis, gingivitis, enteritis, erosive and ulcerative lesions and bleeding from gastrointestinal tract(including melena, hematemesis), pancreatitis, hepatotoxicity (increased liver enzymes, liver failure, acute hepatitis, cirrhosis and fibrosis of the liver, hypoalbuminemia);
• Nervous system: drowsiness, dizziness, headache, hemiparesis, dysarthria, paresis, aphasia, convulsions; against the backdrop of high doses - emotional lability, transient cognitive impairment, encephalopathy (including leukoencephalopathy), unusual cranial sensitivity;
• Organ of vision: visual impairment (including transient blindness), conjunctivitis;
• Respiratory system: rarely - respiratory failure, pulmonary fibrosis, alveolitis, chronic obstructive pulmonary disease (COPD), interstitial pneumonitis (including fatal), symptoms of interstitial pneumonia (potentially dangerous) - shortness of breath, dry cough, fever;
• Skin: itchy skin, erythematous rash, urticaria, pigmentation disorders, photosensitivity, alopecia, telangiectasia, ecchymosis, exfoliative dermatitis, furunculosis, acne, erythema multiforme (Stevens-Johnson syndrome), necrosis and ulceration of the skin, toxic epidermal necrolysis; with psoriasis - burning of the skin, painful erosive plaques on the skin;
• Genitourinary system: cystitis, renal failure or severe nephropathy, proteinuria, azotemia, hematuria, impaired ovo- and spermatogenesis, decreased libido, transient oligospermia, impotence, vaginal discharge, dysmenorrhea, gynecomastia, miscarriage, fetal developmental defects, fetal death, infertility;
• Musculoskeletal system: myalgia, arthralgia, osteoporosis, fractures, osteonecrosis;
• Neoplasms: lymphoma, including reversible;
• Others: excessive sweating, diabetes, allergic reactions(including anaphylactic shock), allergic vasculitis, soft tissue necrosis, tumor lysis syndrome, sudden death, opportunistic infections, life threatening(including pneumocystis pneumonia), cytomegalovirus (CMV) infection (including CMV pneumonia), histoplasmosis, nocardiosis, cryptococcosis, sepsis (including fatal), herpes zoster, herpes simplex and disseminated herpes.

Overdose

For an overdose of Methotrexate, specific symptoms are not characteristic, therefore, it is determined by the level of the active substance of the drug in the blood plasma.

As a treatment, it is recommended to administer a specific antidote - calcium folinate - as soon as possible after taking the drug in high doses preferably within the first hour. Its dose should be equal to or greater than the corresponding dose of methotrexate. Subsequent doses are administered as needed, depending on the content of methotrexate in the blood serum. To avoid precipitation of methotrexate and/or its metabolites in renal tubules alkalization of urine and hydration of the body should be carried out, leading to accelerated withdrawal drug. To minimize the risk of developing nephropathy due to the formation of a precipitate of methotrexate or its metabolites in the urine, it is recommended to additionally determine the pH of the urine before each administration and every 6 hours during the entire period of use of calcium folinate, which is used as an antidote. The introduction of the latter must be continued until the concentration of methotrexate in plasma decreases to a value not exceeding 0.05 μmol / l, and the pH rises to values ​​​​more than 7.

special instructions

The cytotoxicity of the drug requires careful handling. The prescription of the drug can only be experienced specialist. Given the properties and features of the action of Methotrexate, the doctor should inform the patient about the ability of the drug to cause severe, and sometimes fatal side effects and the need to comply strict regime therapy to minimize them.

The use of the drug should be accompanied by careful medical supervision For timely detection signs toxic action, their evaluation, and the adoption of adequate measures.

The appointment must be made on the basis of the full general analysis blood with the determination of platelets, biochemical analysis blood with the establishment of the activity of liver enzymes, serum albumin, bilirubin, examination of kidney function, chest x-ray, if necessary - tests for hepatitis and tuberculosis.

Methotrexate should be taken under conditions of regular monitoring of the state of peripheral blood for the content of the number of leukocytes and platelets. During the first month of therapy, the analysis is carried out first every other day, then at intervals of 3-5 days. In the subsequent period - 1 time in 7-10 days, with remission - 1 time in 1-2 weeks. Before each dose of the drug, the mucous surface of the mouth and pharynx is examined for ulceration. It should be checked: systematically - liver transaminase activity, kidney function (creatinine clearance, urea nitrogen), concentration level uric acid in blood; periodically - fluoroscopic examination of the chest. The state of bone marrow hematopoiesis is checked three times (before therapy, during treatment, after completion of the course).

The action of the drug can cause acute or chronic hepatotoxicity, including fibrosis and cirrhosis of the liver. Chronic hepatotoxicity can result from taking a total cumulative dose of 1.5 g or long-term (2 or more years) methotrexate therapy, and lead to a fatal outcome.

Considering toxic effect methotrexate on the patient's body, the simultaneous appointment of other hepatotoxic drugs should be avoided, except in cases of obvious need.

The degree of the toxic effect of the drug may be due to aggravating concomitant factors, such as obesity, alcoholism, diabetes mellitus and the patient's advanced age.

For objective evaluation liver function, in addition to biochemical parameters, it is recommended to use liver biopsy data obtained before or after 2-4 months of treatment.

In the case of moderate liver fibrosis or signs of cirrhosis, methotrexate should be discontinued; in the diagnosis of mild fibrosis, it is recommended re-holding biopsy after 6 months. With minor histological changes in the liver (mild portal inflammation, fat changes) special care should be taken with further use of the drug.

With ulcerative stomatitis and diarrhea, it is necessary to interrupt methotrexate therapy due to the high risk of developing hemorrhagic enteritis and perforation of the intestinal wall.

Patients should avoid exposure to direct sun rays and ultraviolet irradiation to prevent the development of a photosensitivity reaction.

Consideration should be given to the effect of the drug on immune system when conducting immunological tests and a possible deterioration in the response to vaccination. Therefore, in the period of 3-12 months after discontinuation of the drug, the patient is not shown immunization (except in cases recommended by the doctor), persons living with the patient should cancel immunization against polio. The patient must wear a mask to avoid contact with people who received the polio vaccine.

During the period of treatment, patients of childbearing age must use reliable methods of contraception, as well as after the end of therapy - for men for 3 months, for women - for at least one ovulation cycle.

To reduce the toxicity of high doses of methotrexate after a course of treatment, the patient is shown taking calcium folinate.

Due to the effect of the drug on the central nervous system (dizziness, feeling of fatigue), patients should refrain from administering vehicles or mechanisms during therapy.

Use during pregnancy and lactation

Methotrexate is characterized by teratogenic effects: it can cause birth defects development or fetal death. If pregnancy occurs during treatment with the drug, it is recommended to terminate the pregnancy due to high risk negative impact on the fetus. Methotrexate penetrates into breast milk, therefore, during the course of therapy, it is necessary to stop breast-feeding.

drug interaction

Since the drug is cytotoxic, simultaneous reception any medicines must be agreed with the attending physician. Taking into account the properties and characteristics of Methotrexate, the patient's condition and drug interactions, the doctor will give recommendations to avoid the occurrence of severe side effects.

Analogues

Analogues of Methotrexate are: Vero-Methotrexate, Methotrexate Teva, Methotrexate-Ebeve, Methodject, Metotab.

Terms and conditions of storage

Store in a dark place at temperatures up to 25°C. Keep away from children.

Shelf life - 3 years.

EBEWE Pharma Ges.mbH Nfg. KG, Austria

Active ingredients of Methotrexate Ebewe:

Methotrexate

Release form of Methotrexate Ebeve:

• Tablets 2.5 mg № 50
• Tablets 5 mg № 50
• Tablets 10 mg № 50
• Solution for injection, 10 mg / 1 ml, 1 ml or 5 ml in bottles No. 1
• Solution for injections, 1 ml (10 mg) in ampoules No. 10; 5 ml (50 mg) in ampoules No. 5
• Concentrate for solution for infusion, 5 ml (500 mg) in ampoules No. 5; 10 ml (1000 mg) in ampoules No. 1
• Concentrate for solution for infusion, 5 ml (500 mg) or 10 ml (1000 mg), or 50 ml (5000 mg) in vials

Who is Methotrexate Ebeve indicated for?

• Acute lymphocytic leukemia (maintenance therapy).
• Active rheumatoid arthritis in adults.
• Widespread chronic psoriasis, especially in the elderly and disabled, in case of failure of traditional therapy.

How to use Methotrexate Ebewe?

Pills

Swallow the tablets without chewing, one hour before or 1.5-2 hours after a meal.

Acute lymphocytic leukemia. Methotrexate can be taken orally at doses up to 30 mg/m2. Large doses should be administered parenterally. For the maintenance treatment of acute lymphocytic leukemia in children, methotrexate is administered orally at a dose of 20 mg/m2 once a week and, in addition, is administered intravenously and intrathecally to prevent CNS damage.

Rheumatoid arthritis. The initial dose is 7.5 mg once a week.

In both psoriasis and rheumatoid arthritis, the therapeutic effect is usually noted as early as 6 weeks, after which the condition of patients continues to improve for another 12 or more weeks. If after 6-8 weeks of therapy there are no signs of improvement, as well as signs of toxic effects, doses can be gradually increased by 2.5 mg per week.

Of course, the optimal weekly dose is in the range of 7.5-16 mg, but it should not exceed 20 mg. If there is no effect after 8 weeks of treatment at the maximum dose, methotrexate should be discontinued. After reaching therapeutic effect drug doses should be reduced to the lowest possible level.

Optimal duration therapy with methotrexate has not yet been determined, however, preliminary data indicate that the initial effect is maintained for at least 2 years if maintenance doses are taken. After stopping treatment with methotrexate, the symptoms of the disease may return after 3-6 weeks.

Solution for injection and concentrate

For adults and children, methotrexate can be administered intramuscularly, intravenously (by injection or infusion), intraarterial, intrathecal and intraventricular. Doses are calculated based on body weight or body surface area of ​​patients, with the exception of intrathecal and intraventricular use, when the maximum recommended dose is 15 mg and the maximum concentration is 5 mg / ml. In the case of hematological disorders and impaired liver or kidney function, the dose of the drug should be reduced. High doses of methotrexate (over 100 mg) are usually administered by intravenous infusion, lasting no more than 24 hours. A portion of the dose may be administered by initial rapid intravenous injection.

Methotrexate is used alone or in combination with other cytotoxic drugs, hormones, radiation therapy and surgical methods. Doses and regimens of treatment with methotrexate vary significantly depending on the type of disease. In the treatment of high doses of methotrexate (more than 150 mg / m2), calcium folinate is prescribed to protect normal cells from the toxic effects of the drug. Doses of calcium folinate are determined depending on the dose of methotrexate. Usually, up to 150 mg of calcium folinate is administered in multiple doses over 12 to 24 hours (by intramuscular injection, intravenous injections, intravenous infusion or orally), followed by another 12-25 mg IM, IV, or 15 mg orally (1 capsule) every 6 hours for 48 hours. Protective therapy with calcium folinate usually begins 8-24 hours after the start of the methotrexate infusion. When treated with lower doses of methotrexate (up to 100 mg), it may be sufficient to take 1 capsule (15 mg) of calcium folinate every 6 hours for 48-72 hours.

The following are some examples of methotrexate treatment regimens.

• Leukemia:
  3.3 mg/m2 in combination with other cytostatics once a week for 4-6 weeks.
  2.5 mg/kg every two weeks.
  30 mg/m2 per week (maintenance therapy).
  High doses of 1-12g/m2 (by intravenous infusion lasting 1-6 hours) at intervals of 1-3 weeks.
  20 mg/m2 in combination with other cytostatics once a week.
• Non-Hodgkin's lymphoma:
  500-2000 mg / m2 in combination with other cytostatics 1 time per week or 1 time in 3 weeks. 7500 mg/m2 intravenously once a week.
• Mammary cancer:
  

  40 mg/m2 intravenously in combination with other cytostatics on the first day, the first and third days, or the first and eighth days of the course, or 3 times a year.

• Choriocarcinoma:
  15-30 mg per day for 5 days, with courses repeated after a week or more.

Instructions for medical staff

Ebewe methotrexate does not contain antimicrobial components, so unused solutions must be destroyed.

Infusion solutions are stable for 24 hours when diluted with 0.9% sodium chloride solution, glucose solution or glucose solution in sodium chloride solution.

Other drugs should not be mixed with Ebewe methotrexate in the same infusion solution.

When working with Methotrexate Ebewe, as with other cytotoxic drugs, caution is necessary. The preparation of infusion solutions should be carried out by trained personnel in a specially designated area. Workplace should be covered with disposable sheets of absorbent film-coated paper with reverse side.

Protective gloves and goggles should be worn to prevent accidental contact of methotrexate solutions with the skin or eyes.

Methotrexate does not blister action and should not cause harm in case of skin contact. It should usually be washed off immediately with water. If the skin is irritated, it can be lubricated with a cream. In case of danger of systemic absorption of a significant amount of methotrexate (regardless of the route of entry into the body), it is necessary to take an antidote - calcium foliant (leucovorin).

pregnant medical workers should not work with Methotrexate Ebewe.

Unused solutions, instruments and materials that have been in contact with methotrexate should be destroyed by incineration. There are no specific recommendations regarding the destruction temperature.

When working with Methotrexate, Ebewe should follow the general rules for working with cytostatics. Treatment with methotrexate should be carried out under the supervision of qualified oncologists, dermatologists and rheumatologists who are experienced in the use of antitumor chemotherapeutic agents.

Methotrexate should be used with great caution in cases of bone marrow suppression, renal insufficiency, peptic ulcer, ulcerative colitis, ulcerative stomatitis, diarrhea, poor general condition, as well as in the treatment of young children and the elderly.

In the presence of pleural exudate or ascites, they must be drained before treatment with Methotrexate. If this is not possible, methotrexate therapy should not be given.

If symptoms of gastrointestinal toxicity appear, usually initially stomatitis, treatment with methotrexate should be discontinued. If therapy is continued, hemorrhagic enteritis and intestinal perforation are possible, which is a threat to the patient's life.

Before starting treatment with methotrexate or before repeated courses, it is necessary to conduct an examination of the patient, evaluate the functions of the kidneys and liver, determine the number of blood cells and compare them with past indicators. Patients treated with methotrexate should be closely monitored so that if signs of toxic effects or adverse reactions appear, they can be taken immediately. necessary measures.

During treatment with methotrexate, it is necessary to regularly do such lab tests: complete blood count, urinalysis, kidney function tests and liver function tests. When treating with high doses, it is also necessary to determine the concentration of methotrexate in plasma.

Particular attention should be paid to signs of hepatotoxicity, which may occur in the absence of significant changes in the results of liver tests. Treatment with methotrexate should be discontinued (or not initiated if detected initially) in the event of any abnormalities in the results of liver tests or liver biopsy. Relevant indicators usually return to normal within two weeks, after which, at the discretion of the doctor, methotrexate therapy can be continued.

When is it appropriate to perform a liver biopsy in patients with rheumatoid arthritis (after which cumulative doses or after what duration of therapy) has not yet been determined.

The literature describes cases of pleuropulmonary lesions in patients with rheumatoid arthritis. Physicians must address Special attention for symptoms side effects methotrexate on the respiratory system and advise patients to seek immediate medical attention in case of cough or shortness of breath.

Methotrexate can cause sudden bone marrow depression, even at relatively safe doses. With a significant decrease in the number of leukocytes and platelets, methotrexate therapy should be immediately suspended and appropriate supportive treatment prescribed.

Pregnancy and lactation

Experiments revealed the teratogenic effect of methotrexate. Therefore, it is not recommended for use in women of childbearing age unless the benefit outweighs possible risk. If methotrexate is given during pregnancy or if patients become pregnant during therapy, they should be warned about possible harm for the fetus.

Methotrexate is excreted from mother's milk therefore, breast-feeding during treatment with methotrexate should be discontinued.

If one partner is taking methotrexate, both partners should use contraceptives during the entire period of treatment and at least three months after the end of therapy.

Influence on the ability to drive vehicles and mechanisms.

Depending on individual sensitivity, the drug may adversely affect the ability to drive vehicles and mechanisms.

Side effects of Methotrexate Ebewe

The most common side effects of methotrexate treatment are ulcerative stomatitis, leukopenia, nausea, and stomach upset. Anaphylactic reactions to methotrexate are very rare. Eye irritation, malaise, easy fatigue, fevers, dizziness, loss of libido/impotence, and decreased resistance to infections are also possible. In general, the frequency and intensity of side effects increase with increasing doses.

Side effects can be classified in the following way:

Frequent (> 1/100).

• General- headache, dizziness
• Hematological - leukopenia
• Gastroenterological - nausea, vomiting, stomatitis, diarrhea, anorexia
• Dermatological - alopecia
• Hepatic - a significant increase in the level of liver enzymes
• Others - activation of concomitant infectious processes
• Less common. Hematologic epistaxis, thrombocytopenia
• Dermatological - itching, urticaria
• Pulmonary - pulmonary fibrosis, pneumonitis
• Urogenital - vaginal ulcers

Single cases.

General - impotence

(< 1 / 1000)

• CNS - depression, confusion
• Others - decreased libido, shingles

Dermatological effects.

Possible erythematous rash, itching, urticaria, photosensitivity, changes in skin pigmentation, alopecia, ecchymosis, telangiectasia, acne, furunculosis. At ultraviolet irradiation during methotrexate therapy, psoriatic lesions may worsen. There are reports of the formation of skin ulcers in patients with psoriasis, as well as the "return phenomenon" in patients with skin lesions caused by ionizing or solar radiation.

Isolated cases of Stevens-Johnson syndrome and epidermal necrolysis have been recorded.

The hematopoietic system.

Bone marrow suppression most commonly presents as leukopenia, although thrombocytopenia and anemia, or combinations thereof, may also occur. Infections, sepsis, or various bleeding. There are reports of cases of hypogamaglobulinemia.

Gastrointestinal tract.

Possible inflammation of the mucous membranes (most often stomatitis, although gingivitis, pharyngitis and even enteritis, intestinal ulcers and bleeding are possible). In isolated cases, the action of methotrexate on the mucous membranes of the gastrointestinal tract can lead to malabsorption or toxic megacolon. Nausea, anorexia, vomiting and/or diarrhea are also possible.

Liver.

Often there is a return increase in transaminase levels. After taking methotrexate, especially long-term, there may be a significant increase in the level of liver enzymes, acute liver atrophy, necrosis, fatty metamorphosis, peritoneal fibrosis or cirrhosis with possible fatal consequences.

urogenital system.

In the treatment of methotrexate (usually in high doses), renal failure and uremia may develop. Vaginitis, vaginal ulcers, cystitis, hematuria, and nephropathy are also possible.

Respiratory system.

Rarely, acute or chronic interstitial pneumonitis (often accompanied by eosinophilia) develops, sometimes with fatal consequences. There are also reports of acute pulmonary edema after oral and intrathecal methotrexate. Isolated cases of pulmonary fibrosis have been recorded.

During treatment rheumatoid arthritis methotrexate at any time can lead to potentially serious lung diseases. If symptoms of side effects on the respiratory system appear (especially dry, unproductive cough) it may be appropriate to suspend therapy and carefully examine the patient's condition.

Central nervous system.

Headache, drowsiness, blurred vision are possible. With low-dose methotrexate therapy, minor transient cognitive impairment, mood variability, and unusual sensations in the region of the skull.

There are reports of possible connection between methotrexate treatment and osteoporosis, abnormal (usually "megaloblastic") erythrocyte morphology, development of clinical diabetes, other metabolic changes, and sudden death.

Carcinogenicity, mutagenicity and effects on fertility.

Experiments have shown that methotrexate can cause chromosomal damage in animal somatic cells and human bone marrow cells, however, these effects are transient and reversible. It is likely that the treatment with methotrexate increases the risk of developing neoplastic diseases (lymphomas, of course recurrent), but there is not enough information for final conclusions on this matter. Methotrexate can reduce fertility, cause oligospermia, menstrual function and amenorrhea in women. These effects are usually reversible and disappear upon discontinuation of therapy.

In addition, methotrexate is embryotoxic, abortogenic and teratogenic. Therefore, patients of childbearing age should be informed about the possible effect of methotrexate on reproductive function.

Who is contraindicated for Methotrexate Ebeve?

• Pregnancy and lactation.
• Significant violations of liver function, in particular fibrosis, cirrhosis, hepatitis.
• Significant impairment of kidney function.
• Pathological changes in the blood, in particular bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia.
• Active infectious diseases, AIDS.
• Hypersensitivity to methotrexate.
• bad general state health.

Interaction Methotrexate Ebeve.

The drug has a certain immunosuppressive activity, therefore, when vaccinated during methotrexate therapy, the immune response may be weak. In addition, the use of live vaccines can provoke severe antigenic reactions.

Protein-bound methotrexate can be displaced by salicylates, sulfonamides, diphenylhydantoins, tetracyclines, chloramphenicol, sulfazole, doxorubicin, cyclophosphamide, and barbiturates. With an increase in plasma concentration of unbound methotrexate, toxic effects.

Methotrexate is excreted by active renal secretion and may interact with other drugs that are excreted in the same way. As a result, the concentration of methotrexate in plasma may increase.

In the case of simultaneous use with probenecid, the dose of methotrexate must be reduced.

Vinca alkaloids can increase intracellular concentrations of methotrexate and methotrexate polyglutamates.

During treatment with methotrexate, other nephrotoxic and hepatotoxic drugs should be avoided and alcohol should not be consumed.

Vitamin complexes and iron preparations containing folic acid may alter the body's response to methotrexate.

Non-steroidal anti-inflammatory drugs may reduce renal clearance methotrexate and enhance toxic effects.

In rare cases, the use of folate antagonists (trimethoprim, sulfamethoxazole) during methotrexate therapy can provoke acute pancytopenia.

At simultaneous application etretinate and methotrexate plasma concentrations of the latter may increase and severe hepatitis may develop.

Overdose of Methotrexate Ebeve.

An antidote that neutralizes the acute toxic effect of methotrexate on the hematopoietic system is calcium folinate (leucovorin). It can be used orally, intramuscularly and intravenously (by injection and infusion). In the event of an accidental overdose of methotrexate, calcium folinate is administered no later than one hour later at a dose equal to or higher than the dose of methotrexate. Then several more doses are administered until the concentration of methotrexate in the blood serum falls below 10-7 mol. In case of an overdose of methotrexate, blood transfusion and hemodialysis are also necessary.

Gross formula

C 20 H 22 N 8 O 5

Pharmacological group of the substance Methotrexate

Nosological classification (ICD-10)

CAS code

59-05-2

Characteristics of the substance Methotrexate

Group antimetabolite 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 in color, soluble in water. Molecular weight 454.45.

Pharmacology

pharmachologic effect- antitumor, cytostatic, immunosuppressive.

Inhibits dihydrofolate reductase (DHF), which converts dihydrofolic acid to tetrahydrofolic acid, which is a donor of one-carbon groups in the synthesis of purine nucleotides and thymidylate, necessary for DNA synthesis. In addition, methotrexate undergoes polyglutamination in the cell 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 the synthesis and repair of DNA, cell mitosis, to a lesser extent affects the synthesis of RNA and protein. 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 those of the bone marrow, embryo, mucous membranes of the oral cavity, intestines, and bladder.

It has a cytotoxic effect, has teratogenic properties.

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

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

After oral administration at a dose of 30 mg / m 2 and below, it is rapidly and completely absorbed from the gastrointestinal tract (about 60% bioavailability). In children with leukemia, the absorption rate ranges from 23 to 95%. Absorption decreases significantly when the dose exceeds 80 mg/m 2 (possibly due to the saturation effect). C max is reached after 1-2 hours with oral administration and after 30-60 minutes with intramuscular administration. Reception with food slows down the time required to reach C max by about 30 minutes, but the level of absorption and bioavailability do not change.

After intravenous administration, it is rapidly 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-dependently); after intrathecal injection significant quantities goes to systemic circulation. It is secreted into breast milk, passes through the placenta (has a teratogenic effect on the fetus).

It is metabolized in liver cells and other cells to form polyglutamates (inhibitors of DHF and thymidylate synthetase), which can be converted to methotrexate by the action of hydrolases. Partially metabolized by intestinal microflora (after oral administration). A small amount of polyglutaminated 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 type of tumor. Slightly metabolized (when taking usual doses) to 7-hydroxymethotrexate (solubility in water is 3-5 times lower than that of methotrexate). The accumulation of this metabolite occurs when taking high doses of methotrexate, prescribed for the treatment of osteosarcoma.

The final T 1/2 is dose-dependent and is 3-10 hours with the introduction of low and 8-15 hours with high doses of methotrexate. 80-90% of the intravenous dose is excreted unchanged by the kidneys by glomerular filtration and active tubular secretion within 24 hours, and less than 10% - with bile. The clearance of methotrexate varies widely, decreasing at high doses.

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

The use of methotrexate

Chorionic carcinoma of the uterus, acute lymphocytic leukemia, tumors of the central nervous system (leukemoid infiltration meninges), breast cancer, head and neck cancer, lung cancer, bladder cancer, 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 therapies), rheumatoid arthritis.

Contraindications

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

Application restrictions

Infectious diseases, oral and gastrointestinal ulcers, recent surgery, history of gout or kidney stones (risk of hyperuricemia), elderly and childhood.

Use during pregnancy and lactation

Contraindicated in pregnancy (may cause fetal death or cause congenital malformations).

At the time of treatment should stop breastfeeding.

Side effects of Methotrexate

From the side nervous system and sense organs: encephalopathy (especially with the introduction of multiple doses intrathecally, as well as in patients after brain irradiation), dizziness, headache, blurred vision, drowsiness, aphasia, back pain, muscle stiffness 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 side of cardio-vascular 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, thrombosis renal vein thrombophlebitis, pulmonary embolism).

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

From the digestive 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 side genitourinary system: cystitis, nephropathy, azotemia, hematuria, hyperuricemia or severe nephropathy, dysmenorrhea, unstable oligospermia, impaired oogenesis and spermatogenesis, fetal defects.

From the side 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

Enhanced and prolonged action of methotrexate, leading to intoxication, is facilitated by the simultaneous use of NSAIDs, barbiturates, sulfonamides, corticosteroids, tetracyclines, trimethoprim, chloramphenicol, paraaminobenzoic and paraaminohippuric acids, probenecid. Folic acid and its derivatives reduce effectiveness. Enhances action indirect anticoagulants(derivatives of coumarin or indandione) and increases the risk of bleeding. Drugs of the penicillin group reduce the renal clearance of methotrexate. With the simultaneous use of methotrexate and asparaginase, it is possible to block the action of methotrexate. 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 inhibit bone marrow function. A synergistic cytotoxic effect with cytarabine is possible with simultaneous use. With the simultaneous use of methotrexate (intrathecally) with acyclovir (parenteral) possible neurological disorders. In combination with live virus vaccines, it can cause an intensification of the process of replication of the vaccine virus, an increase in the side effects of the vaccine and a decrease in the production of antibodies in response to the introduction 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 (by mouth, intramuscularly or intravenously). The dose of calcium folinate should be at least equal to the dose of methotrexate and should be given within the first hour; subsequent doses are administered as needed. Increase hydration of the body, carry out alkalization of urine to avoid precipitation of the drug and its metabolites in urinary tract.

Routes of administration

Inside, parenterally(in / m, in / in, intra-arterially, intrathecally), depending on the indications.

Substance Precautions Methotrexate

Apply under close medical supervision. For the 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 1 time in 7-10 days, during remission - 1 time in 1-2 weeks), activity of hepatic transaminases, kidney function, periodically conduct fluoroscopy of the 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 platelet count is less than 75 10 9 /l. An increase in creatinine levels by 50% or more of the initial content requires re-measurement of creatinine clearance. An increase in the level of bilirubin requires intensive detoxification therapy. The study of bone marrow hematopoiesis is recommended before treatment, 1 time during treatment 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 detect signs of intoxication, which is stopped by the administration of calcium folinate).

During treatment at elevated and high 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 injected intravenously (drip) the day before, on the day of treatment and in the next 2-3 days. Treatment with methotrexate in high and high doses is combined with enhanced hydration (up to 2 liters of fluid per day).

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

With the development of diarrhea and ulcerative stomatitis, methotrexate therapy must be interrupted, otherwise it may lead to the development of hemorrhagic enteritis. If signs of pulmonary toxicity (especially dry cough without sputum) appear, treatment with methotrexate is recommended to be discontinued due to the risk of possibly irreversible toxic effects on the lungs. Use with caution in patients with impaired liver and/or kidney function (reduce doses).

The use of alcohol and drugs with hepatotoxicity should be avoided, because. their use in the treatment of methotrexate increases the risk of liver damage; prolonged exposure to the sun. At combined treatment each drug should be taken at the appointed time; if a dose is missed, the drug is not taken, the dose is not doubled.

During the period of treatment, it is not recommended to vaccinate with viral vaccines, contact with people who received the polio vaccine should be avoided, with patients bacterial infections. apply live viral vaccines in patients with leukemia in remission should not be given for at least 3 months after the last course of chemotherapy. Immunization with oral polio vaccine in close contacts of such a patient, especially family members, should be delayed.

The appearance of signs of bone marrow depression, unusual bleeding or hemorrhage, black, tarry stools, blood in the urine or stool, or pinpoint red spots on the skin requires immediate medical attention.

Be careful to avoid accidental cuts with sharp objects (safety razor, scissors), avoid activities contact species sports or other situations in which bleeding or injury is possible.

Agitation is a state of pronounced emotional arousal, accompanied by a feeling of fear and anxiety, speech and restlessness. In a state of agitation, a person has an unconscious need to perform simple automatic movements or develops excessive fussiness.

Agitation is marked emotional arousal accompanied by fear.

Causes

Agitation in some cases is a variant of the norm. For example, it can be triggered by a strong stressful situation - both acute and chronic.

More often agitation is considered as one of the symptoms accompanying the following diseases psyche:

• Alzheimer's disease;
• agitated depression;
• anxiety neurosis;
• catatonic schizophrenia;
• involutional depression;
• affective insanity.

The state of agitation can be provoked by the use of narcotic or psychotropic substances, alcoholic beverages. In addition, pathology occurs against the background of severe infectious diseases.

The mechanism of development of agitation is complex and currently not fully understood. It is assumed that they play an important role:

• cerebral ischemia;
• metabolic disorders;
• influence of toxins;
• neuroreflex mechanisms;
• autoimmune and immune reactions;
• psychological characteristics of the individual.

signs

It is characteristic of agitation that the patient usually does not notice this condition in himself, despite the following pronounced signs:

• motor or speech anxiety;
• hand tremor;
• tachycardia;
• increased sweating;
• pallor of the skin;
• rapid breathing;
• increased blood pressure;
• increase in body temperature.

During an attack, the patient cannot stay in one place for a long time. He loses the ability to reason correctly or establish complex cause-and-effect relationships.

According to medical statistics, it is the state of agitation that is one of the main reasons traumatic injuries medical staff during business hours.

A person in a state of agitation experiences severe anxiety, and sometimes fear, cannot fall asleep and calm down on his own. At the same time, attempts to control his behavior by relatives or friends often lead to an attack of aggression, up to injuring both the patient himself and those around him.

In cases where agitation occurs against the background of an illness, its symptoms, for example, lack of criticality, delusions, hallucinations, join the signs listed above.

Diagnostics

Only a psychiatrist can diagnose a state of agitation after observing the patient for some time. Only taking into account all the features, a specialist can conduct differential diagnosis between agitation and akathisia. Akathisia in its manifestations has much in common with agitation, but the treatment of these conditions requires a different approach.

More often, agitation is considered as one of the symptoms that accompany mental illness.

To find out the reasons that led to the occurrence of agitation, a laboratory and instrumental examination is carried out, including:

• a blood test for the content of thyroid hormones;
• blood test for alcohol content;
• general analysis of blood and urine;
• measurement of blood pressure;
• magnetic resonance or computed tomography brain;
• electroencephalography.

If necessary, other diagnostic methods can be used.

Treatment

Therapy of agitation should be aimed at eliminating the cause that caused its development. If this is a stressful situation, the use of tranquilizers is indicated. With agitation that has arisen against the background of the disease, it is treated.

Drug correction of agitation is undertaken only on the prescription of a doctor and under his control. For this purpose, antipsychotics, antidepressants, antianxiolytics can be used.

Psychotherapy plays an important role in the elimination of agitation. It allows the patient to develop resistance to stressful situations, nervous and physical overwork.

Prevention

Prevention of agitation is treatment mental illness. Mentally healthy people need to avoid stressful situations, stop drinking alcohol and narcotic substances. It is important that a patient prone to agitation receive regular psychotherapeutic support. The skills to resist stress acquired in its course reduce the risk of recurrence of the pathology.

Agitation in some cases is a variant of the norm. For example, it can be triggered by a strong stressful situation - both acute and chronic.

Consequences and complications

Being in a state of agitation, a person can harm both himself and others, damage other people's property. According to medical statistics, it is the state of agitation that is one of the main causes of traumatic injuries to medical staff during working hours.

With timely and full course treatment, the prognosis is favorable. It worsens when the patient has a mental illness, because in this case, repeated episodes are not uncommon.

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Synonyms:

See what "Agitation" is in other dictionaries:

- (fr. agitation). Excitement, restlessness, anxiety, excitement. Dictionary foreign words included in the Russian language. Chudinov A.N., 1910. Agitation [fr. agitation great excitement, excitement] psychol. affective reaction of a person, ... ... Dictionary of foreign words of the Russian language

Cm … Synonym dictionary

agitation- and, well. agitation f. 1. Excitement, excitement. Bezborodko began to walk around with greater agitation, annoyed that he could not explain his thoughts. AB 14 204. An old woman in great agitation. Volodya writes that the main apartment received an order ... ... Historical Dictionary of Gallicisms of the Russian Language

agitation- Great restlessness and motor excitement, accompanied by anxiety. Brief sensible psychology psychiatric dictionary. Ed. igisheva. 2008. agitation ... Great Psychological Encyclopedia

- (from Latin agitare to excite) a clinical disorder. Motor restlessness, need to move. behavioral disorder, at which affective tension uncontrollably turns into movement. A concomitant phenomenon with many mental ... ... Psychological Dictionary

AGITATION, agitation, pl. no, female (French agitation) (colloquial obsolete). Excited state, excitement. "You are in agitation, my friend, you need to calm down." A. Ostrovsky. Explanatory Dictionary of Ushakov. D.N. Ushakov. 1935 1940 ... Explanatory Dictionary of Ushakov Modern Dictionary Russian language Efremova