Methotrexate - instructions for use, dose, side effects, contraindications

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

Description:Round biconvex tablets, covered with a coat from pink to dark pink; On the cross section, two layers of the shell and the core are visible. The layer of the shell is pink to dark pink and the layer is white. The core is from yellow to orange-yellow. In appearance, they must correspond to GF XI, vyl. 2, p. 154.

Pharmacotherapeutic group:Antitumour agent, antimetabolite

ATX: & nbsp

L.01.B.A Analogues of folic acid

L.01.B.A.01 Methotrexate

Pharmacodynamics:

The antineoplastic, cytostatic agent of the antimetabolite group inhibits dihydrofolate reductase, which participates in the reduction of dihydrofolic acid into tetrahydrofolic acid (a carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives).

It inhibits synthesis, DNA repair and cellular mitosis. Especially sensitive to the action of rapidly proliferating tissues: cells of malignant tumors, bone marrow,embryonic cells, epithelial cells of the intestinal mucosa, urinary bladder, oral cavity. Along with the antitumor has an immunosuppressive effect.

Pharmacokinetics:

Absorption at oral intake depends on the dose: when taking 30 mg /m² it is absorbed well, the average bioavailability is 60%. Absorption decreases when taken in doses exceeding 80 mg /m².

In children with leukemia, absorption ranges from 23% to 95%. The time to reach the maximum concentration (TCata) is from 40 minutes to 4 hours. The food slows down the absorption and lowers the Stach. The connection with plasma proteins is about 50%, mainly with albumin.

After distribution in tissues, high concentrations of methotrexate in the form of polyglutamates are found in the liver, kidneys and especially in the spleen, in which methotrexate can be held for several weeks or even months.

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

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

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

Indications:

- Acute lymphoblastic leukemia and non-Hodgkin's lymphomas;

- trophoblastic tumors;

- mushroom-like mycosis in far-advanced stages;

- severe forms of psoriasis;

- rheumatoid arthritis (with ineffectiveness of other methods of therapy).

Contraindications:The use of methotrexate is contraindicated in pregnancy and during lactation, with pronounced changes in kidney and liver function,at hematological disorders (such as bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia), in acute stage of infectious diseases, immunodeficiency syndrome, with increased sensitivity to methotrexate or other component parts of the pill, children under 3 years old.

Carefully:In ascites, swelling in the pleural cavity, peptic ulcer of the stomach and duodenum, ulcerative colitis, dehydration, gout or nephrolithiasis in an anamnesis, previously conducted radiation therapy or chemotherapy, infectious diseases of a viral, fungal or bacterial nature.

Pregnancy and lactation:It has a teratogenic effect: it can cause fetal death, congenital malformation. In the event that a woman becomes pregnant during methotrexate therapy, the issue of termination of pregnancy should be resolved due to the risk of side effects on the fetus. Methotrexate is excreted in breast milk, for the entire course of treatment breastfeeding should be discontinued.

Dosing and Administration:

Methotrexate tablets are used orally. Doses and treatment periods are set individually depending on the chemotherapy schedule.

Trophoblastic tumors:

- 15-30 mg orally daily for 5 days with an interval of one or more weeks (depending on the signs of toxicity). Treatment rates are usually repeated 3 to 5 times.

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

Acute lymphoblastic leukemia (as part of complex therapy):

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

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

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

- 7.5 mg /m² daily for 5 days.

Rheumatoid arthritis:

The initial dose is usually 7.5 mg once a week, which is taken at one time or divided into three doses at an interval of 12 hours. To achieve the optimum - the effect of a weekly dose can be increased, while it should not exceed 20 mg. When the optimal clinical effect is achieved, the dose should be reduced before reaching the lowest effective dose. The optimal duration of therapy is not known. In juvenile chronic arthritis, 10-30 mg / m2 / week (0.3-1 mg / kg) are effective for children.

Psoriasis:

Therapy with methotrexate is carried out at doses of 10 to 25 mg per week. The dose is usually increased gradually, when the optimal clinical effect is achieved, a dose reduction begins before the lowest effective dose is reached.

Mushroom mycosis:

- 25 mg twice a week. Dose reduction or withdrawal of drug administration is determined by the patient's reaction and hematological parameters.

Side effects:

On the part of the hematopoiesis system: anemia (including aplastic), thrombocytopenia, leukopenia, neutropenia, agranulocytosis, eosinophilia, pancytopenia, lymphoproliferative diseases, hypogammaglobulinemia, lymphadenopathy.

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

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

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

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

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

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

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

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

Neoplasms: lymphoma (including reversible).

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

Overdose:

Specific symptoms of methotrexate overdose are absent, diagnosed by the concentration of methotrexate in plasma.

Treatment: The introduction of a specific antidote - calcium folinate whenever possible immediately, preferably within the first hour, at a dose equal to or greater than the dose of methotrexate; subsequent doses are administered as needed, depending on the concentration of methotrexate in the blood serum. To prevent the precipitation of methotrexate and / or its metabolites in the renal tubules, the body is hydrated and alkalinized with urine, which accelerates the excretion of methotrexate. To minimize nephropathy risks through the formation of drug precipitate or its metabolites in the urine must further determine pH of urine before each administration and every 6 h during the whole period of application of calcium folinate as an antidote while the methotrexate concentration in the plasma falls below 0, 05 μmol / l, to provide a pH above 7.

Interaction:

It increases the anticoagulant activity of the derivatives of coumarin or indandione and / or increases the risk of bleeding due to reduction in hepatic synthesis of procoagulant factors and abnormalities of platelet formation.

Increases the concentration of uric acid in the blood, so when treating patients with concomitant hyperuricemia and goutmay need to adjust the dose of antidiagnostic drugs (allopurinol, colchicine, sulfinpyrazone); the use of uricosuric anti-gouty drugs may increase the risk of developing nephropathy associated with increased uric acid production during methotrexate treatment (preferably using allopurinol). Simultaneous reception of salicylates, phenylbutazone, phenytoin, sulfonamides, sulfonylureas, benzoic acid, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and lipid-lowering drugs (colestramine) increases toxicity by displacing methotrexate from binding to albumin and / or reducing tubular secretion, which in some cases can lead to the development of severe toxic effects, sometimes even fatal.

Nonsteroidal anti-inflammatory drugs (NSAID) due to high doses of methotrexate increases the concentration and slow elimination of the latter, which can lead to death from severe hematological and gastrointestinal toxicity.It is recommended to stop taking the phenylbutazone for 7-12 days, piroxicam for 10 days, diflunizal and indomethacin for 24-48 hours, ketoprofen and NSAIDs with short T1 / 2 for 12-24 hours before the infusion of methotrexate in moderate and high doses and for at least 12 hours (depending on the concentration of methotrexate in the blood) after its termination. Care should be taken when combining NSAIDs with low doses of methotrexate (possibly reducing the excretion of methotrexate by the renal tubules). Drugs that block tubular secretion (eg probenecid) increase the toxicity of methotrexate by reducing the excretion of it by the kidneys.

Antibiotics, poorly absorbed in the digestive tract (tetracyclines, chloramphenicol), reduce the absorption of methotrexate and disrupt its metabolism due to suppression of normal intestinal flies.

Retinoids, azathioprine, sulfasalazine, ethanol and other hepatotoxic drugs increase the risk of hepatotoxicity.

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

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

The use of cytarabine 48 hours before or within 10 minutes after the initiation of methotrexate therapy may result in the development of a synergistic cytotoxic effect (correction of the dosing regimen is recommended based on hematologic parameters).

Hematotoxic drugs increase the risk of hematotoxicity of methotrexate.

Methotrexate reduces the clearance of theophylline.

Neomycin for oral administration may decrease the absorption of methotrexate.

In several patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (metoksalen and ultraviolet irradiation (UFO)), skin cancer was detected.

The combination with radiotherapy can increase the risk of bone marrow depression. Methotrexate can reduce the immune response to vaccination with live and inactivated viral vaccines.

Folate-containing medicines (including multivitamins) may decrease the effectiveness of methotrexate therapy.

The appointment of amiodarone to patients receiving methotrexate therapy for psoriasis can cause an exposition of the skin.

Special instructions:

Methotrexate is a cytotoxic drug, so care must be taken when handling it. The drug should be appointed by a doctor who has experience with methotrexate and is familiar with its properties and the characteristics of the action. In view of possible severe and even fatal adverse reactions, patients should be fully informed the doctor about the possible risks and recommended safety measures. For patients undergoing methotrexate therapy should be carried out proper supervision so that signs of possible toxic effects and adverse reactions identified and evaluated in a timely manner.

Before the start or resumption of MTX must be made full blood count with the determination of platelets, blood biochemical tests with the definition of values of liver enzymes, bilirubin, serum albumin, radiological examination of the chest, the study of renal function, if necessary - tests for tuberculosis and hepatitis.

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 a day,then every 3-5 days during the first month, then once every 7-10 days, in the period of remission - once every 1-2 weeks), activity of "liver" transaminases, kidney function (urea nitrogen, creatinine clearance and / or serum creatinine), the concentration of uric acid in the blood serum, periodically perform chest X-ray, examination of the oral and pharyngeal mucosa for ulceration before each use. It is recommended to monitor the state of bone marrow hematopoiesis before treatment, 1 time during the treatment period and at the end of the course.

Methotrexate can potentially lead to the development of symptoms of acute or chronic hepatotoxicity (including fibrosis and cirrhosis, liver). Chronic hepatotoxicity usually develops after long-term use of methotrexate (usually for 2 or more years) or reaching a total cumulative dose of at least 1.5 g and may lead to an unfavorable outcome. Hepatotoxic effect can also be caused by a burdensome, concomitant anamnesis (alcoholism, obesity, diabetes mellitus) and senile age. In view of the toxic effects of the drug on the liver during treatment,refrain from prescribing to patients other hepatotoxic drugs, except in cases of obvious necessity. For patients taking other hepatotoxic drugs (for example, leflunomide), careful monitoring is necessary.

To objectify the liver function, along with biochemical parameters, it is recommended that a liver biopsy be performed before or 2-4 months later. after the beginning of treatment; with a total cumulative dose of 1.5 g and after every additional 1-1.5 g. With moderate liver fibrosis or any degree of cirrhosis, methotrexate therapy is canceled; with fibrosis of light form, it is usually recommended to repeat biopsy after 6 months. During initial therapy, minor histological changes in the liver (minor portal inflammation and fat changes) are possible, which is not a reason for refusal or discontinuation of treatment, but indicates the need for caution when applying the drug.

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

Do not expose unprotected skin to prolonged sun exposure or to abuse the UV lamp (a photosensitization reaction is possible).

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

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

Effect on the ability to drive transp. cf. and fur:Because the methotrexate can influence the central nervous system (fatigue, dizziness), patients taking the drug should refrain from driving or potentially dangerous mechanisms.

Form release / dosage:The tablets covered with a cover, 2,5 mg.

Packaging:

For 10 tablets in a contour mesh box made of polyvinylchloride film and aluminum foil printed lacquered.

For 50 tablets in cans of polymer complete with lids.

Each jar, 5 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

Storage conditions:

In the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:3 years. Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:P N000970 / 01

Date of registration:25.01.2011 / 15.08.2017

Expiration Date:Unlimited

The owner of the registration certificate:VALENTA PHARM, PAO VALENTA PHARM, PAO Russia

Manufacturer: & nbsp

VALENTA PHARMACEUTICS, JSC Russia

Representation: & nbspVALENTA PHARM, PAO VALENTA PHARM, PAO Russia

Information update date: & nbsp10.05.2018

Illustrated instructions

Instructions

Methotrexate (Methotrexate)