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

Excipients: core - sucrose - 60.0 mg, potato starch - 6.45 mg, calcium stearate - 0.7 mg,talc (magnesium hydrosilicate) - 0.35 mg; shell - Sucrose - 62.248 mg dye azorubin - 0.011 mg of polysorbate 80 (Tween-80) - 0.165 mg povidone 30 - 0,408 mg, gelatin - 0.063 mg of titanium dioxide - 1,778 mg, croscarmellose sodium - 0.499 mg colloidal silicon dioxide (aerosil) - 0.549 mg, talc (magnesium hydrosilicate) - 4.195 mg, opaglose 6000 (wax, white carnauba wax, shellac) - 0.084 mg.

Description:Tablets are round, biconvex, covered with a coat from pink to dark pink, three layers are visible on a cross-section.

Pharmacotherapeutic group:Antitumour agent, antimetabolite

ATX: & nbsp

L.01.B.A Analogues of folic acid

L.01.B.A.01 Methotrexate

Pharmacodynamics:Antineoplastic, cytostatic agent of the group of antimetabolites-analogues of folic acid. Inhibits dihydrofolate reductase, which participates in the restoration of dihydrofolic acid to tetrahydrofolic acid (transporter carbon fragments required for synthesis of purine nucleotides and their derivatives). It inhibits synthesis, DNA repair and cellular mitosis (in the S phase). Especially sensitive to the action of methotrexate tissue with high cell proliferation: tumor tissue, bone marrow, epithelial cells of the mucous membranes, embryonic cells.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 50%. Absorption decreases when taken in doses exceeding 80 mg /m² (it is believed, due to saturation).

In children, absorption ranges from 23 to 95%.

The time to reach the maximum concentration (TCmax) is 1-2 hours. The food slows down absorption and decreases (TCmax). The connection with blood plasma proteins is about 50%.

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 bulk - in the liver with the formation of pharmacologically active sex and glutamine form, inhibiting dihydrofolate reductase and thymidine synthesis.

The half-life period (T1 / 2) in the initial phase is 2-4 hours, and in the final phase - 3-10 hours. In chronic renal failure, both phases of elimination of the drug 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 tissues in the form of metabolites.

Indications:Methotrexate in tablets is used when using low doses for the treatment of trophoblastic tumors, acute lymphoblastic leukemia and non-Hodgkin's lymphomas and far-reaching stages of fungal mycosis, severe forms of psoriasis, and also in rheumatoid arthritis when other methods of therapy are ineffective.

Contraindications:The use of methotrexate is contraindicated in pregnancy and during breastfeeding, with marked changes in kidney and liver function, in hematological disorders such as bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia, acute infectious disease, immunodeficiency syndrome, hypersensitivity to methotrexate or other components of the pill, children up to 3 years.

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

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 optimal effect, 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. When juvenile chronic arthritis for children, doses of 10-30 mg /m²/ week (0.3-1 mg / kg).

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 pedal. 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: pancytopenia, leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, anemia, agranulocytosis, eosinophilia.

From the cardiovascular system: pericarditis, exudative pericarditis, thromboembolic events (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolism).

From the urinary system: cystitis, renal failure, nephropathy, azotemia, hematuria.

On the part of the respiratory system: chronic interstitial pneumonitis, pulmonary edema, pulmonary fibrosis, pneumonitis, alveolitis, bronchial asthma, pleural effusion.

From the digestive system: anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, pharyngitis, rarely - enteritis, diarrhea, erosive and ulcerative lesions and bleeding from the gastrointestinal tract, in some cases (with prolonged daily use) - impaired liver function, increased activity of "liver "transaminase, ipeporralny fibrosis and cirrhosis, liver necrosis, fatty liver, pancreatitis.

From the nervous system: encephalopathy (in patients who received radiotherapy on the skull), fatigue, dizziness, headache, aphasia, paresis, hemiparesis, weakness, confusion, ataxia, tremor, irritability, convulsions and coma.

On the part of the reproductive system: violation of the process of oogenesis, spermatogenesis, decreased libido / impotence, changes in fertility, teratogenic effects.

From the skin and skin appendages: cutaneous erythema and / or rash, skin itching, urticaria, telangiectasia, furunculosis, depigmentation or hyperpigmentation, acne, skin peeling, folliculitis, alopecia (rarely), increased photosensitivity, exacerbation of radiation dermatitis.

From the sense organs: conjunctivitis, excessive lacrimation, cataract, photophobia, cortical blindness (at high doses), visual impairment.

Allergic reactions: fever, chills, rash, hives, anaphylaxis, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).

Other: immunosuppression (reduced resistance to infectious diseases), malaise, osteoporosis, hyperuricemia, hemorrhagic syndrome, vasculitis, arthralgia / myalgia, pericardial effusion.

Overdose:

Specific symptoms are absent.

In case of accidental overdose of methotrexate, it is recommended to use a specific antidote - calcium folinate. The administration of calcium folinate should be started as soon as possible, 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 precipitation of methotrexate and / or its metabolites in the renal tubules, hydration of the body and alkalinization of urine are carried out.

Interaction:

The simultaneous use of high doses of methotrexate with various non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid and other salicylates, azaprospan, diclofenac, indomethacin and ketoprofen the toxicity of methotrexate may increase, and in some cases a potentially toxic effect, sometimes even fatal, is possible. With special precautions and appropriate monitoring, the use of methotrexate in low doses (7.5-15 mg per week), in particular in the treatment of rheumatoid arthritis, in combination with NSAIDs is not contraindicated.

Methotrexate increases the anticoagulant activity of coumarin or indanedione derivatives and / or increases the risk of bleeding due to decreased synthesis in the liver of the procoagulant factor and platelet abnormalities.

Simultaneous use of sulfonamides, derivatives of sulfonylurea, phenytoin, phenylbutazone, aminobenzoic 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.

Methotrexate increases the concentration of uric acid in the blood, so when treating patients with concomitant hyperuricemia and gout it may be necessary to adjust the dose of antidotal 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).

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

Retinoids, azathioprine, sulfasalazine increase the risk of hepatotoxicity.Multivitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate therapy.

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).

Neomycin for oral administration may reduce the absorption of methotrexate for oral administration.

Hematotoxic drugs increase the risk of hematotoxicity of methotrexate.

L-asparaginase is a methotrexate antagonist.

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

The administration of amiodarone to patients receiving methotrexate therapy for psoriasis can cause skin ulceration.

Methotrexate reduces the clearance of theophylline.

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

Caution should be exercised with the simultaneous administration of erythrocyte mass and methotrexate.

The combination with radiotherapy can increase the risk of soft tissue necrosis.

Methotrexate may reduce the immunological response to vaccination. With simultaneous administration with a live vaccine, severe antigenic reactions can develop.

Special instructions:

Methotrexate is a cytotoxic drug, so care must be taken when handling it.

To prevent toxicity during the treatment with methotrexate, periodic blood testing (once a week), determination of the content of leukocytes and platelets, and performing of hepatic and renal functional tests are necessary.

With the development of diarrhea and ulcerative stomatitis, methotrexate therapy must be discontinued, otherwise it can lead to the development of hemorrhagic enteritis and to the death of the patient due to perforation of the intestine.

In patients with impaired liver function, the period of excretion of methotrexate is increased, therefore, in such patients therapy should be carried out with extreme caution, with the use of reduced doses.

Impaired renal function is dose dependent.Risk of impairment is elevated in patients with reduced renal function or with dehydration, as well as in patients taking other nephrotoxic drugs.

Particular attention should be given to the manifestations of toxic effects of methotrexate on the liver, which are not always reflected in the results of functional tests. Treatment should not be initiated or should be discontinued if any functional disorders or abnormalities are found in a biopsy examination of the hepatic tissue that are present or developed during therapy. These disorders occur for two weeks, after which it is possible to resume therapy at the discretion of the attending physician.

Currently, there are no recommendations regarding the timing of liver biopsy in patients with rheumatoid arthritis: or depending on the cumulative dose of methotrexate, or the duration of therapy.

Men and women of childbearing age should be treated with methotrexate and at least 3 months after the use of reliable methods of contraception.

Effect on the ability to drive transp. cf. and fur:Some side effects of the drug may adversely affect the ability to drive and perform potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

Form release / dosage:Tablets, coated with a coating of 2.5 mg.

Packaging:

For 10, 50 tablets in a planar cell packaging made of polyvinylchloride film and aluminum foil printed lacquered.

For 10, 20, 30, 40, 50 or 100 tablets in a polymer container for medicines.

One container or 1, 2, 3, 4, 5, 6, 8 or 10 contour mesh packages together with instructions for use in a pack of cardboard.

Storage conditions:Store in a dry, 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 expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-002476/09

Date of registration:27.03.2009

Expiration Date:Unlimited

The owner of the registration certificate:OZONE, LLC OZONE, LLC Russia

Manufacturer: & nbsp

OZONE, LLC Russia

Information update date: & nbsp10.05.2018

Illustrated instructions

Instructions

Methotrexate (Methotrexate)