Methotrexate-SZ - instructions for use, doses, side effects, contraindications

Excipients: core - lactose (milk sugar) - 51.0 mg, microcrystalline cellulose - 55.0 mg,calcium stearate 1.0 mg, crospovidone (clolidone CL, CL-M) 1.0 mg, povidone (kollidone 30) 7.0 mg, talc 2.5 mg; Shell - Opadrai II (series 85) (polyvinyl alcohol, partially hydrolysed - 1.76 mg, talc 0.8 mg, titanium dioxide-0.7668 mg, macrogol (polyethylene glycol 3350) 0.4940 mg, lecithin (soy) -0,14 mg, aluminum carbamazine-based lacquer - 0,0204 mg, luno based on ponso - 0.0164 mg, aluminum lacquer based on indigo carmine - 0,0024 mg).

Description:The tablets covered with a film cover from pink to dark pink color, round biconcave. On the break, the tablets are yellow in color with possible patches of orange or white.

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 for oral administration depends on the dose: when taken 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 (Cmax) is 1-2 hours. The food slows down absorption and reduces C max. The connection with plasma proteins is about 50%.

When taken in therapeutic doses, it practically does not penetrate the BBB. Penetrates into breast milk.

After oral administration, it is partially metabolized by intestinal flora, the main part - in the liver with the formation of pharmacologically active polyglutamine form, inhibiting dihydrofolate reductase and thymidine synthesis.

The half-life in the initial phase is 2-4 hours, and in the final phase - 3-10 hours. In chronic renal failure, both phases of excretion 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, with hematological disorders, including bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia, acute infectious disease, immunodeficiency syndrome, increased sensitivity to methotrexate or other constituents of the tablet, children up to 3 years of age.

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.

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 / m3² 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 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: pancytopenia, leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, anemia, agranulocytosis, eosinophilia.

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) - a violation of liver function,increased activity of "hepatic" transaminases, periportal fibrosis and cirrhosis of the liver, liver necrosis, fatty liver, pancreatitis.

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

From the urinary system: cystitis, nephropathy, impaired renal function (increase in the level of creatinine, hematuria), dysuria.

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

From the respiratory system: chronic interstitial pneumonitis, acute pulmonary edema, pulmonary fibrosis, pneumonitis, alveolitis, bronchial asthma, pleural effusion.

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: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 the precipitation of methotrexate and / or its metabolites in renal tubules, hydration of the body and alkalinization of urine are carried out.

Interaction:

The simultaneous use of high doses of methotrexate with various nonsteroidalanti-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 a decrease in the synthesis of the pro-ovalent factor in the liver and the disruption of platelet formation.

Simultaneous use of sulfonamides, derivatives of sulfonylurea, phenytoin, phenylbutazone, aminobenzoic acid, probenecid, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and lipid-lowering drugs (cholestyramine) increases the toxicity of methotrexate.

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 antidotal 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 digestive 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 treatment, methotrexate requires a periodic blood test (1 time per week), determination of leukocyte and platelet count, conduct of liver and kidney functional tests.

With the development of diarrhea and ulcerative stomatitis, therapy with methotrexate must be interrupted, 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 excretion period 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, film-coated, 2.5 mg.

Packaging:For 10 or 30 tablets in a planar cell package. For 50 tablets in a can of polymer or in a polymer bottle. Each bank or vial, 5 outline cell packs of 10 tablets, 1, 2, 3, 4 contourcell packs of 30 tablets together with instructions for use in a cardboard pack.

Storage conditions:

In a dry, 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 expiration date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:LSR-003881/08

Date of registration:21.05.2008 / 03.06.2015

Expiration Date:Unlimited

The owner of the registration certificate:NORTH STAR, CJSC NORTH STAR, CJSC Russia

Manufacturer: & nbsp

NORTH STAR, CJSC Russia

Information update date: & nbsp10.05.2018

Illustrated instructions

Instructions

Methotrexate-SZ (Methotrexate-SZ)