Description
Release form
Coated tablets.
Packaging
In a blister pack of 10 tablets. In a cardboard package 5 blisters.
In a polymer can of 50 tablets. In a cardboard box 1 can.
Pharmacological action of
Pharmacodynamics of
The antitumor, cytostatic agent of the antimetabolite group inhibits dihydrofolate reductase, which is involved in the reduction of dihydrofolate acid to tetrahydrofolate acid (a carrier of carbon fragments needed for the synthesis of purines and them).
Slows down synthesis, DNA repair and cell mitosis. Particularly sensitive to the action of rapidly proliferating tissues: cells of malignant tumors, bone marrow, embryonic cells, epithelial cells of the intestinal mucosa, bladder, and oral cavity. Along with antitumor, it has an immunosuppressive effect.
Pharmacokinetics
Oral absorption in a dose-dependent manner: when taken 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 Cmax is from 40 minutes to 4 hours. Food slows down absorption and reduces Cmax. Communication with plasma proteins – 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 retained for several weeks or even months.
When taken in therapeutic doses, it practically does not penetrate the blood-brain barrier. Penetrates into breast milk.
Following oral administration, it is partially metabolized by the intestinal flora, the main part is in the liver (regardless of the route of administration) with the formation of a pharmacologically active polyglutamine form, which also inhibits dihydrofolate reductase and thymidine synthesis. T1 / 2 in patients receiving less than 30 mg / m2 of the drug in the initial phase is 2-4 hours, and in the final phase (which is long) – 3-10 hours when using small and 8-15 hours when using large doses the drug. In chronic renal failure, both phases of drug withdrawal can be significantly prolonged.
It is excreted mainly by the kidneys unchanged by glomerular filtration and tubular secretion, with bile excreted up to 10% (with subsequent reabsorption in the intestine). Withdrawal of the drug in patients with impaired renal function, expressed as 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 lymphomas
trophoblastic tumors
fungal mycosis in advanced stages of
severe psoriasis
rheumatoid arthritis (with other treatments ineffective).
Contraindications
The use of methotrexate is contraindicated: during pregnancy and during lactation
with severe changes in renal and hepatic function
with hematologic disorders (such as bone marrow hypoplasia, leukopenia, thrombocytopenia, and acute anemia syndrome)
with hypersensitivity to methotrexate or other components of the
tablet for children under 3 years of age.
Precautions: for ascites, effusion in the pleural cavity, gastric and duodenal ulcer, ulcerative colitis, dehydration, gout or nephrolithiasis in the anamnesis, previous radiation therapy or chemotherapy, infectious diseases of a viral, fungal or bacterial nature.
Composition
1 tablet contains:
Active substances: methotrexate 2.5 mg.
Excipients: sugar (sucrose) – 43.97 mg, potato starch – 21.82 mg, talc – 680 μg, calcium stearate – 340 μg, crospovidone – 340 μg, povidone – 350 μg.
Shell composition: sugar (sucrose) – 32.5865 mg, magnesium hydroxycarbonate hydrate – 20.457 mg, wheat flour – 16.144 mg, povidone – 166 μg, gelatin – 138 μg, dye azorubine (E122) (carmuazine, acid red dye 2C) – 16.6 μg, titanium dioxide – 450 μg, wax – 27.9 μg, talc – 14 μg.
Dosage and administration
Methotrexate tablets are used orally. Doses and periods of treatment are set individually depending on the chemotherapy regimen.
Trophoblastic tumors: 15-30 mg orally daily for 5 days with an interval of one or more weeks (depending on signs of toxicity). Treatment courses 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 prednisone until remission is achieved, then 15 mg / m2 once a week or 2.5 mg / kg every 14 days.
Non-Hodgkin lymphomas (as part of complex therapy): 15-20 mg / m2 per 1 dose 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 once or divided into three doses with an interval of 12 hours. To achieve the optimal effect, the weekly dose can be increased, while it should not exceed 20 mg. When an optimal clinical effect is achieved, a dose reduction should be started until the lowest effective dose is achieved. The optimal duration of therapy is not known. In juvenile chronic arthritis for children, doses of 10-30 mg / m2 / week (0.3-1 mg / kg) are effective.
Psoriasis:
Methotrexate is administered in doses of 10 to 25 mg per week. The dose is usually increased gradually, upon reaching the optimal clinical effect, the dose is reduced to the lowest effective dose.
Mushroom mycosis: 25 mg 2 times a week. Dose reduction or withdrawal of the drug is determined by the patient’s response and hematological parameters.
Side effects of
From the hemopoietic system: anemia (including aplastic), thrombocytopenia, leukopenia, neutropenia, agranulocytosis, eosinophilia, pancytopenia, lymphoproliferative disease, hypogammaglobulinemia, lymphadenopathy. digestive system: anorexia, nausea, vomiting, stomatitis, gingivitis, pharyngitis, enteritis, erosive and ulcerative lesions and bleeding from the gastrointestinal tract (including melena, hematomesis), hepatotoxicity (acute hepatitis, fibrosis and cirrhosis, liver failure hypoalbuminemia, increased activity of hepatic transaminases), pancreatitis.
From the nervous system: headache, dizziness, drowsiness, dysarthria, aphasia, hemiparesis, paresis, convulsions when used in high doses – transient impairment of cognitive functions, 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, decreased blood pressure, thromboembolism (including arterial thrombosis, cerebral vascular 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, impaired spermatozoa and ovogenesis, transient oligospermia, decreased libido, impotence, dysmenorrhea, vaginal discharge, gynecomastia, infertility, miscarriage, miscarriage, miscarriage, miscarriage, miscarriage fetus.
From the skin: erythematous rash, itching of the skin, urticaria, photosensitivity, violation of skin pigmentation, alopecia, ecchymosis, telangiectasia, acne, furunculosis, erythema multiforme (including Stevens-Johnson syndrome), toxic epidermal necrosis and necrosis of the skin, necrosis and necrosis , 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).
General reactions: allergic reactions up to anaphylactic shock, allergic vasculitis, tumor lysis syndrome, soft tissue necrosis, sudden death, 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, excessive sweating.
Drug Interaction
Increases the aico-coagulant activity of coumarin or indandione derivatives and / or increases the risk of bleeding by reducing procoagulant factor synthesis in the liver and impaired platelet formation.
Increases the concentration of uric acid in the blood, so the treatment of patients with concomitant hyperuricemia and gout may require dose adjustment of anti-gout drugs (allopurinol, colchicine, sulfinpyrazone) The use of uricosuric anti-gout medications may increase the risk of nephropathy associated with increased uric acid formation against methotrexate treatment (preferably allopurinol). Simultaneous salicylates, phenylbutazone, phenytin, sulfinylamine, sulfonylurea derivatives, aminobenzoic acid, pyrimetric acid, pyrimidine / or reduction of tubular secretion, which in some cases may lead to the development of severe toxic effects, sometimes even with death.
Non-steroidal anti-inflammatory drugs (NSAIDs) increase the concentration and delay the elimination of methotrexate in high doses of methotrexate, which can result in fatal hematologic and gastrointestinal intoxication. It is recommended to discontinue phenylbutazone for 7-12 days, piroxicam for 10 days, diflunisal and indomethacin for 24-48 h, ketoprofen and NSAIDs with short T1 / 2 for 12-24 h before moderate and high doses of methotrexate infusion and for at least 12 h (depending on the concentration of methotrexate in the blood) after its end. Caution should be exercised when combining NSAIDs with low doses of methotrexate (renal excretion of methotrexate may decrease). Drugs that block tubular secretion (such as probenecid), increase the toxicity of methotrexate by reducing its excretion by the kidneys.
Antibiotics, poorly absorbed in the gastrointestinal tract (tetracyclines, chloramphenicol), reduce the absorption of methotrexate and disrupt its metabolism due to the suppression of normal intestinal microflora.
Retinoids, azathioprine, sulfasalazine, ethanol and other hepatotoxic drugs increase the risk of hepatotoxicity.
L-asparaginase reduces the severity of the antitumor action of methotrexate by inhibiting cell replication.
Anesthesia using dinitrogen oxide can lead to the development of unpredictable severe myelosuppression and stomatitis.
The use of cytarabine 48 h before or within 10 min after initiation of methotrexate therapy may lead to the development of a synergistic cytotoxic effect (dosage adjustment is recommended based on hematological monitoring).
Hematotoxic drugs increase the risk of hematotoxicity of methotrexate.
Methotrexate reduces the clearance of theophylline.
Neomycin for oral administration may reduce methotrexate absorption. Several patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (methoxaline and ultraviolet radiation (UVR)) have been diagnosed with skin cancer.
Combination with radiation therapy may increase the risk of bone marrow depression. Methotrexate may reduce the immune response to vaccination with live and inactivated viral vaccines.
Folate-containing medicines (including multivitamins) may reduce the effectiveness of methotrexate therapy.
Prescribing amiodarone to patients receiving methotrexate therapy for psoriasis may cause skin manifestation.
overdose
There are no specific symptoms of overdose with methotrexate, diagnosed by plasma methotrexate concentration.
Treatment: The introduction of a specific antidote – folinate calcium, 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 appropriate, depending on the concentration of methotrexate in the serum. To prevent the precipitation of methotrexate and / or its metabolites in the renal tubules, hydration of the body and alkalinization of urine are performed, which speeds up the excretion of methotrexate. To minimize the risk of nephropathy as a result of sedimentation of the drug or its metabolites in the urine, urinary pH should be further determined before each administration and every 6 h throughout the period of folinate calcium administration as an antidote until the plasma methotrexate concentration is below 0.05 μmol / l to ensure a pH above 7.
Storage conditions
Store in a dark place at a temperature not exceeding 25 ° C. Keep out of the reach of children.
The Expiration of
is 3 years.
Deystvuyuschee substances
Methotrexate
pharmacy delivery terms Prescription
dosage form
dosage form
tablets
Northern Star, Russia
