Methotrexate-SZ, 2.5mg 50 pcs.

Antitumor, cytostatic agent of antimetabolite group, inhibits dihydrofolate reductase involved in the reduction of dihydrofolic acid to tetrahydrofolic acid (carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives).

Inhibits synthesis, DNA repair and cellular mitosis. Especially sensitive to its action are rapidly proliferating tissues: cells of malignant tumors, bone marrow, embryonic cells, epithelial cells of mucous coat of intestine, bladder, oral cavity. Along with anti-tumor, it has immunosuppressive effects.

PHARMACOKINETICS

Absorption when taken orally depends on the dose: when taken 30 mg/m2 is well absorbed, the average bioavailability is 60%. Absorption is reduced when administered in doses greater than 80 mg/m2.

In children with leukemia, absorption ranges from 23% to 95%. Time of reaching Cmax is from 40 min to 4 h. Food slows down absorption and reduces Cmax. Binding with plasma proteins is about 50%, mainly with albumin.

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

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

After oral administration it is partially metabolized by gut flora, the main part – in liver (regardless of route of administration) with formation of pharmacologically active polyglutamine form, which also inhibits dihydrofolate reductase and thymidine synthesis. The T1/2 in patients receiving less than 30 mg/m2 of the drug is 2-4 h in the initial phase and 3-10 h in the final phase (which is prolonged) when using low doses and 8-15 h when using high doses of the drug. In chronic renal failure both phases of drug excretion may be significantly prolonged.

The drug is excreted mainly by kidneys unchanged by glomerular filtration and tubular secretion, about 10% is excreted in bile (with subsequent reabsorption in intestine). Excretion of the drug in patients with impaired renal function, marked ascites or transudate is significantly delayed. When repeated administration it accumulates in tissues as polyglutamates.

Indications

Active ingredient

Composition

Active ingredients:

Methotrexate 2.5 mg

How to take, the dosage

Ingestion. Doses and periods of treatment are set individually depending on the chemotherapy regimen.

Trophoblastic tumors:

– 15-30 mg orally daily for 5 days at intervals 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 at intervals of at least 1 month. A 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 is achieved, then 15 mg/m2 once weekly or 2.5 mg/kg every 14 days.

Non-Hodgkin’s lymphoma (as part of complex therapy):

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

– 7.5 mg/m2 daily for 5 days.

Rheumatoid arthritis:

The starting dose is usually 7.5 mg once weekly, taken once daily or divided into three doses 12 hours apart. For optimal effect, the weekly dose may be increased, but should not exceed 20 mg. When optimal clinical effect is achieved, dose reduction should be initiated until the lowest effective dose is achieved. The optimal duration of therapy is not known. In juvenile chronic arthritis, doses of 10-30 mg/m2/week (0.3-1 mg/kg) are effective in children.

Psoriasis:

Methotrexate therapy is given in doses of 10 to 25 mg/week. The dose is usually increased gradually; when optimal clinical effect is achieved, dose reduction is started until the lowest effective dose is achieved.

Interaction

Increased and prolonged action of methotrexate, leading to intoxication, contributes to the simultaneous use of NSAIDs, barbiturates, sulfonamides, corticosteroids, tetracyclines, trimethoprim, chloramphenicol, paraaminobenzoic and paraaminohippuric acids, probenecid. Folic acid and its derivatives reduce the effectiveness. It increases the effect of indirect anticoagulants (coumarin or indandion derivatives) and increases the risk of bleeding. Drugs of penicillin group reduce renal clearance of methotrexate. Concomitant use of methotrexate and asparaginase may block action of methotrexate. Neomycin (oral) may reduce absorption of methotrexate (oral). Drugs causing abnormal blood changes increase leukopenia and/or thrombocytopenia if these drugs have the same effect as methotrexate on bone marrow function. Other drugs that inhibit bone marrow function or radiation therapy potentiate the effect and additively inhibit bone marrow function. Synergistic cytotoxic effect with cytarabine is possible when used concomitantly. When concomitant use of methotrexate (intrathecal) with acyclovir (parenterally) neurological disorders are possible. In combination with live virus vaccines may cause intensification of the replication process of the vaccine virus, increased side effects of the vaccine and reduced antibody production in response to the administration of both live and inactivated vaccines.

Special Instructions

Conception should be avoided during methotrexate treatment and after it (men – 3 months after treatment, women – at least one ovulation cycle). After methotrexate treatment it is recommended to use calcium folinate to reduce the toxic effects of high doses of the drug.

The necessary rules for the use and destruction of the drug should be observed.

Contraindications

The use of methotrexate is contraindicated in pregnancy and during lactation, with marked changes in renal and liver function, hematological disorders (such as bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia), in the acute phase of infectious diseases, immunodeficiency syndrome, hypersensitivity to methotrexate or other components of the tablet, children under 3 years old.

With caution. In ascites, pleural effusion, gastric and duodenal ulcer, ulcerative colitis, dehydration, history of gout or nephrolithiasis, previous radiation therapy or chemotherapy, infectious diseases of viral, fungal or bacterial nature.

Side effects

Blood system disorders: anemia (including aplastic), thrombocytopenia, leukopenia, neutropenia, agranulocytosis, eosinophilia, pancytopenia, lymphoproliferative diseases, hypogammaglobulinemia, lymphadenopathy.

Digestive system disorders: Anorexia, nausea, vomiting, stomatitis, gingivitis, pharyngitis, enteritis, erosive ulcerative lesions and bleeding from the GI tract (including melena, hematemesis), hepatotoxicity (acute hepatitis, liver fibrosis and cirrhosis, liver failure, hypoalbuminemia, increased activity of “liver” transaminases), pancreatitis.

Nervous system disorders: headache, dizziness, somnolence, dysarthria, aphasia, hemiparesis, paresis, convulsions; when used in high doses – transient cognitive impairment, emotional lability; unusual cranial sensitivity, encephalopathy (including leukoencephalopathy).

VIight: conjunctivitis, visual impairment (including transient blindness).

Cardiovascular system disorders: pericarditis, pericardial effusion, decreased BP, thromboembolism (including arterial thrombosis, cerebral thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolism).

Respiratory system disorders: rare – 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.

Urogenital system disorders: severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria, impaired spermatogenesis and ovogenesis, transient oligospermia, decreased libido, impotence, dysmenorrhea, vaginal discharge, gynecomastia, sterility, miscarriage, fetal death, fetal defects.

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

Musculoskeletal system: arthralgia, myalgia, osteoporosis, osteonecrosis, fractures.

Novoplasms: lymphoma (including reversible).

General reactions: Allergic reactions up to and including 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), nocardiasis, histoplasmosis, cryptococcosis, infections caused by Herpes zoster and Herpes simplex (including disseminated herpes), diabetes, excessive sweating.

Overdose

Symptoms: no specific symptoms.

Treatment: immediate administration of calcium folinate to neutralize the myelotoxic effects of methotrexate (oral, IM or IV). 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 should be given as needed. Increase hydration of the body, conduct alkalinization of urine in order to avoid precipitation of the drug and its metabolites in the urinary tract.

Pregnancy use

It has teratogenic effect: it can cause fetal death and congenital malformations.

If a woman becomes pregnant during treatment with methotrexate, she should consider stopping the pregnancy due to the risk of adverse effects on the fetus.

Methotrexate is excreted with breast milk, so breastfeeding should be stopped for the duration of treatment.

Similarities