Methotrexate-Ebeve 10 mg/ml 5 ml, 5 pcs.

Pharmacodynamics

Antitumor drug from the group of antimetabolites – analogues of folic acid. Along with antitumor, it has immunosuppressive action.

Inhibits dihydrofolate reductase, which is involved in the reduction of dihydrofolic acid to tetrahydrofolic acid – a carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives.

Inhibits synthesis, DNA repair and cellular mitosis (in S-phase). Tissues with high cell proliferation are particularly sensitive to the action of methotrexate: tumor tissue, bone marrow, mucosal epithelial cells, embryonic cells. In addition, methotrexate has immunosuppressive properties.

Pharmacokinetics

Intake

Gastrointestinal absorption when taken orally depends on the dose: when taken 30 mg/m2 is well absorbed, the average bioavailability is 50%. Absorption is reduced at doses of >80 mg/m2 (probably due to saturation). Food slows down absorption of methotrexate and reduces Cmax. Tmax is 1-2 h when administered orally and 30-60 min when administered by injection.

Distribution

Binding to plasma proteins is about 50%.

When administered in therapeutic doses, regardless of the route of administration, methotrexate has almost no penetration through the BBB (after intrathecal administration high concentrations are achieved in the cerebrospinal fluid). It is excreted with the breast milk.

Metabolism

After oral administration methotrexate is partially metabolized by gut flora, the main part – in the liver (regardless of route of administration) to form pharmacologically active polyglutamine form, which inhibits dihydrofolatreductaeu and thymidine synthesis.

Elimation

The T1/2 in the initial phase is 2-4 h, and in the final phase (which is prolonged) is 3-10 h with conventional doses and 8-15 h with high doses of the drug.

It is excreted unchanged mainly with urine by glomerular filtration and tubular secretion (when administered intravenously 80-90% is excreted within 24 hours), with bile up to 10% is excreted (with subsequent reabsorption in the intestine). In repeated administrations it accumulates in tissues as metabolites.

Pharmacokinetics in special clinical cases

In children with leukemia absorption ranges from 23 to 95%.

In chronic renal failure, both phases of drug excretion may be significantly prolonged. Excretion of the drug in patients with impaired renal function, marked ascites or transudate is significantly delayed.

Indications

Active ingredient

Composition

Injection solution

Active ingredient: methotrexate.

Auxiliary substances: sodium chloride, sodium hydroxide, water for injection.

1 vial (1 ampoule) of 1 or 5 ml. The package contains 5 vials (5 ampoules).

How to take, the dosage

Methotrexate is included in many chemotherapy regimens, and therefore the route of administration, regimen and dose should be guided by the literature in each individual case.

Methotrexate-Ebev Injection can be given intravenously, intravenously, or intrathecally. Methotrexate-Ebeve tablets should be taken orally before meals, without chewing.

For trophoblastic tumors, 15-30 mg orally or intramuscularly, daily for 5 days at intervals of ≥1 week (depending on signs of toxicity). Or 50 mg once every 5 days at intervals of ≥1 month. Treatment courses are usually repeated 3 to 5 times up to a total dose of 300-400 mg.

In solid tumors in combination with other antitumor drugs, 30-40 mg/m2 by IV infusion once a week.

In leukemia or lymphoma, 200-500 mg/m2 by IV infusion once every 2-4 weeks.

In neuroleukemia, 12 mg/m2 intrathecally for 15-30 seconds once or twice a week.

When treating children, the dose is adjusted according to age:

Pending administration, the cerebrospinal fluid should be removed in an amount approximately equal to the volume of the drug to be injected.

When high-dose therapy is used, 2 to 15 g/m2 as a 4-6-hour IV infusion at 1-5 week intervals, followed by mandatory administration of calcium folinate, which usually begins 24 h after the start of methotrexate infusion and is given every 6 h at a dose of 3-40 mg/m2 (usually 15 mg/m2) or higher depending on the serum methotrexate concentration for 48-72 h.

In rheumatoid arthritis, the starting dose is usually 7.5 mg once a week, which is administered once daily by IV, IM, or intravenously at 2.5 mg every 12 h (3 doses total). The weekly dose may be increased, but should not exceed 20 mg, to achieve optimal effect. 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 psoriasis, the oral, intravenous, or intravenous doses are 10 to 25 mg per week. The dose is usually built up gradually; when optimal clinical effect is achieved, start reducing the dose until the lowest effective dose is achieved.

In fungal mycosis, 50 mg/m once weekly or 25 mg twice weekly, or oral 2.5 mg/day for several weeks or months. Dose reduction or discontinuation of the drug is determined by the patient’s response and hematologic parameters.

Interaction

When concomitant use of high doses of methotrexate with various NSAIDs (including aspirin and other salicylates, azapropazon, dichlofenac, indomethacin and ketoprofen) toxicity of methotrexate may increase. In some cases severe toxic effects are possible, sometimes even fatal. With observance of special precautions and proper monitoring the use of methotrexate in low doses (7.5-15 mg per week), in particular in treatment of rheumatoid arthritis, in combination with NSAIDs is not contraindicated.

When used concomitantly with sulfonamides, sulfonylurea derivatives, phenytoin, phenylbutazone, aminobenzoic acid, probenecid, pyrimethamine or trimethoprim, a number of antibiotics (including penicillin and penicillin).including penicillin, tetracycline, chloramphenicol), indirect anticoagulants and hypolipidemic drugs (colestyramine) increases toxicity of methotrexate. Antibiotics poorly absorbed from the gastrointestinal tract (including tetracyclines, chloramphenicol) decrease absorption of methotrexate and impair its metabolism due to suppression of normal intestinal microflora.

When concomitant use of retinoids, azathioprine, sulfasalazine increases the risk of hepatotoxicity. Parenteral use of acyclovir combined with intrathecal administration of methotrexate increases the risk of neurologic disorders.

The simultaneous use of methotrexate with multivitamin preparations containing folic acid or its derivatives may decrease the effectiveness of methotrexate therapy.

L-asparaginase is an antagonist of methotrexate.

Anesthesia with dinitrogen oxide with methotrexate therapy can lead to unpredictable severe myelosuppression and stomatitis.

In concomitant use with methotrexate, amiodarone may contribute to skin ulceration.

Methotrexate reduces the clearance of theophylline.

A few patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (methoxalen and UVA) have been found to have skin cancer.

Caution should be exercised when using red blood cell mass and methotrexate at the same time.

Combining methotrexate therapy with radiotherapy may increase the risk of soft tissue necrosis.

Methotrexate may decrease immunological response to vaccination; severe antigenic reactions may develop if the drug is given simultaneously with live vaccine.

Special Instructions

Cautions must be taken with methotrexate.

Preservative dosage forms (benzyl alcohol) should not be used for intrathecal administration and high dose therapy.

High dose methotrexate requires close patient monitoring for early detection of the first signs of toxic reactions.

High-dose therapy should only be given by experienced chemotherapists who can monitor the plasma concentration of methotrexate in the hospital under cover of calcium folinate.

At high-dose and high-dose methotrexate therapy, the patient’s urine pH should be controlled: on the day of administration and the following 2-3 days, the urine reaction should be alkaline. This is achieved by intravenous drop infusion of a mixture consisting of 40 ml of 4.2% sodium bicarbonate solution and 400-800 ml of isotonic sodium chloride solution, the day before, the day of treatment and the next 2-3 days.

The treatment with methotrexate in higher and higher doses should be combined with increased hydration – up to 2 liters per day.

The administration of methotrexate in doses ≥2 g/m3 should be performed under control of its serum concentration. Normal is considered to be decrease of methotrexate content in blood serum in 22 hours after injection by 2 times in comparison with initial level. Increase of creatinine level by ≥50% from the initial level and/or increase of bilirubin level requires intensive detoxification therapy. For treatment of psoriasis methotrexate is indicated only for patients with severe disease that is resistant to other types of therapy.

To prevent toxicity during treatment with methotrexate, periodic blood counts (once weekly), white blood cell and platelet counts, and liver and kidney function tests should be performed.

In case of development of diarrhea and ulcerative stomatitis, therapy with methotrexate should be discontinued to prevent development of hemorrhagic enteritis and patient death due to intestinal perforation.

In patients with impaired liver function, the elimination time of methotrexate is prolonged, so therapy with the drug should be given with extreme caution, with lowering of doses.

Renal function impairment is dose-dependent. The risk of impairment is increased in patients with decreased renal function or dehydration, as well as in patients taking other nephrotoxic drugs.

Influence on ability to drive vehicles and other mechanisms requiring increased concentration

Some side effects of the drug may adversely affect the ability to drive and perform potentially hazardous activities requiring increased concentration and quick psychomotor reactions.

Contraindications

With caution: The drug should be used in cases of ascites, pleural effusions, peptic ulcer, ulcerative colitis, dehydration, history of gout or nephrolithiasis, previous radiation therapy or chemotherapy, infectious diseases of viral, fungal or bacterial origin.

Side effects

Hematopoietic system: leukopenia, neutropenia, lymphopenia (especially T lymphocytes), thrombocytopenia, anemia.

Digestive system disorders: Anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, pharyngitis; rarely – enteritis, diarrhea, gastrointestinal ulcers, gastrointestinal bleeding; in individual cases (with prolonged daily use) – impaired liver function, increased activity of liver transaminases, periportal fibrosis and cirrhosis, liver necrosis, fatty liver degeneration, pancreatitis.

From the CNS and peripheral nervous system: Encephalopathy (when multiple doses are given intrathecally, cranial radiation therapy), fatigue, weakness, confusion, ataxia, tremor, irritability, seizures, coma; when methotrexate is given intrathecally, dizziness, blurred vision, headache, back pain, neck muscle rigidity, seizures, paralysis, hemiparesis.

Respiratory system: rarely – interstitial pneumonitis, pulmonary fibrosis, exacerbation of lung infections.

Urinary system: cystitis, nephropathy, renal dysfunction (increased creatinine level, hematuria).

Reproductive system: disorders of oogenesis, spermatogenesis, decreased libido/impotence, changed fertility, teratogenic effects.

Sensory system disorders: conjunctivitis, excessive lacrimation, cataracts, photophobia, cortical blindness (in high doses), visual impairment.

Dermatological reactions: erythema and/or rash, skin itching, telangiectasia, furunculosis, depigmentation or hyperpigmentation, acne, skin peeling, folliculitis, alopecia (rare), exacerbation of radiation dermatitis.

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

Others: immunosuppression (decreased resistance to infectious diseases), malaise, osteoporosis, hyperuricemia, vasculitis, arthralgia/myalgia.

Overdose

Treatment: immediately, preferably within the first hour, start administration of a specific antidote – calcium folinate in 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 the urine are performed.

In case of overdose during intrathecal administration, repeated lumbar punctures should be performed immediately to ensure rapid drainage of cerebrospinal fluid. Neurosurgical intervention with ventriculolumbar perfusion is possible. All these procedures should be performed with intensive supportive therapy and high-dose systemic administration of calcium folinate.

Similarities