Methotrexate-Ebeve, solution for injection 10mg/ml syringe 1.5ml 1pc

Composition

1 syringe for injection contains:

Active ingredient:

methotrexate 15 mg

Pharmacological action

Pharmacodynamics

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

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

Pharmacokinetics

Suction

Absorption from the gastrointestinal tract when taken orally depends on the dose: when taking 30 mg / m2, it is absorbed well, the average bioavailability is 50%. Absorption decreases when taken at doses >80 mg / m2 (probably due to saturation). Food slows down the absorption of methotrexate and reduces Cmax. Tmax is 1-2 hours when taken orally and 30-60 minutes when administered intravenously.

Distribution

Binding to plasma proteins is about 50%.

When taken in therapeutic doses, regardless of the route of use, methotrexate practically does not penetrate the BBB (after intrathecal use, high concentrations are achieved in the cerebrospinal fluid). It is excreted in breast milk.

Metabolism

After oral use, methotrexate is partially metabolized by the intestinal flora, the main part – in the liver (regardless of the route of use) with the formation of a pharmacologically active polyglutamine form that inhibits dihydrofolate reductase and thymidine synthesis.

Elimination

of T1 / 2 in the initial phase is 2-4 hours, and in the final phase (which is prolonged) is 3-10 hours when using normal doses and 8-15 hours-when using high doses of the drug.

It is excreted unchanged mainly in the urine by glomerular filtration and tubular secretion (with intravenous use,80-90% is excreted within 24 hours), with bile up to 10% is excreted (with subsequent reabsorption in the intestine). With repeated use, it accumulates in the tissues in the form of metabolites.

Pharmacokinetics in special clinical cases

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

In chronic renal failure, both phases of drug elimination can be significantly prolonged. Elimination of the drug in patients with impaired renal function, severe ascites or transudate is significantly slowed.

Indications

• Trophoblastic tumor;
• acute lymphoblastic and myeloblastic leukemias;
• neuroleukemia;
• non-Hodgkin’s lymphoma, including lymphosarcoma;
• breast cancer, squamous cell carcinoma of the head and neck, lung cancer, skin cancer, cervical cancer, vulvar cancer, esophageal cancer, kidney cancer, bladder cancer, testicular cancer, ovarian cancer, penile cancer, retinoblastoma, medulloblastoma;
• osteosarcoma and soft tissue sarcoma;
• mycosis fungoides (advanced stage);
• severe psoriasis, psoriatic arthritis, rheumatoid arthritis, dermatomyositis, SLE, ankylosing spondylitis (after failure of standard therapy).

Contraindications

• Severe anemia, leukopenia, neutropenia, thrombocytopenia;
• renal failure;
• liver failure;
• pregnancy;
• breast-feeding period;
• hypersensitivity to methotrexate and/or any other component of the drug.

With caution: the drug should be used for ascites, pleural effusions, peptic ulcer of the stomach and duodenum, ulcerative colitis, dehydration, gout or nephrolithiasis in the anamnesis, previous radiation therapy or chemotherapy, infectious diseases of a viral, fungal or bacterial nature.

Side effects

From the hematopoietic system: leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, anemia.

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

From the central nervous system and peripheral nervous system: encephalopathy (with multiple doses administered intrathecally, radiation therapy in the skull), fatigue, weakness, confusion, ataxia, tremor, irritability, convulsions, coma; with intrathecal use of methotrexate – dizziness, blurred vision, headache, back pain, stiffness of the occipital muscles, convulsions, paralysis, hemiparesis.

From the respiratory system: rarely-interstitial pneumonitis, pulmonary fibrosis, exacerbation of lung infections.

From the urinary system: cystitis, nephropathy, impaired renal function (increased creatinine, hematuria).

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

From the sensory organs: conjunctivitis, excessive lacrimation, cataracts, photophobia, cortical blindness (when used in high doses), visual impairment.

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

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

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

Interaction

Concomitant use of high-dose methotrexate with various NSAIDs (including aspirin and other salicylates, azapropazone, dichlofenac, Indometacin and ketoprofen) methotrexate toxicity may increase. In some cases, a severe toxic effect is possible, sometimes even fatal. If special precautions are taken and appropriate monitoring is carried out, 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.

Concomitant use with sulfonamides, sulfonylurea derivatives, phenytoin, phenylbutazone, aminobenzoic acid, probenecid, pyrimethamine or trimethoprim, a number of antibiotics (including penicillin, tetracycline, chloramphenicol), indirect anticoagulants and lipid-lowering drugs (colestyramine) increases the toxicity of methotrexate. Antibiotics that are poorly absorbed from the gastrointestinal tract (including tetracyclines, chloramphenicol), reduce the absorption of methotrexate and disrupt its metabolism due to the suppression of normal intestinal microflora.

When used concomitantly with methotrexate, retinoids, azathioprine, and sulfasalazine increase the risk of hepatotoxicity. Parenteral use of acyclovir with intrathecal use of methotrexate increases the risk of neurological disorders.

Concomitant use of methotrexate with multivitamins containing folic acid or its derivatives may reduce the effectiveness of methotrexate therapy.

L-asparaginase is a methotrexate antagonist.

Performing anesthesia with dinitrogen oxide on the background of methotrexate therapy can lead to the development of unpredictable severe myelosuppression and stomatitis.

When used concomitantly with methotrexate, amiodarone may contribute to skin ulceration.

Methotrexate reduces theophylline clearance.

Several patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (metoxalen and UFO) were diagnosed with skin cancer.

Caution should be exercised when using red blood cell mass and methotrexate simultaneously.

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

Methotrexate may reduce the immunological response to vaccination; severe antigenic reactions may occur when the drug is co-administered with a live vaccine.

How to take it, course of use and dosage

Methotrexate is part of many chemotherapeutic treatment regimens, and therefore, when choosing the route of use, regimen and doses in each individual case, you should be guided by the data of the specialized literature.

Methotrexate-Ebeve for injection can be administered intravenously, intravenously, intravenously or intrathecally. Methotrexate-Ebeve tablets should be taken orally before meals, without chewing.

For trophoblastic tumors – 15-30 mg orally or in / m, daily for 5 days with an interval of ≥1 week (depending on the signs of toxicity). Or 50 mg once every 5 days with an interval of ≥1 month. Courses of treatment are usually repeated from 3 to 5 times up to a total dose of 300-400 mg.

For solid tumors in combination with other antitumor drugs-30-40 mg / m2 IV jet 1 time per week.

For leukemias or lymphomas-200-500 mg / m2 by intravenous infusion 1 time in 2-4 weeks.

With neuroleukemia – 12 mg / m2 intrathecally for 15-30 seconds 1 or 2 times a week.

In the treatment of children, the dose is selected depending on the age:

• children under the age of 1 year are prescribed 6 mg;
• children under the age of 1 year-8 mg;
• children aged 2 years – 10 mg;
• children over 3 years-12 mg.

Before use, the cerebrospinal fluid should be removed in a volume approximately equal to the volume of the drug to be administered.

When applying high-dose therapy is from 2 to 15 g/m 2 in the form of 4-6 hours on/in infusion every 1 to 5 weeks with obligatory subsequent use of calcium folinate, which usually start 24 hours after beginning of methotrexate infusion and administered every 6 h at a dose of 3-40 mg/m 2 (usually 15 mg/m 2) and higher depending on the concentration of methotrexate in the blood serum within 48-72 hours

In rheumatoid arthritis, the initial dose is usually 7.5 mg once a week, which is administered simultaneously intravenously, intramuscularly or orally-2.5 mg every 12 hours (a total of 3 doses). To achieve the optimal effect, the weekly dose can be increased, but it should not exceed 20 mg. When the optimal clinical effect is achieved, dose reduction should be initiated until the lowest effective dose is reached. The optimal duration of therapy is not known.

For psoriasis, oral, intravenous or intravenous jet in doses from 10 to 25 mg per week. The dose is usually increased gradually, and when the optimal clinical effect is achieved, the dose is reduced until the lowest effective dose is reached.

For fungal mycosis in / m 50 mg 1 time a week or 25 mg 2 times a week or inside 2.5 mg/day for several weeks or months. Dose reduction or discontinuation of the drug is determined by the patient’s response and hematological parameters.

Overdose

Symptoms: mainly symptoms associated with suppression of the hematopoietic system are observed.

Treatment: The specific antidote of methotrexate is calcium folinate. It neutralizes the adverse toxic effects.

In case of accidental overdose, no later than one hour after the use of methotrexate, calcium folinate (IV or iv) is administered at a dose equal to or exceeding the dose of methotrexate. use of calcium folinate is continued until the concentration of methotrexate in the blood serum decreases below the level of 10-7 mmol/l.

In case of a significant overdose, hydration of the body and alkalinization of urine (pH greater than 7) may be required to prevent precipitation of methotrexate and / or its metabolites in the renal tubules. Hemodialysis and peritoneal dialysis do not improve methotrexate elimination. Intensive intermittent hemodialysis using highly permeable (“high-flux”) dialysers allows for effective clearance of methotrexate.

In case of overdose with intrathecal use, repeated lumbar punctures should be performed immediately to ensure rapid drainage of the cerebrospinal fluid, neurosurgical intervention with ventriculolumbal perfusion is possible. All these procedures should be performed against the background of intensive maintenance therapy and systemic use of large doses of calcium folinate.

Special instructions

Caution should be exercised when using methotrexate.

Dosage forms containing preservatives (benzyl alcohol) should not be used for intrathecal use or for high-dose therapy.

When high doses of methotrexate are administered, careful monitoring of the patient is necessary for early detection of the first signs of toxic reactions.

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

During therapy with methotrexate in elevated and high doses, the patient’s urine pH should be monitored: on the day of use and in the next 2-3 days, the urine reaction should be alkaline. This is achieved by intravenous drip use of a mixture consisting of 40 ml of a 4.2% sodium bicarbonate solution and 400-800 ml of an isotonic sodium chloride solution, on the eve, on the day of treatment and in the next 2-3 days.

Treatment with methotrexate in increased and high doses should be combined with increased hydration-up to 2 liters / day.

use of methotrexate at a dose of ≥2 g / m3 should be carried out under the control of its concentration in the blood serum. A 2-fold decrease in the level of methotrexate in the blood serum 22 hours after use is considered normal compared to the initial level. An increase in creatinine levels by ≥50% from the initial level and/or an increase in bilirubin levels require intensive detoxification therapy.

For the treatment of psoriasis, methotrexate is prescribed only to patients with a severe form of the disease that does not respond to other types of therapy.

To prevent toxicity during treatment with methotrexate, a blood test should be performed periodically (once a week), the content of white blood cells and platelets should be determined, and liver and renal function tests should be performed.

If diarrhea and ulcerative stomatitis develop, methotrexate therapy should be interrupted to avoid the development of hemorrhagic enteritis and death of the patient due to intestinal perforation.

In patients with impaired liver function, the elimination period of methotrexate is prolonged, so therapy with the drug should be carried out with extreme caution, with a decrease in doses.

Impaired renal function depends on the dose. The risk of impairment is increased in patients with reduced renal function or dehydration, as well as in patients taking other nephrotoxic drugs.

Influence on the ability to drive vehicles and other mechanisms that require increased concentration of attention

Some side effects of the drug may negatively affect the ability to drive a car and perform potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Form of production

Methotrexate-Ebeve solution for injection.

Storage conditions

Keep out of the reach of children, protected from light at a temperature not exceeding 25°C.

See expiration date. on the packaging.

Active ingredient

Methotrexate

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Purpose

For adults as prescribed by a doctor, for children as prescribed by a doctor

Indications

Cancer, Psoriasis, Rheumatoid Arthritis, Breast Cancer