Methotrexate-Teva, 25 mg/ml 2 ml

Pharmacotherapeutic group: antitumor drug, antimetabolite.

ATX code: L01BA01

Pharmacological properties

Pharmacodynamics. An antitumor, cytostatic agent of the group of antimetabolite analogues of folic acid. It inhibits dihydrofolate reductase, which takes part 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 (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.

In addition to anti-tumor effects, it also has immunosuppressive effects.

Pharmacokinetics. Time to reach maximum concentration (C_max) with intramuscular administration is 30-60 minutes. Binding to plasma proteins is about 50%.

When administered in therapeutic doses, regardless of the route of administration, it practically does not penetrate through the BBB (after intrathecal administration high concentrations are achieved in the cerebrospinal fluid). It penetrates into breast milk.

It is metabolized in the liver to form pharmacologically active polyglutamine form which inhibits dihydrofolate reductase and thymidine synthesis.

The elimination half-life in the initial phase is 2-4 h, and in the final phase (which is prolonged) – 3-10 h when using conventional 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 eliminated mainly by kidneys in unchanged form through glomerular filtration and tubular secretion (when administered intravenously 80-90% is eliminated within 24 hours), about 10% is eliminated with bile (with subsequent reabsorption in the intestine). Excretion in patients with impaired renal function, marked ascites or transudate is significantly delayed. During repeated administration the drug accumulates in tissues as metabolites.

Indications

Active ingredient

Composition

How to take, the dosage

Methotrexate is part of many chemotherapeutic regimens, and therefore the route of administration, regimen and dosage should be guided by the data in the literature in each individual case.

Methotrexate for injection can be given intramuscularly, intravenously, intraarterially, or intrathecally.

The following dosing regimens are used:

Trophoblastic tumors: 15-30 mg intramuscularly, daily for 5 days at one or more weekly intervals (depending on signs of toxicity). Or 50 mg once every 5 days at intervals of at least 1 month. Treatment courses are usually repeated 3 to 5 times up to a total dose of 300-400 mg.

Solid tumors: in combination with other antitumor drugs, 30-40 mg/m2 intravenously by IV stream once a week.

Leukemia and lymphoma: 200-500 mg/m2 by intravenous infusion once every 2-4 weeks. Neuroleukemia: 12 mg/m2 intrathecally for 15-30 seconds once or twice a week. When treating children, the dose is adjusted according to the age of the child: children under 1 year of age are prescribed 6 mg, children 1 year of age 8 mg, children 2 years of age 10 mg, children 3 years and older 12 mg. Before administration, spinal fluid should be removed in an amount approximately equal to the volume of the drug to be injected.

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

Rheumatoid arthritis: Initial dose is usually 7.5 mg once weekly, administered once daily intravenously or intramuscularly, or 2.5 mg every 12 hours (3 doses total). 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. Psoriasis: intramuscularly or intravenously in doses ranging from 10-25 mg per week. The dose is usually increased gradually; when optimal clinical effect is achieved, dose reduction is initiated until the lowest effective dose is achieved. Fungal mycosis: intramuscularly 50 mg once weekly or 25 mg twice weekly for several weeks or months. Dose reduction or discontinuation of the drug is determined by the patient’s response and hematological parameters.

Interaction

Simultaneous use of high doses of methotrexate with various nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and other salicylates, azapropazone, diclofenac, indomethacin and ketoprofen – methotrexate toxicity may increase, and in some cases severe toxic effects, sometimes even fatal, are possible. 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.

. Concomitant use of sulfonamides, sulfonylurea derivatives, phenytoin, phenylbutazone, aminobenzoic acid, probenecid, pyrimethamine or trimethoprim, several antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and hypolipidemic drugs (cholestyramine) increases toxicity of methotrexate.

The retinoids, azathioprine, sulfasalazine increase the risk of hepatotoxicity. Parenteral use of acyclovir against intrathecal administration of methotrexate increases the risk of neurological disorders.

Polivitamin preparations containing folic acid or its derivatives may decrease the effectiveness of therapy with methotrexate.

L-asparaginase is an antagonist of methotrexate.

The administration of anesthesia with dinitrogen oxide can lead to the development of unpredictable severe myelosuppression and stomatitis.

Amiodarone may contribute to skin ulceration.

Methotrexate decreases the clearance of theophylline.

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

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

Combination with radiotherapy may increase the risk of soft tissue necrosis.

Methotrexate may decrease the immunological response to vaccination. Severe antigenic reactions may develop if administered concomitantly with live vaccine.

Special Instructions

Methotrexate is cytotoxic, so care must be taken when handling it.

Preservative dosage forms containing preservatives, particularly benzyl alcohol, should not be used for intrathecal administration and high-dose therapy.

When administering high doses of methotrexate, close monitoring of the patient is necessary for early detection of the first signs of toxic reactions.

High-dose therapy should only be given by experienced chemotherapists under inpatient monitoring of plasma methotrexate concentrations under cover of calcium folinate.

During therapy with methotrexate at higher and higher doses, urine pH should be monitored: on the day of injection 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 0.9% sodium chloride solution the day before, the day of therapy and the following 2-3 days.

Methotrexate treatment in higher and higher doses should be combined with increased hydration up to 2 liters of fluid per day.

The administration of methotrexate at a dose of 2 g/m2 and higher is performed under control of its serum concentration. Reduction of methotrexate content in blood serum in 22 hours after injection by a factor of 2 from the initial level is considered normal. Elevation of creatinine level by 50% or more of the initial level and/or increase in bilirubin level requires intensive detoxification therapy.

To treat psoriasis, methotrexate is indicated only in patients with a severe form of the disease that cannot be treated by other therapies.

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

If diarrhea and ulcerative stomatitis develop, therapy with methotrexate should be discontinued, otherwise it may lead to hemorrhagic enteritis and death of the patient due to intestinal perforation.

In patients with impaired liver function the elimination period of methotrexate is longer, so in these patients therapy should be given with extreme caution, using reduced doses.

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

Men and women of childbearing age should use reliable contraception during treatment with methotrexate and for at least 3 months after.

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

Contraindications

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

Side effects

Blood organs: leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, anemia.

Digestive system disorders: Anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, pharyngitis, rarely – enteritis, diarrhea, erosive ulcerative lesions and bleeding from the gastrointestinal tract, in some cases (with long-term daily use) – liver impairment, increased activity of “liver” transaminases, periportal fibrosis and cirrhosis of the liver, liver necrosis, fatty liver degeneration, pancreatitis.

Nervous system disorders: encephalopathy, especially when multiple doses are administered intrathecally and in patients who have received radiation therapy to the cranial area. There have also been reports of fatigue, weakness, confusion, ataxia, tremor, irritability, seizures and coma. Acute adverse events caused by intrathecal administration of methotrexate may include dizziness, blurred vision, headache, back pain, neck stiffness, seizures, paralysis, and hemiparesis.

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

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

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

Skin and skin appendages: erythema and/or rash, pruritus, urticaria, telangiectasia, furunculosis, depigmentation or hyperpigmentation, acne, skin peeling, folliculitis, alopecia (rare), photosensitivity, exacerbation of radiation dermatitis.

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

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

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

Overdose

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