Methotrexate

Methotrexate is an immunosuppressive drug and chemotherapy. It is used to treat certain types of cancer or to control severe psoriasis or rheumatoid arthritis.

How does it work?

This drug is part of the group of pharmaceutical antineoplastics used to treat cancer.

Methotrexate refers to antianginal, vasodilating, coronary dilating agents. It is included in the group of analog drugs (generics) of folic acid, which plays an important role in the work of various human systems and organs.

It has the property of inhibiting the processes in which dihydrofolic acid is converted to tetrahydrofolic acid.

It can disrupt the synthesis during the metabolism of thymidyl acid. Methotrexate also inhibits purine production. As a result, DNA synthesis is suppressed in the body. The process of cell reproduction, the synthesis of RNA, as well as proteins, are disrupted.

Methotrexate also has immunosuppressant properties.

Indications for use

This drug is used to treat various types of cancer, in particular:

• acute lymphocytic leukemia;
• non-Hodgkin lymphoma;
• breast cancer;
• choriocarcinomas;
• severe cases of psoriasis or rheumatoid arthritis.

Contraindications

The drug should not be used if the patient has previously had a hypersensitivity (allergy) to one of the components that make up the drug – both primary and secondary.

Methotrexate is also contraindicated for use in the following conditions:

• significant violations of the liver and/or kidneys;
• alcoholism;
• disorders of the hematopoietic system (leukopenia, anemia, etc.);
• severe, acute or chronic infections (tuberculosis, HIV);
• oral ulcers, gastrointestinal tract;
• use with live vaccines during the treatment period.

Avoid foods/drinks containing tannin or caffeine.

The drug is incompatible with oxidants and acids.

Pregnancy and breastfeeding

Treatment of pregnant women with this drug is contraindicated.

During the treatment with this drug, breastfeeding should be suspended.

Dosage and administration

Tablets are taken orally. The doses and periods of treatment are determined 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 simultaneously 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:

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 one.

Overdose

An overdose of this drug can cause violations of the hematopoiesis system.

Calcium folinate, which has the ability to neutralize the toxic effects of methotrexate, is recommended as an antidote.

Side effects

The drug can cause the following side effects:

• effusion in the pericardial cavity, pericardial tamponade;
• inhibition of bone marrow function (leukopenia, thrombocytopenia, anemia, pancytopenia);
• drowsiness, headache, fatigue;
• encephalopathy, subacute myelopathy;
• visual impairment, pain, myasthenia gravis, seizures, paralysis, ataxia, dementia, coma;
• eye irritation, cataracts, photophobia, conjunctivitis;
• pneumonitis, cough, shortness of breath, asthma, fever;
• nosebleeds, alveolitis, pleural effusion;
• disorders of the stomach, stomatitis, nausea, anorexia, dyspepsia;
• diarrhea, oral ulcers;
• gastrointestinal ulcers, impaired renal function, impaired urination;
• exanthema, erythema, itching;
• alopecia, vasculitis, allergic urticaria;
• arthralgia, myalgia, osteoporosis;
• increase susceptibility to infections;
• worsened wound healing.

Drug interaction

• Methotrexate increases the anticoagulant activity of coumarin or indandion derivatives and/or increases the risk of bleeding by reducing the synthesis of the procoagulant factor in the liver and impaired platelet formation;
• Methotrexate increases the concentration of uric acid in the blood, therefore, in the treatment of patients with concomitant hyperuricemia and gout, a dose adjustment of antigout drugs (allopurinol, colchicine, sulfinpyrazone) may be required; the use of uricosuric antigout medications may increase the risk of developing nephropathy associated with increased uric acid formation during treatment with methotrexate (allopurinol is preferred). The simultaneous administration of salicylates, phenylbutazone, phenytoin, sulfanilamides, sulfonylurea derivatives, aminobenzoic acid, pyrimethamine or a trimethoprim, a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and hypolipidemic dependence of the drug results in / or decrease in tubular secretion, which in some cases can cause severe toxic effects (sometimes even fatal);
• Nonsteroidal anti-inflammatory drugs (NSAIDs) against the background of high doses of methotrexate increase the concentration and slow down the elimination of the latter, which can lead to death from severe hematological and gastrointestinal intoxication. It is recommended to stop taking phenylbutazone 7-12 days, piroxicam 10 days, diflunisal and indomethacin 24-48 hours, ketoprofen and NSAIDs with a short T1 / 2 12-24 hours before the methotrexate infusion in moderate and high doses and during at least 12 hours (depending on the concentration of methotrexate in the blood) after its completion. Caution should be exercised when combining NSAIDs with low doses of methotrexate (NSAIDs may decrease the excretion of methotrexate by the renal tubules). Medicines that block tubular secretion (for example, probenecid) increase the toxicity of methotrexate by reducing its excretion by the kidneys;
• Antibiotics that are 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 effect of methotrexate by inhibiting cell replication;
• Anesthesia using dinitrogen oxide can cause unpredictable severe myelosuppression and stomatitis;
• The use of cytarabine 48 hours before or within 10 minutes after the start of methotrexate therapy can cause a synergistic cytotoxic effect (it is recommended to adjust the dosage regimen based on the control of hematological parameters);
• Hematotoxic drugs increase the risk of hematotoxicity of methotrexate;
• Methotrexate reduces theophylline clearance;
• Neomycin for oral administration may decrease the absorption of methotrexate. Several patients with psoriasis or mycosis fungoides treated with methotrexate in combination with PUVA therapy (methoxsalen and ultraviolet irradiation (UV)) have been diagnosed with skin cancer;
• A combination with radiation therapy may increase the risk of bone marrow depression. Methotrexate may decrease the immune response to vaccination with live and inactivated viral vaccines;
• Folate-containing drugs (including multivitamins) may decrease the effectiveness of methotrexate therapy;
• The administration of amiodarone to patients receiving methotrexate therapy for psoriasis can cause skin ulceration.

Special instructions

• Dosage forms containing preservatives (benzyl alcohol) cannot be used with high-dose therapy;
• With the introduction of high doses of methotrexate, careful monitoring of the patient is required for the early detection of the first signs of toxic reactions;
• High-dose therapy should be carried out only by experienced chemotherapists who can control the concentration of methotrexate in plasma in stationary conditions under the cover of calcium folinate;
• Treatment with methotrexate in high and high doses should be combined with enhanced hydration – up to 2 l / day;
• The introduction of methotrexate in a dose of ≥2 g / m3 should be carried out under the control of its concentration in blood serum. A decrease in the content of methotrexate in blood serum 22 hours after administration by 2 times compared to the initial level is considered normal. An increase in creatinine by ≥50% of the initial content and/or an increase in the level of bilirubin require intensive detoxification therapy;
• For the treatment of psoriasis, methotrexate is prescribed only to patients with a severe form of the disease that is not amenable to other types of therapy;
• To prevent toxicity during the treatment with methotrexate, a blood test should be performed periodically (1 time per week), the content of leukocytes and platelets should be determined, and liver and kidney function tests should be performed;
• With diarrhea and ulcerative stomatitis, methotrexate therapy should be interrupted to avoid hemorrhagic enteritis and death of the patient due to the perforation of the intestine;
• In patients with impaired liver function, the period of excretion of methotrexate is increased, therefore, drug therapy should be carried out with extreme caution, with a lower dose;
• Impaired renal function is dose-dependent. The risk of impairment is increased in patients with reduced renal function or dehydration, as well as in patients taking other nephrotoxic drugs;
• Some side effects of the drug can adversely affect the ability to drive a car and perform potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Overdose

Treatment: you should immediately (preferably within the first hour) introduce the first dose 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 serum. To prevent precipitation of methotrexate and/or its metabolites in the renal tubules, the body is hydrated and alkalinized.