Methotrexate (Tablets) Instructions for Use

Marketing Authorization Holder

Novosibkhimpharm, JSC (Russia)

Manufactured By

Valenta Pharm, JSC (Russia)

ATC Code

L01BA01 (Methotrexate)

Active Substance

Methotrexate (Rec.INN registered by WHO)

Dosage Form

Methotrexate

Coated tablets 2.5 mg: 50 pcs.

Dosage Form, Packaging, and Composition

50 pcs. – polymer jars (1) – cardboard packs.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antineoplastic, cytostatic agent from the group of antimetabolites, it suppresses 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).

It inhibits synthesis, DNA repair, and cell mitosis. Rapidly proliferating tissues are particularly sensitive to its action: cells of malignant tumors, bone marrow, embryonic cells, epithelial cells of the intestinal mucosa, bladder, and oral cavity. Along with the antineoplastic effect, it has an immunosuppressive effect.

Pharmacokinetics

Absorption after oral administration is dose-dependent: when taking 30 mg/m², it is well absorbed, with an average bioavailability of 60%. Absorption decreases when taken in doses exceeding 80 mg/m².

In children with leukemia, absorption ranges from 23% to 95%. Time to reach C_max is from 40 min to 4 hours. Food slows absorption and reduces C_max. Plasma protein binding is about 50%, predominantly with albumin.

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

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

After oral administration, it is partially metabolized by the intestinal flora, the main part is metabolized in the liver (regardless of the route of administration) with the formation of a pharmacologically active polyglutamic form, which also inhibits dihydrofolate reductase and thymidine synthesis. T_1/2 in patients receiving less than 30 mg/m² of the drug is 2-4 hours in the initial phase, and in the terminal phase (which is prolonged) – 3-10 hours when using small doses and 8-15 hours when using large doses of the drug. In chronic renal failure, both phases of drug elimination can be significantly prolonged.

It is excreted primarily by the kidneys unchanged through glomerular filtration and tubular secretion, up to 10% is excreted with bile (with subsequent reabsorption in the intestine). Elimination of the drug in patients with impaired renal function, severe ascites, or transudate is significantly slowed. With repeated administration, it accumulates in tissues in the form of polyglutamates.

Indications

• Acute lymphoblastic leukemia and non-Hodgkin’s lymphomas;
• Trophoblastic tumors;
• Advanced stages of mycosis fungoides;
• Severe forms of psoriasis;
• Rheumatoid arthritis (when other therapy methods are ineffective).

ICD codes

Dosage Regimen

Methotrexate tablets are taken orally. Doses and duration of treatment are set 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. A course of treatment requires 300-400 mg.

Acute lymphoblastic leukemia (as part of combination therapy)

• 3.3 mg/m² in combination with prednisone until remission is achieved, then 15 mg/m² twice a week or 2.5 mg/kg every 14 days.

Non-Hodgkin’s lymphomas (as part of combination therapy)

• 15-20 mg/m² in a single dose twice a week;
• 7.5 mg/m² daily for 5 days.

Rheumatoid arthritis

The initial dose is usually 7.5 mg once a week, taken at once or divided into three doses at 12-hour intervals. 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, the dose should be reduced to the lowest effective dose. The optimal duration of therapy is unknown. For juvenile chronic arthritis in children, doses of 10-30 mg/m²/week (0.3-1 mg/kg) are effective.

Psoriasis

Methotrexate therapy is carried out in doses from 10 to 25 mg per week. The dose is usually increased gradually; upon achieving the optimal clinical effect, the dose is reduced to the lowest effective dose.

Mycosis fungoides

• 25 mg twice a week. Dose reduction or discontinuation of the drug is determined by the patient’s response and hematological parameters.

Adverse Reactions

From the hematopoietic system anemia (including aplastic), thrombocytopenia, leukopenia, neutropenia, agranulocytosis, eosinophilia, pancytopenia, lymphoproliferative diseases, hypogammaglobulinemia, lymphadenopathy.

From the digestive system anorexia, nausea, vomiting, stomatitis, gingivitis, pharyngitis, enteritis, erosive-ulcerative lesions and bleeding from the gastrointestinal tract (including melena, hematemesis), hepatotoxicity (acute hepatitis, fibrosis and cirrhosis of the liver, liver failure, hypoalbuminemia, increased activity of “liver” transaminases), pancreatitis.

From the nervous system headache, dizziness, drowsiness, dysarthria, aphasia, hemiparesis, paresis, convulsions; when used in high doses – transient cognitive impairment, emotional lability; unusual cranial sensitivity, encephalopathy (including leukoencephalopathy).

From the organ of vision conjunctivitis, visual impairment (including transient blindness).

From the cardiovascular system pericarditis, pericardial effusion, decreased blood pressure, thromboembolism (including arterial thrombosis, cerebral vascular thrombosis, deep vein thrombosis, retinal vein thrombosis, thrombophlebitis, pulmonary embolism).

From the respiratory system rarely – 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.

From the genitourinary system severe nephropathy or renal failure, azotemia, cystitis, hematuria, proteinuria, impaired spermatogenesis and oogenesis, transient oligospermia, decreased libido, impotence, dysmenorrhea, vaginal discharge, gynecomastia, infertility, miscarriage, fetal death, fetal developmental defects.

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

From the musculoskeletal system arthralgia, myalgia, osteoporosis, osteonecrosis, fractures.

Neoplasms lymphoma (including reversible).

General reactions allergic reactions up to 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), nocardiosis, histoplasmosis, cryptococcosis, infections caused by Herpes zoster and Herpes simplex (including disseminated herpes), diabetes mellitus, increased sweating.

Contraindications

Use of methotrexate is contraindicated during pregnancy and breastfeeding, with severe impairment of renal and liver function, with hematological disorders (such as bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia), in the acute stage of infectious diseases, immunodeficiency syndrome, with hypersensitivity to methotrexate or other components of the tablet, children under 3 years of age.

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

Use in Pregnancy and Lactation

It has a teratogenic effect: it can cause fetal death, congenital malformations. If a woman becomes pregnant during methotrexate therapy, the issue of pregnancy termination should be considered due to the risk of adverse effects on the fetus. Methotrexate is excreted in breast milk; breastfeeding should be discontinued for the entire course of treatment.

Use in Hepatic Impairment

Use of methotrexate is contraindicated in severe impairment of liver function.

Use in Renal Impairment

Use of methotrexate is contraindicated in severe impairment of renal function.

Elimination of the drug in patients with impaired renal function is significantly slowed. With repeated administration, it accumulates in tissues in the form of polyglutamates.

Pediatric Use

Use of methotrexate is contraindicated in children under 3 years of age.

Special Precautions

Methotrexate is a cytotoxic drug, so caution must be exercised when handling it. The drug should be prescribed by a physician experienced in the use of methotrexate and familiar with its properties and characteristics of action. Due to the possible development of severe and even fatal adverse reactions, patients must be fully informed by the doctor about the possible risks and recommended safety measures. Patients undergoing methotrexate therapy should be properly monitored so that signs of possible toxic effects and adverse reactions are identified and assessed in a timely manner.

Before starting or resuming methotrexate therapy, a complete blood count with platelet count, a biochemical blood test with determination of liver enzyme levels, bilirubin, serum albumin, chest X-ray, renal function examination, and, if necessary, tests for tuberculosis and hepatitis should be performed.

For timely detection of intoxication symptoms, it is necessary to monitor the state of peripheral blood (leukocyte and platelet count: initially every other day, then every 3-5 days during the first month, then once every 7-10 days, during remission – once every 1-2 weeks), the activity of “liver” transaminases, renal function (blood urea nitrogen, creatinine clearance and/or serum creatinine), serum uric acid concentration, periodically perform chest X-ray fluoroscopy, examination of the oral and pharyngeal mucosa for ulcers before each use. Monitoring of bone marrow hematopoiesis is recommended before treatment, once during treatment, and at the end of the course.

Methotrexate can potentially lead to the development of symptoms of acute or chronic hepatotoxicity (including fibrosis and cirrhosis of the liver). Chronic hepatotoxicity usually develops after long-term use of methotrexate (usually for 2 or more years) or upon reaching a total cumulative dose of at least 1.5 g and can lead to an unfavorable outcome. The hepatotoxic effect can also be due to a burdened concomitant history (alcoholism, obesity, diabetes mellitus) and old age. Due to the toxic effect of the drug on the liver, during treatment, patients should refrain from prescribing other hepatotoxic drugs except in cases of obvious necessity. Patients taking other hepatotoxic drugs (e.g., leflunomide) should be carefully monitored.

To objectify liver function, along with biochemical parameters, a liver biopsy is recommended before starting or 2-4 months after starting treatment; at a total cumulative dose of 1.5 g and after each additional 1-1.5 g. In case of moderate liver fibrosis or any degree of cirrhosis, methotrexate therapy is discontinued; in case of mild fibrosis, a repeat biopsy is usually recommended after 6 months. During initial therapy, minor histological changes in the liver (minor portal inflammation and fatty changes) are possible, which is not a reason for refusing or discontinuing treatment, but indicates the need for caution when using the drug.

If diarrhea and ulcerative stomatitis develop, methotrexate therapy must be interrupted due to the high risk of developing hemorrhagic enteritis and intestinal wall perforation, which can lead to the patient’s death.

Unprotected skin should not be exposed to too long sun exposure or overuse of a UV lamp (a photosensitization reaction is possible). Due to its effect on the immune system, Methotrexate may impair the response to vaccination and affect the results of immunological tests. It is necessary to avoid immunization (unless approved by a doctor) in the interval from 3 to 12 months after taking the drug; other family members living with the patient should avoid immunization with oral polio vaccine (avoid contact with people who have received the polio vaccine, or wear a protective mask covering the nose and mouth). Patients of childbearing age of both sexes and their partners should use reliable contraceptive measures during methotrexate treatment and after treatment for at least 3 months – men and for at least one ovulatory cycle – women.

After a course of treatment with high doses of methotrexate, the use of calcium folinate is recommended to reduce its toxicity.

Since Methotrexate can affect the central nervous system (feeling of fatigue, dizziness), patients taking the drug should refrain from driving vehicles or operating potentially dangerous machinery.

Overdose

There are no specific symptoms of methotrexate overdose; it is diagnosed by the concentration of methotrexate in plasma.

Treatment Administration of the specific antidote – calcium folinate as soon as possible, preferably within the first hour, in a dose equal to or exceeding 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, body hydration and urine alkalinization are performed, which accelerates the excretion of methotrexate. To minimize the risk of nephropathy due to the precipitation of the drug or its metabolites in the urine, it is necessary to additionally determine urine pH before each administration and every 6 hours throughout the entire period of using calcium folinate as an antidote, until the plasma concentration of methotrexate falls below 0.05 µmol/L, to ensure a pH above 7.

Drug Interactions

It increases the anticoagulant activity of coumarin or indandione derivatives and/or increases the risk of bleeding by reducing the synthesis of procoagulant factor in the liver and impairing platelet formation.

It increases the concentration of uric acid in the blood, so when treating patients with concomitant hyperuricemia and gout, dose adjustment of antigout drugs (allopurinol, colchicine, sulfinpyrazone) may be required; the use of uricosuric antigout drugs may increase the risk of nephropathy associated with increased uric acid formation during methotrexate treatment (allopurinol is preferred). Simultaneous intake of salicylates, phenylbutazone, phenytoin, sulfonamides, sulfonylurea derivatives, aminobenzoic acid, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and hypolipidemic drugs (cholestyramine) increases toxicity by displacing methotrexate from binding with albumins and/or reducing tubular secretion, which in some cases can cause the development of severe toxic effects, sometimes even fatal.

Non-steroidal anti-inflammatory drugs (NSAIDs) against the background of high doses of methotrexate increase its concentration and slow down elimination, which can lead to death from severe hematological and gastrointestinal intoxication. It is recommended to discontinue phenylbutazone 7-12 days, piroxicam 10 days, diflunisal and indomethacin 24-48 hours, ketoprofen and NSAIDs with short T_1/2 12-24 hours before methotrexate infusion in moderate and high doses and for 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 (possible reduction in methotrexate excretion by renal tubules). Drugs that block tubular secretion (e.g., 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 by suppressing the normal intestinal flora.

Retinoids, azathioprine, sulfasalazine, ethanol, and other hepatotoxic medications increase the risk of hepatotoxicity.

L-asparaginase reduces the severity of the antitumor effect of methotrexate by inhibiting cell replication.

Anesthesia using nitrous oxide may lead to the development of unpredictable severe myelosuppression and stomatitis.

The use of cytarabine 48 hours before or within 10 minutes after the start of methotrexate therapy may cause a synergistic cytotoxic effect (it is recommended to adjust the dosage regimen based on the monitoring of hematological parameters).

Hematotoxic medications increase the risk of methotrexate hematotoxicity.

Methotrexate reduces the clearance of theophylline.

Oral neomycin may reduce the absorption of methotrexate.

In several patients with psoriasis or mycosis fungoides treated with methotrexate in combination with PUVA therapy (methoxsalen and ultraviolet radiation (UVR)), skin cancer was detected.

Combination with radiation therapy may increase the risk of bone marrow suppression.

Methotrexate may reduce the immune response to vaccination with live and inactivated viral vaccines.

Folate-containing medications (including multivitamins) may reduce the effectiveness of methotrexate therapy.

Prescribing amiodarone to patients receiving methotrexate therapy for psoriasis may cause skin ulceration.

Storage Conditions

Store the drug in a place protected from light at a temperature not exceeding 25°C (77°F). Keep out of reach of children.

Shelf Life

The shelf life is 3 years. Do not use after the expiration date printed on the package.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.