Methotrexat Lachema (Solution) Instructions for Use

ATC Code

L01BA01 (Methotrexate)

Active Substance

Methotrexate (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antineoplastic, cytostatic agent from the group of antimetabolites – folic acid analogs.

It 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).

It inhibits synthesis, DNA repair, and cellular mitosis (in the S-phase). Tissues with high cell proliferation are particularly sensitive to the action of methotrexate: tumor tissue, bone marrow, epithelial cells of mucous membranes, embryonic cells.

The mechanism of action in rheumatoid arthritis is associated with the immunomodulatory and anti-inflammatory action of the drug and is due to the induction of apoptosis of rapidly proliferating cells (activated T-lymphocytes, fibroblasts, synoviocytes), inhibition of the synthesis of pro-inflammatory cytokines (interleukin (IL)-1, tumor necrosis factor alpha), enhancement of the synthesis of anti-inflammatory cytokines IL-4, IL-10, and suppression of metalloproteinase activity.

In patients with rheumatoid arthritis, the use of methotrexate reduces symptoms of inflammation (pain, swelling, stiffness), however, there is a limited number of studies on long-term use (regarding the ability to maintain remission in rheumatoid arthritis).

In psoriasis, the growth rate of keratinocytes in psoriatic plaques is increased compared to the normal proliferation of skin cells. This difference in cell proliferation is the basis for the use of methotrexate for the treatment of psoriasis.

Pharmacokinetics

After intramuscular administration, the C_max of methotrexate in blood plasma is reached within 30-60 minutes. The systemic absorption of methotrexate after administration into the abdomen and thigh subcutaneously is the same. After intravenous administration, it is rapidly distributed within a volume equivalent to the total volume of body fluids. The initial V_d is 0.18 L/kg (18% of body weight), the equilibrium volume of distribution is 0.4-0.8 L/kg (40-80% of body weight). 50-60% of methotrexate circulating in the vascular bed is bound to proteins (mainly albumin). Competitive displacement is possible with simultaneous use with sulfonamides, salicylates, tetracyclines, chloramphenicols, phenytoin. Methotrexate does not penetrate the blood-brain barrier when used in therapeutic doses. High concentrations of methotrexate in the CNS can be achieved with intrathecal administration.

Methotrexate undergoes hepatic and intracellular metabolism with the formation of a pharmacologically active polyglutamate form, which also inhibits dihydrofolate reductase and thymidine synthesis. A small amount of methotrexate polyglutamate may remain in tissues for a long period of time. The retention and prolongation of action of active methotrexate metabolites vary depending on the type of cells, tissues, and tumors. The mean T_1/2 values for methotrexate used in doses of less than 30 mg/m² are 6-7 hours. In patients receiving high doses of methotrexate, T_1/2 is 8-17 hours. In chronic renal failure, both phases of methotrexate elimination can be significantly prolonged.

It is excreted primarily by the kidneys unchanged by glomerular filtration and tubular secretion (after IV administration, 80-90% is excreted within 24 hours), up to 10% is excreted with bile (with subsequent reabsorption in the intestine). Methotrexate accumulates in the liver, kidneys, and organs for several weeks or months. With repeated administration, it accumulates in tissues in the form of polyglutamates.

Indications

Trophoblastic tumors; acute leukemias (especially lymphoblastic and myeloblastic variants); neuroleukemia; non-Hodgkin’s lymphomas (including lymphosarcoma); breast cancer, squamous cell carcinoma of the head and neck, lung cancer, skin cancer, cervical cancer, vulvar cancer, esophageal cancer, bladder cancer, testicular cancer, ovarian cancer, penile cancer, retinoblastoma, medulloblastoma; osteogenic sarcoma and soft tissue sarcoma; mycosis fungoides (advanced stages);

Severe forms of psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile chronic arthritis, dermatomyositis, systemic lupus erythematosus, ankylosing spondylitis (when standard therapy is ineffective).

ICD codes

Dosage Regimen

Solution

It is taken orally, administered intravenously, intramuscularly, subcutaneously, intralumbally. The dosage regimen is set individually, depending on the indications and stage of the disease, the patient’s age, the state of the hematopoietic system, the anticancer therapy regimen, and the dosage form used.

It is necessary to strictly follow the instructions in the instructions for methotrexate preparations regarding the use of the appropriate dosage forms and methods of administration of methotrexate, depending on the indications.

Adverse Reactions

From the digestive system: ulcerative stomatitis, anorexia, gingivitis, pharyngitis, nausea are possible; rarely – diarrhea, melena, enteritis, pancreatitis; in some cases (with long-term daily use) – liver necrosis, cirrhosis, fatty atrophy, periportal liver fibrosis.

From the hematopoietic system: leukopenia, anemia, thrombocytopenia.

From the CNS: feeling of fatigue, dizziness; rarely – headache, aphasia, drowsiness, convulsions.

From the reproductive system: disorders of oogenesis and spermatogenesis, oligospermia, menstrual cycle disorders, decreased libido, impotence.

From the urinary system: hematuria, cystitis, severe renal dysfunction.

Allergic reactions: chills, decreased resistance to infection; rarely – urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome.

Dermatological reactions: skin rash, photosensitivity, pigmentation disorders, telangiectasias, acne, furunculosis.

From the cardiovascular system: infrequently – vasculitis; rarely – pericarditis, pericardial effusion, cardiac tamponade, decreased blood pressure, thromboembolic complications (including cerebral vessel thrombosis and arterial thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism).

From the blood and lymphatic system: often – leukopenia, thrombocytopenia, anemia; infrequently – pancytopenia, agranulocytosis, hematopoietic disorders; rarely – megaloblastic anemia; very rarely – severe bone marrow function depression, aplastic anemia, enlarged lymph nodes, lymphoproliferative diseases (partially reversible), eosinophilia, neutropenia. The first signs of these complications, which are life-threatening, are fever, sore throat, mouth ulcers, flu-like symptoms, nosebleeds, and skin hemorrhages. The use of methotrexate must be stopped immediately if the blood cell count decreases significantly.

From the immune system: infrequently – allergic reactions, anaphylactic shock, immunosuppression.

Infectious diseases: very rarely – sepsis, opportunistic infections (in some cases may be fatal), infections caused by Cytomegalovirus; frequency unknown – cases of nocardiosis, histoplasmosis and cryptococcal fungal infections, disseminated form of herpes simplex have been reported.

From the nervous system: often – headache, increased fatigue, drowsiness; infrequently – depression, confusion, dizziness, convulsions; rarely – mood changes; very rarely – pain, muscle weakness or paresthesia in the limbs, taste disturbance (metallic taste), acute aseptic meningitis with meningism (paralysis, vomiting), insomnia; frequency unknown – ringing in the ears.

From the organ of vision: rarely – severe visual impairment; very rarely – conjunctivitis, retinopathy.

Benign, malignant and unspecified neoplasms: infrequently – isolated cases of lymphomas that regress upon discontinuation of methotrexate treatment.

From the respiratory system: often – pulmonary complications due to interstitial pneumonitis/alveolitis, including fatal – regardless of the dose and duration of methotrexate treatment (typical symptoms: malaise, dry non-productive cough, shortness of breath progressing to shortness of breath at rest, chest pain, fever. If the above adverse reactions are suspected, the use of methotrexate is stopped immediately, infections, including pneumonia, must be ruled out); infrequently – pulmonary fibrosis; rarely – pharyngitis, apnea, bronchial asthma, shortness of breath, abnormal results of instrumental studies of lung function; very rarely – pneumonia caused by Pneumocystis carinii and other lung infections, difficulty breathing, chronic obstructive pulmonary disease, pleural effusion.

From the digestive system: very often – decreased appetite, nausea, vomiting (especially during the first 24-48 hours after methotrexate administration), abdominal pain, inflammation and ulcers in the mucous membrane of the mouth and throat, stomatitis, dyspepsia; often – diarrhea (especially in the first 24-48 hours after methotrexate use); infrequently – ulcers, gastrointestinal bleeding; rarely – enteritis, melena, gingivitis, malabsorption syndrome; very rarely – vomiting with blood, toxic megacolon.

From the liver and biliary tract: very often – increased activity of liver enzymes (ALT, AST), increased activity of ALP, increased concentration of bilirubin; infrequently – liver steatosis, liver fibrosis, liver cirrhosis (may appear even in the case of regular monitoring of normal liver transaminase values); rarely – acute hepatitis and hepatotoxicity; very rarely – reactivation of chronic hepatitis, acute liver dystrophy, liver failure (most often noted is hepatitis caused by the herpes simplex virus and accompanied by liver failure).

From the skin and subcutaneous tissues: often – exanthema, erythema, skin itching; infrequently – urticaria, photosensitivity, increased skin pigmentation, hair loss, abnormal wound healing, enlarged rheumatic nodules, herpes zoster, painful ulcerations of psoriatic plaques (exacerbation of plaque psoriasis may occur during UV radiation therapy and simultaneous use of methotrexate), severe toxic reactions, vasculitis, allergic vasculitis, herpetiform skin rashes, Stevens-Johnson syndrome, toxic epidermal necrolysis (Lyell’s syndrome); rarely – changes in nail pigmentation, onycholysis, petechiae, ecchymoses, multiforme erythema, erythematous skin rash; very rarely – acute paronychia, furunculosis, telangiectasias, hidradenitis.

From the musculoskeletal system: infrequently – arthralgia, myalgia, osteoporosis; rarely – stress fractures, osteonecrosis.

From the urinary system: infrequently – inflammation and ulceration of the bladder (possibly with hematuria), dysuria; rarely – renal failure, oliguria, anuria, azotemia; very rarely – proteinuria.

From the reproductive system: infrequently – vaginitis; rarely – oligospermia, menstrual cycle disorders; very rarely – decreased libido, impotence, vaginal discharge, infertility, gynecomastia; frequency unknown – disorders of oogenesis and spermatogenesis, teratogenic effect.

From the endocrine system: frequency unknown – diabetes mellitus, metabolic disorders.

Local reactions: with intramuscular administration infrequently – burning or tissue damage (formation of sterile abscesses, destruction of fat deposits) at the injection site.

Very rarely: fever. Usually, with subcutaneous administration, Methotrexate is well tolerated; to date, only mild local reactions have been noted, which decreased during treatment.

Other: infrequently – decreased serum albumin concentration, hypogammaglobulinemia; rarely – fever.

The frequency and severity of adverse reactions to methotrexate depend on the dose and frequency of use. Since severe adverse reactions can also occur at low doses, it is extremely important that patients undergo medical examination regularly and at short intervals.

Contraindications

Hypersensitivity to methotrexate; severe renal failure; severe hepatic failure; alcohol abuse; history of disorders of the hematopoietic system (in particular, bone marrow hypoplasia, leukopenia, thrombocytopenia or clinically significant anemia); immunodeficiency; severe acute and chronic infectious diseases, such as tuberculosis and HIV infection; concomitant vaccination with live vaccines; oral ulcers, active phase gastrointestinal ulcers; simultaneous use of methotrexate at a dose of ≥15 mg/week with acetylsalicylic acid; pregnancy; breastfeeding period.

With caution in patients with impaired liver and kidney function, diabetes mellitus, obesity, prior therapy with hepatotoxic drugs, dehydration, ascites, bone marrow suppression, pleural or peritoneal effusion, parasitic and infectious diseases of viral, fungal or bacterial nature – risk of developing severe generalized disease (current or recently suffered, including recent contact with a patient) – herpes simplex, herpes zoster (viremic phase), chickenpox, measles, amebiasis, strongyloidiasis (established or suspected), gout (including history) or urate nephrourolithiasis (including history), infection and inflammation of the oral mucosa, vomiting, diarrhea, gastric and duodenal ulcers, ulcerative colitis, obstructive gastrointestinal diseases, prior chemotherapy or radiation therapy, asthenia, aciduria (urine pH less than 7), in children and elderly patients.

Use in Pregnancy and Lactation

Methotrexate is contraindicated for use during pregnancy. If use during lactation is necessary, breastfeeding should be discontinued.

Women of childbearing potential should use reliable methods of contraception during methotrexate therapy.

Experimental studies have established the embryotoxic and teratogenic effects of methotrexate.

Use in Hepatic Impairment

Contraindicated in severe hepatic impairment. Use with caution in patients with hepatic impairment.

Use in Renal Impairment

Contraindicated in severe renal impairment. Use with caution in patients with renal impairment.

Pediatric Use

Use in children under 3 years of age is not recommended due to insufficient data on the safety and efficacy of methotrexate in this age group.

Use in children should be with caution – strictly according to indications, in age/body surface area-appropriate recommended doses and dosage forms. It is necessary to strictly follow the instructions in the methotrexate drug labeling regarding contraindications for the use of specific methotrexate dosage forms in children of different ages.

Geriatric Use

Use with caution in elderly patients (over 65 years of age). This category of patients may require dose reduction of methotrexate, as liver and kidney function deteriorate with age, and folate levels in the body decrease.

Special Precautions

Methotrexate should not be used in patients with ascites, pleural effusion, gastric and duodenal ulcer, ulcerative colitis, gout, or nephropathy (including history).

Not recommended for use in patients with chickenpox (including recently contracted or after contact with infected individuals), herpes zoster, and other acute infectious diseases.

Before starting therapy and during treatment, peripheral blood counts, liver and kidney function, and chest X-ray should be monitored.

When treating rheumatoid arthritis or psoriasis, a complete blood count should be performed at least once a month, and liver or kidney function laboratory tests at least once every 1-2 months.

When used for psoriasis, local treatment of the disease should not be interrupted. In case of overdose, administration of calcium folinate is recommended (but not later than 4 hours after).

When conducting combined antitumor therapy, special caution should be exercised when methotrexate in high doses is used concomitantly with drugs that have nephrotoxic effects (e.g., cisplatin).

Vaccination of patients and their family members is not recommended.

Methotrexate (even in low doses) should be combined with acetylsalicylic acid with caution.

Experimental studies have established the carcinogenic and mutagenic effects of methotrexate.

Methotrexate is a cytotoxic agent and must be handled with care. Methotrexate should be prescribed by a physician experienced in its use and familiar with the properties and characteristics of methotrexate. Before prescribing methotrexate, it is necessary to ensure the availability of plasma concentration determination.

Given the possibility of severe toxic reactions, including fatal ones, the physician must inform the patient in detail about the potential risk and necessary precautions. Methotrexate, especially in medium and high doses, should be used only in patients with potentially life-threatening malignant neoplasms. Cases of fatal toxicity manifestations during methotrexate therapy have been described. Discontinuation of methotrexate does not always lead to complete resolution of adverse events.

During methotrexate treatment, patients should be under close medical supervision for the timely detection of signs of possible toxic effects and adverse reactions.

Due to the possibility of serious (and potentially fatal) toxic reactions, Methotrexate should be used only in patients with severe, persistent, and disabling forms of psoriasis that are not amenable to other treatments. Patients receiving methotrexate treatment should be carefully monitored to identify and evaluate signs of possible toxic effects or adverse reactions with minimal delay.

Before starting methotrexate treatment or resuming therapy after a break, a clinical blood test with leukocyte differential and platelet count, assessment of liver transaminase activity, bilirubin concentration, plasma albumin, plasma uric acid concentration, kidney function (blood urea nitrogen, creatinine clearance and/or plasma creatinine), and chest X-ray should be performed. If clinically indicated, tests to rule out tuberculosis and viral hepatitis should be prescribed.

Prescription of high doses of methotrexate is possible only in case of normal plasma creatinine concentration. If an increase in creatinine concentration is noted, the methotrexate dose should be reduced; if creatinine concentration increases by more than 2 mg/dL, Methotrexate should not be used. Before combination therapy including high-dose methotrexate treatment, the white blood cell and platelet counts should be above the minimum values specified in the treatment protocol (white blood cell count from 1000 to 1500/µL, platelet count from 50,000 to 100,000/µL).

Leukopenia and thrombocytopenia typically develop within 4 to 14 days after methotrexate administration. Sometimes a second leukopenic phase occurs, developing within 12 to 21 days.

Megablastic anemia has been described in elderly patients during prolonged methotrexate therapy.

During methotrexate treatment, the following examinations are performed (monthly for the first 6 months, then at least every 3 months; when increasing doses, it is advisable to increase the frequency of examinations)

1. Examination of the oral cavity and pharynx to detect changes in the mucous membranes.
2. Blood test with leukocyte differential and platelet count. Even when used in usual therapeutic doses, Methotrexate can suddenly cause bone marrow suppression. In case of a significant decrease in white blood cell or platelet count, methotrexate treatment is immediately discontinued and symptomatic supportive therapy is prescribed. Patients should be instructed to immediately report any signs and symptoms indicating the development of an infection to their physician. With concomitant therapy or previously administered therapy with hematotoxic drugs (e.g., leflunomide), radiation therapy, careful monitoring of white blood cell and platelet counts in the blood is necessary. If necessary, bone marrow biopsy is advisable.
3. Liver function tests. During prolonged use of methotrexate, acute hepatitis and manifestations of chronic hepatotoxicity (fibrosis and cirrhosis of the liver) may develop. Special attention should be paid to identifying signs of liver damage. Methotrexate treatment should not be started or should be suspended if abnormalities in liver function tests or liver biopsy are detected. During methotrexate therapy, a 2-3-fold transient increase in liver transaminase activity may occur, usually asymptomatic. As a rule, this is not a reason to change the treatment regimen; usually the indicators normalize within 2 weeks, after which treatment may be resumed at the physician’s discretion. However, if a persistent increase in liver transaminase activity is detected, dose reduction or discontinuation of methotrexate treatment is necessary. Since Methotrexate has a toxic effect on the liver, other hepatotoxic drugs should not be used without clear necessity during treatment. Ethanol consumption should also be avoided or strongly reduced. Special attention should be paid to monitoring liver enzyme activity in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular, leflunomide).

In case of prolonged treatment, especially of severe forms of psoriasis, including psoriatic arthritis, due to the possible hepatotoxic effect of methotrexate, considering that fibrotic and/or cirrhotic changes can develop against the background of normal liver tests, liver biopsy is necessary in the following cases

• In patients without risk factors before reaching a total cumulative dose of 1.0-1.5 g;
• In the presence of such risk factors as alcohol abuse, persistent increase in liver transaminase activity, chronic viral hepatitis, family history of liver disease, as well as for patients with less significant risk factors, such as diabetes mellitus, obesity, historical data on exposure to hepatotoxic drugs/chemicals, liver biopsy should be performed 2-4 months after the start of treatment. After reaching a total cumulative dose of 1.0-1.5 g, a repeat liver biopsy is recommended.

Liver biopsy is not indicated in elderly patients; in patients with active acute diseases (e.g., respiratory system); in patients with contraindications to liver biopsy (e.g., unstable hemodynamics, altered coagulation parameters); in patients with an unfavorable prognosis regarding life expectancy.

If liver biopsy reveals only mild changes (grade I, II, or IIIa on the Roenigk scale), continuation of methotrexate therapy is possible provided the patient’s condition is carefully monitored. Methotrexate should be discontinued in case of moderate or severe changes (grade IIIb and IV on the Roenigk scale), or in case of refusal of liver biopsy by a patient who has a persistent increase in liver transaminase activity. In case of moderate fibrosis or liver cirrhosis, Methotrexate should be discontinued; in case of minimal fibrosis, a repeat liver biopsy in 6 months is recommended. Such changes as fatty liver degeneration or mild inflammation of the portal veins are quite often detected on liver biopsy in patients receiving Methotrexate. Although the detection of such changes, as a rule, is not a reason for deciding on the inappropriateness or discontinuation of methotrexate therapy, caution should be exercised when treating such patients.

1. Renal function tests and urinalysis. Since Methotrexate is excreted primarily by the kidneys, in patients with impaired renal function, an increase in plasma methotrexate concentration may be observed, which can lead to severe adverse reactions. The condition of patients in whom impaired renal function is possible (e.g., elderly patients) must be carefully monitored. This is especially important in case of concomitant therapy with drugs that reduce methotrexate excretion, have an adverse effect on the kidneys (in particular, NSAIDs) or on the hematopoietic system. Cases of severe adverse effects have been described in patients taking NSAIDs during methotrexate therapy (especially in high doses), including cases of severe bone marrow suppression, aplastic anemia, gastrointestinal damage, and fatal outcome. During methotrexate infusion, urine excretion and its pH value should also be monitored. To reduce renal toxicity and to prevent renal failure during high-dose methotrexate treatment, adequate intravenous fluid provision and urine alkalinization (pH > 7) are absolutely necessary. Methotrexate treatment may impair renal function with an increase in certain laboratory parameters (creatinine, urea, uric acid in serum), which can lead to acute renal failure with oliguria/anuria. This is probably due to the precipitation of methotrexate and its metabolites in the renal tubules.
2. Examination of the respiratory system. It is necessary to carefully monitor for symptoms of possible development of lung function impairment and, if necessary, prescribe appropriate tests to monitor lung function. The appearance during methotrexate treatment of corresponding symptoms (especially dry, non-productive cough) or the development of nonspecific pneumonitis may indicate a potential risk of lung damage. In such cases, Methotrexate should be discontinued and a thorough examination of the patient should be performed. Although the clinical picture may vary, in typical cases where respiratory symptoms are caused by methotrexate use, fever, cough with shortness of breath, hypoxemia, and pulmonary infiltrates on X-rays are observed. Lung damage caused by methotrexate use can occur regardless of the duration of its use, the doses used (cases of lung damage have been described with the use of methotrexate in low doses, including 7.5 mg/week). Infectious nature of the disease should be excluded during differential diagnosis. During methotrexate therapy, potentially dangerous (up to fatal) opportunistic infections, including Pneumocystis pneumonia, may develop. In case of development of respiratory symptoms in a patient receiving Methotrexate, pneumonia caused by Pneumocystis jirovecii should be ruled out.

In case of an increase in the methotrexate dose, the frequency of examinations should be increased.

Due to the immunosuppressive effect of methotrexate, immunization should be avoided (unless approved by the physician) directly during treatment and in the interval from 3 to 12 months after completion of methotrexate use; family members living with the patient should avoid immunization with oral polio vaccine (the patient should avoid contact with people who have received the polio vaccine, or wear a protective mask covering the nose and mouth). Also, due to the possible influence of methotrexate on the immune system, distortion of the results of vaccine efficacy assessment and tests (immunological procedures for registering immune response) is possible.

If during methotrexate therapy phenomena of stomatitis or diarrhea, hemoptysis, melena, or appearance of blood impurities in the stool are noted, the drug should be immediately discontinued due to the high risk of developing potentially fatal complications, such as hemorrhagic enteritis and intestinal wall perforation.

Such symptoms as fever, sore throat, flu-like symptoms, ulceration of the oral mucosa, pronounced general weakness, hemoptysis, hemorrhagic rash may be precursors to the development of life-threatening complications.

If a patient is found to have conditions leading to the accumulation of a significant amount of fluid in body cavities (hydrothorax, ascites), given the prolongation of the drug’s half-life in such patients, methotrexate therapy should be conducted with caution; before starting therapy, the fluid should be evacuated by drainage, or the use of methotrexate should be abandoned.

Special caution should be exercised when treating patients with insulin-dependent diabetes mellitus, as cases of liver cirrhosis development without a preceding increase in liver transaminase activity have been described.

Like other cytostatic drugs, Methotrexate can cause the development of tumor lysis syndrome in patients with rapidly growing malignant neoplasms. To prevent the development of this complication, appropriate supportive therapy measures should be taken.

The use of methotrexate in combination with radiation therapy may lead to an increased risk of soft tissue necrosis or osteonecrosis.

The condition of patients with prior radiation therapy, as well as impaired general condition, should be especially carefully monitored.

Dehydration can also potentiate the toxic effect of methotrexate, so if conditions develop that may lead to dehydration (severe vomiting, diarrhea), methotrexate therapy should be interrupted until these conditions resolve. Cases of leukoencephalopathy have been described in patients receiving therapy with high doses of methotrexate, including orally, in combination with calcium folinate (without prior head radiation therapy).

When using methotrexate for acute lymphoblastic leukemia, pain in the left epigastric region may occur due to the development of an inflammatory process in the spleen capsule against the background of tumor cell breakdown.

It is recommended to interrupt methotrexate treatment 1 week before surgery and resume 1 or 2 weeks after the operation.

Special caution should be exercised when using methotrexate in patients with active infections. The use of methotrexate in patients with immunodeficiency syndrome is contraindicated.

When body temperature is elevated (above 38°C (100.4°F)), the elimination of methotrexate is significantly slowed.

Methotrexate may increase the risk of developing neoplasms (mainly lymphomas). Malignant lymphomas can also develop in patients receiving Methotrexate in low doses. In such cases, Methotrexate should be discontinued. If spontaneous regression of the lymphoma is not observed, therapy with other cytotoxic drugs is prescribed.

Before starting methotrexate treatment, pregnancy must be ruled out. Methotrexate has an embryotoxic effect, promotes abortion and the formation of fetal developmental abnormalities. Methotrexate therapy is accompanied by suppression of spermatogenesis and oogenesis, which can lead to decreased fertility. After discontinuation of methotrexate therapy, these effects spontaneously regress. During methotrexate therapy and for 6 months after its completion, patients are recommended to use contraceptive measures. Patients of reproductive age, as well as their partners, should be informed about the possible influence of methotrexate on fertility and fetal development. Men of reproductive age should be warned about the existing risks; fatherhood is not recommended during treatment and for 6 months after methotrexate discontinuation. Since irreversible infertility may develop during treatment, men should consider the possibility of cryopreservation of sperm in a bank before starting treatment.

During methotrexate use, the likelihood of developing dermatitis and skin burns under the influence of solar and ultraviolet radiation increases. Unprotected skin should not be exposed to too long solar radiation or overuse of UV lamp (a photosensitivity reaction is possible). In patients with psoriasis, exacerbation of the disease may occur during UV radiation while being treated with the drug.

During high-dose therapy, precipitation of methotrexate or its metabolites in the renal tubules is possible. In such cases, as a prevention of this complication, infusion therapy and urine alkalinization to achieve a pH of 6.5-7.0 via oral or intravenous administration of sodium bicarbonate or acetazolamide is recommended.

During methotrexate therapy, exacerbation of chronic viral hepatitis (reactivation of hepatitis B or C virus) is possible. Cases of hepatitis B virus reactivation after methotrexate discontinuation have also been described. If it is necessary to prescribe methotrexate to a patient with a history of viral hepatitis, a thorough clinical and laboratory examination should be performed.

The presence of pleural effusion, ascites, gastrointestinal tract obstruction, concomitant therapy with cisplatin, dehydration, impaired liver function, or decreased urine pH slows the excretion of methotrexate, which may lead to an increase in its plasma concentration. It is extremely important to detect the accumulation of methotrexate in the body within the first 48 hours, as irreversible consequences of its toxicity may develop.

Particular caution should be exercised when using methotrexate in elderly patients; their condition should be monitored more frequently than in younger patients for the detection of early signs of therapy toxicity.

In pediatric patients with acute lymphoblastic leukemia, the development of severe neurotoxicity is possible during the use of medium (1 g/m²) doses of methotrexate, which most often manifests clinically as a generalized or partial epileptic seizure. The development of leukoencephalopathy and/or microangiopathic calcifications has been described during instrumental examinations in such patients.

When using high doses of methotrexate, the development of transient acute neurological symptoms has been described, which can manifest, including, as behavioral changes, focal sensory disturbances (including transient blindness) and motor system disturbances, and reflex impairment. The exact causes of these adverse reactions are unknown.

When using methotrexate at a dose above 100 mg/m², the use of leucovorin “rescue therapy” is mandatory 42-48 hours after methotrexate administration. The dose of leucovorin is determined based on the magnitude of the methotrexate dose used and the duration of its infusion.

The concentration of methotrexate must be determined at 24, 48, 72 hours and, if necessary, for an extended period to determine the optimal duration of leucovorin therapy. The use of methotrexate concomitantly with a red blood cell infusion (within 24 hours) requires careful monitoring of the patient’s condition, as an increase in the plasma concentration of methotrexate is possible.

Measures should be taken to prevent methotrexate solutions from coming into contact with the skin and mucous membranes. If methotrexate accidentally comes into contact with the skin or mucous membranes, the affected area should be immediately rinsed with plenty of water.

Effect on the Ability to Drive Vehicles and Operate Machinery

Due to the likelihood of developing side effects of methotrexate, such as drowsiness, headache, and confusion, caution should be exercised when engaging in potentially hazardous activities that require increased concentration and speed of psychomotor reactions.

If the described adverse events occur, one should refrain from performing these activities.

Drug Interactions

When used concomitantly with vitamin preparations containing folic acid or its derivatives, a decrease in the effectiveness of methotrexate is possible.

Concomitant use of NSAIDs in high doses may lead to an increase in the plasma concentration of methotrexate and a prolongation of its T_1/2, as well as an increase in the concentration of non-albumin-bound methotrexate, which in turn enhances the toxic effects of methotrexate (primarily on the gastrointestinal tract and hematopoietic system).

When methotrexate is used concomitantly with penicillins (even in low doses), an enhancement of its toxic effects is possible.

When used concomitantly with sulfonamides, especially with co-trimoxazole, there is a risk of enhanced myelodepressive effect.

When nitrous oxide is used in patients receiving Methotrexate, the development of severe unpredictable myelodepression and stomatitis is possible.

When valproic acid is used concomitantly with methotrexate, a decrease in its plasma concentration is possible.

Cholestyramine binds Methotrexate, reduces its enterohepatic recirculation, leading to a decrease in its plasma concentration.

When used concomitantly with mercaptopurine, an increase in its bioavailability is possible due to impaired metabolism during the “first pass” through the liver.

Neomycin and paromomycin reduce the absorption of methotrexate from the gastrointestinal tract.

In patients receiving omeprazole, an increase in the plasma concentration of methotrexate is possible.

When used concomitantly with probenecid, a 3- to 4-fold increase in the plasma concentration of methotrexate is possible due to a decrease in its renal excretion.

When methotrexate is used concomitantly with retinoids, an increased risk of hepatotoxic effects is possible.

Salicylates potentiate the effect of methotrexate by reducing its renal excretion.

After a course of treatment with tetracycline, Methotrexate, even used in low doses, can have a toxic effect.

When methotrexate and fluorouracil are administered sequentially, a synergistic effect is possible; fluorouracil administered before methotrexate may reduce its toxicity.

Cisplatin has a nephrotoxic effect and therefore may reduce the renal excretion of methotrexate, leading to increased toxicity.

The likelihood of a hepatotoxic effect of methotrexate increases in the case of regular alcohol consumption and concomitant use of other hepatotoxic drugs.

During combination therapy with methotrexate and leflunomide, the frequency of pancytopenia and hepatotoxic effects increases.

An increase in toxicity is possible when using cyclosporine in patients who received Methotrexate.

Concomitant use of indirect anticoagulants and hypolipidemic drugs ( cholestyramine) enhances the toxicity of methotrexate.

During treatment with methotrexate, excessive consumption of beverages containing caffeine and theophylline (coffee, sweet caffeinated drinks, black tea) should be avoided.

Methotrexate reduces the clearance of theophylline.

Methotrexate should not be mixed with other medicines and solvents.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

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.