Methortrit (Solution) Instructions for Use

Marketing Authorization Holder

S.C. Rompharm Company S.R.L. (Romania)

ATC Code

L01BA01 (Methotrexate)

Active Substance

Methotrexate (Rec.INN registered by WHO)

Dosage Form

Methortrit

Solution for injection 10 mg/1 ml: fl. 0.75 ml, 1 ml, 1.5 ml or 2 ml 1 pc. in a set with a needle for s/c administration

Dosage Form, Packaging, and Composition

Solution for injection yellow in color, transparent.

Excipients : sodium chloride – 7 mg, sodium hydroxide solution 2M – 1.76 mg (22 µl), sodium hydroxide solution 1M – to pH 8.5±0.1, water for injection – to 1 ml.

0.75 ml – syringes of colorless glass (1) – contour cell packs (1) in a set with a needle for s/c administration – cardboard boxes.
1 ml – syringes of colorless glass (1) – contour cell packs (1) in a set with a needle for s/c administration – cardboard boxes.
1.5 ml – syringes of colorless glass (1) – contour cell packs (1) in a set with a needle for s/c administration – cardboard boxes.
2 ml – syringes of colorless glass (1) – contour cell packs (1) in a set with a needle for s/c administration – cardboard boxes.

Clinical-Pharmacological Group

Antineoplastic drug

Pharmacotherapeutic Group

Antineoplastic agent, antimetabolite

Pharmacological Action

Antineoplastic, cytostatic agent of the antimetabolite group – 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 cell 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 the symptoms of inflammation (pain, swelling, stiffness), but 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 after 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 concentration of methotrexate in the CNS can be achieved with intrathecal administration. Methotrexate undergoes hepatic and intracellular metabolism to form 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 when using methotrexate in doses 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 mainly by the kidneys unchanged by glomerular filtration and tubular secretion (with intravenous 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

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 on the use of the appropriate dosage forms and methods of methotrexate administration, 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 function impairment.

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, lymph node enlargement, 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, it is necessary to exclude infections, including pneumonia); infrequently – pulmonary fibrosis; rarely – pharyngitis, apnea, bronchial asthma, shortness of breath, abnormal results of instrumental lung function tests; 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 – hepatic steatosis, liver fibrosis, liver cirrhosis (may appear even in case of regular detection of normal liver transaminase values during monitoring); rarely – acute hepatitis and hepatotoxicity; very rarely – reactivation of chronic hepatitis, acute liver dystrophy, liver failure (hepatitis caused by herpes simplex virus and accompanied by liver failure is most often noted).

From the skin and subcutaneous tissues: often – exanthema, erythema, skin itching; infrequently – urticaria, photosensitivity, increased skin pigmentation, hair loss, abnormal wound healing, increase in rheumatic nodules, herpes zoster, painful ulcerations of psoriatic plaques (exacerbation of plaque psoriasis may occur during UV 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 of 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 hematopoietic system disorders (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 (currently or recently, including recent contact with a patient) – herpes simplex, herpes zoster (viremic phase), varicella, measles, amebiasis, strongyloidiasis (established or suspected), gout (including in the anamnesis) or urate nephrourolithiasis (including in the anamnesis), infection and inflammation of the oral mucosa, vomiting, diarrhea, gastric and duodenal ulcer, 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 during pregnancy. If use during lactation is necessary, breastfeeding should be discontinued.

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

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

Use in Hepatic Impairment

Contraindicated in severe liver function impairment. Use with caution in the presence of liver function impairment.

Use in Renal Impairment

Contraindicated in severe kidney function impairment. Use with caution in the presence of kidney function 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 doses and dosage forms recommended according to age/body surface area. It is necessary to strictly follow the instructions in the prescribing information for methotrexate preparations 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 old). In this category of patients, a reduction in methotrexate doses may be required, as liver and kidney function deteriorates with age, and folate levels in the body decrease.

Special Precautions

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

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

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

When treating rheumatoid arthritis or psoriasis, a complete blood count should be performed at least once a month, and laboratory tests of liver or kidney function 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 no later than 4 hours).

When conducting combined antitumor therapy, special caution should be exercised when using methotrexate in high doses concomitantly with drugs that have nephrotoxic effects (for example, with cisplatin).

Vaccination of patients and their family members is not recommended.

Caution should be exercised when combining Methotrexate (even in low doses) with acetylsalicylic acid.

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

Methotrexate is a cytotoxic agent and should be handled with care. Methotrexate should be prescribed by a physician experienced in its use and familiar with the properties and characteristics of methotrexate’s action. Before prescribing methotrexate, it should be ensured that it is possible to determine its plasma concentration.

Given the possibility of developing severe toxic reactions, including fatal ones, the physician must inform the patient in detail about the possible 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 manifestations of toxicity 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 careful 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), as well as 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 the creatinine concentration increases by more than 2 mg/dL, Methotrexate should not be used. Before combination therapy including high-dose methotrexate treatment, the leukocyte and platelet counts should be above the minimum values specified in the treatment protocol (leukocyte count from 1000 to 1500/μL, platelet count from 50,000 to 100,000/μL).

Leukopenia and thrombocytopenia usually develop within 4 to 14 days after methotrexate administration. Sometimes a second leukopenic phase develops, occurring between 12 and 21 days.

Development of megaloblastic anemia during prolonged methotrexate therapy has been described in elderly patients.

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 leukocyte or platelet count, methotrexate treatment is immediately discontinued and symptomatic supportive therapy is prescribed. Patients should be instructed to immediately report to the physician any signs and symptoms indicating the development of an infection. With concomitant therapy or previously administered therapy with hematotoxic drugs (e.g., leflunomide), radiation therapy, careful monitoring of leukocyte and platelet counts in the blood is necessary. If necessary, a 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 results 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, a reduction in dose 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, a 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, anamnestic data on exposure to hepatotoxic drugs/chemicals, a 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, changes in coagulation parameters); in patients with an unfavorable prognosis regarding life expectancy.

If the 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 detection 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 detection 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 kidney function, an increase in plasma methotrexate concentration may be observed, which can lead to severe adverse reactions. The condition of patients in whom impaired kidney 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 supply and urine alkalinization (pH > 7) are absolutely necessary. Methotrexate treatment may impair kidney 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 danger 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, there is an increase in body temperature, cough with shortness of breath, hypoxemia, as well as pulmonary infiltrates on X-rays. 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). In differential diagnosis, an infectious nature of the disease should be excluded. 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 the 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, severe 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 observed when treating patients with insulin-dependent diabetes mellitus, as cases of liver cirrhosis development without a prior 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 can 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 radiation therapy to the head area).

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 rises (above 38°C (100.4°F)), the elimination of methotrexate is significantly slowed down.

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 anomalies. 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 excessive use of UV lamps (a photosensitivity reaction is possible). In patients with psoriasis, exacerbation of the disease may occur against the background of UV radiation during treatment with the drug.

During therapy with high doses, 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 are recommended.

Against the background of methotrexate therapy, an 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, 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 elimination 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 the development of irreversible consequences of its toxicity is possible.

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 during instrumental examinations in such patients has been described.

When using high doses of methotrexate, the development of transient acute neurological symptoms has been described, which may include behavioral changes, local sensory disturbances (including transient blindness) and motor system disturbances, and impaired reflexes. The exact causes of these adverse reactions are unknown.

When using methotrexate at a dose above 100 mg/m², the use of “rescue therapy” with calcium folinate 42-48 hours after methotrexate administration is mandatory. The dose of calcium folinate is determined depending 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 calcium folinate therapy. The use of methotrexate concomitantly with 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 probability of developing side effects of methotrexate, such as drowsiness, headache, and confusion, caution should be exercised when engaging in potentially hazardous activities requiring increased concentration and speed of psychomotor reactions.

If the described undesirable effects occur, one should refrain from performing these activities.

Drug Interactions

With simultaneous use with vitamin preparations containing folic acid or its derivatives, a decrease in the effectiveness of methotrexate is possible.

Simultaneous 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 methotrexate not bound to plasma albumin, which in turn enhances the toxic effects of methotrexate (primarily on the gastrointestinal tract and hematopoietic system).

With simultaneous use of methotrexate (even in low doses) with penicillins, an enhancement of its toxic effects is possible.

With simultaneous use with sulfonamides, especially co-trimoxazole, there is a risk of enhanced myelodepressive action.

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

With simultaneous use of valproic acid 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.

With simultaneous use 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.

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

With simultaneous use of methotrexate with retinoids, an increased risk of hepatotoxic action is possible.

Salicylates potentiate the action of methotrexate due to a decrease in its renal excretion.

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

With sequential administration of methotrexate and fluorouracil, 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 the hepatotoxic effect of methotrexate increases in the case of regular alcohol consumption and concomitant use of other hepatotoxic drugs.

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

An increase in toxicity is possible with the use of cyclosporine in patients who received Methotrexate.

Simultaneous 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 medicinal products 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.