Methotrexate-Ebeve, 10 mg/ml 5 ml

Antitumor drug from the group of antimetabolites – analogues of folic acid. Along with antitumor, it has immunosuppressive effect.

Inhibits dihydrofolate reductase, which participates in the reduction of dihydrofolic acid to tetrahydrofolic acid – the carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives.

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

When the cell proliferation of malignant tissue is greater than in most normal tissue, methotrexate can lead to disruption of malignant growth without irreversible damage to normal tissue.

The mechanism of action in rheumatoid arthritis is unknown; it may be due to the immunosuppressive properties of methotrexate.

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

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

Indications

– trophoblastic tumors;

– acute leukemia (especially lymphoblastic and myeloblastic variants);

– neuroleukemia;

– non-Hodgkin’s lymphoma, including lymphosarcoma;

– breast cancer, squamous cell head and neck cancer, lung cancer, skin cancer, cervical cancer, vulvar cancer, esophageal cancer, kidney cancer, bladder cancer, testicular cancer, ovarian cancer, penile cancer, retinoblastoma, medulloblastoma;

– osteogenic sarcoma and soft tissue sarcomas;

– fungal mycosis (advanced stages);

– severe forms of psoriasis, psoriatic arthritis, rheumatoid arthritis, dermatomyositis, SLE, ankylosing spondylitis (if standard therapy is not effective).

Active ingredient

How to take, the dosage

Methotrexate is included in many chemotherapy regimens, and therefore the route of administration, regimen, and dosages should be guided by the literature in each individual case.

Methotrexate-Ebeve Injection can be given intravenously, intravenously, intravenously, or intrathecally.

For trophoblastic tumors, 15-30 mg v/m, daily for 5 days at ≥1 week intervals (depending on signs of toxicity). Or 50 mg once every 5 days at intervals of at least 1 month. Treatment courses are usually repeated 3 to 5 times up to a total dose of 300-400 mg.

In solid tumors in combination with other antitumor drugs, 30-40 mg/m2 by IV infusion once a week.

In leukemia or lymphoma, 200-500 mg/m2 by IV infusion once every 2-4 weeks.

In neuroleukemia, 12 mg/m2 intrathecal for 15-30 seconds once or twice a week.

When treating children, the dose is adjusted according to age: children under 1 year of age are prescribed 6 mg, children aged 1 year 8 mg, children aged 2 years 10 mg, children over 3 years 12 mg.

Before administration, spinal fluid should be removed in an amount approximately equal to the volume of the drug to be injected.

When using high-dose therapy, 2 to 15 g/m2 as a 4-6-hour IV infusion at 1-5 week intervals, followed by mandatory administration of calcium folinate, which usually begins 24 h after the start of methotrexate infusion and administered every 6 h at a dose of 3-40 mg/m2 (usually 15 mg/m2) or higher depending on the serum concentration of methotrexate for 48-72 h.

In rheumatoid arthritis, the starting dose is usually 7.5 mg once a week, which is administered once daily by infusion, 2.5 mg every 12 h (3 doses total). For optimal effect, the weekly dose may be increased, but should not exceed 20 mg. When optimal clinical effect is achieved, dose reduction should be initiated until the lowest effective dose is achieved. The optimal duration of therapy is unknown.

In psoriasis, the dose is administered by injection in m/m or by IV fluids at doses of 10 to 25 mg per week. The dose is usually increased gradually; when optimal clinical effect is achieved, dose reduction is initiated until the lowest effective dose is achieved.

In fungal mycosis, 50 mg once weekly or 25 mg twice weekly for several weeks or months. Dose reduction or discontinuation of the drug is determined by the patient’s response and hematologic parameters.

Interaction

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

In combination therapy with methotrexate and leflunomide, the incidence of pancytopenia and hepatotoxic effects increases.

The oral antibiotics (tetracyclines, chloramphenicol and non-absorbable broad spectrum antibiotics) may decrease gastrointestinal absorption of methotrexate and interfere with enterohepatic circulation by inhibiting gut microflora or inhibiting bacterial metabolism.

Penicillins, ciprofloxacin, cephalothin, glycopeptides may decrease renal clearance of methotrexate, which may increase its serum concentrations and increase toxic effects on the hematopoietic system and the GIT.

Probenecid, weak organic acids (e.g., “loop” diuretics) and pyrazoles (phenylbutazone) may delay elimination of methotrexate, which may increase its serum concentration and hematological toxicity.

The risk of toxic effects of methotrexate increases when combined with NSAIDs or salicylates.

When concomitant therapy with drugs that may have adverse effects on bone marrow (e.g., sulfonamides, trimethoprim/sulfamethoxazole, chloramphenicol, pyrimethamine), the possibility of more pronounced hematologic disorders should be considered.

The toxic effects of methotrexate may increase with concomitant therapy with folate-deficient drugs (e.g., trimethoprim/sulfamethoxazole).

The concomitant use of indirect anticoagulants and hypolipidemic drugs (cholestyramine) increases the toxicity of methotrexate.

In combined use of antirheumatic drugs (e.g., gold salts, penicillamine, hydroxychloroquine, azathioprine, cyclosporine) and methotrexate the toxic effect of the latter is not increased. In case of concomitant use of sulfasalazine and methotrexate the effect of the latter may be potentiated due to inhibition of folic acid synthesis.

When methotrexate and proton pump inhibitors (e.g., omeprazole or pantoprazole) are used together, renal elimination of methotrexate may be delayed, and pantoprazole may inhibit renal elimination of the 7-hydroxymethotrexate metabolite, which in one case was followed by myalgia and tremor.

An excessive consumption of beverages containing caffeine and theophylline (coffee, sweet beverages containing caffeine, black tea) should be avoided during treatment with methotrexate. Methotrexate decreases theophylline clearance.

The pharmacokinetic interaction between methotrexate and flucloxacillin and anticonvulsants should be taken into account (decreases methotrexate concentration in blood), 5-fluorouracil (increases half-life of 5-fluorouracil).

In case of co-administration with other cytostatics methotrexate clearance may decrease.

Vitamin preparations or oral iron preparations containing folic acid may alter the response to therapy with methotrexate.

Mixed solutions of methotrexate with chlorpromazine hydrochloride, droperidol, idarubicin, metoclopramide hydrochloride, heparin, prednisolone sodium phosphate and promethazine hydrochloride may precipitate or cloud the solution.

Due to competitive binding to serum albumin when using methotrexate concomitantly with phenylbutazones, phenytoin, toxicity of methotrexate may be increased.

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

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

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

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

L-asparaginase is an antagonist of methotrexate.

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

Amiodarone may contribute to skin ulceration.

Parenteral use of acyclovir against the background of intrathecal administration of methotrexate increases the risk of neurological disorders.

Special Instructions

Methotrexate may only be prescribed by an oncologist experienced in antineoplastic chemotherapy. Given the risk of severe toxic reactions, including death, the physician must inform the patient in detail about the possible risks and the necessary safety precautions.

If significant pleural fluid or ascites is detected in a patient, the fluid should be evacuated by drainage before starting methotrexate therapy or methotrexate should not be used.

The appearance of symptoms of toxic esophageal injury, the earliest of which is stomatitis, requires temporary discontinuation of methotrexate therapy due to the high risk of hemorrhagic enteritis and intestinal perforation, with fatal outcome if therapy is continued.

Patients should be closely monitored during treatment with methotrexate to detect timely signs of possible toxic effects and adverse effects. Given the risk of severe or even fatal toxic reactions, patients should be informed in detail about possible complications and recommended precautions.

Before starting treatment with methotrexate or when resuming therapy after a break, a clinical blood count with leukocyte count and platelet count, liver enzymes activity, bilirubin concentration, serum albumin concentration, as well as chest radiography and functional renal tests should be performed. If clinically indicated, studies to rule out tuberculosis and hepatitis are prescribed.

In the course of treatment with methotrexate (monthly for the first 6 months and at least every 3 months thereafter, with increasing doses it is reasonable to increase the frequency of examinations) the following examinations are performed:

1. Oral and throat examinations to detect mucosal changes.

2. Blood tests with determination of the white blood cell count and platelet count. Even when used in normal therapeutic doses, methotrexate can suddenly cause suppression of the hematopoietic system. In case of a significant decrease in the number of white blood cells or platelets, treatment with methotrexate is stopped immediately, and symptomatic supportive therapy is prescribed. Patients should be instructed to inform the physician immediately of any signs and symptoms suggestive of infection. If concomitant therapy with hematotoxic drugs (e.g., leflunomide), the number of white blood cells and platelets in the blood should be monitored closely.

3. Functional liver function tests. Particular attention should be paid to detect signs of liver damage. Treatment with methotrexate should not be initiated or should be suspended if there are any abnormalities in the results of liver function tests or liver biopsy. Usually values return to normal within two weeks, after which treatment may be resumed at the discretion of the physician. When methotrexate is used for rheumatologic indications, there is no reason to perform a liver biopsy to monitor the hepatotoxic effects of the drug. When treating psoriasis patients, the appropriateness of liver biopsy before or during methotrexate treatment should be evaluated based on current scientific recommendations. Such an assessment should differentiate between patients without risk factors and those in a risk group (e.g., those with a history of alcohol abuse, persistent elevated liver enzyme activity, a history of liver disease, a family history of hereditary liver disease, diabetics, obese patients, and those who have previously taken hepatotoxic drugs or been in contact with hepatotoxic chemicals). In case of persistent increase in hepatic enzyme activity it is necessary to reduce doses or discontinue treatment with methotrexate.

Because methotrexate has a toxic effect on the liver, other hepatotoxic drugs should not be prescribed without a clear need during treatment with the drug. Alcohol consumption should also be avoided or greatly reduced. Liver enzyme activity should be monitored particularly carefully in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular, with leflunomide).

4. Functional renal tests and urinalysis. Since methotrexate is excreted mainly by the kidneys, patients with impaired renal function may experience elevated blood concentrations of methotrexate, which may result in severe adverse reactions. It is necessary to carefully monitor the condition of patients who may have impaired renal function (e.g., elderly patients). This is especially important in case of concomitant therapy with drugs that reduce methotrexate excretion, have adverse effect on the kidneys (in particular, NSAIDs) or on the hematopoietic system. Dehydration can also potentiate the toxic effects of methotrexate.

5. Respiratory investigation. The symptoms of possible pulmonary dysfunction should be closely monitored and a pulmonary function study should be ordered if necessary. Pulmonary disease requires prompt diagnosis and withdrawal of methotrexate. If symptoms occur during treatment with methotrexate (particularly a dry, unproductive cough) or if nonspecific pneumonitis develops, this may indicate a potential risk of lung disease. In such cases, methotrexate should be withdrawn and the patient should be carefully evaluated. Although the clinical picture may vary, the typical patient with methotrexate-induced lung disease will present with elevated body temperature, cough with dyspnea, hypoxemia, and pulmonary infiltrates on x-rays. In the differential diagnosis, infectious diseases should be excluded. Pulmonary involvement may be seen with treatment with methotrexate in any dose.

6 Because methotrexate affects the immune system, it may alter the response to vaccination and affect immunological test results. Particular caution is needed when treating patients with inactive, chronic infections (such as shingles, tuberculosis, hepatitis B or C) because of their possible activation. Vaccination with live vaccines should not be performed during treatment with methotrexate.

It is recommended that treatment with methotrexate be stopped one week before surgery and restarted one or two weeks after surgery.

The elimination of methotrexate is significantly delayed if body temperature increases (over 38°C).

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

Before treatment with Methotrexate-Ebeve, pregnancy should be excluded. Methotrexate has embryotoxic effect, promotes pregnancy termination and formation of fetal abnormalities. Methotrexate therapy is accompanied by inhibition of spermatogenesis and ovogenesis, which may lead to reduced fertility. These effects spontaneously regress after cancellation of methotrexate therapy. During the treatment with methotrexate and for 6 months after its completion, patients are recommended to use contraception. Patients of reproductive age as well as their partners should be informed about the possible effects of methotrexate on fertility and development.

The life-threatening effects of intrathecal administration of methotrexate are well known, so the ratio of risk to expected benefits of therapy should be evaluated on a case-by-case basis. The drug should be withdrawn at the first signs of serious side effects.

In high-dose therapy, precipitation of methotrexate or its metabolites in the renal tubules is possible. In such cases as prevention of this complication it is recommended to give infusion therapy and to alkalize urine to pH 6.5-7.0 by oral or intravenous administration of sodium bicarbonate (5 tablets of 625 mg every 3 hours) or acetazolamide (500 mg orally 4 times per day).

Methotrexate-Ebeve contains no preservatives, so only single withdrawals from the container are allowed, and unused solutions must be disposed of.

Infusion solutions with a methotrexate concentration of 0.1 mg/ml or 3 mg/ml prepared by diluting Methotrexate-Ebeve with 0.9% sodium chloride solution, 5% glucose solution, 10% glucose solution, and Ringer’s lactate solution, are physically and chemically stable for at least 24 h if stored in a light-protected place, at 5±3°C or room temperature (20-25°C). Microbiologically, the infusion solution should be administered immediately after preparation.

Methotrexate-Ebeve must not be mixed with other medicinal products in the same infusion bag or bottle.

When manipulating methotrexate solutions, the rules for handling cytotoxic substances must be followed. Pregnant health care workers should not work with the drug.

A precautions should be taken to prevent contact of methotrexate solutions with skin and mucous membranes. If the drug does come into contact with skin or mucous membranes, the affected area should be immediately rinsed with large amounts of water.

The remains of the drug and all instruments and materials used to prepare Methotrexate-Ebeve infusion solutions must be disposed of in accordance with the standard hospital procedure for disposal of cytotoxic waste, in compliance with current hazardous waste disposal regulations.

Impact on driving and operating ability

Because of the potential for side effects such as drowsiness, headache, and confusion, caution should be exercised when engaging in potentially hazardous activities that require increased concentration and rapid psychomotor reactions.

Contraindications

– significant renal insufficiency (CK<20 ml/min);

– significant hepatic insufficiency;

– alcohol abuse;

– history of hematopoietic disorders (in particular, bone marrow hypoplasia, leukopenia, thrombocytopenia, or clinically significant anemia);

– severe acute and chronic infectious diseases such as tuberculosis and HIV infection;

– concomitant live vaccination;

– oral ulcers, active gastrointestinal ulcers;

– concomitant use of methotrexate at a dose of ≥15 mg/week. with acetylsalicylic acid;

– pregnancy;

– lactation;

– hypersensitivity to methotrexate and/or any other component of the drug;

. The drug is used with caution in patients with hepatic and renal dysfunction, diabetes mellitus, obesity and previous exposure to hepatotoxic drugs, dehydration, ascites, suppression of medullary hematopoiesis, pleural or peritoneal effusions, parasitic and infectious diseases of viral of fungal or bacterial nature – risk of severe generalized disease (current or recent, including recent exposure – herpes simplex, herpes zoster (viremic phase), varicella, measles, amebiasis, strongyloidiasis (established or suspected)) Gout (incl.or urate nephrolithiasis (including history), oral mucosa infection and inflammation, vomiting, diarrhea, gastric and duodenal ulcer, ulcerative colitis, obstructive GI disease, prior chemo- or radiation therapy, asthenia, aciduria (urine pH less than 7), and in children and older patients.

Side effects

According to WHO adverse effects are classified according to their frequency of development as follows: very common (≥1/10), common (≥1/100 to < 1/10), infrequent (≥1/1000 to < 1/100), rare (≥1/10 000 to < 1/1000), very rare (< 1/10 000); frequency is unknown – according to available data it was impossible to determine the incidence.

Hematopoietic system: frequently – suppression of bone marrow function (leukopenia, thrombocytopenia, anemia); infrequently – pancytopenia; very rarely – severe progressive suppression of bone marrow function, agranulocytosis; frequency is unknown – megaloblastic anemia.

Central nervous system disorders: Frequent – somnolence, headache, fatigue; infrequent – depression, confusion, mood changes; rare – with low-dose methotrexate use – transient minor cognitive impairment, unusual sensations in the skull area; very rare – pain, myasthenia or paresthesias in the extremities, perversion of taste (metallic taste in the mouth), epileptic seizures, meningism, paralysis, insomnia.

Sense organs: often – visual disorders; infrequently – eye irritation; rarely – conjunctivitis.

Respiratory system: often – chronic interstitial pneumonitis (symptoms indicating potentially serious lung damage in interstitial pneumonitis: Dry, unproductive cough, shortened breathing, increased body temperature); infrequent – alveolitis, pleural effusion; rare – pulmonary fibrosis, pneumocystis pneumonia, bronchial asthma; very rare – pleural pain and thickening of pleural sheets (when treated with methotrexate in high doses), acute pulmonary edema.

Digestive system disorders: very common – stomatitis, nausea, inflammation of mucous membranes, loss of appetite, dyspepsia, anorexia, significant increase in liver transaminase activity; frequent – diarrhea, ulceration of oral mucosa; infrequent – enteritis, vomiting, liver cirrhosis, liver fibrosis, liver steatosis; rare – ulceration of GI mucosa; very rare – malabsorption syndrome, toxic megacolon.

Urinary system disorders: infrequent – bladder inflammation and ulceration, renal dysfunction, urinary disorders; rarely – renal failure, oliguria, anuria, electrolyte balance disorders.

The skin: often – exanthema, erythema, pruritus, infrequently – photosensitivity, alopecia, herpes zoster, vasculitis, herpetiform skin rash, urticaria, rarely – increased pigmentation, very rare – Stevens-Johnson syndrome, epidermal necrolysis (Lyell syndrome). On exposure to ultraviolet radiation, increased psoriatic skin lesions, increased nail pigmentation, acute paronychia, furunculosis, and hidradenitis.

Muscular system disorders: infrequent – arthralgia, myalgia, osteoporosis.

Cardiovascular system: common – vasculitis, bleeding in various localizations; infrequent – effusion into the pericardial cavity; rare – cardiac tamponade, nasal bleeding.

The immune system: very common – decreased resistance to infection, pharyngitis; infrequent – hypogammaglobulinemia; rare – sepsis; very rare – anaphylactic reactions, increased number of rheumatoid nodules.

Reproductive system disorders: infrequent – vaginal ulceration and inflammation; very rare – loss of libido, impotence, oligospermia, menstrual disorders, vaginal discharge.

Others: often – chills, malaise, fever, necrosis; rarely – deterioration of wound healing. When administered by injection, burning sensation or tissue damage (formation of sterile abscess, destruction of adipose tissue) at the injection site; very rare – benign, malignant and non-specific neoplasms (including cysts and polyps), lymphoma, which in some cases regress after withdrawal of methotrexate; frequency unknown – diabetes, other metabolic disorders, sudden death.

Adverse reactions during intrathecal administration of methotrexate

Acute: chemical arachnoiditis manifested by headache, back or shoulder pain, posterior neck muscle stiffness, and fever.

Subacute: paresis (usually transient), paraplegia, cerebellar dysfunction.

Chronic: leukoencephalopathy manifested by irritability, confusion, ataxia, muscle plasticity, sometimes convulsions, dementia, somnolence, coma, in rare cases with fatal outcome. The incidence of leukoencephalopathy increases with the combination of radiotherapy to the cranial region and intrathecal injection of methotrexate.

Overdose

Symptoms: mainly symptoms associated with suppression of the hematopoietic system are observed.

Treatment: a specific antidote to methotrexate is calcium folinate. It neutralizes the adverse toxic effects.

In case of accidental overdose no later than one hour after methotrexate administration, calcium folinate is administered (IV or IV/m) in a dose equal to or greater than the dose of methotrexate. Calcium folinate administration is continued until methotrexate serum concentration decreases below 10-7 mmol/L.

In significant overdose, hydration of the body and alkalization of the urine (pH greater than 7) may be required to prevent precipitation of methotrexate and/or its metabolites in the renal tubules. Hemodialysis and peritoneal dialysis do not improve methotrexate elimination. Intensive intermittent hemodialysis using “high-flux” dialyzers can provide effective clearance of methotrexate.

In case of overdose during intrathecal administration, repeated lumbar punctures should be performed immediately to ensure rapid drainage of cerebrospinal fluid, possibly neurosurgical intervention with ventriculolumbar perfusion. All these procedures should be performed against a background of intensive supportive therapy and systemic administration of high doses of calcium folinate.

Similarities