Methotrexate-Ebeve solution for injection 10mg/ml 5ml vial, 1pc

Composition

1 ml-methotrexate 10 mg. Auxiliary substances: sodium hydroxide – 1.783 mg, sodium chloride-6.9 mg, water d / i-988.317 mg

Pharmacological action

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

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.

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

When the cell proliferation of malignant tissues is greater than in most normal tissues, methotrexate can disrupt the growth of malignancies without permanently damaging normal tissue.

The mechanism of action in rheumatoid arthritis is unknown, possibly due to the immunosuppressive properties of methotrexate.

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

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

Indications

— trophoblastic tumor;

acute leukemia (especially lymphoblastic and myeloblastic options);

— neuroleukemia;

— non-Hodgkin’s lymphoma, including lymphosarcoma;

breast cancer, squamous cell carcinoma of the head and neck, 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 sarcoma;

— mycosis fungoides (advanced stage);

— severe psoriasis, psoriatic arthritis, rheumatoid arthritis, dermatomyositis, SLE, ankylosing spondylitis (after failure of standard therapy).

Contraindications

— severe renal failure (CC<20 ml/min);

— severe hepatic impairment;

— alcohol abuse;

— violations of the hematopoietic system in history (in particular, bone marrow hypoplasia, leukopenia, thrombocytopenia or clinically significant anemia);

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

— concomitant vaccination with live vaccines;

— ulcer of the mouth, ulcers of the gastrointestinal tract in the active phase;

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

— pregnancy;

— lactation period;

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

Use the drug with caution if patients have impaired liver and kidney function, diabetes mellitus, obesity and previous exposure to hepatotoxic drugs, dehydration, ascites, bone marrow hematopoiesis, pleural or peritoneal effusion, parasitic and infectious diseases of a viral, fungal or bacterial nature – the risk of developing a severe generalized disease (currently or recently transferred, including recent contact with the patient – herpes simplex, herpes zoster (viremic phase), chickenpox, measles, amoebiasis, strongyloidosis (established or suspected)); gout (including in the anamnesis) or urate nephrourolithiasis (including in the anamnesis), infection and inflammation of the oral mucosa, vomiting, diarrhea, stomach and duodenal ulcer, ulcerative colitis, obstructive gastrointestinal diseases that precede chemotherapy or radiation therapy, asthenia, aciduria (urine pH less than 7), as well as in children and elderly patients.

Side effects

According to WHO, adverse events are classified according to their frequency as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (

From the hematopoietic system:  often-bone marrow suppression (leukopenia, thrombocytopenia, anemia); infrequently – pancytopenia; very rarely – severe progressive bone marrow suppression, agranulocytosis; frequency unknown – megaloblastic anemia.

From the central nervous system:  often-drowsiness, headache, fatigue; infrequently-depression, confusion, mood changes; rarely – when using methotrexate in low doses-transient slight cognitive impairment, unusual sensations in the skull; very rarely-pain, myasthenia gravis or paresthesia in the extremities, taste distortion (metallic taste in the mouth), epileptic seizures, meningism, paralysis, insomnia.

From the side of the senses:  often-visual disturbances; infrequently-eye irritation; rarely-conjunctivitis.

Respiratory system disorders:  often – chronic interstitial pneumonitis (symptoms indicating potentially serious lung damage in interstitial pneumonitis: dry, unproductive cough, shortness of breath, increased body temperature); infrequently – alveolitis, pleural effusion; rarely – pulmonary fibrosis, pneumocystis pneumonia, bronchial asthma; very rarely – pleural pain and thickening of pleural leaves (with high-dose methotrexate treatment), acute pulmonary edema.

From the digestive system:  very often – stomatitis, nausea, inflammation of the mucous membranes, loss of appetite, dyspepsia, anorexia, a significant increase in the activity of hepatic transaminases; often-diarrhea, ulceration of the oral mucosa; infrequently – enteritis, vomiting, cirrhosis of the liver, liver fibrosis, liver steatosis; rarely – ulceration of the gastrointestinal mucosa; very rarely – malabsorption syndrome, toxic megacolon.

From the urinary system:  infrequently-inflammation and ulceration of the bladder, impaired kidney function, urination disorders; rarely-renal failure, oliguria, anuria, electrolyte balance disorders.

From the side of the skin:  often-exanthema, erythema, pruritus; infrequently-photosensitivity, alopecia, shingles, vasculitis, herpetiform rashes on the skin, urticaria; rarely-increased pigmentation; very rarely-Stevens-Johnson syndrome, epidermal necrolysis (Lyell’s syndrome). When exposed to ultraviolet radiation, increased psoriatic skin lesions, increased nail pigmentation, acute paronychia, furunculosis and hydradenitis.

Musculoskeletal disorders:  infrequently – arthralgia, myalgia, osteoporosis.

From the cardiovascular system:  often – vasculitis, bleeding of various localization; infrequently-effusion into the pericardial cavity; rarely-cardiac tamponade, nosebleeds.

From the immune system:  very often-decreased resistance to infections, pharyngitis; infrequently-hypogammaglobulinemia; rarely-sepsis; very rarely-anaphylactic reactions, an increase in the number of rheumatoid nodules.

From the side of the reproductive system:  infrequently-ulceration and inflammation of the vagina; very rarely-loss of libido, impotence, oligospermia, menstrual disorders, vaginal discharge.

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

Adverse reactions with intrathecal use of methotrexate

Sharp:  chemical arachnoiditis, manifested by headache, back or shoulder pain, stiffness of the muscles of the back of the neck and fever.

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

Chronic diseases:  leukoencephalopathy, manifested by irritability, confusion, ataxia, muscle plasticity, sometimes convulsions, dementia, drowsiness, coma, in rare cases with a fatal outcome. With the combination of radiation therapy to the skull and intrathecal use of methotrexate, the incidence of leukoencephalopathy increases.

Interaction

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

Combined therapy with methotrexate and leflunomide increases the incidence of pancytopenia and hepatotoxic effects.

Oral antibiotics (tetracyclines, chloramphenicol and nonabsorbable broad-spectrum antibiotics) they can reduce the absorption of methotrexate in the gastrointestinal tract and interfere with enterohepatic circulation due to inhibition of intestinal microflora or inhibition of bacterial metabolism.

Penicillins, ciprofloxacin, cephalotin, glycopeptides can reduce the renal clearance of methotrexate, which can increase its concentration in the blood serum and increase the toxic effect on the hematopoietic system and gastrointestinal tract.

Probenecid, weak organic acids (such as loop diuretics) and pyrazoles (phenylbutazone) They can slow down the elimination of methotrexate, as a result of which its concentration in the blood serum may increase and hematological toxicity may increase.

The risk of toxic effects of methotrexate increases when used in combination with NSAIDs or salicylates.

Concomitant therapy with drugs that may have an adverse effect on the bone marrow (for example, sulfonamides, trimethoprim / sulfamethoxazole, chloramphenicol, pyrimethamine) should take into account the possibility of developing more pronounced hematological disorders.

With concomitant therapy with drugs that cause folate deficiency (for example, trimethoprim/sulfamethoxazole), the toxic effect of methotrexate may increase.

Concomitant use of indirect anticoagulants and lipid-lowering drugs (cholestyramine) increases the toxicity of methotrexate.

When combined with antirheumatic drugs (for example, gold salts, penicillamines, hydroxychloroquines, azathioprines, cyclosporins) and methotrexate, the toxic effect of the latter does not increase. In the case of simultaneous use of sulfasalazine and methotrexate, the effect of the latter may be potentiated due to inhibition of folic acid synthesis.

When combined with methotrexate and proton pump inhibitors (for example, omeprazole or pantoprazole) renal elimination of methotrexate may be delayed, and pantoprazole may inhibit renal elimination of the 7-hydroxymethotrexate metabolite, which in one case was accompanied by the development of myalgia and tremor.

During treatment with methotrexate, excessive consumption of beverages containing caffeine and theophylline (coffee, sugary drinks containing caffeine, black tea) should be avoided. Methotrexate reduces theophylline clearance.

It is necessary to take into account the pharmacokinetic interaction between methotrexate and flucloxacillin and anticonvulsants (the concentration of methotrexate in the blood decreases),5-fluorouracil (the half-life of 5-fluorouracil increases).

In the case of co-use with other cytostatics, the clearance of methotrexate may decrease.

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

When mixing methotrexate solutions with chlorpromazine hydrochloride, droperidol, idarubicin, metoclopramide hydrochloride, heparin, prednisone sodium phosphate and promethazine hydrochloride, precipitation or turbidity of the solution may occur.

Due to the competitive binding to serum albumin, the toxicity of methotrexate may be increased when methotrexate is co-administered with phenylbutazones, phenytoin.

In several patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (methoxalen and ultraviolet radiation) skin cancer was detected.

Caution should be exercised when red blood cell mass and methotrexate are administered simultaneously.

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

Methotrexate may reduce the immunological response to vaccination. When administered concomitantly with a live vaccine, severe antigenic reactions may develop.

L-asparaginase is a methotrexate antagonist.

Performing anesthesia using dinitrogen oxide can lead to the development of unpredictable severe myelosuppression and stomatitis.

Amiodarone may contribute to skin ulceration.

Parenteral use of acyclovir with intrathecal use of methotrexate increases the risk of neurological disorders.

How to take, course of use and dosage

Methotrexate is part of many chemotherapeutic treatment regimens, and therefore, when choosing the route of use, regimen and doses in each individual case, you should be guided by the data of the specialized literature.

Methotrexate-Ebeve for injection can be administered intravenously, intravenously, intravenously or intrathecally.

For trophoblastic tumors – 15-30 mg iv, daily for 5 days with an interval of ≥1 week (depending on the signs of toxicity). Or 50 mg once every 5 days with an interval of at least 1 month. Courses of treatment are usually repeated from 3 to 5 times up to a total dose of 300-400 mg.

For solid tumors in combination with other antitumor drugs-30-40 mg / m2 IV jet 1 time per week.

For leukemias or lymphomas-200-500 mg / m2 by intravenous infusion 1 time in 2-4 weeks.

With neuroleukemia – 12 mg / m2 intrathecally for 15-30 seconds 1 or 2 times a week.

In the treatment of children, the dose is selected depending on the age: children under the age of 1 year are prescribed 6 mg, children under the age of 1 year-8 mg, children under the age of 2 years-10 mg, children over 3 years-12 mg.

Before use, the cerebrospinal fluid should be removed in a volume approximately equal to the volume of the drug to be administered.

When applying high-dose therapy is from 2 to 15 g/m 2 in the form of 4-6 hours on/in infusion every 1 to 5 weeks with obligatory subsequent use of calcium folinate, which usually start 24 hours after beginning of methotrexate infusion and administered every 6 h at a dose of 3-40 mg/m 2 (usually 15 mg/m 2) and higher depending on the concentration of methotrexate in the blood serum within 48-72 hours

In rheumatoid arthritis, the initial dose is usually 7.5 mg once a week, which is administered simultaneously in / in, in / m 2.5 mg every 12 hours (a total of 3 doses). To achieve an optimal effect, the weekly dose can be increased, but it should not exceed 20 mg. When the optimal clinical effect is achieved, dose reduction should be initiated until the lowest effective dose is reached. The optimal duration of therapy is unknown.

For psoriasis, i. m or i. v. jet in doses from 10 to 25 mg per week. The dose is usually increased gradually, and when the optimal clinical effect is achieved, the dose is reduced until the lowest effective dose is reached.

For fungal mycosis in / m,50 mg 1 time a week or 25 mg 2 times a week for several weeks or months. Dose reduction or discontinuation of the drug is determined by the patient’s response and hematological parameters.

Overdose

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

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

In case of accidental overdose, no later than one hour after the use of methotrexate, calcium folinate (IV or iv) is administered at a dose equal to or exceeding the dose of methotrexate. use of calcium folinate is continued until the concentration of methotrexate in the blood serum decreases below the level of 10-7 mmol/l.

In case of a significant overdose, hydration of the body and alkalinization of 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 highly permeable (“high-flux”) dialysers allows for effective clearance of methotrexate.

In case of overdose with intrathecal use, repeated lumbar punctures should be performed immediately to ensure rapid drainage of the cerebrospinal fluid, neurosurgical intervention with ventriculolumbal perfusion is possible. All these procedures should be performed against the background of intensive maintenance therapy and systemic use of large doses of calcium folinate.

Special instructions

Methotrexate can only be prescribed by an oncologist who has experience with antineoplastic chemotherapy. Taking into account the risk of developing severe toxic reactions, including fatal ones, the doctor must inform the patient in detail about the possible risk and the necessary safety measures.

If the patient has a significant amount of fluid in the pleural cavities or ascites, the fluid should be evacuated by drainage before starting methotrexate therapy, or the use of methotrexate should be discontinued.

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

During treatment with methotrexate, patients should be carefully monitored for signs of possible toxic effects and adverse effects in a timely manner. 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, it is necessary to conduct a clinical blood test with the calculation of the leukocyte formula and platelet count, evaluate the activity of liver enzymes, bilirubin concentration, serum albumin, as well as chest X-ray examination and renal function tests. If there are clinical indications, studies are prescribed to exclude tuberculosis and hepatitis.

During treatment with methotrexate (monthly in the first 6 months and at least every 3 months in the future, with increasing doses, it is advisable to increase the frequency of examinations), the following studies are carried out::

1. Examination of the oral cavity and throat to detect changes in the mucous membranes.

2. Blood test with determination of the leukocyte formula 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 immediately discontinued and symptomatic maintenance therapy is prescribed. Patients should be instructed to immediately report any signs and symptoms that indicate the development of an infection to the doctor. When concomitant therapy with hematotoxic drugs (for example, leflunomide), it is necessary to carefully monitor the number of white blood cells and platelets in the blood.

3. Functional liver tests. Special attention should be paid to identifying signs of liver damage. Treatment with methotrexate should not be initiated or suspended in the event of any abnormalities in the results of liver function tests or liver biopsies. Usually, the indicators return to normal within two weeks, after which treatment can be resumed by a doctor’s decision. When using methotrexate for rheumatological indications, there is no reason to perform a liver biopsy to monitor the hepatotoxic effect of the drug. When treating patients with psoriasis, it is necessary to evaluate the feasibility of performing a liver biopsy before or during treatment with methotrexate, based on current scientific recommendations. This assessment should differentiate between patients without risk factors and those at risk (for example, those who have previously abused alcohol, with persistently elevated levels of liver enzyme activity, a history of liver disease, a family history of hereditary liver diseases, diabetic patients, obese patients, and those who have previously taken hepatotoxic drugs or come into contact with hepatotoxic chemicals). If there is a persistent increase in the activity of liver enzymes, it is necessary to reduce the dose or discontinue treatment with methotrexate.

Since methotrexate has a toxic effect on the liver, other hepatotoxic drugs should not be prescribed during treatment with the drug without obvious necessity. You should also avoid or greatly reduce your alcohol intake. Especially carefully monitor the activity of liver enzymes should be in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular, leflunomide).

4. Functional renal tests and urinalysis. Since methotrexate is mainly excreted by the kidneys, patients with impaired renal function may experience an increase in the concentration of methotrexate in the blood, which can lead to severe adverse reactions. Patients who may have impaired renal function should be carefully monitored (for example, elderly patients). This is especially important in the case of concomitant therapy with drugs that reduce the excretion of methotrexate, have an adverse effect on the kidneys (in particular, NSAIDs) or on the hematopoietic system. Dehydration can also potentiate the toxic effects of methotrexate.

5. Examination of the respiratory system. It is necessary to carefully monitor the symptoms of possible development of lung function disorders and, if necessary, prescribe a study of lung function. Lung diseases require rapid diagnosis and withdrawal of methotrexate. The appearance of appropriate symptoms during treatment with methotrexate (especially dry, unproductive cough) or the development of non-specific pneumonitis may indicate a potential risk of lung damage. In such cases, methotrexate is discontinued and the patient is carefully examined. Although the clinical picture may vary, a typical patient with lung disease caused by methotrexate use has fever, cough with shortness of breath, hypoxemia, and pulmonary infiltrates on X-rays. In the differential diagnosis, infectious diseases should be excluded. Lung damage can occur when treated with methotrexate in any dose.

6. Because methotrexate affects the immune system, it can alter the response to vaccination and affect the results of immunological tests. Special care should be taken when treating patients with inactive, chronic infections (such as shingles, tuberculosis, hepatitis B or C) due to their possible activation. Live vaccines should not be given during treatment with methotrexate.

It is recommended to interrupt treatment with methotrexate one week before surgery and resume one or two weeks after surgery.

With an increase in body temperature (more than 38°C), the elimination of methotrexate slows down significantly.

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

Before starting treatment with Methotrexate-Ebeve, pregnancy should be excluded. Methotrexate has an embryotoxic effect, contributes to the termination of pregnancy and the formation of fetal abnormalities. Methotrexate therapy is associated with inhibition of spermatogenesis and ovogenesis, which can lead to a decrease in fertility. After discontinuation of methotrexate therapy, these effects spontaneously regress. During the period of 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 effects of methotrexate on reproduction and development.

The life-threatening consequences of intrathecal use of methotrexate are well known, so the risk-benefit ratio of therapy should be evaluated in each individual case. When the first signs of serious side effects appear, the drug is canceled.

With high-dose therapy, precipitation of methotrexate or its metabolites in the renal tubules may occur. In such cases, as a prevention of this complication, it is recommended to conduct infusion therapy and alkalinization of urine until pH 6.5-7.0 is reached by oral or intravenous use of sodium bicarbonate (5 tablets of 625 mg every 3 hours) or acetazolamide (500 mg orally 4 times / day).

Methotrexate-Ebeve does not contain preservatives, so only a single sample of the drug is allowed from the container, 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 hours when stored in a dark place at a temperature of 5±3°C or room temperature (20-25°C). From a microbiological point of view, the infusion solution should be administered immediately after preparation.

Methotrexate-Ebeve should not be mixed with other medications in the same infusion bag or vial.

When manipulating methotrexate solutions, it is necessary to observe the rules for handling cytotoxic substances. Pregnant healthcare professionals should not work with the drug.

Measures should be taken to prevent methotrexate solutions from getting on the skin and mucous membranes. If the drug still gets on the skin or mucous membranes, the affected area is immediately washed with plenty of water.

Drug residues, all tools and materials that were used to prepare solutions for infusion of Methotrexate-Ebeve should be disposed of in accordance with the standard hospital procedure for the disposal of cytotoxic substance waste, taking into account the current regulations for the disposal of hazardous waste.

Influence on the ability to drive motor vehicles and manage mechanisms

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

Form of production

The solution for injection is yellow, transparent, free of foreign particles.

Storage conditions

The drug should be stored out of the reach of children, protected from light at a temperature of 15-25°C.

Shelf

life is 3 years.

Active ingredient

Methotrexate

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection