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

Composition

Active ingredient:

methotrexate-10,000 mg;

excipients:

sodium hydroxide – 1,783 mg,

sodium chloride-6,900 mg,

water for injection-988,317 mg

Pharmacological action

Pharmacodynamics

Antitumor, cytostatic agent of the group of antimetabolites – analogues of folic acid, which has an immunosuppressive and anti-inflammatory 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 associated with the immunomodulatory and anti-inflammatory effects 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 anti-inflammatory cytokines (interleukin (IL) -1, tumor necrosis factor alpha), increased 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 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.

Pharmacokinetics

When administered intramuscularly, the maximum concentration of methotrexate in blood plasma is reached within 30-60 minutes. Leukemic patients are characterized by a wide interindividual variability ranging from 1 to 3 hours. Relative bioavailability in patients with rheumatoid arthritis is comparable after intramuscular or subcutaneous injection with the same doses of the drug. Systemic absorption of methotrexate after use under the skin of the abdomen and thigh is the same. After intravenous use, the primary distribution is 0.18 l/kg (18% of body weight). The saturation dose distribution is about 0.4-0.8 l / kg (40% – 80% of body weight).

About 50% of methotrexate binds to plasma proteins, mainly albumins. Competitive displacement is possible when used simultaneously with sulfonamides, salicylates, tetracyclines, chloramphenicol, and phenytoin.

Methotrexate does not cross the blood-brain barrier when used in therapeutic doses. A high concentration of methotrexate in the central nervous system can be achieved by intrathecal use.

Methotrexate undergoes hepatic and intracellular metabolism to form a pharmacologically active polyglutamine form that also inhibits dihydrofolate reductase and thymidine synthesis. A small amount of methotrexate polyglutamate can remain in the tissues for an extended period of time. Maintenance and prolongation of the active metabolites of the drug vary depending on the type of cells, tissues and tumors.

The average half-life of methotrexate at a dose of less than 30 mg / m2 is 6-7 hours. In patients receiving high doses of methotrexate, the elimination half-life is 8 to 17 hours. In chronic renal failure, both phases of methotrexate elimination can be significantly prolonged.

From 80 to 90% of the dose taken is excreted unchanged by glomerular filtration and tubular secretion within 24 hours. No more than 10% or less of the administered dose is excreted in the bile, followed by reabsorption in the intestine.

Impaired renal function, severe ascites or transudate, as well as concomitant use of drugs such as weak organic acids, which also undergo tubular secretion, can significantly increase the concentration of methotrexate in the blood serum. According to the distribution, methotrexate accumulates in the liver, kidneys and spleen as polyglutamates and can be retained in these organs for several weeks or months.

For children In children treated with methotrexate for the treatment of acute lymphocytic leukemia (6.3 to 30 mg / m2) or juvenile idiopathic arthritis (3.75 to 26.2 mg/m2), the final half-life was 0.7 to 5.8 hours and 0.9 to 2.3 hours, respectively.

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;
• osteosarcoma and soft tissue sarcoma;
• mycosis fungoides (advanced stage);
• severe psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile chronic arthritis, dermatomyositis, systemic lupus erythematosus, ankylosing spondylitis (after failure of standard therapy).

Contraindications

• hypersensitivity to methotrexate and/or any other component of the drug;
• severe renal insufficiency (creatinine clearance less than 30 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;
• concomitant vaccination with live vaccines;
• mouth ulcers, peptic ulcer of the gastrointestinal tract in the active phase;
• pregnancy;
• lactation breast;
• concomitant use of methotrexate in a dose of 15 mg/week or more with acetylsalicylic acid.

Use with caution in patients with impaired liver and kidney function, diabetes mellitus, obesity and previous therapy with hepatotoxic drugs, dehydration, ascites, suppression of bone marrow hematopoiesis, pleural or peritoneal effusion, parasitic and infectious diseases of a viral, fungal or bacterial nature – 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, peptic ulcer of the stomach and duodenum, ulcerative colitis, obstructive diseases of the gastrointestinal tract, preceding chemotherapy or radiation therapy asthenia, aciduria (urine pH less than 7), in children and elderly patients.

Side effects

According to the world health organization (who) adverse events classified according to the frequency of their development as follows: very often (≥1/10), often (from ≥1/100 to Infectious and parasitic diseases often: herpes zoster; infrequent: opportunistic infections, including pneumonia (including fatal); rare: sepsis (including, very rarely fatal); very rare: Nocardia, histoplasmosis, cryptococcosis, hepatitis and disseminated infections caused by herpes simplex virus, infections caused by cytomegalovirus (including pneumonia); frequency unknown: reactivation of hepatitis b virus, hepatitis C.

Benign, malignant, and unspecified neoplasms (including cysts and polyps) infrequently: lymphoma; very rare: tumor lysis syndrome.

Disorders of the blood and lymphatic system are very common: leukopenia, thrombocytopenia; common: anemia, pancytopenia, agranulocytosis; rare: megaloblastic anemia; very rare: aplastic anemia, lymphadenopathy and lymphoproliferative diseases, eosinophilia, neutropenia, severe progressive suppression of bone marrow function.

Immune system disorders infrequently: allergic reactions, anaphylactic shock, allergic vasculitis, fever, immunosuppression; very rare: hypogammaglobulinemia.

Metabolic and nutritional disorders infrequently: diabetes mellitus.

Mental disorders infrequently: depression; rarely: transient cognitive impairment, emotional lability.Nervous system disorders common: headache, fatigue, drowsiness, paresthesia; infrequently: convulsions, development of hemiparesis, vertigo (dizziness), confusion, encephalopathy/leukoencephalopathy (including fatal cases); rarely: paresis, speech disorders, including dysarthria and aphasia, myelopathy (with intrathecal use); very rarely: unpleasant sensations in the head, myasthenia gravis, pain in the extremities, taste distortion (metallic taste in the mouth), acute aseptic meningitis with symptoms meningitis (paralysis, vomiting), insomnia; frequency unknown: increased pressure in the spinal canal (after intrathecal use), development of spinal cord hernia (after intrathecal use for periventricular lymphoma).

Visual disturbances rare: visual disturbances (blurred vision, including severe visual disturbances of unclear etiology); very rare: periorbital edema, blepharitis, lacrimation, photophobia, conjunctivitis, transient blindness, vision loss.

Cardiac disorders rare: hypotension (low blood pressure); very rare: pericarditis, pericardial effusion (including cardiac tamponade).

Vascular disorders infrequently: vasculitis; rarely: thromboembolic complications (including arterial thrombosis, cerebral vascular thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism).

Respiratory, thoracic and mediastinal disorders common: interstitial pneumonitis/alveolitis (including fatal ones, regardless of the dose and duration of methotrexate therapy). Symptoms that indicate potentially serious lung damage in interstitial pneumonitis: dry, unproductive cough, shortness of breath that progresses to shortness of breath at rest, chest pain, fever. If these symptoms occur, treatment with methotrexate should be stopped immediately, and lower respiratory tract infections should also be excluded. infrequently: pulmonary fibrosis, pleural effusion; rarely: pharyngitis, apnea, nosebleeds; very rare: chronic obstructive pulmonary disease (COPD), asthma-like reactions (accompanied by cough, shortness of breath, abnormalities in functional pulmonary tests), pneumonia caused by Pneumocystis carinii, acute pulmonary edema; frequency unknown: respiratory paralysis.

Gastrointestinal disorders are very common: stomatitis, abdominal pain, loss of appetite, nausea and vomiting (especially in the first 24-48 hours after the start of treatment), dyspepsia; common: diarrhea; infrequently: ulceration of the mucous membrane of the gastrointestinal tract( GIT), bleeding from the gastrointestinal tract, pancreatitis; rarely: enteritis, gingivitis, melena, malabsorption syndrome; very rare: hematemesis (bloody vomiting), toxic megacolon; frequency unknown: non-infectious peritonitis.

Disorders of the liver and biliary tract are very common: increased activity of “hepatic” transaminases, alkaline phosphatase, increased concentration of bilirubin in blood plasma; often: development of steatosis, fibrosis or cirrhosis of the liver, hypoalbuminemia; rarely: acute hepatitis and other manifestations of hepatotoxicity; very rare: exacerbation of chronic hepatitis, acute liver dystrophy (including against the background of acute herpetic hepatitis), acute liver failure, liver necrosis.

Skin and subcutaneous tissue disorders common: exanthema, erythematous rash, pruritus of the skin; Infrequently: alopecia, erythema multiforme (including malignant exudative erythema [Stevens-Johnson syndrome]), toxic epidermal necrolysis (Lyell’s syndrome), herpetiform skin rashes, photosensitivity, urticaria, increased skin pigmentation, delayed wound healing; rarely: acne, skin ulceration, ecchymosis, skin nodules, painful erosions, psoriatic plaques, nail pigmentation, onycholysis, increased size of rheumatoid nodules; very rare: furunculosis, telangiectasia, acute paronychia, hydradenitis; frequency unknown: skin necrosis (at the injection site). Against the background of methotrexate therapy, complications from psoriatic nodules may develop due to exposure to ultraviolet radiation.

Musculoskeletal and connective tissue disorders infrequently: arthralgia, myalgia, osteoporosis; rarely: marching (fatigue) fracture.

From the side of the kidneys and urinary tract very often: reduced creatinine clearance; infrequently: severe nephropathy, renal failure, cystitis with ulceration of the bladder mucosa, dysuria (urinary disorders), oliguria, anuria; rarely: hyperuricemia, increased urea concentration in blood plasma, increased creatinine concentration in blood plasma; very rare: azotemia, hematuria, proteinuria.

Effects on pregnancy, postpartum and perinatal conditions Infrequently: fetal malformations; rarely: premature termination of pregnancy; very rare: fetal death.

Genital and breast disorders infrequently: vaginitis and ulceration of the vaginal mucosa; rarely: menstrual disorders; very rare: disorders of spermatogenesis or egg maturation, impotence, infertility, loss of libido, transient oligospermia, abnormal vaginal discharge, menstrual disorders, gynecomastia.

Adverse reactions that occur with intrathecal use of methotrexate: acute chemical arachnoiditis (clinical manifestations include headache, dorsalgia, numbness in the neck and fever), subacute myelopathy (paresis or paraplegia in the innervation area of one or more affected spinal cord roots), chronic leukoencephalopathy, whose manifestations include confusion, increased irritability, drowsiness, ataxia, dementia, convulsions and the development of a comatose state. In case of progression, these manifestations of toxicity can lead to the death of the patient.

The combined use of intrathecal methotrexate and brain radiation increases the risk of developing leukoencephalopathy. After intrathecal use of the drug, the patient’s condition should be carefully monitored for possible signs of neurotoxicity (meningism, paralysis, encephalopathy).

Interaction

The likelihood of hepatotoxic effects of methotrexate increases with regular use of ethanol and concomitant use of other hepatotoxic drugs (for example, azathioprine, leflunomide, sulfasalazine, retinoids). Combined therapy with methotrexate and leflunomide increases the incidence of pancytopenia and hepatotoxic effects.

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

Probenecid, weak organic acids (for example, loop diuretics) and pyrazoles (phenylbutazone) can slow the elimination of methotrexate, which can increase its concentration in blood plasma and increase hematological toxicity.

The risk of toxic effects of methotrexate increases when combined with nonsteroidal anti-inflammatory drugs or salicylates, especially in patients with impaired renal function. If necessary, simultaneous use should monitor the peripheral blood picture (counting of formed blood elements) and kidney function.

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. The development of pancytopenia when using methotrexate in combination with co-trimoxazole or pyrimethamine is described.

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 (colestyramine) increases the toxicity of methotrexate.

Increases the concentration of uric acid in the blood, so in the treatment of patients with concomitant hyperuricemia and gout, dose adjustment of anti-gouty agents (allopurinol, colchicine, sulfinpyrazone) may be required; the use of uricosuric anti-gouty drugs may increase the risk of developing nephropathy associated with increased uric acid formation during treatment with methotrexate (if necessary, concomitant use is preferable to use allopurinol).

When combined with antirheumatic drugs (for example, gold salts, penicillamines, hydroxychloroquines, azathioprine, cyclosporine) 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 antiepileptic drugs (the concentration of methotrexate in the blood decreases), fluorouracil (the half-life of fluorouracil increases).

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

Medications and other products containing folic or folinic acids (including multivitamins) may reduce the effectiveness of drug therapy (while reducing the toxic effect of methotrexate).

Due to the competitive binding to plasma proteins with simultaneous use of methotrexate, the toxicity of methotrexate may be increased against the background of the use of derivatives of amidopyrine, paraaminobenzoic acid, barbiturates, doxorubicin, oral contraceptives, phenylbutazone, phenytoin, probenecid, salicylates, sulfonamides, tetracyclines and tranquilizers.

Several patients with psoriasis or fungal mycosis treated with methotrexate in combination with PUVA therapy (methoxalene and ultraviolet radiation) were diagnosed with skin cancer.

Combination with radiation therapy may increase the risk of soft tissue necrosis.

Methotrexate may reduce the immunological response to vaccination. When used concomitantly with a live vaccine, severe antigenic reactions may develop. Asparaginase reduces the antitumor effect of methotrexate by inhibiting cell replication.

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

Amiodarone may contribute to skin ulceration.

Concomitant use of mercaptopurine and methotrexate increases the plasma concentration and bioavailability of the former, probably due to inhibition of its metabolism. When combined therapy may require adjustment of the dose of mercaptopurine.

Oral neomycin may reduce the absorption of oral methotrexate.

The use of colestyramine may interfere with hepatic-intestinal methotrexate recycling, increasing drug elimination.

Drugs that can cause folate deficiency (sulfonamides, trimethoprim / sulfamethoxazole) in the body or reduce tubular secretion (ciprofloxacin, paraminobenzoic acid, nonsteroidal anti-inflammatory drugs, probenecid, salicylates, sulfonamides, weak organic acids) can increase the myelosuppressive effect of methotrexate.

The combined use of methotrexate and glucocorticosteroids can provoke the development of disseminated herpetic infection, the development of postherpetic neuralgia.

Combined therapy with cytarabine increases the risk of adverse events from the nervous system, including headache, paralysis, coma, and stroke-like episodes.

Prescribing procarbazine with high doses of methotrexate increases the risk of renal impairment.

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.

The drug Methotrexate-Ebeve in the dosage form of a solution for injection can be administered intramuscularly, subcutaneously, intravenously, intraarterially or intrathecally. Doses of the drug over 100 mg / m2 are administered only intravenously by drip! The solution is pre-diluted with 5% dextrose solution. When using high doses of the drug (above 100 mg/m2), subsequent use of calcium folinate is mandatory.

Methotrexate for the treatment of rheumatic diseases or skin diseases should only be used once a week! Improper use of methotrexate can lead to the development of serious adverse effects, including death.

The following dosage regimens are used:

Trophoblastic tumors: 15-30 mg intramuscularly, daily for 5 days with an interval of one or more weeks (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. Solid tumors: in combination with other antitumor drugs 30-40 mg / m2 intravenously jet 1 time a week.

Leukemias and lymphomas: 200-500 mg / m2 by intravenous infusion once every 2-4 weeks.

Neuroleukemia: 12 mg / m2 intrathecally for 15-30 seconds 1 or 2 times a week.

When treating children, the dose is selected depending on the age of the child: children under the age of 1 year are prescribed 6 mg, children aged 1 year-8 mg, children aged 2 years-10 mg, children aged 3 years and older-12 mg. Before use, the cerebrospinal fluid should be removed in a volume approximately equal to the volume of the drug to be administered. For intrathecal use, methotrexate is diluted to a concentration of 1 mg / ml in 0.9% isotonic sodium chloride solution. Enter intrathecally with caution.

Exceeding the recommended dose for intrathecal use significantly increases the risk of severe manifestations of toxicity. Carefully: do not enter calcium folinate intrathecally!

Fungal mycosis: intramuscularly 50 mg once a week or 25 mg twice a week per day for several weeks or months. Dose reduction or discontinuation of the drug is determined by the patient’s response and hematological parameters.

Dermatomyositis: adults 7.5-15 mg per week; children 2.5-7.5 mg per week. In the future, the dose is reduced until the lowest effective dose is reached and used for a long time, for months, in combination with a maintenance dose of glucocorticosteroids.

Systemic lupus erythematosus: adults 15 mg per week; children 7.5-10 mg / m2. The course of treatment is 6-8 weeks, then a maintenance dose is applied for many months.

Psoriasis and psoriatic arthritis: a week before starting treatment, it is recommended to enter a parenteral test dose of 5-10 mg of methotrexate to detect an intolerance reaction. The recommended starting dose is 7.5 mg of methotrexate once a week by intramuscular, intravenous or subcutaneous injection. The dose should be gradually increased, and the maximum dose should not exceed 30 mg of methotrexate per week. The response to treatment usually occurs 2-6 weeks after the start of the drug. When the optimal clinical effect is achieved, start reducing the dose until the lowest effective dose is reached.

Rheumatoid arthritis: The initial dose is usually 7.5 mg once a week, which is administered simultaneously intravenously, intramuscularly or subcutaneously. To achieve an optimal effect, the weekly dose can be gradually increased (2.5 mg per week), while it should not exceed 20 mg. When the optimal clinical effect is achieved (usually 4-8 weeks after the start of therapy), dose reduction should be initiated until the lowest effective maintenance dose is reached. The optimal duration of therapy is not established, in each specific case, the duration of therapy is determined by the doctor.

Juvenile chronic arthritis: in children under 16 years of age at a dose of 10-20 mg / m2 1 time per week. Usually, the effective dose is 10-15 mg / m2 per week. Initially, the drug is used in a half dose. If well tolerated, the full dose is applied after a week. In children and adolescents, if parenteral use of the drug is necessary, due to the fact that the available data on the safety of intravenous use are limited, the subcutaneous or intramuscular route of use should be used. Due to limited data on the efficacy and safety of methotrexate in children under 3 years of age, it is not recommended to use the drug in this group of patients. When using methotrexate in children as an immunosuppressive therapy (for psoriasis, rheumatoid arthritis, juvenile chronic arthritis, dermatomyositis and systemic lupus erythematosus), the benefit/risk ratio of use should be carefully considered.

Method of using the syringe (pre-filled) Subcutaneously. The injection needle included in the package is intended only for subcutaneous use of the drug Methotrexate-Ebeve. The pre-filled syringe is equipped with a special automatic needle protection system.

Choose a place to administer the drug. When applying subcutaneously, choose a place where you can capture a 2-3 cm fold of skin, usually in the abdomen or thighs, as shown in the picture. If someone can help you, you can get an injection in your forearm. If the intended injection site is the abdominal area, then it is necessary to retreat at least 3 fingers ‘ width from the navel. It is recommended to alternate the sides (left, right) of the injections, as well as choose different places on the hips or abdomen. Do not subcutaneously administer the drug near scars, bruises, reddened or swollen areas, or close to the groin. To minimize bruising, it is recommended to avoid injections into the skin with a visible network of small blood vessels on the surface. Remove the inner package containing the pre-filled syringe and needle. Open the inner package by pulling on the notched corner. Remove the syringe.

Remove the grey rubber cap from the syringe without touching the opened inner part of the syringe. Place the syringe back in its inner packaging without fear of the yellow solution spreading.

Make sure that the integrity of the protective label is not compromised. Remove the cap, attach the needle without removing the protective cover, and attach the needle to the syringe. Before using the syringe, the intended injection site should be pre-disinfected.

By pulling the cap (strictly at right angles), remove it. Do not touch the protective cover of the needle. Use two fingers to form a skin fold, then quickly insert the needle completely into the skin (at about a 90-degree angle), until the protective mechanism is fully retracted inside. Slowly insert the contents of the syringe under the skin. Carefully pull out the needle, and then it will automatically retract into the syringe.

If you notice blood at the injection site after removing the needle, apply a cotton swab to the injection site until the blood or medication is absorbed. Small bleeding or drug leakage will soon stop. If necessary, apply a bandage. Do not rub the injection site.

If the skin turns yellow at the injection site, do not worry, within one or two days the drug is absorbed, and the skin color returns to normal. This may occur due to improper subcutaneous injection or insufficient needle length.

Patients with impaired renal function should adjust the dose depending on creatinine clearance (with a creatinine clearance of 30-50 ml/min, the dose is reduced by 50%, with a creatinine clearance of less than 30 ml/min, the use of methotrexate is contraindicated).

In patients with impaired liver function, the drug Methotrexate-Ebeve is used with caution. Methotrexate should not be used if the plasma bilirubin concentration exceeds 5 mg / dl (85.5 mmol / L).

Elderly patients (over 65 years of age) it may be necessary to reduce the dose of methotrexate, because with age, the function of the liver and kidneys deteriorates, as well as a decrease in the content of folate in the body.

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 use of methotrexate, calcium folinate is administered (intravenously or intramuscularly) 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, immediately after an overdose is detected, repeated lumbar punctures should be performed 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

The drug Methotrexate-Ebeve is a cytotoxic drug, so caution should be exercised when handling it. The drug should be prescribed by a doctor who has experience with the use of methotrexate and is familiar with its properties and features of action. Before prescribing methotrexate, make sure that it is possible to determine the plasma concentration of the drug.

Taking into account the possibility of developing severe toxic reactions, including those with a fatal outcome, the doctor must inform the patient in detail about the possible risk and the necessary precautions. Methotrexate, especially in medium and high doses, should only be used in patients with potentially life-threatening malignancies. Cases of fatal manifestations of toxicity during drug therapy are described. Withdrawal of methotrexate does not always lead to a complete resolution of adverse events.

The safety and potential benefits of using high doses of methotrexate outside of approved indications have not been established.

During treatment with Methotrexate-Ebeve, patients should be closely monitored in order to detect signs of possible toxic effects and adverse effects in a timely manner. When using the drug for non-oncological indications, the patient should pay special attention to the fact that the drug is not taken daily, but once a week.

Before starting treatment with Methotrexate-Ebeve 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 “hepatic” transaminases, the concentration of bilirubin, plasma albumin, uric acid concentration in blood plasma, kidney function (urea nitrogen, creatinine clearance and/or plasma creatinine), as well as chest X-ray examination. If there are clinical indications, studies are prescribed to exclude tuberculosis and viral hepatitis.

Prescribing high doses of methotrexate is possible only if the concentration of creatinine in the blood plasma is normal. If there is an increase in creatinine concentration, the dose of the drug should be reduced, if the creatinine concentration increases by more than 2 mg/dl, the drug should not be used.

Leukopenia and thrombocytopenia usually develop within 4 to 14 days of methotrexate use. Sometimes there is a development of the second leukopenic phase, which develops in the period from 12 to 21 days.

In elderly patients, the development of megaloblastic anemia is described against the background of long-term methotrexate therapy.

During treatment with Methotrexate-Ebeve (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 pharynx 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 hematopoiesis suppression. In case of a significant decrease in the number of white blood cells or platelets, treatment with Methotrexate-Ebeve 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 or previously conducted therapy with hematotoxic drugs( for example, leflunomide), radiation therapy, it is necessary to carefully monitor the number of white blood cells and platelets in the blood. If necessary, it is advisable to perform a bone marrow biopsy.

3. Functional liver tests. Against the background of prolonged use of methotrexate, acute hepatitis and chronic hepatotoxicity phenomena (fibrosis and cirrhosis of the liver) may develop. Special attention should be paid to identifying signs of liver damage. Treatment with Methotrexate-Ebeve should not be initiated or suspended if abnormalities in liver function tests or liver biopsies are detected. Against the background of drug therapy, a 2-3 – fold transient increase in the activity of “hepatic” transaminases is possible, as a rule, asymptomatic. As a rule, this is not a reason to change the treatment regimen, usually the indicators normalize within two weeks, after which treatment can be resumed by the doctor’s decision. However, if a persistent increase in the activity of “hepatic” transaminases is detected, it is necessary to reduce the dose or cancel treatment with Methotrexate-Ebeve. Since the drug Methotrexate-Ebeve has a toxic effect on the liver, other hepatotoxic drugs should not be used during treatment with the drug without obvious need. You should also avoid or greatly reduce your ethanol 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).

In the case of long-term treatment, especially severe forms of psoriasis, including psoriatic arthritis, due to the possible hepatotoxic effects of methotrexate, given that fibrotic and/or cirrhotic changes can develop against the background of normal liver tests, a liver biopsy is necessary in the following cases:: 1. In patients without risk factors, liver biopsy is not indicated until the total cumulative dose of 1.0-1.5 g is reached. 2. In the presence of such risk factors as alcohol abuse, persistent increase in the activity of “liver transaminases”, chronic viral hepatitis, family history of liver disease, as well as for patients with less significant risk factors, such as diabetes mellitus, obesity, history of exposure to hepatotoxic drugs/chemicals, liver biopsy should be performed 2-4 months after the start of treatment. After reaching the total cumulative dose of 1.0-1.5 g, a second liver biopsy is recommended.

Liver biopsy is not indicated in elderly patients; in patients with active acute diseases (for example, the respiratory system); in patients with contraindications to liver biopsy (for example, unstable hemodynamics, changes in coagulogram parameters); in patients with an unfavorable prognosis for life expectancy. If a liver biopsy reveals only minor changes (grade I, II, or IIIa on the Roenigk scale), methotrexate therapy may be continued if the patient’s condition is carefully monitored.

The drug should be discontinued if moderate or pronounced changes are detected (grade IIIb and IV on the Roenigk scale), or if a liver biopsy of a patient who has a persistent increase in the activity of “hepatic” transaminases is refused. If moderate fibrosis or cirrhosis of the liver is detected, methotrexate should be discontinued; in the case of minimal fibrosis, a second liver biopsy is recommended after 6 months. Changes such as fatty liver disease or mild portal vein inflammation are quite common in liver biopsies in patients receiving methotrexate. Although the detection of such changes is usually not a reason to make a decision on the impracticability or discontinuation of methotrexate therapy, caution should be exercised when treating such patients.

4. Functional renal tests and urinalysis. Since the drug Methotrexate-Ebeve is mainly excreted by the kidneys, patients with impaired renal function may experience an increase in the concentration of methotrexate in blood plasma, which may result in 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, which have an adverse effect on the kidneys (in particular, nonsteroidal anti-inflammatory drugs (NSAIDs)). or on the hematopoietic system. Cases of severe side effects in patients taking NSAIDs on the background of methotrexate therapy (especially in high doses) are described, including cases of severe bone marrow hematopoiesis, aplastic anemia, gastrointestinal tract damage and death.

5. Examination of the respiratory system. It is necessary to carefully monitor the symptoms of possible development of impaired lung function and, if necessary, prescribe appropriate studies to monitor lung function. The appearance of appropriate symptoms (especially dry, unproductive cough) or the development of non-specific pneumonitis during treatment with Methotrexate-Ebeve may indicate a potential risk of lung damage. In such cases, the drug Methotrexate-Ebeve should be discontinued and a thorough examination of the patient should be carried out.

Although the clinical picture may vary, in typical cases where respiratory symptoms are caused by the use of the drug Methotrexate-Ebeve, there is an increase in body temperature, cough with shortness of breath, hypoxemia, and pulmonary infiltrates on X-rays. Lung damage caused by the use of methotrexate can occur regardless of the prescription of the drug, the doses used (cases of lung damage with the use of methotrexate in low doses, including 7.5 mg/week, have been described). Differential diagnosis should exclude the infectious nature of the disease. Against the background of methotrexate therapy, potentially dangerous (up to fatal) opportunistic infections, including pneumocystis pneumonia, may develop. If symptoms from the respiratory system develop in a patient receiving methotrexate, pneumonia caused by Pneumocystis carinii should be excluded.

If the dose of the drug is increased, the frequency of examinations should be increased. Due to the immunosuppressive effect of methotrexate, it is necessary to refuse immunization (if it is not approved by the doctor) during treatment with the drug and in the interval from 3 to 12 months after the end of taking the drug; family members of the patient living with him should refuse immunization with the 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).

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

Symptoms such as fever, sore throat, flu-like symptoms, ulceration of the oral mucosa, severe general weakness, hemoptysis, and hemorrhagic rash can be harbingers of life-threatening complications.

If a patient has conditions that lead to the accumulation of a significant amount of fluid in the body cavities (hydrothorax, ascites), taking into account the prolongation of the drug’s half-life in such patients, therapy with Methotrexate-Ebeve should be carried out with caution, before starting therapy with the drug, the fluid should be evacuated by drainage, or the drug should be discontinued.

Special care should be taken in the treatment of patients with insulin-dependent diabetes mellitus, as cases of cirrhosis of the liver have been described without a previous increase in the activity of “hepatic” transaminases.

Like other cytotoxic drugs, methotrexate can cause the development of tumor lysis syndrome in patients with rapidly growing malignancies. To prevent the development of this complication, appropriate maintenance therapy measures should be taken. The use of methotrexate in combination with radiation therapy may increase the risk of developing soft tissue necrosis or osteonecrosis.

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

Dehydration can also potentiate the toxic effect of the drug Methotrexate-Ebeve, so if conditions develop that can lead to the development of dehydration (severe vomiting, diarrhea), methotrexate therapy should be interrupted until these conditions resolve.

Cases of leukoencephalopathy have been described in patients treated with high doses of methotrexate, including orally, in combination with calcium folinate (without previous radiation therapy to the head).

When using methotrexate for acute lymphocytic leukemia, there may be pain in the left epigastric region, due to the development of an inflammatory process in the spleen capsule against the background of the collapse of tumor cells.

It is recommended to discontinue treatment with Methotrexate-Ebeve one week before surgery and resume one or two weeks after surgery. Special care should be taken when using methotrexate in patients with active infections. The use of methotrexate in patients with immunodeficiency syndrome is contraindicated.

With an increase in body temperature (more than 38 °C), the elimination of methotrexate slows down significantly. The drug Methotrexate-Ebeve may increase the risk of developing neoplasms (mainly lymphomas). Malignant lymphomas can also develop in patients receiving low-dose Methotrexate-Ebeve. In such cases, the drug should be discontinued. If spontaneous regression of lymphoma is not observed, therapy with other cytotoxic drugs is prescribed.

Before starting treatment with Methotrexate-Ebeve, pregnancy should be excluded. The drug Methotrexate-Ebeve has an embryotoxic effect, contributes to the termination of pregnancy and the formation of fetal abnormalities. Methotrexate-Ebeve therapy is accompanied by inhibition of spermatogenesis and ovogenesis, which can lead to a decrease in fertility. After discontinuation of drug therapy, these effects spontaneously regress. During treatment with Methotrexate-Ebeve and for six 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-Ebeve on fetal reproduction and development. Men of reproductive age should be warned about the risks involved, and paternity is not recommended during treatment and for 6 months after discontinuation of the drug.

Since irreversible infertility may occur during treatment, men should consider cryo-preserving sperm in a jar before starting treatment.

Against the background of the use of methotrexate, the likelihood of developing dermatitis and burns of the skin under the influence of solar and ultraviolet radiation (UV) increases. Do not expose unprotected skin to too much sun exposure or abuse the UV lamp (photosensitization reaction is possible). In patients with psoriasis, the disease may worsen against the background of UV radiation during treatment with methotrexate.

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 alkalization of urine until pH 6.5-7.0 is reached by oral (5 tablets of 625 mg every 3 hours) or intravenous administration of sodium bicarbonate or acetazolamide (500 mg orally four times a day).

Against the background of methotrexate therapy, an exacerbation of chronic viral hepatitis (reactivation of the hepatitis B or C virus) is possible. Cases of hepatitis B virus reactivation after methotrexate withdrawal are also described. If it is necessary to prescribe the drug to a patient with a history of viral hepatitis, a thorough clinical and laboratory examination should be carried out. The presence of pleural effusion, ascites, gastrointestinal patency disorders, concomitant cisplatin therapy, dehydration, liver function disorders or a decrease in urine pH slows down the excretion of methotrexate, which may increase the concentration of the drug in blood plasma. It is extremely important to detect the accumulation of the drug in the body during the first 48 hours, as it is possible to develop irreversible consequences of drug toxicity.

Special care should be taken when using the drug in elderly patients, their condition should be monitored more often than in younger patients, for early signs of toxicity of therapy. Pediatric treatment protocols should be followed in the treatment of paediatric patients.

Pediatric patients with acute lymphoblastic leukemia may develop severe neurotoxicity with 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 studies in such patients is described.

When using high doses of methotrexate, the development of transient acute neurological symptoms is described, which can be manifested, including behavioral changes, local sensory disorders (including short-term blindness) and the motor system, and impaired reflexes. The exact causes of these adverse reactions are unknown.

When using methotrexate at a dose higher than 100 mg / m2, it is mandatory to use” rescue therapy ” with calcium folinate 42-48 hours after use of methotrexate.

The dose of calcium folinate is determined depending on the size of the applied dose of methotrexate, the duration of its infusion. The concentration of methotrexate should be determined after 24,48 and 72 hours and, if necessary, for a long time, to determine the optimal duration of calcium folinate therapy. The use of methotrexate together with an infusion of red blood cell mass (within 24 hours) requires careful monitoring of the patient’s condition, since it is possible to increase the plasma concentration of the drug.

Influence on the ability to drive vehicles and 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. If the described adverse events occur, you should refrain from performing these types of activities.

Special precautions for disposal of unused medicinal products

Drug residues, all tools and materials that were used to prepare solutions for the 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.

Active ingredient

Methotrexate

Conditions of release from pharmacies

By prescription

Dosage form

solution for injection

Purpose

For adults as prescribed by a doctor, for children as prescribed by a doctor

Indications

Cancer, Breast Cancer, Rheumatoid Arthritis, Psoriasis