Methotrexate-Ebwee - instructions for use, doses, side effects, contraindications

Composition:Per 1 ml: active substance: methotrexate - 10,000 mg; Excipients: sodium hydroxide - 1,783 mg, sodium chloride - 6,900 mg, water for injection - 988,317 mg.

Description:The clear solution is yellow.

Pharmacotherapeutic group:Antitumor agent, antimetabolite.

ATX: & nbsp

L.01.B.A Analogues of folic acid

L.01.B.A.01 Methotrexate

Pharmacodynamics:Antitumor, cytostatic agent of the group of antimetabolites - analogues of folic acid, which has immunosuppressive and anti-inflammatory action. Inhibits dihydrofolate reductase, which participates in the restoration of dihydrofolic acid to tetrahydrofolic acid (transporter carbon fragments required for synthesis of purine nucleotides and their derivatives). It inhibits synthesis, DNA repair and cellular mitosis (during the synthesis phase). Especially sensitive to the action of methotrexate tissue with high cell proliferation: tumor tissue, bone marrow, epithelial cells of the mucous membranes, embryonic cells. When the cellular proliferation of malignant tissues is greater than in most normal tissues, methotrexate can lead to a disruption in the growth of malignant formations without irreversible damage to normal tissue.
The mechanism of action for rheumatoid arthritis is associated with the immunomodulatory and anti-inflammatory action of the drug and is due to the induction of apoptosis of rapidly proliferating cells (activated T-lymphocytes, fibroblasts, synoviocytes),inhibition of the synthesis of anti-inflammatory cytokines (interleukin (IL) -1, tumor necrosis factor alpha), increased synthesis of anti-inflammatory cytokines IL-4, IL-10 and inhibition of metalloproteinase activity.
In patients with rheumatoid arthritis, methotrexate reduces symptoms of inflammation (pain, swelling, stiffness), but there are a limited number of studies with long-term use of methotrexate (in relation to the ability to maintain remission in rheumatoid arthritis).
In psoriasis, the growth rate of keratinocytes in psoriatic plaques increases as compared to normal proliferation of skin cells. This difference in cell proliferation is the basis for the use of methotrexate for the treatment of psoriasis.

Pharmacokinetics:With intramuscular injection, the maximum concentration of methotrexate in the blood plasma is reached within 30-60 minutes. Leukemia patients are characterized by a wide interindividual variability ranging from 1 to 3 hours. The relative bioavailability in patients with rheumatoid arthritis is comparable after intramuscular or subcutaneous injection with equal doses of the drug.Systemic absorption of methotrexate after administration under the skin of the abdomen and thigh is the same.
After intravenous administration, the primary distribution is 0.18 l / kg (18% of body weight). The distribution of the saturation dose is about 0.4-0.8 l / kg (40% - 80% of the body weight).
About 50% of methotrexate binds to blood plasma proteins, mainly with albumins. Perhaps competitive displacement with simultaneous use with sulfonamides, salicylates, tetracyclines, chloramphenicols, phenytoin.
Methotrexate does not penetrate the blood-brain barrier when applied at therapeutic doses. A high concentration of methotrexate in the central nervous system can be achieved with intrathecal administration.
Methotrexate undergoes hepatic and intracellular metabolism with the formation of a pharmacologically active polyglutamine form, also inhibiting dihydrofolate reductase and thymidine synthesis. A small amount of methotrexate polyglutamate may remain in the tissues for a long period of time. The preservation and prolongation of the action of active metabolites of the drug differ depending on the type of cells, tissues and tumors.
Mean values of the half-life for methotrexate in a dose of less than 30 mg / m² are 6-7 hours. In patients receiving high doses of methotrexate, the half-life is 8 to 17 hours. In chronic renal failure, both phases of excretion of methotrexate can be significantly lengthened.
From 80 to 90% of the dose taken is unchanged by glomerular filtration and tubular secretion within 24 hours. No more than 10% or less of the administered dose is withdrawn from the bile, followed by reabsorption in the intestine.
Impaired renal function, severe ascites or transudate, and simultaneous use of drugs such as weak organic acids, which also undergo tubular secretion, can significantly increase the serum concentration of methotrexate. In accordance with the distribution methotrexate cumulates in the liver, kidney and spleen in the form of polyglutamates and can stay in these organs for several weeks or months.
Children methotrexate usually completely absorbed after parenteral administration. After intramuscular injection, the maximum concentration in the blood plasma is reached after 30-60 minutes.
In children who received methotrexate for the treatment of acute lymphocytic leukemia (from 6.3 to 30 mg / m² ) or juvenile idiopathic arthritis (from 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 tumors;
- Acute leukemia (especially lymphoblastic and myeloblast variants);
- Neuroleukemia;
- non-Hodgkin's lymphomas, including lymphosarcoma;
- Breast cancer, squamous cell carcinoma of the head and neck, lung cancer, skin cancer, cervical cancer, vulvar cancer, esophageal cancer, kidney cancer, bladder cancer, testicular cancer, ovarian cancer, penile cancer, retinoblastoma, medulloblastoma;
- osteogenic sarcoma and soft tissue sarcoma;
- mushroom mycosis (far advanced stages);
- severe forms of psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile chronic arthritis, dermatomyositis, systemic lupus erythematosus, ankylosing spondylitis (with ineffective standard therapy).

Contraindications:- hypersensitivity to methotrexate and / or any other component of the drug;
- marked renal failure (creatinine clearance less than 30 ml / min);
- severe hepatic impairment;
- Alcohol abuse;
- violations from the hemopoietic system in the 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;
- ulcers of the oral cavity, peptic ulcer of the gastrointestinal tract in the active phase;
- Pregnancy;
- the period of breastfeeding;
- simultaneous use of methotrexate in a dose of 15 mg / week or more with acetylsalicylic acid.

Carefully:To use caution in the presence of patients of the liver and kidneys, diabetes, obesity and previous therapy with hepatotoxic drugs, dehydration, ascites, suppression of bone marrow hematopoiesis, pleural or peritoneal effusion, parasitic and infectious diseases of viral, fungal or bacterial origin - the risk of severe generalized disease (currently or recently transferred, including the recent contact with the patient) - herpes simplex, herpes zoster (sup nomic phase), chicken pox, measles; amebiasis; strongyloidiasis (established or suspected); gout (including history) or urate nefrourolitiaza (includingin anamnesis), infections and inflammation of the oral mucosa, vomiting, diarrhea, peptic ulcer and duodenal ulcer, ulcerative colitis, obstructive diseases of the gastrointestinal tract, previous chemotherapy or radiation therapy, asthenia, aciduria (urine pH less than 7 ), in children and elderly patients.

Pregnancy and lactation:The use of methotrexate during pregnancy can cause serious malformations of the fetus (an increase in the frequency of malformations of the bones of the skull, cardiovascular system and limbs by a factor of 14), so the drug Methotrexate-Ebwee is contraindicated during pregnancy.
If pregnancy occurred during methotrexate treatment, you should consult with experts regarding the risk of adverse effects of methotrexate on the fetus. Patients of reproductive age (both women and men) should use effective contraception during and for at least 6 months after the end of treatment with Methotrexate-Ebene.
Methotrexate penetrates into breast milk in concentrations dangerous to the baby. Therefore, during treatment with methotrexate, breastfeeding should be discontinued.

Dosing and Administration:Methotrexate is included in many chemotherapy regimens, therefore, when choosing the route of administration, regimen and dosage in each individual case, reference should be made to the literature.
Megotrexate-Ebweve preparation in a dosage form for injection can be administered intramuscularly, subcutaneously, intravenously, intraarterially or intrathecally.
Doses of the drug over 100 mg / m² inject only intravenously drip! The solution is pre-diluted with 5% dextrose solution. When applying high doses of the drug (above 100 mg / m-), the subsequent administration of calcium folinate is mandatory.
Methotrexate for the treatment of rheumatic diseases or skin diseases should only be applied once a week! Incorrect use of methotrexate can lead to the development of serious adverse effects, including fatal. The following dosing regimes are used:
Trophoblastic tumors: 15-30 mg intramuscularly, daily for 5 days with an interval of one or more weeks (depending on signs of toxicity). Or 50 mg once every 5 days with an interval of at least 1 month.Treatment rates are usually repeated 3 to 5 times to a total dose of 300-400 mg.
Solid tumors: in combination with other antitumour agents
with preparations of 30-40 mg / m² intravenously sprayed once a week. Leukemia and lymphoma: 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.
In the treatment of 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 2 years 10 mg, children 3 years and older 12 mg. Before administration, it is necessary to remove cerebrospinal fluid in a volume approximately equal to the volume of the drug to be injected. For intrathecal administration methotrexate diluted to a concentration of 1 mg / ml in a 0.9% isotonic sodium chloride solution. Intrathecal injection should be done with caution. Exceeding the recommended dose with intrathecal administration significantly increases the risk of significant manifestations of toxicity.
Caution: do not enter calcium folinate intrathecally!
Mushroom mycosis: intramuscularly 50 mg once a week or 25 mg twice a week per day for several weeks or months.Dose reduction or withdrawal of drug administration is determined by the patient's response and hematological parameters.
Dermatomyositis: adults of 7.5-15 mg per week; children 2.5-7.5 mg per week. In the future, the dose is reduced to the lowest effective dose and applied for a long time, months, in conjunction 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 the start of treatment, it is recommended that a parenteral test dose of 5-10 mg of methotrexate be used to detect an intolerance reaction.
The recommended initial dose of 7.5 mg of methotrexate once a week is intramuscular, intravenous or subcutaneous. The dose should be gradually increased, while 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, the dose is reduced until the lowest effective dose is reached.
Rheumatoid arthritis: the initial dose is usually 7.5 mg once a week, which is injected intravenously, intramuscularly or subcutaneously. To achieve the 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), the dose should be reduced before reaching the lowest effective maintenance dose.
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 in a dose of 10-20 mg / m² 1 time a week. Typically, the effective dose is 10-15 mg / m² in Week. Initially, the drug is used in a half dose. Subject to good tolerability, a full dose is used every other week. In children and adolescents, if necessary, parenteral administration of the drug, due to the fact that the available safety data for intravenous administration are limited, a subcutaneous or intramuscular route of administration 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 should be carefully considered.
The method of using a syringe (pre-filled) Subcutaneously.
The injection needle included in the package is intended only for subcutaneous administration of the drug Methotrexate-Ebwe.
The pre-filled syringe is equipped with a special automatic needle protection system.

Choose a place to administer the drug. With subcutaneous application, select a place where you can grab the skin fold 2-3 cm, usually in the abdominal or hip area, as shown. If someone helps you, then it is possible to inject in the forearm. If the intended injection site is the abdominal region, then it is necessary to retreat, at least a distance of 3 fingers from the navel. It is recommended to alternate sides (left, right) of injections, and also to choose different places on the hips or abdomen.
Do not subcutaneously inject the drug near the scars, bruises, reddened or swollen areas, or close to the groin.To minimize bruising, it is advisable to avoid injections into the skin with a mesh visible on the surface of small blood vessels. Remove the inner package containing the pre-filled syringe and needle. Open the inner packing by pulling the notched corner. Remove the syringe.
Remove the gray rubber cap from the syringe without touching the opened inner part of the syringe. Place the syringe back into the inner package, without fearing that the yellow solution can spread. Ensure that the integrity of the protective label is not compromised. Remove the cap, attach the needle, without removing the protective cover from it, fix the needle on the syringe. Before using the syringe, the intended injection site should be disinfected.
Pulling the cap (strictly at a right angle), remove it. Do not touch the protective shell of the needle.
With two fingers, form a skin fold, with a quick movement, insert the needle completely into the skin (approximately at an angle of 90 degrees), until the protective mechanism is fully retracted. Slowly insert the contents of the syringe under the skin. Carefully pull out the needle, after which it will automatically retract into the syringe.
If you notice blood at the injection site after removal of the needle, attach a cotton swab on the injection site to absorb blood or medication. A slight bleeding or leakage of the drug will soon stop. If necessary, apply a bandage. Do not rub the injection site.
If the injection site skin becomes yellow, do not worry, for one or two days, the drug is absorbed and the skin color back to normal. This may be due to improper subcutaneous injection or insufficient needle length. Patients with impaired renal function necessary dose adjustments depending on the creatinine clearance (with creatinine clearance of 30-50 ml / minute dose reduced by 50%, with creatinine clearance less than 30 mL / min methotrexate contraindicated).
In patients with impaired liver function, drug Methotrexate Ebewe used with caution. Methotrexate It should not be used with a plasma bilirubin concentration of more than 5 mg / dL (85.5 μmol / L). Elderly patients (over 65 years) may require dose reduction of methotrexate as age deteriorating function of the liver and kidneys, as well as reduction of folates in the body.

Side effects:According to the World Health Organization (WHO), adverse events are classified according to their frequency of development as follows: very often (≥ 1/10), often (from ≥ 1/100 to <1/10), infrequently (from ≥ 1/1000 to <1/100), rarely (from ≥ 1/10000 to <1/1000), very rarely (<1/10000); frequency is unknown - according to available data, it was not possible to establish the frequency of occurrence.
Infectious and parasitic diseases
often: herpes zoster; infrequently: opportunistic infections, including pneumonia (including fatal ones); rarely: sepsis (including, very rarely - fatal); very rarely: nocardiosis, histoplasmosis, cryptococcosis, hepatitis and disseminated infections caused by the herpes simplex virus, infections caused by cytomegalovirus (including pneumonia); frequency unknown: reactivation of the hepatitis B virus, hepatitis C.
Benign, malignant and unspecified neoplasms (including cysts and polyps)
infrequently: lymphoma; very rarely: tumor lysis syndrome.
Disorders from the blood and lymphatic system very often: leukopenia, thrombocytopenia; often: anemia, pancytopenia, agranulocytosis; rarely: megaloblastic anemia; very rarely: aplastic anemia,lymphadenopathy and lymphoproliferative diseases, eosinophilia, neutropenia, severe progressive depression of bone marrow function.
Immune system disorders
infrequently: allergic reactions, anaphylactic shock, allergic vasculitis, fever, immunosuppression; very rarely: hypogammaglobulemia.
Disorders from the metabolism and nutrition
infrequently: diabetes mellitus.
Disorders of the psyche
infrequently: depression; rarely: transient cognitive impairment, emotional lability.
Disturbances from the nervous system
often: headache, fatigue, drowsiness, paresthesia; infrequently: convulsions, development of hemiparesis, vertigo (dizziness), confusion, encephalopathy / leukoencephalonia (including lethal cases);
rarely: paresis, speech disorders, including dysarthria and aphasia, myelopathy (with intrathecal injection); very rarely: unpleasant sensations in the head, myasthenia gravis, pain in the extremities, taste distortion (metallic taste in the mouth), acute aseptic meningitis with the phenomena of meningism (paralysis, vomiting),insomnia; The frequency is unknown: increased pressure in the spinal canal (after intrathecal administration), development of the hernia of the spinal cord (after intrathecal administration for periventricular lymphoma).
Disturbances on the part of the organ of sight
rarely: visual impairment (blurred vision, including severe visual impairment of unclear etiology);
very rarely: periorbital edema, blepharitis, lacrimation, photophobia, conjunctivitis, transient blindness, loss of vision.
Heart Disease
rarely: arterial hypotension (lowering blood pressure); very rarely: pericarditis, effusion into the pericardial cavity (including cardiac tamponade).
Vascular disorders
infrequently: vasculitis; rarely: thromboembolic complications (including arterial thrombosis, cerebral thrombosis, thrombophlebitis, deep vein thrombosis, retinal vein thrombosis, pulmonary embolism).
Disturbances from the respiratory system, chest and mediastinal organs
often: interstitial pneumonitis / alveolitis (including
fatal, regardless of the dose and duration of methotrexate therapy).Symptoms that indicate a potentially serious lung injury with interstitial pneumonitis: dry, unproductive cough, shortness of breath, progressing to restlessness at rest, chest pain, fever. If these symptoms occur, treatment with methotrexate should be stopped immediately, and lower respiratory tract infections should also be avoided. infrequently: pulmonary fibrosis, effusion into the pleural cavity; rarely: pharyngitis, apnea, epistaxis; very rarely: chronic obstructive pulmonary disease (COPD), reactions like bronchial asthma (accompanied by coughing, shortness of breath, abnormalities in functional pulmonary tests), pneumonia caused by Pneumocystis carinii, acute pulmonary edema; frequency unknown: paralysis of respiration.
Disorders from the gastrointestinal tract
very often: stomatitis, pain in the abdomen, loss of appetite, nausea and vomiting (especially in the first 24-48 hours after the start of treatment), indigestion; often: 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 rarely: hematemesis (bloody vomiting), toxic megacolon; frequency unknown: non-infectious peritonitis.
Disturbances from the liver and bile ducts
very often: an increase in the activity of "liver" transaminases, alkaline phosphatase, an increase in the concentration of bilirubin in the blood plasma; often: the development of steatosis, fibrosis or cirrhosis of the liver, giooalbuminemia; rarely: acute hepatitis and other manifestations of hepatotoxicity; very rarely: exacerbation of chronic hepatitis, acute dystrophy of the liver (including against the background of acute herpetic hepatitis), acute liver failure, necrosis of the liver.
Disturbances from the skin and subcutaneous tissues
often: exanthema, erythematous rash, itching of the skin; infrequently: alopecia, erythema multiforme (including erythema malignant erythema [Stevens-Johnson syndrome]), toxic epidermal necrolysis (Lyell's syndrome), herpetiform skin rashes, photosensitivity, urticaria, increased skin pigmentation, slow healing of wounds; rarely: acne, skin ulceration, ecchymosis, the appearance of nodules on the skin, painful erosions, psoriatic plaques, pigmentation of nails, onycholysis, an increase in the size of rheumatoid nodules; very rarely: furunculosis, telangiectasia, acute paronychia, hydradenitis; frequency unknown: necrosis of the skin (at the site of administration).
On the background of methotrexate therapy, the development of complications from psoriatic nodules due to exposure to ultraviolet radiation is possible.
From the musculoskeletal system and connective tissue
infrequently: arthralgia, myalgia, osteoporosis; rarely: march (fatigue) fracture.
From the side of the kidneys and urinary tract
very often: decreased creatinine clearance; infrequently: severe nephropathy, renal insufficiency, cystitis with ulceration of the mucous membrane of the bladder, dysuria (urination disorder), oliguria, anuria; rarely: gipsuricemia, increased urea concentration in blood plasma, increased creatinine concentration in the blood plasma; very rarely: azotemia, hematuria, proteinuria.
Influence on the course of pregnancy, postpartum and perinatal conditions
infrequently: fetal development abnormalities; rarely: premature termination of pregnancy; very rarely: the death of the fetus.
Violations of the genitals and mammary gland
infrequently: vaginitis and ulceration of the vaginal mucosa; rarely: menstrual irregularities; very rarely: impaired spermatogenesis or maturation of the egg, impotence, infertility,loss of libido, transient oligospermia, pathological vaginal discharge, menstrual irregularities, gynecomastia.
Undesirable reactions arising from intrathecal administration of methotrexate: Acute chemical arachnoiditis (clinical manifestations include headache, dorsalgia, numbness in the neck and fever), subacute mislopathy (paresis or paraplegia in the innervation 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 coma. In the case of progression, these manifestations of toxicity can lead to death of the patient.
The combined use of intrathecal methotrexate and brain irradiation increases the risk of leukoencephalopathy. After the intrathecal administration of the drug, the patient's condition should be carefully monitored for the development of possible signs of neurotoxicity (meningism, paralysis, encephalopathy).

Overdose:Symptoms: mainly observed symptoms associated with the oppression of the hematopoiesis system.
Treatment: specific antidote of methotrexate is calcium folinate. It neutralizes adverse toxic effects.
In case of accidental overdose, not later than one hour after the administration of methotrexate, calcium folinate (intravenously or intramuscularly) at a dose equal to or greater than the dose of methotrexate. The administration of calcium folinate is continued until the serum levels of methotrexate are lower than level 10^-7 mmol / l.
If there is a significant overdose, it may be necessary to hydrate the organism and alkalinize urine (pH more than 7) to prevent precipitation of methotrexate and / or its metabolites in the renal tubules. Hemodialysis and peritoneal dialysis do not improve the elimination of methotrexate. Ensuring effective clearance of methotrexate allows intensive intermittent hemodialysis using high-flux dialyzers.
In case of an overdose with intrathecal injection, immediately after an overdose is detected, repeated lumbar punctures should be performed to ensure rapid drainage of cerebrospinal fluid, possibly neurosurgical intervention with ventricululumbral perfusion.All these procedures should be performed against a background of intensive maintenance therapy and systemic administration of large doses of calcium folinate.

Interaction:The likelihood of hepatotoxic action of methotrexate increases in the case of regular use of ethanol and the concomitant use of other hepatotoxic drugs (for example, azathioprine, leflunomide, sulfasalazine, retinoids). With combined therapy with methotrexate and leflunomide, the incidence of pancytopenia and hepatotoxicity increases.
Penicillium, ciprofloxacin, cephalothin, glycopeptides can reduce the renal clearance of methotrexate, as a result of which its concentration in the blood plasma can increase and the toxic effect on the hematopoiesis and gastrointestinal system may be intensified.
Probenetz, weak organic acids (for example, loop diuretics) and pyrazoles (phenylbutazone) can slow down the elimination of methotrexate, which can increase its plasma concentration and increase hematological toxicity.
The risk of toxic effects of methotrexate is increased in the case of combined use with non-steroidal anti-inflammatory drugs or salicylates, especially in patients with impaired renal function.If it is necessary to simultaneously apply, you should monitor the peripheral blood picture (counting blood cells) and kidney function. With concomitant therapy with drugs that may have adverse effects on the bone marrow (eg, sulfonamides, trimethoprim / sulfamethoxazole, chloramphenicol, pyrimethamine), the possibility of developing more severe hematologic disorders should be taken into account. The development of pancytopenia with the use of methotrexate in combination with cotrimoxazole or pyrimethamine is described. With concomitant therapy with medications that cause folate deficiency (eg, trimethoprim / sulfamethoxazole), the toxic effect of methotrexate may be enhanced. Simultaneous use of indirect anticoagulants and lipid-lowering drugs (colestramine) increases the toxicity of methotrexate.
Increases the concentration of uric acid in the blood, therefore, in the treatment of patients with concomitant hyperuricemia and gout, correction of the dose of antidotal agents (allopurinol, colchicine, sulfinpyrazone); the use of uricosuric anti-gouty drugs may increase the risk of developing nephropathy associated with increased uric acid formation when methotrexate is being treated (if concomitant use is desired, allopurinol).
In the combined use of antirheumatic drugs (eg, gold salts, penicillamines, hydroxychloroquines, azathioprine, ciclosporin) and methotrexate, the toxic effect of the latter is not enhanced. In the case of simultaneous application of sulfasalazine and methotrexate, the action of the latter can be potentiated by inhibiting the synthesis of folic acid.
When combined with methotrexate and proton pump inhibitors (eg, omeprazole or pantoprazole), renal elimination of methotrexate may be delayed, and pantoprazole can inhibit renal elimination of the metabolite of 7-hydroxymethogrexate, which in one case was accompanied by the development of myalgia and tremor.
During treatment with methotrexate, excessive drinking should be avoided. caffeine and theophylline (coffee, sweet drinks, containing caffeine, Black tea). Methotrexate reduces the clearance of theophylline.
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.
Medicinal products and other products containing folic or folinic acids (including multivitamins) can reduce the effectiveness of drug therapy (while reducing the toxic effect of methotrexate).
Due to competitive binding to blood plasma proteins with simultaneous use of methotrexate, the toxicity of methotrexate can be increased by the use of amidopyrine derivatives, paraaminoboisoic acid, barbiturates, doxorubicinia, oral contraceptives, phenylbutazone, phenytoidea, probenecid, salicylates, sulfonamides, tetracyclines and tranquilizers. In several patients with psoriasis or fungal mycosis,treated with methotrexate in combination with PUVA therapy (metoksalen and ultraviolet irradiation), skin cancer was detected.
The combination with radiotherapy can increase the risk of soft tissue necrosis.
Methotrexate may reduce the immunological response to vaccination. When used simultaneously with a live vaccine, severe antigenic reactions can develop.
Asparaginase reduces the severity of the antitumor effect of methotrexate by inhibiting cell replication.
Conduction of anesthesia with the use of diitrogen oxide can lead to the development of unpredictable severe myelosuppression and stomatitis. Amiodarone can promote ulceration of the skin.
Simultaneous use of mercaptopurine and methotrexate increases the plasma concentration, and the bioavailability of the former, probably due to inhibition of its metabolism. When co-therapy may require a dose adjustment of mercaptopurine.
Neomycin for oral administration may reduce the absorption of methotrexate for oral administration.
The use of colestyramine can disrupt the hepatic intestinal recirculation of methotrexate, increasing the elimination of the drug.Preparations that can cause folate deficiency (sulfonamides, trimethoprim / sulfamethoxazole) in the body or reduce tubular secretion (ciprofloxation, paraminobenzoic acid, nonsteroidal anti-inflammatory drugs, probenecid, salicylates, sulfonamides, weak organic acids) can enhance myelosuppressive effects of methotrexate.
The combined use of methotrexate and glucocorticosteroids can provoke the development of disseminated herpetic infection, the development of postherpetic neuralgia.
Against the background of joint therapy with cytarabine, the risk of unwanted phenomena from the nervous system increases, including headache, paralysis, coma, stroke-like episodes. The administration of procarbazine against the background of high doses of methotrexate increases the risk of impaired renal function.

Special instructions:The drug Methotrexate-Ebweze is a cytotoxic drug, so care must be taken when handling it. The drug should be appointed by a doctor who has experience with methotrexate and is familiar with its properties and the characteristics of the action.Before the appointment of methotrexate, you should make sure that you can determine the plasma concentration of the drug.
Taking into account the possibility of developing severe toxic reactions, including fatalities, the doctor must inform the patient in detail about the possible risk and necessary precautions.
Methotrexate, especially in moderate to high doses, should be used only in patients with potentially life-threatening malignant tumors. Cases of fatal manifestations of toxicity against the background of drug therapy are described. The abolition of methotrexate does not always lead to a complete resolution of undesirable phenomena.
The safety and potential benefits of using high doses of methotrexate outside the approved indications are not established.
During treatment with the drug Methotrexate-Ebwe, patients should be carefully monitored in order to identify signs of possible toxic effects and adverse effects in a timely manner. When using the drug for non-oncologic indications, it is necessary to pay special attention to the patient that the drug is taken every day, but once a week.
Before starting treatment with Methotrexate-Ebene or with the resumption of therapy after a break, it is necessary to conduct a clinical blood test with counting the leukocyte formula and the number of platelets, assess the activity of "liver" transaminases, bilirubin concentration, plasma albumin, uric acid concentration in the blood plasma, kidney function urea nitrogen, creatinine clearance and / or plasma serum creatinine), and chest X-ray. In the presence of clinical indications, studies are prescribed to exclude tuberculosis and viral hepatitis.
The appointment of high doses of methotrexate is possible only in the case of a normal concentration of creatinine in the blood plasma. If there is an increase in creatinine concentration, the dose of the drug should be reduced, if the creatinine concentration is increased by more than 2 mg / dL, the drug should not be used.
Leukopenia and thrombocytopenia, as a rule, develop in a period of 4 to 14 days after the administration of methotrexate. Sometimes there is a development of the second leukopenic phase, which develops in a period of 12 to 21 days.
In elderly patients, the development of megaloblastic anemia is described against the background of prolonged therapy with methotrexate.
In the process of treatment with the drug Methotrexate-Ebwe (monthly in the first 6 months and at least every 3 months thereafter, with increasing doses it is advisable to increase the frequency of the examinations), the following studies are carried out:
1. Examination of the oral cavity and pharynx to detect changes in the mucous membranes.
2. A blood test with the definition of the leukocyte formula and the number of platelets. Even when used in conventional therapeutic doses methotrexate can suddenly cause oppression of hematopoiesis. In the case of a significant decrease in the number of white blood cells or platelets, treatment with Methotrexate-Ebene immediately stop and prescribe symptomatic maintenance therapy.
Patients should be instructed to immediately inform the doctor of any signs and symptoms that indicate the development of the infection. With concomitant or previously conducted therapy with hematotoxic drugs (eg leflunomide), radiation therapy should be closely monitored for the number of leukocytes 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, the development of acute hepatitis and the phenomena of chronic hepatotoxicity (fibrosis and cirrhosis of the liver) is possible. Particular attention should be given to identifying signs of liver damage. Treatment with Methoskrysat-Ebewe should not be started or should be stopped if there are abnormalities in the results of functional liver tests or liver biopsy. Against the background of drug therapy, a 2-3-fold transient increase in the activity of "liver" transaminases, as a rule,
asymptomatic. As a rule, this is not an excuse for changing the treatment regimen, usually the indicators are normalized within two weeks, after which the treatment can be resumed by the doctor's decision. However, in case of a persistent increase in the activity of "hepatic" transaminases, a dose reduction or withdrawal of treatment with the drug Methotrexate-Ebweze is necessary. Since the drug Methotrexate-Ebwee has a toxic effect on the liver, during the treatment with the drug should not without the obvious need to use other hepatotoxic drugs. Also, ethanol consumption should be avoided or greatly reduced.Particularly closely monitor the activity of "hepatic" enzymes followed in patients receiving concomitant therapy with other hepatotoxic and hematotoxic drugs (in particular, leflunomide).
In the case of prolonged treatment, especially severe forms of psoriasis, including psoriatic arthritis, due to possible hepatotoxic effects of methotrexate, given that fibrotic and / or cirrhotic changes can develop against a background of normal hepatic samples, liver biopsy is necessary in the following cases:
1. In patients without risk factors, a liver biopsy is not shown before a total cumulative dose of 1.0-1.5 g is achieved.
2. Against the background of the presence of such risk factors as alcohol abuse, persistent increase in activity of "hepatic" transamaz, chronic viral hepatitis, family history of liver disease, and also for patients with less significant risk factors, such as diabetes, obesity, anamnestic data exposure to hepatotoxic drugs / chemicals, liver biopsy should be performed 2-4 months after the start of treatment.After reaching a total cumulative dose of 1.0-1.5 g, repeated liver biopsy is recommended.
A 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 only small changes (degree I, II or IIIa on the Roenigk scale) are detected with liver biopsy, methotrexate therapy may be continued, provided that the patient's condition is carefully monitored. The drug should be withdrawn in case of moderate or severe changes (IIIb and IV degree on the Roenigk scale), or in case of refusal of a liver biopsy of a patient who has a persistent increase in the activity of "liver" transaminases. In the case of a moderate diagnosis of fibrosis or cirrhosis of the liver methotrexate should be abolished, in the case of minimal fibrosis, repeated liver biopsy is recommended after 6 months. Such changes,as fatty liver dystrophy or mild inflammation of portal veins are a fairly common finding in liver biopsy in patients receiving methotrexate. Although the detection of such changes, as a rule, is not the reason for deciding whether it is inexpedient or canceling methotrexate therapy, caution should be exercised in the treatment of such patients.
4. Functional renal tests and urinalysis. Since the drug Methotrexate-Ebweet is excreted mainly by the kidneys, in patients with impaired renal function, an increase in the concentration of methotrexate in the blood plasma can occur, resulting in severe adverse reactions. It is necessary to carefully monitor the condition of patients who may have impaired renal function (eg, 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 hematopoiesis system. Cases of severe adverse effects in patients are described,who took NSAIDs with methotrexate therapy (especially in high doses), including cases of severe oppression of bone marrow hematopoiesis, aplastic anemia, gastrointestinal lesions and death.
5. Examination of the respiratory system. It is necessary to closely monitor the symptoms of possible development of pulmonary function disorders and, if necessary, assign appropriate studies to monitor lung function. The appearance of the corresponding symptomatology (especially dry, unproductive cough) during the treatment with Methotrexate-Ebweze or the development of nonspecific pneumonitis may indicate a potential lung injury. In such cases, the drug Methotrexate-Ebweave should be withdrawn and a thorough examination of the patient should be carried out. Although the clinical picture may vary, in typical cases where the symptoms from the respiratory system are caused by the use of the drug Methotrexate-Ebwee, there is an increase in body temperature, cough with shortness of breath, hypoxemia, and pulmonary infiltrates on X-rays. The defeat of the lungs, caused by the use of methotrexate,may occur regardless of the prescription of the drug, the dosages used (cases of lung injury with low-dose methotrexate, including 7.5 mg / week) are described. In differential diagnosis, the infectious nature of the disease should be excluded. On the background of methotrexate therapy, the development of potentially dangerous (up to the lethal outcome) opportunistic infections, including piemacic pneumonia, is possible. In the case of development of symptoms from the respiratory system, the patient receiving methotrexate, pneumonia due to Pneumocystis carinii should be excluded.
In the case of increasing the dose of the drug, the frequency of the 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 completion of the drug intake; family members of the patient living with it should opt out of immunization with oral polio vaccine (the patient should avoid contact with people who have received a polio vaccine, or wear a face mask covering the nose and mouth).
If the symptoms of stomatitis or diarrhea, hemoptysis, melena or the appearance of blood impurities in the stool are noted against the background of methotrexate therapy, the drug should be immediately discontinued because of 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, pronounced general weakness, hemoptysis, hemorrhagic rash may be harbingers of life-threatening complications.
If the patient experiences conditions that lead to accumulation of a significant amount of fluid in the body cavities (hydrothorax, ascites), taking into account the elongation of the half-life of the drug in such patients, therapy with Metrostrans-Ebewe should be carried out with caution, before starting therapy with the drug, the liquid should be evacuated by drainage, or refuse to use the drug.
Particular care should be taken when treating patients with insulin-dependent diabetes mellitus, since cases of liver cirrhosis have been reported without a previous increase in the activity of "liver" transaminases.
Like other cytotoxic drugs, methotrexate can cause the development of tumor lysis syndrome in patients with intensively growing malignancies. To prevent the development of this complication, appropriate measures of maintenance therapy should be taken. The use of methotrexate in combination with radiotherapy can lead to an increased risk of soft tissue necrosis or osteonecrosis.
It is necessary to closely monitor the condition of patients with previous radiation therapy, as well as the disturbed general condition.
Dehydration can also potentiate the toxic effect of the drug Methotrexate-Ebwe, therefore, in the development of conditions that can lead to the development of dehydration (severe vomiting, diarrhea), methotrexate therapy should be discontinued until these conditions are resolved.
The cases of development of leukoencephalopathy in patients receiving high-dose methotrexate therapy, including oral, in combination with calcium folinate (without previous radiation therapy on the head area) are described. When methotrexate is used for acute lymphatic leukemia, pain in the left epigastric region can occur, due to the development of the inflammatory process in the spleen capsule against the background of the disintegration of tumor cells.
It is recommended to discontinue treatment with Methotrexate-Ebweave for one pedulin before surgery and resume one or two weeks after the operation. Special care should be taken with 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 significantly slows down.
The drug Methotrexate-Ebwee can increase the risk of developing neoplasms (mainly lymphomas). Malignant lymphomas can also develop in patients receiving the drug Methotrexate-Ebweve in low doses. In such cases, the drug should be discontinued. If spontaneous regression of lymphoma is not observed, prescribe therapy with other cytotoxic drugs.
Before starting treatment with the drug Methotrexate-Ebeva, pregnancy should be excluded. The drug Methotrexate-Ebwee has an embryotoxic effect, promotes the termination of pregnancy and the formation of fetal development abnormalities. Therapy with the drug Methotrexate-Ebwee is accompanied by oppression of spermatogenesis and ovogenesis, which can lead to a decrease in fertility.After the abolition of drug therapy, these effects spontaneously regress. During the period of therapy with the drug Methotrexate-Ebwe, and for six months after its completion, patients are advised to use contraceptive measures. Patients of reproductive age, as well as their partners, should be informed about the possible effect of the drug Methotrexate-Ebene on reproductive and fetal development. Men of reproductive age should be warned about the risks, paternity is not recommended during treatment and within 6 months after the drug is discontinued. Since in the process of treatment possible the development of irreversible infertility, men should consider the possibility of cryopreservation of sperm in the bank before the treatment.
The use of methotrexate increases the likelihood of dermatitis and skin burns caused by sun and ultraviolet radiation (UV). Do not expose unprotected skin to prolonged sun exposure or abuse the UV lamp (a photosensitization reaction is possible). In patients with psoriasis, an exacerbation of the disease may occur on the background of UV irradiation during treatment with methotrexate.
When therapy with high doses, precipitation of methotrexate or its metabolites in the renal tubules may occur. In such cases, as a prophylaxis of this complication, it is recommended to perform infusion therapy and alkalinization of urine to achieve a pH of 6.5-7.0 by oral (5 tablets of 625 mg every 3 hours) or intravenous sodium bicarbonate or acetazolamide (500 mg orally four times per day). On the background of methotrexate therapy, exacerbation of chronic viral hepatitis (reactivation of the hepatitis B or C virus) is possible. Also, cases of reactivation of the hepatitis B virus after the withdrawal of methotrexate are described. If it is necessary to prescribe the drug to a patient with an anamnesis of viral hepatitis, a thorough clinical and laboratory examination should be carried out.
The presence of pleural effusion, ascites, abnormalities of the gastrointestinal tract, concomitant cisplatin therapy, dehydration, impaired liver function or a decrease in urine pH slows the excretion of methotrexate, resulting in an increase in the concentration of the drug in the blood plasma. It is extremely important to detect cumulation of the drug in the body within the first 48 hours, since it is possible to develop irreversible effects of toxicity of the drug.Particular caution should be exercised when using the drug in elderly patients, their condition should be monitored more often than in younger patients, to identify early signs of toxicity of therapy. Pediatric treatment protocols should be used in the treatment of pediatric patients.
In pediatric patients with acute lymphoblastic leukemia, a marked neurotoxicity may develop with the use of averages (1 g / m² ) doses of methotrexate, which is most often manifested clinically as a generalized or partial epileptic seizure. The development of leukoencephalopathy and / or microangiopathic calcification in the course of instrumental studies in such patients is described.
When high doses of methotrexate are used, the development of transient acute neurological symptoms is described, which can be manifested, including behavioral changes, by local disturbances from the sense organs (including short-term blindness) and the motor system, and reflex reflexes. The exact reasons for the development of these unwanted reactions are unknown. When using methotrexate in a dose above 100 mg / m² it is obligatory to apply the "salvage therapy" calcium folinate 42-48 hours after the administration of methotrexate. The dose of calcium folinata is determined depending on the amount of 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 folate therapy. The use of methotrexate together with the infusion of erythrocyte mass (within 24 hours) requires careful monitoring of the patient's condition, since it is possible to increase the plasma concentration of the drug.
Special precautions for the destruction of unused medications
Remains of the preparation, all tools and materials used to prepare solutions for the infusion of the drug Metotrexate-Ebwee, should be destroyed in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account existing regulations for the destruction of hazardous waste.

Effect on the ability to drive transp. cf.and fur:Because of the likelihood of side effects such as drowsiness, headache and confusion, care should be taken when practicing potentially dangerous activities that require a high concentration of attention and speed of psychomotor reactions. When these undesirable phenomena appear, one should refrain from performing these activities.

Form release / dosage:Solution for injection 10 mg / ml (7.5 mg / 0.75 ml, 10 mg / 1 ml, 15 mg / 1.5 ml, 50 mg / 5 ml).

Packaging:Primary packaging
Vials / ampoules
1 ml or 5 ml in bottles of colorless glass (type 1 Hept.F.), sealed with a rubber stopper (Hearth.F.), under an aluminum run-off, with a hole for the needle in the center, closed with a protective Teflon cap.
1 ml or 5 ml in dark glass ampoules with a break point.
Syringes (pre-filled)
0.75 ml, 1.0 ml, 1.5 ml or 2.0 ml in disposable sterile syringes of colorless glass (type 1 Hept.F.), with a polystyrene piston, a plunger made of bromobutyl rubber and a polypropylene backstopper, as well as with the Luer Lock screw cap and a double protective cap consisting of external plastic and internal bromobutyl screw caps.
Secondary packaging
Vials / ampoules
One bottle together with instructions for use in a cardboard pack.
For 10 ampoules of 1 ml or 5 ampoules of 5 ml in an open or closed blister of PVC.
1 blister together with instructions for use in a cardboard pack.
Syringes (pre-filled)
1 disposable, sterile, pre-filled syringe complete with 1 or 2 sterile needles with automatic needle protection system (to prevent injury due to needle mischief through negligence) or without it in a PVC blister.
1 blister together with instructions for use in a cardboard pack.

Storage conditions:In the dark place at a temperature of 15 to 25 ° C. Keep out of the reach of children!

Shelf life:Vials / ampoules of 1 ml and 5 ml - 3 years.
Disposable syringes for 0.75 ml and 1.5 ml for 2 years.
Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015225 / 03

Date of registration:07.10.2008 / 03.07.2015

Expiration Date:Unlimited

The owner of the registration certificate:Ebewe Pharma Gesmb.b. Nfg. KGEbewe Pharma Gesmb.b. Nfg. KG Austria

Manufacturer: & nbsp

EBEWE PHARMA, Ges.m.b.H.Nfg.KG Austria

Representation: & nbspSANDOZ SANDOZ Switzerland

Information update date: & nbsp2016-09-12

Illustrated instructions

Instructions

Methotrexate-Ebwe (Methotrexate-Ebewe)