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

Composition:1 tablet contains: active substance: methotrexate 2.5 mg, 5 mg, 10 mg; Excipients: starch corn 20.3 / 40.6 / 81.2 mg, silicon dioxide colloid 0.8 / 1.6 / 3.2 mg, lactose monohydrate 78.6 / 157.2 / 314.4 mg, magnesium stearate 1, 6 / 3,2 / 6,4 mg, microcrystalline cellulose 16.2 / 32.4 / 64.8 mg.

Description:

Tablets 2.5 mg: round flat pills of light yellow color (admissions from yellow to red are allowed).

Tablets 5 mg: round biconvex tablets of light yellow color (yellow to red inclusions are allowed) with dividing risk with bevelled edges on one side.

Tablets 10 mg: oblong biconvex tablets of light yellow color (yellow to red inclusions are allowed) with dividing risk with chamfered edges on one side.

Pharmacotherapeutic group:Antitumor agent antimetabolite, immunosuppressive agent

ATX: & nbsp

L.01.B.A Analogues of folic acid

L.01.B.A.01 Methotrexate

Pharmacodynamics:

Antineoplastic, cytostatic agent of the group of antimetabolites - analogues of folic acid. 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 unknown, perhaps this action is due to the immunosuppressive properties of methotrexate.

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 in comparison with normal proliferation of skin cells. This difference in cell proliferation is the basis for the use of methotrexate for the treatment of psoriasis.

Pharmacokinetics:

Suction when taken orally depends on the dose. The average bioavailability is 60%. Absorption decreases when taken in doses exceeding 80 mg / m², possibly due to the saturation effect. In children with leukemia, absorption ranges from 23 to 95%.Time to reach the maximum concentration of the drug for oral intake of 4 hours. Food slows down absorption and reduces the maximum concentration of methotrexate in the plasma. The connection with plasma proteins is 50%, mainly with albumin.

When administered at therapeutic doses, it does not penetrate the blood-brain barrier (high concentrations are achieved after intrathecal injection in the cerebrospinal fluid). Penetrates into breast milk.

After oral administration, it is partially metabolized by intestinal microflora, the main part - in the liver with the formation of pharmacologically active polyglutamine form, also inhibiting dihydrofolate reductase and thymidine synthesis.

The half-life of methotrexate in patients receiving the drug in doses less than 30 mg / m², in the initial phase is 2-4 hours, and in the final phase -3-10 hours when small and 8-15 hours - when applying large doses of the drug. In chronic renal failure, both phases of excretion of methotrexate can be significantly elongated.

Renal excretion is the main way of excretion, and depends on the dose and mode of administration. 80% to 90% is excreted unchanged by glomerular filtration and tubular secretion within 24 hours.A small amount (no more than 10% of the administered dose) is excreted with bile, followed by reabsorption in the intestine.

Impaired renal function, severe ascites or transudate, and simultaneous use of drugs such as weak organic acids that are also exposed to tubular secretion, can significantly increase serum concentrations 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.

In children, bioavailability ranges from 23% to 95%. The time to reach the maximum concentration of methotrexate in the blood plasma varies from 0.67 to 4 hours with a dose of 15 mg / m². Absorption of methotrexate in children decreases with doses above 40 mg / m². The half-life is 0.7-5.8 hours.

Indications:

- Supportive therapy of acute lymphoblastic leukemia;

- non-Hodgkin's lymphomas;

- trophoblastic tumors;

- mushroom mycosis (far advanced stages);

- rheumatoid arthritis in adults;

- Juvenile arthritis in the form of polyarthritis, in the absence of response to therapy with nonsteroidal anti-inflammatory drugs (NSAIDs);

- severe forms of psoriasis in adults, with no response to other therapies, including phototherapy, PUVA therapy, retinoic therapy.

Contraindications:

- Hypersensitivity to methotrexate and / or any other component of the drug;

- severe renal dysfunction (creatinine clearance less than 30 ml / min);

- Severe dysfunction of the liver (bilirubin in the serum of more than 5 mg / dl (85.5 mmol / l));

- 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;

- excessive consumption of ethanol;

- a syndrome of an immunodeficiency;

- concomitant vaccination with live vaccines;

- ulceration of the mucous membrane of the oral cavity, gastrointestinal tract in the active phase;

- Pregnancy;

- the period of breastfeeding;

- children's age till 3 years;

- simultaneous use of methotrexate in a dose of 15 mg / week or more with acetylsalicylic acid.

Carefully:With caution apply in the presence of patients with impaired liver and kidney function,diabetes, obesity and previous therapy with hepatotoxic drugs, dehydration, ascites, oppression of bone marrow hematopoiesis, pleural or peritoneal effusion, parasitic and infectious diseases of viral, fungal or bacterial nature - the risk of developing a severe generalized disease (currently or recently transferred, including a recent contact with the patient) - herpes simplex, herpes zoster (viremic phase), chicken pox, measles; amoebiasis, strongyloidiasis (or suspected); gout (including history) or urate nephrourolythiasis (including in the anamnesis), infections and inflammation of the oral mucosa, vomiting, diarrhea, peptic ulcer and duodenal ulcer, ulcerative colitis, obstructive diseases gastrointestinal - intestinal tract, previous chemotherapy or radiotherapy, asthenia, aciduria (urine pH less than 7), lactase deficiency, lactose intolerance, glucose-galactose malabsorption syndrome, in children and elderly patients.

Pregnancy and lactation:

When using the drug Methotrexate-Ebwee during pregnancy, there were cases of spontaneous abortion,fetal death and / or congenital defects (an increase in the frequency of the developmental defects of the skull, cardiovascular system and extremities 14 times), so the drug Methotrexate-Ebwee is contraindicated in pregnancy.

If pregnancy occurred during the treatment with Methotrexate-Ebene, it is necessary to consult with specialists regarding the risk of adverse effects of the drug on the fetus. Patients of reproductive age (both women and men) should use effective methods of contraception during and for at least 6 months after the end of treatment with Methotrexate-Ebene.

The drug Methotrexate-Ebweet penetrates into breast milk in concentrations dangerous to the baby. Therefore, during the treatment of the drug, breastfeeding should be discontinued.

Dosing and Administration:

Inside, 1 hour before or 1.5-2 hours after eating, without chewing. Doses and treatment periods are set individually.

The drug Methotrexate-Ebweve in tablets is used when using low doses in the form of monotherapy or in combination with other cytotoxic agents, hormone therapy,radiation therapy and surgical intervention, for the treatment of a wide range of neoplastic diseases, so the dose and treatment regimen can vary considerably. High doses of methotrexate (more than 30 mg / m²) are usually administered by intravenous infusions with a duration of no more than 24 chw. Supportive therapy of acute lymphoblastic leukemia Supportive therapy in a dose of 15 mg / m² 2 times per week. For maintenance therapy, a dose of 2.5 mg / kg can also be used every 14 days as part of a combination therapy.

Non-Hodgkin's lymphomas (as part of complex therapy)

- 15-20 mg / m² for 1 reception 2 times a week;

- 7.5 mg / m² daily for 5 days.

Treatment is conducted in several courses at intervals of 7-10 days. The recommended dose of Methotrexate-Ebwee in the treatment of Burkitt's lymphoma (stages I and II) is 10 to 25 mg / day orally for 4 to 8 days. Treatment can consist of several courses, separated by periods of break from 7 to 10 days. In the III stage of Burkitt's lymphoma, the drug Methotrexate-Ebwee is usually used in combination with other antitumor drugs.

The recommended dose for the treatment of stage III lymphosarcoma is from 0.625 to 2.5 mg / kg / day in combination with other antitumor drugs.

Trophoblastic tumors

15-30 mg orally, daily for 5 days with an interval of one or more weeks (depending on the signs of toxicity). Treatment rates are usually repeated 3 to 5 times.

- 50 mg once every 5 days with an interval of at least 1 month. The course of treatment requires 300-400 mg.

The effectiveness of therapy is usually assessed by measuring the concentration of chorionic gonadotropin in the urine every 24 hours.

Mushroom mycosis (cutaneous T-cell lymphoma)

5-50 mg once a week. Dose reduction and discontinuation of therapy are performed according to hematological parameters and clinical condition of the patient.

Rheumatoid arthritis

The initial dose is usually 7.5 mg once a week, which is taken concurrently. The therapeutic effect is achieved within 6 weeks, while the improvement of the patient's condition occurs after an additional 12 weeks of the drug or more. If there is no response to therapy after 6-8 weeks and there are no toxic symptoms, the dose of the drug can be gradually increased by 2.5 mg per week.

Usually the optimal dose is from 7.5 to 15 mg, with the dose not exceeding 20 mg per week.

If there is no response to therapy after 8 weeks of the drug at the maximum dose, methotrexate should be canceled. When the response to therapy is reached, the maintenance dose should be reduced to the lowest possible level. The optimal duration of therapy is not currently known, but preliminary data show that the effect is preserved for 2 years with continued use of the drug in a maintenance dose. After discontinuation of therapy, symptoms can resume within 3-6 weeks.

The recommended dose in children and adolescents with juvenile chronic arthritis in the form of polyarthritis is 10-15 mg / m² body surface area / week. In refractory cases, the weekly dose of the drug can be increased to 20 mg / m² body surface area / week. However, as the dose is increased, the frequency of monitoring the patient's condition is also shown.

Patients with juvenile chronic arthritis should always be referred to the department of rheumatology, specializing in the therapy of children / adolescents.

Psoriasis

Methotrexate therapy is given at doses of 7.5 to 25 mg once a week or alternatively, the planned weekly dose can be divided into 3 divided doses at 12 hour intervals.The dose is usually increased gradually, when the optimal clinical effect is achieved, the dose is reduced to the lowest effective dose.

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. Patients with severe renal dysfunction a dose adjustment is required depending on the creatinine clearance (with a creatinine clearance of 30-50 ml / min, the dose is reduced by 50%, with creatinine clearance less than 30 ml / min methotrexate should not be used).

Patients with severe hepatic impairment

Methotrexate-Ebweve is 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 of age) it may be necessary to reduce the dose of methotrexate, since the liver and kidney function deteriorates with age.

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: iodicardiosis, histoplasmosis, cryptococcosis, hepatitis and disseminated infections caused by the 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) infrequent: lymphoma.

Violations of the blood and lymphatic system

very often: leukopenia, thrombocytopenia; often: anemia, pancytopenia, agranulocytosis; infrequently: epistaxis; rarely: megaloblastic anemia; very rare: severe progressive depression of bone marrow function, aplastic anemia, lymphadenopathy and lymphoproliferative diseases, eosinophilia, neutropenia;

Immune system disorders

infrequently: allergic reactions, anaphylactic shock, allergic vasculitis, fever, immunosuppression; very rarely: hypogammaglobulinemia.

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: development of hemiparesis, vertigo (dizziness), confusion, convulsions; rarely: paresis, speech disorders, including dysarthria and aphasia, leukoencephalopathy; 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. frequency unknown: ringing in the ears.

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 be avoided; infrequently: pulmonary fibrosis, effusion into the pleural cavity; rarely: pharyngitis, apnea; very rarely: chronic obstructive pulmonary disease (COPD), reactions,similar to bronchial asthma (accompanied by cough, shortness of breath, abnormalities in functional pulmonary tests), pneumonia caused by Pneumocystis carinii.

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); 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, hypoalbuminemia; rarely: acute hepatitis and other manifestations of hepatotoxicity; Very rarely: exacerbation of chronic hepatitis, acute dystrophy of the liver (in the city against the background of acute herpetic hepatitis), liver necrosis, acute liver failure.

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, skin necrosis, exfoliative dermatitis, photosensitivity, hives, increased skin pigmentation, slow healing 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, telangiograzia, acute paronychia.

Against 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; frequency unknown: osteonecrosis.

From the side of the kidneys and urinary tract

very often: decreased creatinine clearance; infrequently: severe nephropathy,renal failure, cystitis with ulceration of the mucous membrane of the urinary bladder, dysuria (urination disorder), oliguria, anuria; rarely: hyperuricemia, increased urea concentration in the 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.

Overdose:

Symptoms: mainly symptoms associated with oppression of the hematopoiesis system and on the part of the digestive system are observed. Treatment: specific antidote of methotrexate is calcium folinate. It neutralizes adverse toxic effects.

In case of accidental overdose, no later than 4-5 hours after methotrexate administration, enter calcium folinate (intravenously or intramuscularly) at a dose equal to or greater than the dose of methotrexate. Introduction of calcium folinate continue to decrease in serum methotrexate concentration below 10 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.

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. Antibiotics for oral administration (tetracyclines, chloramphenicol, rifaximin) can reduce methotrexate absorption in the gastrointestinal tract and interfere with the intestinal hepatic circulation of methotrexate due to the inhibition of bacterial metabolism (inhibits the growth of the intestinal microflora).

Penicillins, 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.

Probeptide, weak organic acids (for example, loop diuretics) and pyrazoles (feilbutazone) can slow down the elimination of methotrexate, so that its concentration in the blood plasma may increase and hematological toxicity may increase.

The risk of toxic effects of methotrexate is increased in the case of combined use with non-steroidal anti-inflammatory drugs (NSAIDs) 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,which may have an adverse effect 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 co-trimoxazole or pyrimetamy 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 hypolipidemic drugs (tyramine wheels) 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, pienylamines, hydroxychloroquines, azathioprines, cyclosporins) and methotrexate, the toxic effect of the latter is not enhanced. In the case of simultaneous application of sulfasalazip and methotrexate, the action of the latter may 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 the renal elimination of the metabolite 7-hydroxymethotrexate, 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 fluorouracil half-life is determined).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, paraaminobenzoic acid, barbiturates, doxorubicin, oral contraceptives, phenylbutazone, phenytoin, probenecid, salicylates, sulfonamides, tetracyclines and tranquilizers.

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

Anesthesia using dinitrogen oxide can lead to unpredictable severe myelosuppression and stomatitis.

Amiodarone can promote skin ulceration.

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 colostiramia 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 (ciprofloxacin, parimipobenzoic acid, NSAIDs, 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.

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.

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. The abolition of methotrexate does not always lead to a complete resolution of undesirable phenomena.

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-oncological indications, it is necessary to pay special attention to the patient that the drug is not 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.

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, it is necessary to closely monitor 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 Methotrexate-Ebwee should not be initiated or should be discontinued if abnormalities in the results of functional liver tests or liver biopsy are detected. Against the background of drug therapy, a 2-3 fold transient increase in the activity of "liver" transaminases, as a rule, is 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 risk factors such as alcohol abuse, a persistent increase in the activity of "liver" transaminases, chronic viral hepatitis, a family history of liver disease, as well as for patients with a less significant risk factors such as diabetes, obesity, medical history data Effects gepatogoksicheskih drugs / chemicals liver biopsy should be performed within 2-4 months after starting 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,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 (grade I, II or IIIa on the Roenigk scale) are detected with liver biopsy, continued therapy with methotrexate may be possible, 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. If mild fibrosis or liver cirrhosis is detected 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 identification 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 decrease the excretion of methotrexate, which have an adverse effect on the kidney (in particular, NSAIDs) or on the hematopoiesis system. The cases of severe adverse effects in patients taking NSAIDs against methotrexate therapy (especially in high doses) are described, including cases of development 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. Lung damage 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 / idel) have been 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 fatal outcome) opportunistic infections, including pneumocystis 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 the accumulation of a significant amount of fluid in body cavities (hydrothorax, ascites), taking into account the elongation of the half-life of the drug in such patients, therapy with Methotrexate-Ebweve should be carried out with caution, before starting therapy with the drug, the liquid should be evacuated by drainage, or refuse the use of 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 malignant tumors. 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, so when developing conditions that can lead to the development of dehydration (severe vomiting, diarrhea), methotrexate therapy should be discontinued before 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 one week before surgery and resume one or two weeks after surgery.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 MeTrexate-Ebevs 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 cryo-preservation 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.

Special precautions when destroying an unused preparation

Remains of the drug Metotrexate-Ebwee should be destroyed in accordance with the standard hospital procedure for the disposal of cytotoxic substances, taking into account the existing regulatory acts on 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.

Form release / dosage:Tablets 2.5 mg, 5 mg, 10 mg.

Packaging:

Primary packaging

Tablets of 2.5 mg: 50 tablets in a white polypropylene bottle with a plug of low-density polyethylene.

Tablets 5 mg: 20 or 50 tablets in a white polypropylene bottle with a plug of low density polyethylene.

Tablets 10 mg: 10 or 50 tablets in a white polypropylene bottle with a plug of low-density polyethylene.

Secondary packaging

One bottle is placed in a cardboard box together with the Instruction for Use.

Storage conditions:In the dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children!

Shelf life:

3 years.

Do not use after the expiry date printed on the package.

Terms of leave from pharmacies:On prescription

Registration number:П N015225 / 02

Date of registration:07.10.2008 / 01.07.2014

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: & nbsp11.05.2018

Illustrated instructions

Instructions

Methotrexate-Ebwe (Methotrexate-Ebewe)