Description of the drug METOTREKSAT-EBEVE
When used simultaneously with vitamin preparations containing folic acid or its derivatives, the effectiveness of methotrexate may be reduced.
The simultaneous use of NSAIDs in high doses can lead to an increase in the concentration of methotrexate in plasma and to prolongation of its T1/2, as well as an increase in the concentration of methotrexate not associated with plasma albumin, which in turn increases the toxic effects of methotrexate (primarily on the gastrointestinal tract and system hematopoiesis).
When used simultaneously with penicillins, methotrexate (even in low doses) may increase its toxic effects.
When used simultaneously with sulfonamides, especially with co-trimoxazole, there is a risk of increased myelosuppressive effects.
When using nitrous oxide in patients receiving methotrexate, severe unpredictable myelodepression and stomatitis may develop.
When used simultaneously with methotrexate, valproic acid may reduce its concentration in the blood plasma.
Cholestyramine binds methotrexate, reduces its enterohepatic recirculation, which leads to a decrease in its concentration in the blood plasma.
When used simultaneously with mercaptopurine, it is possible to increase its bioavailability due to impaired metabolism during the “first pass” through the liver.
Neomycin and paromomycin reduce the absorption of methotrexate from the gastrointestinal tract.
In patients receiving omeprazole, the concentration of methotrexate in the blood plasma may increase.
When used simultaneously with probenecid, a 3-4 fold increase in the concentration of methotrexate in the blood plasma is possible due to a decrease in its renal excretion.
With simultaneous use of methotrexate with retinoids, the risk of hepatotoxicity may increase.
Salicylates potentiate the effect of methotrexate by reducing its renal excretion.
After a course of treatment with tetracycline, methotrexate, used even in low doses, can have a toxic effect.
With sequential administration of methotrexate and fluorouracil, synergistic action is possible; fluorouracil administered before methotrexate may reduce its toxicity.
Cisplatin is nephrotoxic and may therefore reduce the renal excretion of methotrexate, resulting in increased toxicity.
Increased toxicity is possible when using cyclosporine in patients receiving methotrexate.
Methotrexate-Ebeve Solution, syringe, 1 piece, 0.75 ml, 7.5 mg, for injection
Side effect
According to WHO, adverse effects are classified according to their frequency as follows: very common (≥ .1/10), common (≥ .1/100 to less than 1/10), uncommon (≥ .1/1000 to less 1/100), rare (from ≥ .1/10,000 to less than 1/1000), very rare (less than 1/10,000). frequency unknown - based on available data, it was not possible to determine the frequency of occurrence. From the hematopoietic system: often - suppression of bone marrow function (leukopenia, thrombocytopenia, anemia). infrequently - pancytopenia. very rarely - severe progressive depression of bone marrow function, agranulocytosis. frequency unknown - megaloblastic anemia. From the central nervous system: often - drowsiness, headache, fatigue. infrequently - depression, confusion, mood changes. rarely - when using methotrexate in low doses - transient slight impairment of cognitive functions, unusual sensations in the cranial area. very rarely - pain, myasthenia gravis or paresthesia in the extremities, perversion of taste (metallic taste in the mouth), epileptic seizures, meningism, paralysis, insomnia. From the senses: often - visual impairment. uncommon - eye irritation. rarely - conjunctivitis. From the respiratory system: often - chronic interstitial pneumonitis (symptoms indicating potentially serious damage to the lungs with interstitial pneumonitis: dry, unproductive cough, shortening of breathing, increased body temperature). infrequently - alveolitis, pleural effusion. rarely - pulmonary fibrosis, Pneumocystis pneumonia, bronchial asthma. very rarely - pleural pain and thickening of the pleura (when treated with methotrexate in high doses), acute pulmonary edema. From the digestive system: very often - stomatitis, nausea, inflammation of the mucous membranes, loss of appetite, dyspepsia, anorexia, a significant increase in the activity of liver transaminases. often - diarrhea, ulceration of the oral mucosa. infrequently - enteritis, vomiting, liver cirrhosis, liver fibrosis, liver steatosis. rarely - ulceration of the gastrointestinal mucosa. very rarely - malabsorption syndrome, toxic megacolon. From the urinary system: infrequently - inflammation and ulceration of the bladder, impaired renal function, urinary disorders. rarely - renal failure, oliguria, anuria, electrolyte imbalance. From the skin: often - exanthema, erythema, itching. uncommon - photosensitivity, alopecia, herpes zoster, vasculitis, skin rashes herpetiformis, urticaria. rarely - increased pigmentation. very rarely - Stevens-Johnson syndrome, epidermal necrolysis (Lyell's syndrome). When exposed to ultraviolet radiation, increased psoriatic skin lesions, increased pigmentation of nails, acute paronychia, furunculosis and hidradenitis. From the musculoskeletal system: infrequently - arthralgia, myalgia, osteoporosis. From the cardiovascular system: often - vasculitis, bleeding of various locations. infrequently - effusion into the pericardial cavity. rarely - cardiac tamponade, nosebleeds. From the immune system: very often - decreased resistance to infections, pharyngitis. infrequently - hypogammaglobulinemia. rarely - sepsis. very rarely - anaphylactic reactions, increased number of rheumatoid nodules. From the reproductive system: infrequently - ulceration and inflammation of the vagina. very rarely - loss of libido, impotence, oligospermia, menstrual disorders, vaginal discharge. Other: often - chills, malaise, fever, necrosis. rarely - deterioration of wound healing. With intramuscular injection - a burning sensation or tissue damage (formation of a sterile abscess, destruction of adipose tissue) at the injection site. very rarely - benign, malignant and nonspecific neoplasms (including cysts and polyps), lymphomas, which in some cases regress after discontinuation of methotrexate. frequency unknown - diabetes, other metabolic disorders, sudden death. Adverse reactions with intrathecal methotrexate Acute: chemical arachnoiditis, manifested by headache, back or shoulder pain, stiffness of the muscles in the back of the neck and fever. Subacute: paresis (usually transient), paraplegia, impaired cerebellar function. Chronic: leukoencephalopathy, manifested by irritability, confusion, ataxia, muscle plasticity, sometimes convulsions, dementia, drowsiness, coma, in rare cases with death. When combining radiation therapy to the cranial area and intrathecal administration of methotrexate, the incidence of leukoencephalopathy increases.
Methotrexate-SZ
Registration number
LSR-003881/08
Dosage form
film-coated tablets
Compound
1 film-coated tablet contains: active substance: methotrexate 2.5 mg excipients: core - lactose (milk sugar) - 51.0 mg, microcrystalline cellulose - 55.0 mg, calcium stearate -1.0 mg, crospovidone (kollidon CL, CL-M) -1.0 mg, povidone (kollidon 30) - 7.0 mg, talc - 2.5 mg; shell - Opadry II (series 85) (polyvinyl alcohol, partially hydrolyzed - 1.76 mg, talc - 0.8 mg, titanium dioxide - 0.7668 mg, macrogol (polyethylene glycol 3350) - 0.4940 mg, lecithin (soy) - 0.14 mg, aluminum varnish based on carmoisine - 0.0204 mg, aluminum varnish based on Ponceau - 0.0164 mg, aluminum varnish based on indigo carmine - 0.0024 mg).
Description
Film-coated tablets, pink to dark pink, round, biconvex. On the break, the tablets are yellow with possible splashes of orange or white.
ATX code
[L01BA01]
Pharmacological properties
Pharmacodynamics.
Antitumor, cytostatic agent of the group
antimetabolite analogues of folic acid. Inhibits dihydrofolate reductase involved in the reduction
digicrofolic acid into tetrahydrofolic acid (a carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives).
Inhibits DNA synthesis, repair and cell mitosis (in S-phase). Tissues with high cell proliferation are especially sensitive to the action of methotrexate: tumor tissue, bone marrow, epithelial cells of the mucous membranes, embryonic cells. Along with antitumor, it has an immunosuppressive effect.
Pharmacokinetics.
Oral absorption depends on the dose: when taken 30 mg/m; is well absorbed, average bioavailability is 50%. Absorption is reduced when taken in doses exceeding 80 mg/m2 (believed to be due to saturation). In children, absorption ranges from 23 to 95%.
The time to reach maximum concentration (C „,.) is 1-2 hours. Food slows down absorption and reduces C,>. Communication with plasma proteins is about 50%.
When taken in therapeutic doses, it practically does not penetrate the BBB. Passes into breast milk.
After oral administration, it is partially metabolized by the intestinal flora, the main part - in the liver with the formation of a pharmacologically active polyglutamine form that inhibits distropholate reductase and the synthesis of thymcin.
The half-life in the initial phase is 24 hours, and in the final phase - 3-10 hours. In chronic renal failure, both phases of drug elimination can be significantly prolonged. Excreted mainly by the kidneys unchanged through glomerular filtration and tubular secretion, up to 10% is excreted with bile. (followed by reabsorption in the intestine). The elimination of the drug in patients with impaired renal function, severe ascites or transudate is significantly slowed down. With repeated administrations, it accumulates in tissues in the form of metabolites.
Indications for use
Methotrexate tablets are used in low doses to treat trophoblastic tumors, acute lymphoblastic leukemia and non-Hodgkin's lymphomas and advanced stages of mycosis fungoides, severe forms of psoriasis, as well as for rheumatoid arthritis when other methods of therapy are ineffective.
Contraindications
The use of methotrexate is contraindicated during pregnancy and lactation, with pronounced changes in kidney and liver function, with hematological disorders, including bone marrow hypoplasia, leukopenia, thrombocytopenia, anemia, with the acute stage of infectious diseases, immunodeficiency syndrome, with hypersensitivity to methotrexate or other components of the tablet, children under 3 years of age With caution: with ascites, effusion into the pleural cavity, gastric and duodenal ulcers, ulcerative colitis, dehydration, gout or nephrolithiasis in history, previous radiation therapy or chemotherapy, infectious diseases viral, fibrous or bacterial nature.
Directions for use and doses
Methotrexate tablets are used orally. Doses and duration of treatment are determined individually depending on the chemotherapy regimen.
Trophoblastic tumors:
- 15-30 mg orally, daily for 5 days at intervals of one or more weeks (depending on signs of toxicity). Courses of treatment are usually repeated 3 to 5 times.
- 50 mg 1 time every 5 days with an interval of at least 1 month. The course of treatment requires 300400 mg.
Acute lymphoblastic leukemia (as part of complex therapy):
- 3.3 mg/m2 in combination with prednisolone until remission is achieved, then 15 mg/m2 2 times a week or 2.5 mg/kg every 14 days.
Non-Hodgin lymphomas (as part of complex therapy):
- 15-20 mg/m2 per dose, 2 times a week;
— 7.5 mg/m2 daily for 5 days Rheumatoid arthritis:
The starting dose is usually 7.5 mg once a week, taken at once or divided into three doses 12 hours apart. To achieve optimal effect, the weekly dose can be increased, but it should not exceed 20 mg. When optimal clinical effect is achieved, dose reduction should begin to achieve the lowest effective dose.
The optimal duration of therapy is unknown. For juvenile chronic arthritis, doses of 10-30 mg/m2/week (0.3-1 mg/kg) are effective for children.
Psoriasis:
Methotrexate therapy is carried out in doses of 10 to 25 mg per week. The dose is usually increased gradually; when the optimal clinical effect is achieved, the dose is reduced until the lowest effective dose is reached.
Fungioid mycosis:
25 mg 2 times a week. Reducing the dose or discontinuing the drug is determined by the patient’s response and hematological parameters.
Side effect
From the hematopoietic system: pancytopenia,
leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, anemia, agranulocytosis, eosinophilia.
From the digestive system: anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, pharyngitis, rarely - enteritis, diarrhea, erosive and ulcerative lesions and bleeding from the gastrointestinal tract, in some cases (with long-term daily use)
- impaired liver function, increased activity of “liver” transaminases, periportal fibrosis and cirrhosis of the liver, liver necrosis, fatty liver, pancreatitis.
From the nervous system: encephalopathy (in patients who received radiation therapy to the cranial area), increased fatigue, dizziness, headache, aphasia, paresis, hemiparesis, weakness, confusion, ataxia, tremor, irritability, convulsions and coma.
From the urinary system: cystitis,
nephropathy, renal dysfunction (increased creatinine levels, hematuria), dysuria.
From the reproductive system: disruption of the process of oogenesis, spermatogenesis, decreased libido/impotence, changes in fertility, teratogenic effects.
From the respiratory system: chronic interstitial pneumonitis, acute pulmonary edema, pulmonary fibrosis, pneumonitis, alveolitis, bronchial asthma, pleural effusion.
From the skin and skin appendages: skin erythema and/or rash, skin itching, urticaria, telangiectasia, furunculosis, depigmentation or hyperpigmentation, acne, skin peeling, folliculitis, alopecia (rare), increased photosensitivity, exacerbation of radiation dermatitis.
From the senses: conjunctivitis, excessive lacrimation, cataracts, photophobia, cortical blindness (at high doses), visual impairment.
Allergic reactions: fever, chills, rash, urticaria, anaphylaxis, malignant exudative erythema (Stevens-Johnson syndrome), toxic epidermal necrolysis (Lyell's syndrome).
Other: immunosuppression (decreased resistance to infectious diseases), malaise, osteoporosis, hyperuricemia, hemorrhagic syndrome, vasculitis, arthralgia/myalgia, pericardial effusion.
Overdose
In case of accidental overdose of methotrexate, it is recommended to use a specific antidote - calcium folinate. Administration of calcium folinate should be started as soon as possible, preferably within the first hour, at a dose equal to or greater than the dose of methotrexate; subsequent doses are administered as needed depending on the concentration of methotrexate in the blood serum. To prevent precipitation of methotrexate and/or its metabolites in the renal tubules, the body is hydrated and the urine is alkalinized.
Interaction with other drugs
With the simultaneous use of high doses of Methotrexate-SZ with various non-steroidal anti-inflammatory drugs (NSAIDs), including acetylsalicylic acid and other salicylates, azapropazone, diclofenac, indomethacin and ketoprofen, the toxicity of methotrexate may increase, and in some cases severe toxicity is possible, sometimes even fatal outcome. Subject to special precautions and appropriate monitoring, the use of methotrexate in low doses (7.5-15 mg per week), particularly in the treatment of rheumatoid arthritis, in combination with NSAIDs is not contraindicated.
Methotrexate increases the anticoagulant activity of coumarin derivatives or itzazzin and/or increases the risk of bleeding by reducing the synthesis of a procoagulant factor in the liver and impairing platelet formation. The simultaneous use of sulfonamides, sulfonylurea derivatives, phenytoin, phenylbutazone, aminobenzoic acid, probenecid, pyrimethamine or trimethoprim, a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anticoagulants and hypolipcemic drugs (cholestyramine) increases the toxicity of methotrexate. Methotrexate increases the concentration of uric acid in the blood, therefore, when treating patients with concomitant hyperuricemia and gout, dose adjustment of anti-gout medications (allopurinol, colchicine, sulfinpyrazone) may be required; the use of uricosuric anti-gout drugs may increase the risk of developing nephropathy associated with increased formation of uric acid during treatment with methotrexate (it is preferable to use allopurinol).
Antibiotics that are poorly absorbed from the gastrointestinal tract (tetracyclines, chloramphenicol) reduce the absorption of methotrexate and disrupt its metabolism due to suppression of normal intestinal microflora.
Retinoids, azathioprine, sulfasalazine increase the risk of hepatotoxicity. Multivitamin preparations containing folic acid or its derivatives may reduce the effectiveness of methotrexate therapy.
The use of cytarabine 48 hours before or within 10 minutes after the start of methotrexate therapy may cause the development of a synergistic cytotoxic effect (adjustment of the dosage regimen is recommended based on monitoring hematological parameters).
Oral neomycin may decrease the absorption of oral methotrexate.
Hematotoxic drugs increase the risk of developing methotrexate hematotoxicity. L-asparaginase is an antagonist of methotrexate. Anesthesia using dinitrogen oxide can lead to the development of unpredictable severe myelosuppression and stomatitis.
Administration of amiodarone to patients receiving methotrexate therapy for psoriasis may cause skin ulceration. Methotrexate reduces the clearance of theophylline.
Several patients with psoriasis or mycosis fungoides treated with methotrexate in combination with PUVA therapy (methoxsalen and ultraviolet radiation) have been diagnosed with skin cancer. Caution should be exercised when administering packed red blood cells and methotrexate simultaneously.
Combination with radiotherapy may increase the risk of soft tissue necrosis. Methotrexate may reduce the immunological response to vaccination. When administered simultaneously with a live vaccine, severe antigenic reactions may develop.
special instructions
Methotrexate-SZ is a cytotoxic drug, so care must be taken when handling it.
To prevent toxicity during treatment with Methotrexate-SZ, periodic blood tests (once a week), determination of the content of leukocytes and platelets, and liver and kidney function tests are required. If diarrhea and ulcerative stomatitis develop, therapy with Methotrexate-SZ must be interrupted, otherwise this may lead to the development of hemorrhagic enteritis and the death of the patient due to intestinal perforation.
In patients with impaired liver function, the elimination period of Methotrexate-SZ is increased, therefore, in such patients, therapy should be carried out with extreme caution, using reduced doses.
Renal dysfunction is dose dependent. The risk of impairment is increased in patients with reduced renal function or dehydration, as well as in patients taking other nephrotoxic drugs.
Particular attention should be paid to the manifestations of the toxic effect of methotrexate on the liver, which are not always reflected in the results of functional tests. Treatment should not be started or should be discontinued if any functional impairment or abnormal liver biopsy is detected that is present or develops during therapy. These disturbances subside within two weeks, after which therapy can be resumed at the discretion of the attending physician.
There are currently no recommendations regarding the timing of liver biopsy in patients with rheumatoid arthritis: either based on the cumulative dose of methotrexate or the duration of therapy.
Men and women of childbearing age should use reliable methods of contraception during treatment with methotrexate and for at least 3 months after. Some side effects of the drug may negatively affect the ability to drive a car and perform potentially dangerous activities that require increased concentration and speed of psychomotor reactions.
Release form
Film-coated tablets, 2.5 mg.
10 or 30 tablets in blister packs. 50 tablets in a polymer jar or in a polymer bottle. Each jar or bottle, 5 blister packs of 10 tablets, 1, 2, 3, 4 blister packs of 30 tablets, along with instructions for use in a cardboard box.
Best before date
3 years. Do not use after the expiration date stated on the packaging.
Storage conditions
In a dry place, protected from light, at a temperature not exceeding 25 ° C. Keep out of the reach of children.
Vacation conditions
Dispensed by prescription.
Prescription drug
Prescription drug