Methotrexate Ebeve pills coated 10mg N50
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Active ingredients
Methotrexate
Release form
Pills
Composition
Active ingredient: methotrexate. Excipients: lactose monohydrate, corn starch, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate
Pharmacological effect
Antitumor, cytostatic agent of the group of antimetabolites-analogues of folic acid. Inhibits dihydrofolate reductase involved in the reduction of dihydrofolic acid to tetrahydrofolic acid (carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives). Inhibits synthesis, DNA repair and cell mitosis (in the S phase). Particularly sensitive to the action of methotrexate tissue with high cell proliferation are tumor tissue, bone marrow, mucous membrane epithelium cells, and embryonic cells. In addition, methotrexate has immunosuppressive properties. Along with antitumor, it has an immunosuppressive effect.
Pharmacokinetics
Oral absorption depends on the dose: when taken 30 mg / m is well absorbed, the average bioavailability is 50%. Absorption is reduced when taken in doses exceeding 80 mg / m (believed due to saturation). In children with leukemia, absorption ranges from 23 to 95%. The time to reach the maximum concentration (Cmax) is 1-2 hours at oral and 30-60 minutes - with the / m introduction. Food slows down the absorption and reduces Cmax. Communication with plasma proteins is about 50%. When taken in therapeutic doses, regardless of the route of administration, it practically does not penetrate through the BBB (after intrathecal administration, high concentrations are achieved in the cerebrospinal fluid). It penetrates into breast milk. After oral administration, it is partially metabolized by intestinal flora, the main part - in the liver (regardless of the route of administration) with the formation of a pharmacologically active polyglutamine form that inhibits dihydrofolate reductase and thymidine synthesis. The half-life in the initial phase is 2-4 hours, and in the final phase (which is long) - 3-10 hours using normal doses and 8-15 hours - using high doses of the drug. In chronic renal failure, both phases of the elimination of the drug can be significantly prolonged. It is mainly excreted by the kidneys in unchanged form by glomerular filtration and tubular secretion (with i.v. administration 80-90% is eliminated within 24 hours), with bile up to 10% subsequent intestinal reabsorption).Removal of the drug in patients with impaired renal function, ascites or transudate expressed is significantly slowed down. When repeated injections accumulates in the tissues in the form of metabolites
Indications
• Trophoblastic tumors • Acute leukemia (lymphoblastic and myeloblastic variants) • Neuroleukemia • Non-Hodgkin lymphomas, including lymphosarcomas , kidney cancer, bladder cancer, testicular cancer, ovarian cancer, penile cancer, retinoblastoma, medulloblastoma • osteogenic sarcoma and soft tissue sarcoma • fungal mycosis (advanced stages) • severe forms of psoriasis, psoriatic arthritis, rheumatoid arthritis, d rmatomiozit, systemic lupus erythematosus, ankylosing spondylitis (after failure of standard therapy)
Contraindications
Hypersensitivity to methotrexate and / or any other component of the drug. • Pregnancy and breastfeeding. • Severe anemia, leukopenia; neutropenia, thrombocytopenia, renal or hepatic insufficiency, chicken pox (including recently transferred), herpes zoster and other infectious diseases. With caution: ascites, effusion in the pleural cavity, peptic ulcer of the stomach and duodenum, ulcerative colitis, dehydration history of gout or nephrolithiasis, previous radiation therapy or chemotherapy
Precautionary measures
Side effects caused by taking methotrexate may adversely affect vehicle control.
Use during pregnancy and lactation
Contraindicated
Dosage and administration
Methotrexate-Ebeve pills are taken orally before eating, without chewing. Apply the following dosing regimens: Trophoblastic tumors: 15-30 mg orally, daily for 5 days with an interval of one or more weeks (depending on signs of toxicity). Or 50 mg 1 time in 5 days with an interval of at least 1 month. The course of treatment is usually repeated from 3 to 5 times to a total dose of 300-400 mg. Rheumatoid arthritis: the initial dose is usually 7.5 mg once a week, which is administered all at once, or 2.5 mg every 12 hours (total 3 doses).To achieve the optimal effect, the weekly dose may be increased, and it should not exceed 20 mg. When the optimal clinical effect is achieved, the dose should be reduced to the lowest effective dose. The optimal duration of treatment is not known. Psoriasis: by mouth in doses of 10-25 mg per week. The dose is usually increased gradually, when the optimal clinical effect is reached, a dose reduction is started until the lowest effective dose is reached. Fungal mycosis: orally 2.5 mg per day for several weeks or months. Dose reduction or withdrawal of the drug is determined by the patient's response and hematological parameters
Side effects
On the part of the blood-forming organs: leukopenia, neutropenia, lymphopenia (especially T-lymphocytes), thrombocytopenia, anemia. On the part of the digestive system: anorexia, nausea, vomiting, stomatitis, gingivitis, glossitis, pharyngitis; rarely - enteritis, diarrhea, erosive-ulcerative lesions and bleeding from the gastrointestinal tract. In some cases (with long-term daily use) - abnormal liver function, increased activity of "liver" transaminases, periportal fibrosis and cirrhosis of the liver; liver necrosis, fatty degeneration of the liver; pancreatitis. From the nervous system: encephalopathy, especially with the introduction of multiple doses intrathecal, as well as in patients who received radiation therapy in the skull. There are also reports of fatigue, weakness, confusion, ataxia, tremor, irritability, convulsions and coma. Acute Adverse events caused by intrathecal administration of methotrexate may include dizziness, blurred vision, headache, pain in the back, stiffness of the back of the neck, convulsions, paralysis, hemiparesis. From the urinary system: cystitis, nephropathy, impaired kidney function creatinine, hematuria). On the reproductive system: impaired oogenesis, spermatogenesis, changes in fertility, teratogenic effects. On the skin and skin appendages: skin erythema and / or rash, alopecia (Ed. co), increased photosensitivity, furunculosis, depigmentation or hyperpigmentation, acne, peeling of the skin, blistering, folliculitis. Allergic reactions: fever, chills,rash, urticaria, anaphylaxis. For the senses: conjunctivitis, excessive tearing, cataracts, photophobia, cortical blindness (at high doses), blurred vision. For the respiratory system: rarely - interstitial pneumonitis, pulmonary fibrosis, exacerbation of pulmonary infections. Others: immunosuppression (reduced resistance to infectious diseases), malaise, osteoporosis, hyperuricemia, vasculitis
Overdose
The simultaneous use of high doses of methotrexate with various nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and other salicylates, azapropazone, diclofenac, indomethacin and ketoprofen, the toxicity of methotrexate can be enhanced, and in some cases it may be a heavy toxic effect, sometimes even with lethal outcome. With special precautions and appropriate monitoring, the use of low-dose methotrexate (7.5-15 mg per week), in particular in the treatment of rheumatoid arthritis, in combination with NSAIDs is not contraindicated. The simultaneous use of sulfonamides derived from sulfonylurea, phenytoin, phenylbutazone, aminobenzoic acid, probenicide, pyrimethamine or trimethoprim; a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anti-coagulants, and other anti-toxic drugs (cholestyramine) enhances the toxicity of methotrexate. azathioprine, sulfasalazine increases the risk of hepatotoxicity. Polyvitaminic preparations containing folic acid or its derivatives may reduce the effectiveness of methotrexate therapy. L-asparaginase is antagonist of methotrexate. Anesthesia with the use of dinitrogen oxide can lead to the development of an unpredictable methostrexate antagonist. skin ulceration. Metotrexat reduces theophylline clearance. In several patients with psoriasis or fungal mycosis, x methotrexate therapy in combination with PUVA-treatment (methoxsalen and UV irradiation) was identified cancer kozhi.Sleduet careful simultaneous introduction of packed red cells and metotreksata.Sochetanie with radiotherapy may increase the risk of necrosis of soft tkaney.Metotreksat may reduce the immunologic response to vaccination.When administered simultaneously with a live vaccine, severe antigen reactions may develop.
Interaction with other drugs
The simultaneous use of high doses of methotrexate with various nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin and other salicylates, azapropazone, diclofenac, indomethacin and ketoprofen, the toxicity of methotrexate can be enhanced, and in some cases it may be a heavy toxic effect, sometimes even with lethal outcome. With special precautions and appropriate monitoring, the use of low-dose methotrexate (7.5-15 mg per week), in particular in the treatment of rheumatoid arthritis, in combination with NSAIDs is not contraindicated. The simultaneous use of sulfonamides derived from sulfonylurea, phenytoin, phenylbutazone, aminobenzoic acid, probenicide, pyrimethamine or trimethoprim; a number of antibiotics (penicillin, tetracycline, chloramphenicol), indirect anti-coagulants, and other anti-toxic drugs (cholestyramine) enhances the toxicity of methotrexate. azathioprine, sulfasalazine increases the risk of hepatotoxicity. Polyvitaminic preparations containing folic acid or its derivatives may reduce the effectiveness of methotrexate therapy. L-asparaginase is antagonist of methotrexate. Anesthesia with the use of dinitrogen oxide can lead to the development of an unpredictable methostrexate antagonist. skin ulceration. Metotrexat reduces theophylline clearance. In several patients with psoriasis or fungal mycosis, x methotrexate therapy in combination with PUVA-treatment (methoxsalen and UV irradiation) was identified cancer kozhi.Sleduet careful simultaneous introduction of packed red cells and metotreksata.Sochetanie with radiotherapy may increase the risk of necrosis of soft tkaney.Metotreksat may reduce the immunologic response to vaccination. When administered simultaneously with a live vaccine, severe antigen reactions may develop.
special instructions
Methotrexate is a cytotoxic drug, so care must be taken when handling it. Dosage forms containing preservatives, in particular benzyl alcohol, should not be used for intrathecal administration or for high-dose therapy. toxic reactions. High-dose therapy should be carried out only by experienced chemotherapists who can control the concentration of methotrexate in plasma in stationary conditions under the cover of calcium folinata. During therapy with methotrexate in high and high doses, it is necessary to monitor urine pH: on the day of administration and in the next 2-3 days the urine reaction should be alkaline. This is achieved by intravenous drip infusion of a mixture consisting of 40 ml of 4.2% sodium bicarbonate solution and 400-800 ml of isotonic sodium chloride solution the day before, on the day of treatment and for the next 2-3 days. Treatment with methotrexate in high and high doses should be combined with enhanced hydration to 2 liters of fluid per day. Administration of methotrexate at a dose of 2 g / m2 and above is carried out under the control of its concentration in serum. It is considered normal to decrease the content of methotrexate in the serum after 22 hours after administration by 2 times compared with the initial level. Increasing the level of creatinine by 50% or more of the initial content and / or increasing the level of bilirubin require intensive detoxification therapy. For the treatment of psoriasis, methotrexate is prescribed only to patients with a severe form of the disease who cannot be treated with other types of therapy. blood count (1 time per week), determination of white blood cell and platelet counts, liver and kidney function tests. With the development of diarrhea and ulcerative therapy with methotrexate must be interrupted, otherwise it may lead to the development of hemorrhagic enteritis and to the death of the patient due to bowel perforation. doses. Impairment of renal function 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. Men and women of childbearing age during treatment with methotrexate and for at least 3 months after should use reliable contraceptive methods