Description
Pharmacological effect anti-inflammatory effect. It inhibits dihydrofolate reductase, which is involved in the reduction of dihydrofolic acid to tetrahydrofolic acid (a carrier of carbon fragments necessary for the synthesis of purine nucleotides and their derivatives). It inhibits the synthesis, DNA repair and cell mitosis (in the synthesis phase). Particularly sensitive to the action of methotrexate are tissues with high cell proliferation: tumor tissue, bone marrow, epithelial cells of the mucous membranes, embryonic cells. When the cell proliferation of malignant tissues is greater than in most normal tissues, methotrexate can lead to impaired growth of malignant tumors without irreversible damage to normal tissue. The mechanism of action in rheumatoid arthritis is associated with the immunomodulating and anti-inflammatory effect of the drug and is caused by 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-enhancing tumor synthesis alpha) cytokines IL-4, IL-10 and inhibition of the activity of metalloproteinases. In patients with rheumatoid arthritis, the use of methotrexate reduces the symptoms of inflammation (pain, swelling, stiffness), however, there are a limited number of studies with prolonged use of methotrexate (regarding the ability to maintain remission in rheumatoid arthritis). With psoriasis, the growth rate of keratinocytes in psoriatic plaques increases compared 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 With intramuscular administration, the maximum concentration of methotrexate in blood plasma is reached within 30-60 minutes. Leukemic patients are characterized by wide interindividual variability ranging from 1 to 3 hours. The relative bioavailability in patients with rheumatoid arthritis is comparable after intramuscular or subcutaneous injection when using the same dose 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 body weight). About 50% of methotrexate binds to plasma proteins, mainly with albumin. Competitive displacement is possible with simultaneous use with sulfonamides, salicylates, tetracyclines, chloramphenicol, phenytoin. Methotrexate does not cross the blood-brain barrier when used in therapeutic doses. A high concentration of methotrexate in the central nervous system can be achieved with intrathecal administration. Methotrexate undergoes hepatic and intracellular metabolism with the formation of a pharmacologically active polyglutamine form, which also inhibits dihydrofolate reductase and thymidine synthesis. A small amount of polyglutamate methotrexate may remain in the tissues for a long period of time. Preservation and prolongation of the action of the active metabolites of the drug vary depending on the type of cells, tissues and tumors. The average half-life with methotrexate at a dose of less than 30 mg / m2 is 6-7 hours. For patients receiving high doses of methotrexate, the half-life is from 8 to 17 hours. In chronic renal failure, both phases of methotrexate excretion can be significantly extended. From 80 to 90% of the dose taken is excreted unchanged by glomerular filtration and tubular secretion for 24 hours. Not more than 10% or less of the administered dose is excreted with bile, followed by reabsorption in the intestine. Impaired renal function, severe ascites or transudate, as well as the simultaneous use of drugs, such as weak organic acids, which also undergo tubular secretion, can significantly increase the concentration of methotrexate in serum. In accordance with the distribution, methotrexate accumulates in the liver, kidneys and spleen in the form of polyglutamates and can linger in these organs for several weeks or months. In children In children receiving methotrexate for the treatment of acute lymphocytic leukemia (6.3 to 30 mg / m ) Or juvenile idiopathic arthritis (3.75 to 26.2 mg / m ), the final half-life ranged from 0.7 to 5.8 hours and 0.9 to 2.3 hours, respectively.
Indications
trophoblastic tumors acute leukemia (especially lymphoblastic and myeloblastic variants) non-Hodgkin’s neuroleukemia, including 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 fungoid mycosis (advanced stages) severe forms of psoriasis, psoriatic arthritis, rheumatoid arthritis, juvenile chronic arthritis, dermatoma lupus erythematosus, ankylosing spondylitis (with the ineffectiveness of standard therapy).
Contraindications
hypersensitivity to methotrexate and / or any other component of the drug severe renal failure (creatinine clearance less than 30 ml / min) severe liver failure history of alcohol abuse of the blood system (in particular, bone marrow hypoplasia thrombocytopenia or clinically significant anemia) severe acute and chronic infectious diseases, such as tuberculosis and HIV infection, concomitant vaccination with live vaccines for oral ulcers, gastrointestinal ulcers in the active phase, pregnancy, lactation, simultaneous use of methotrexate at a dose of 15 mg / week and more with acetylsalicylic acid.
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 ( 1/100 to Infectious and parasitic diseases often: herpes zoster infrequently: opportunistic infections, including pneumonia (including fatal), rarely: sepsis (including, very rarely, fatal), very rarely: nocardiosis, histoplasmosis, cryptococcosis, hepatitis and disseminated herpes simplex virus infections, infections caused by cytomegalovirus ( including pneumonia) frequency unknown: reactivation of hepatitis B virus, hepatitis C. Benign, malignant and unspecified neoplasms (including cysts and polyps) infrequently: lymphoma is very rare: tumor lysis syndrome. Violations of the blood system and lymphatic system are very common: leukopenia, thrombocytopenia often: anemia, pancytopenia, agranulocytosis rarely: megaloblastic anemia very rarely: aplastic anemia, lymphadenopathy and lymphoproliferative diseases, eosinophilia, neutropenia, severe progressive inhibition of bone marrow function. Immune system disorders are rare: allergic reactions, anaphylactic shock, allergic vasculitis, fever, immunosuppression are very rare: hypogammaglobulinemia. Metabolic and nutritional disorders infrequently: diabetes. Mental disorders infrequently: depression is rare: transient violation of cognitive functions, emotional lability. Disturbances from the nervous system often: headache, increased fatigue, drowsiness, paresthesia infrequently: cramps, development of hemiparesis, vertigo (dizziness), confusion, encephalopathy / leukoencephalopathy (including fatal cases) rarely: paresis, speech disorders, including dysarthria and aphasia, myelopathy (with intrathecal administration) is very rare: discomfort in the head area, myasthenia gravis, pain in the extremities, taste perversion (metallic taste in the mouth), acute aseptic meningitis with the phenomena of meningism (paralysis, vomiting), insomnia, frequency is unknown: increased pressure in the spinal canal (after intrathecal injection), development of a hernia of the spinal cord (after intrathecal administration for periventricular lymphoma). Violations of the organ of vision are rare: visual impairment (blurred vision, including severe visual impairment of unknown etiology) is very rare: periorbital edema, blepharitis, lacrimation, photophobia, conjunctivitis, transient blindness, loss of vision. Heart abnormalities rarely: arterial hypotension (lowering blood pressure) is very rare: 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). Disorders from the respiratory system, chest and mediastinal organs often: interstitial pneumonitis / alveolitis (including fatal, regardless of the dose and duration of methotrexate therapy). Symptoms of potentially serious lung damage with interstitial pneumonitis: dry, unproductive cough, shortness of breath, progressing to shortness of breath at rest, chest pain, fever. If these symptoms occur, treatment with methotrexate should be stopped immediately, and lower respiratory tract infections should also be excluded. infrequently: pulmonary fibrosis, effusion into the pleural cavity rarely: pharyngitis, apnea, epistaxis is very rare: chronic obstructive pulmonary disease (COPD), reactions similar to bronchial asthma (accompanied by coughing, shortness of breath, deviations in functional lung tests), pneumonia caused by Pneumocystis carinii, acute pulmonary edema frequency unknown: respiratory paralysis. Gastrointestinal disorders are very common: stomatitis, abdominal pain, loss of appetite, nausea and vomiting (especially in the first 24-48 hours after starting treatment), dyspepsia often: diarrhea infrequently: ulceration of the gastrointestinal mucosa ( Gastrointestinal tract), gastrointestinal bleeding, rare pancreatitis: enteritis, gingivitis, melena, malabsorption syndrome is very rare: hematemesis (bloody vomiting), toxic megacolon frequency unknown: non-infectious peritonitis. Violations of the liver and biliary tract are very common: increased activity of “hepatic” transaminases, alkaline phosphatase, increased plasma bilirubin concentration often: 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 liver dystrophy (including against the background of acute herpetic hepatitis), acute liver failure, liver necrosis. Disorders of the skin and subcutaneous tissues often: exanthema, erythematous rash, itching of the skin infrequently: alopecia, erythema multiforme (including malignant exudative erythema [Stevens-Johnson syndrome]), toxic epidermal necrolysis (Lyell syndrome), herpetiform rash photosensitivity, urticaria, increased pigmentation of the skin, slow healing of wounds rarely: acne, ulceration of the skin, ecchymoses, the appearance of nodules on the skin, painful erosion, psoriatic plaques, nail pigmentation, onycholysis, an increase in the size of rheumatoid nodules are very rare: furunculosis, telangiectasia, acute paronychia, hydradenitis frequency is unknown: skin necrosis (at the injection site). 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: marching (fatigue) fracture. From the kidneys and urinary tract very often: creatinine clearance is infrequent infrequent: severe nephropathy, renal failure, cystitis with ulceration of the mucous membrane of the bladder, dysuria (urination disorders), oliguria, anuria rarely: hyperuricemia, an increase in the concentration of urea in blood plasma, an increase in the concentration of creatinine in blood plasma is very rare: azotemia, hematuria, proteinuria. Influence on the course of pregnancy, postpartum and perinatal conditions infrequently: abnormalities of the fetus rarely: premature termination of pregnancy is very rare: fetal death. Violations of the genitals and mammary gland are rare: vaginitis and ulceration of the vaginal mucosa are rare: menstrual irregularities are very rare: impaired spermatogenesis or egg maturation, impotence, infertility, loss of libido, transient oligospermia, abnormal vaginal discharge, menstrual irregularities, gynecomastia. Adverse reactions resulting from intrathecal methotrexate administration: acute chemical arachnoiditis (clinical manifestations include headache, dorsalgia, numbness in the neck and fever), subacute myelopathy (paresis or paraplegia in the area of innervation of one or more affected roots of the spinal cord), chronic leukoencephalopathy, whose manifestations include confusion, increased irritability, drowsiness, ataxia, dementia, cramps and development of coma. In case of progression, these manifestations of toxicity can lead to the death of the patient. The combined use of intrathecal methotrexate and brain irradiation increases the risk of developing leukoencephalopathy. After 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 of
Symptoms: mainly symptoms associated with inhibition of the hematopoietic system are observed. Treatment: a specific antidote of methotrexate is calcium folinate. It neutralizes adverse toxic effects. In case of accidental overdose no later than an hour after the administration of methotrexate, calcium folinate is administered (intravenously or intramuscularly) at a dose equal to or higher than the dose of methotrexate. The introduction of calcium folinate continues until the concentration of methotrexate in the blood serum decreases below the level of 10-7 mmol / L. With a significant overdose, hydration of the body and alkalization of urine (pH greater than 7) may be required to prevent precipitation of methotrexate and / or its metabolites in the renal tubules. Hemodialysis and peritoneal dialysis do not improve elimination of methotrexate. Intensive intermittent hemodialysis using highly permeable (“high-flux”) dialyzers allows for the effective clearance of methotrexate. In case of an overdose with intrathecal administration, immediately after an overdose is detected, repeated lumbar punctures should be performed to ensure fast drainage of cerebrospinal fluid, neurosurgical intervention with ventriculolumbar perfusion is possible. All these procedures should be performed against the background of intensive supportive care and systemic administration of large doses of calcium folinate.
active substance
Methotrexate
Terms of delivery from
pharmacies Prescription
dosage form
injection
