Methotrexate injection syringe 10mg/ml 1 ml №1

Antitumor drug

Mechanism of action

An antitumor drug from the group of antimetabolites - folic acid analogues. Along with antitumor has an immunosuppressive effect.

Inhibits dihydrofolate reductase 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.

Inhibits synthesis, DNA repair and cell mitosis (during the synthesis phase). Particularly sensitive to the action of methotrexate tissue with high cell proliferation: tumor tissue, bone marrow, mucous membrane epithelium cells, embryonic cells.

When cell proliferation of malignant tissue is greater than in most normal tissues, methotrexate can lead to an abnormal growth of malignant tumors 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, the use of methotrexate reduces the symptoms of inflammation (pain, swelling, stiffness), but there is a limited number of studies with long-term use of methotrexate (regarding the ability to maintain remission in rheumatoid arthritis).

In 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.

Suction and distribution

When v / m introduction C_max Plasma methotrexate is reached within 30-60 minutes. For leukemic patients, there is a wide interindividual variability ranging from 1 to 3 hours.

After the on / in the introduction of the primary distribution is 0.18 l / kg (18% of body weight). The saturation dose distribution is about 0.4-0.8 l / kg (40% -80% of body weight).

Plasma protein binding is about 50%, predominantly with albumin.Competitive extrusion is possible with simultaneous use with sulfonamides, salicylates, tetracyclines, chloramphenicols, phenytaine.

When taken in therapeutic doses, methotrexate does not penetrate the BBB. High concentrations of methotrexate in the CNS can be achieved with intrathecal administration.

Metabolism

Methotrexate undergoes hepatic and intracellular metabolism to form a pharmacologically active polyglutamine form, which also inhibits dihydrofolate reductase and thymidine synthesis. A small amount of methotrexate polyglutamate can remain in the tissues for a long period of time. Preservation and prolongation of the active metabolites of the drug vary depending on the type of cells, tissues and tumors.

Removal

Average T_1/2 with the use of methotrexate in a dose of less than 30 mg / m² make up 6-7 hours. In patients receiving high doses of methotrexate, T_1/2 ranges from 8 to 17 h.

From 80 to 90% of the accepted dose is excreted unchanged by glomerular filtration and tubular secretion within 24 hours. With bile, no more than 10% or less of the administered dose is excreted, followed by intestinal reabsorption.

Pharmacokinetics in special clinical situations

Atchronic renal failure both phases of the elimination of the drug can be significantly lengthened.

Impaired renal function, pronounced ascites or transudate, as well as the simultaneous use of drugs such as weak organic acids, which are also subject to tubular secretion, can significantly increase the concentration of methotrexate in serum. In accordance with the distribution of methotrexate, it accumulates in the liver, kidneys and spleen in the form of polyglutamates and may linger in these organs for several weeks or months.

- trophoblastic tumors;

- acute leukemia (especially lymphoblastic and myeloblastic variants);

- neuroleukemia;

- Non-Hodgkin lymphomas, including lymphosarcoma;

- breast cancer, squamous cell head and neck cancer, lung cancer, skin cancer, cervical cancer, vulvar cancer, esophageal cancer, kidney cancer, bladder cancer, testicular cancer, ovarian cancer, penile cancer, retinoblastoma, medulloblastoma;

- osteogenic sarcoma and soft tissue sarcoma;

- mushroom mycosis (advanced stages);

- severe forms of psoriasis, psoriatic arthritis, rheumatoid arthritis, dermatomyositis, SLE, ankylosing spondylitis (with the ineffectiveness of standard therapy).

- severe renal failure (CC <20 ml / min);

- severe liver failure;

- alcohol abuse;

- violations of the hematopoietic system in history (in particular, bone marrow hypoplasia, leukopenia, thrombocytopenia, or clinically significant anemia);

- severe acute and chronic infectious diseases such as tuberculosis and HIV infection;

- concomitant vaccination with live vaccines;

- ulcers of the oral cavity, ulcers of the gastrointestinal tract in the active phase;

- simultaneous use of methotrexate at a dose of ≥15 mg / week. with Acetylsalicylic acid;

- pregnancy;

- lactation period;

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

Carefullyuse the drug in patients with impaired liver and kidney function, diabetes, obesity and previous exposure to hepatotoxic drugs, dehydration, ascites, bone marrow hematopoietic suppression, pleural or peritoneal effusion, parasitic and infectious diseases of a viral, fungal or bacterial nature - the risk of developing a severe generalized diseases (currently or recently experienced, including recent contact with a patient - herpes simplex, herpes zoster) (viremic Skye phase), chicken pox, measles, amoebiasis, strongyloidiasis (or suspected)); gout (including a history of) or uric nephrolurithiasis (including a history), infections and inflammations of the oral mucosa, vomiting, diarrhea, gastric ulcer and duodenal ulcer, ulcerative colitis, obstructive gastrointestinal diseases, Chemotherapy or radiation therapy, asthenia, aciduria (urine pH less than 7), as well as in children and elderly patients.

Adverse reactions

According to WHO, undesirable effects 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 / 10 000 to <1/1000), very rarely (<1/10 000); frequency is unknown - according to the available data it was not possible to establish the frequency of occurrence.

Hemic and lymphatic: often- inhibition 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 side of the central nervous system:often - drowsiness, headache, fatigue; infrequently - depression, confusion, mood changes; seldom - with the use of methotrexate in low doses - transient small impairments of cognitive functions, unusual sensations in the skull; very rarely - pain, myasthenia gravis or paresthesias in the limbs, taste perversion (metallic taste in the mouth), seizures, meningism, paralysis, insomnia.

Special senses:often - visual impairment; infrequently - eye irritation; seldom- conjunctivitis.

Respiratory:often - chronic interstitial pneumonitis (symptoms suggestive of potentially serious lung damage in interstitial pneumonitis: dry, non-productive cough, shortened breathing, increased body temperature); infrequently - alveolitis, pleural effusion; seldom - pulmonary fibrosis, pneumocystic pneumonia, bronchial asthma; very rarely - pleural pain and thickening of the pleura (with high-dose methotrexate treatment), 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 hepatic 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, renal dysfunction, and urination disorders; rarely - renal failure, oliguria, anuria, electrolyte imbalance.

From the skin:often - exanthema, erythema, itching; infrequently - photosensitivity, alopecia, shingles, vasculitis, herpetiform skin rash, urticaria; rarely - increased pigmentation; very rarely - Stevens-Johnson syndrome, epidermal necrolysis (Lyell's syndrome). When exposed to ultraviolet radiation, increased psoriatic skin lesions, increased nail pigmentation, acute paronychia, furunculosis and hydradenitis.

From the musculoskeletal system:infrequently - arthralgia, myalgia, osteoporosis.

Since the cardiovascular system:often - vasculitis, bleeding of various localization; infrequently, effusion into the pericardial cavity; rarely - cardiac tamponade, nasal bleeding.

On the part of the immune system:very often - a decrease in resistance to infections, pharyngitis; infrequently, hypogammaglobulinemia; rarely, sepsis; very rarely - Anaphylactic reactions , an increase in the 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, impaired wound healing. When i / m administration - a burning sensation or tissue damage (the formation of a sterile abscess, the destruction of adipose tissue) at the injection site; very rarely, benign, malignant and non-specific neoplasms (including cysts and polyps), lymphomas, which in some cases regress after discontinuation of methotrexate; frequency is unknown - diabetes, other metabolic disorders, sudden death.

Adverse reactions with intrathecal administration of methotrexate

Acute:chemical arachnoiditis, manifested by headache, pain in the back or shoulders, stiff muscles in the back of the neck and fever.

Subacute:paresis (usually transient), paraplegia, dysfunction of the cerebellum.

Chronic:leukoencephalopathy, manifested by irritability, confusion, ataxia, muscle plasticity, sometimes convulsions, dementia, drowsiness, coma, and in rare cases with a fatal outcome. When combining radiation therapy to the region of the skull and intrathecal administration of methotrexate, the incidence of leukoencephalopathy increases.

Symptoms: symptoms mainly associated with depression of the hematopoietic system are observed.

Treatment:The specific antidote to methotrexate is Calcium folinate. It neutralizes adverse toxic effects.

In case of an accidental overdose, no later than one hour after administration of methotrexate, calcium folinate (i.v. or v / m) is administered in a dose equal to or greater than the dose of methotrexate.The introduction of calcium folinate is continued until the concentration of methotrexate in serum is below 10 level.^-7 mmol / l.

With a significant overdose, hydration of the body and alkalization of urine (pH over 7) may be necessary to prevent the precipitation of methotrexate and / or its metabolites in the renal tubules. Hemodialysis and peritoneal dialysis do not improve the elimination of methotrexate. Intensive intermittent hemodialysis using high-permeable ("high-flux") dialyzers provides effective clearance of methotrexate.

In case of overdose with intrathecal administration, repeated lumbar punctures should be performed immediately to ensure rapid drainage of the cerebrospinal fluid, possibly neurosurgical intervention with ventriculo-lumbar perfusion. All these procedures should be performed on the background of intensive maintenance therapy and systemic administration of large doses of calcium folinate.

Methotrexate can only be prescribed by an oncologist with experience in antineoplastic chemotherapy. Taking into account the risk of developing severe toxic reactions, including fatal ones, the physician is obliged to inform the patient in detail about the possible risk and necessary safety measures.

When a significant amount of fluid in the pleural cavities or ascites is detected in a patient, the fluid should be evacuated by drainage before starting treatment with methotrexate or discontinuing the use of methotrexate.

The appearance of symptoms of toxic lesions of the digestive system, the earliest of which is stomatitis, requires a temporary cessation of therapy with methotrexate due to the high risk of developing hemorrhagic enteritis and intestinal perforation with a lethal outcome if therapy continues.

During treatment with methotrexate, patients should be carefully monitored in order to timely detect signs of possible toxic effects and adverse effects. Given the risk of severe or even fatal toxic reactions, patients should be informed in detail about possible complications and recommended precautions.

Before starting treatment with methotrexate or when resuming therapy after a break, a blood test with leukocyte count and platelet count should be performed, the activity of liver enzymes, the concentration of bilirubin, serum albumin, as well as chest x-ray and functional renal tests should be evaluated. If there is clinical evidence, studies are prescribed to rule out tuberculosis and hepatitis.

In the process of treatment with methotrexate (every month for the first 6 months and no less than every 3 months thereafter, with increasing doses, it is advisable to increase the frequency of examinations) the following studies are conducted:

1. Examination of the mouth and throat to detect changes in the mucous membranes.

2. Blood test with the definition of leukocyte formula and platelet count. Even when used in conventional therapeutic doses, methotrexate can suddenly cause depression of the hematopoietic system. In the case of a significant reduction in the number of leukocytes or platelets, treatment with methotrexate is immediately stopped and symptomatic supportive therapy is prescribed. Patients should be instructed to immediately inform the doctor about any signs and symptoms indicating the development of infection. With concomitant therapy with hematotoxic drugs (eg, leflunomide), it is necessary to closely monitor the number of leukocytes and platelets in the blood.

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