Methotrexate injection 10mg/ml 5 ml №1

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 (with regard torheumatoid 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.

Pharmacokinetics

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 / m²make up 6-7 hours. In patients receiving high doses of methotrexate, T_1/2ranges 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.

Indications

- 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).

Dosing regimen

Methotrexate is a part of many chemotherapeutic treatment regimens, and therefore in choosing the route of administration, regimen and doses in each individual case, one should be guided by the data of special literature.

Methotrexate-Ebeve for injection can be injected in a / m, in / in, in / a or intrathecal.

Attrophoblastic tumors -at 15-30 mg / m, daily for 5 days with an interval of ≥1 week (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.

Atsolid tumorsin combination with other anticancer drugs - 30-40 mg / m² in / in the jet 1 time per week.

Atleukemia or lymphomas -200-500 mg / m² by iv infusion 1 time in 2-4 weeks.

Atneuroleukemia -12 mg / m² intrathecally within 15-30 seconds 1 or 2 times a week.

When treating children, the dose is selected depending on age:children under 1 year prescribe 6 mg1 year old children - 8 mg,children aged 2 years- 10 mg,children over 3 years old - 12 mg.

Before the introduction, the cerebrospinal fluid should be removed in a volume approximately equal to the volume of the medicinal product to be introduced.

When appliedhigh-dose therapy - from 2 to 15 g / m² in the form of a 4-6 hour intravenous infusion with an interval of 1-5 weeks with the mandatory subsequent administration of Calcium folinate, which usually starts 24 hours after the start of the infusion of methotrexate and is administered every 6 hours at a dose of 3-40 mg / m² (usually 15 mg / m²) and higher, depending on the concentration of methotrexate in the serum for 48-72 hours

Atrheumatoid arthritisThe initial dose is usually 7.5 mg 1 time per week, which is administered simultaneously in / in, in / m 2.5 mg every 12 hours (3 doses total). To achieve an optimal effect, the weekly dose may be increased, but 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 unknown.

Atpsoriasisin / m or / in jet in doses of 10 to 25 mg per week. The dose is usually increased gradually, when the optimal clinical effect is reached, the dose reduction begins until the lowest effective dose is reached.

Atmushroom mycosisi / m 50 mg 1 time per week or 25 mg 2 times per week for several weeks or months. Dose reduction or withdrawal of the drug is determined by the patient's response and hematological parameters.

Side effect

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.

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

On the part of the respiratory system: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 mucous membranes, loss of appetite, dyspepsia ,anorexia, a significant increase in liver transaminase activity; 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.

Contraindications

- 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 in history) or urate nephrourolithiasis (including in history), infections and inflammation of the oral mucosa, vomiting, diarrhea,gastric ulcer and duodenal ulcer, ulcerative colitis, obstructive gastrointestinal diseases, previous Chemotherapy or radiation therapy, asthenia, aciduria (urine pH less than 7), as well as in children and elderly patients.

Use during pregnancy and lactation

Acceptance of methotrexate during pregnancy can cause serious malformations of the fetus (an increase in the incidence of malformations of the skull, cardiovascular system and limbs 14 times), therefore Methotrexate-Ebeve is contraindicated during pregnancy.

If pregnancy occurs during methotrexate treatment, you should consult with specialists about the risk of adverse effects of methotrexate on the fetus.

Patients of reproductive age (both women and men) must use effective contraception during and at least 6 months after the end of treatment with Methotrexate-Ebeve.