Methotrexate - instructions for use, dose, side effects, contraindications

Pharmacodynamics:The inhibitor of dehydrofolate reductase, which converts dehydrofolic to tetrahydrofolic acid, which is a donor of single-carbon groups in the synthesis of thymidalate and purine nucleotides involved in DNA synthesis. Inside the cells methotrexate by polyglutamination it is converted into active metabolites that inhibit folate-dependent enzymes: 5-aminoimidazole-4-carboxamidoribonucleotide (AKAIR) trans-amylase and thymidylate synthetase. Antitumor activity is determined by a violation of the synthesis of folates.
Folic acid is necessary for the synthesis of de novo purine and pyrimide bases. Suppresses cellular mitosis, synthesis and DNA repair. It shows activity against tissues with high proliferative activity of cells, so it has S-phase specificity. It inhibits the growth of malignant neoplasms. It shows tropism to cells of tumors of the bone marrow, mucous membranes of the mouth, intestines, bladder, embryo.
The use of methotrexate for the treatment of rheumatoid arthritis is due to the influence on purine metabolism, inhibition of T and B lymphocyte activity, inhibition of binding of IL 1 to membrane receptors, increased sensitivity of CD95 activated T cells, leading to the development of apoptosis.

Pharmacokinetics:

After oral administration, fasted to 60% is absorbed in the gastrointestinal tract. The maximum concentration in the blood plasma is achieved 1-2 hours after ingestion,after 30-60 minutes - with intramuscular injection. The connection with plasma proteins is about 50%.

The therapeutic effect develops after the onset of admission. Metabolism in the liver to active polyglutamins that persist in the tissues for several months.

The half-life is 3-10 hours. Elimination by the kidneys after a single injection for 24 hours in unchanged form, about 10% is eliminated with feces.

Indications:

It is used for acute lymphatic leukemia, skin cancer, trophoblastic disease, cancer of the renal pelvis and ureters, esophageal cancer, squamous cell carcinoma of the head and neck, penile cancer, medulloblastoma, rhinoblastoma, and lymphogranulomatosis. Used to treat severe forms of psoriasis and rheumatoid arthritis.

ICD-10

II.C64-C68.C67 Malignant neoplasm of bladder

II.C81-C96.C81 Hodgkin's disease [lymphogranulomatosis]

II.C81-C96 Malignant neoplasms of lymphoid, hematopoietic and related tissues

II.C69-C72.C71 Malignant neoplasm of brain

II.C69-C72 Malignant neoplasms of the eye, brain and other parts of the central nervous system

II.C60-C63.C62 Malignant neoplasm of testis

II.C60-C63 Malignant neoplasm of male genital organs

II.C51-C58.C58 Malignant neoplasm of placenta

II.C51-C58.C54 Malignant neoplasm of uterine body

II.C51-C58.C53 Malignant neoplasm of cervix

II.C51-C58 Malignant neoplasms of female genital organs

II.C50.C50 Malignant neoplasm of breast

II.C45-C49.C49 Malignant neoplasm of other types of connective and soft tissue

II.C40-C41.C40 Malignant neoplasm of bones and articular cartilages of extremities

II.C30-C39 Malignant neoplasms of respiratory and thoracic organs

II.C15-C26.C16 Malignant neoplasm of stomach

XII.L40-L45.L40 Psoriasis

II.C81-C96.C91.0 Acute lymphoblastic leukemia

Contraindications:

Leukopenia, thrombocytopenia, immunodeficiency states, severe disorders of the liver and kidneys.

Individual intolerance.

Carefully:

Ulcers of the oral cavity and gastrointestinal tract, gout, infectious diseases, childhood and advanced age.

Pregnancy and lactation:

Recommendations for FDA - category X. Has teratogenic effect, contraindicated in pregnancy and lactation.

Dosing and Administration:

Application in children

Inside or intramuscularly at 20-40 mg / m² weekly.

Adults

Inside before meals: the initial dose is 2.5-5 mg with a gradual increase to 7.5-25 mg / week.

Intravenous: 1000-1200 mg / m² for 1-6 hours. Repeated infusion is carried out after 1-3 weeks.

For psoriasis: inside by 10-50 mg once a week.

With rheumatoid arthritis: 5-15 mg intramuscularly once a week.

The highest daily dose: 1200 mg / m².

The highest single dose: 1200 mg / m².

Side effects:

Central and peripheral nervous system: fatigue, dizziness, aphasia, convulsions.

The system of hematopoiesis: anemia, thrombocytopenia, and leukopenia.

Digestive system: ulcerative stomatitis, anorexia, nausea, rarely - melena, diarrhea, pancreatitis, fatty degeneration of the liver.

Urinary system: hematuria, cystitis.

Reproductive system: oligospermia, decreased libido, menstrual irregularities, impotence.

Allergic reactions.

Overdose:

Symtomas: increased side effects.

Treatment: administration of calcium folinate at a dose equal to or greater than the dose of methotrexate. Hemodialysis.

Interaction:

The intensification of toxic effects is observed with simultaneous application with non-steroidal anti-inflammatory drugs, barbiturates, corticosteroids,sulfonamides, tetracyclines, paraamino-hippuric and paraaminobenzoic acid, probenecid, chloramphenicol.

The effectiveness of folic acid and its derivatives decreases.

There is a blockage of methotrexate asparaginase when used simultaneously.

Reduces absorption of the drug with simultaneous neomycin.

The combination with live viral vaccines leads to an intensification of replication of the vaccine virus and an increase in the side effects of vaccination.

Strengthens the action of coumarinic and indanedium anticoagulants.

Incompatible with nitric oxide, since it is possible to develop severe myelosuppression.

Special instructions:

People of reproductive age are recommended to use reliable contraceptives in the treatment of methotrexate and within three months after the end of therapy.

Instructions

Methotrexate (Methotrexatum)