Index of drugs

In combination with glucocorticoids and / or other immunosuppressants and treatments to improve the survival of transplanted organs, such as the kidneys, heart and liver, and the reduction of glucocorticoid doses in renal transplant patients. In monotherapy or, more commonly, in combination with glucocorticosteroids and / or other drugs and procedures, it has demonstrated therapeutic efficacy (including dose reduction or complete cessation of glucocorticoids) in some patients suffering from the following diseases: severe rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis / polymyositis, autoimmune chronic-active hepatitis, pemphigus vulgaris, periarteritis nodosa, autoimmune hemolytic anemia, chronic idiopathic thrombocytopenic purpura refractory to treatment.

1 tabl powl. contains 25 mg or 50 mg of azathioprine.

The imidazole derivative of 6-mercaptopurine with immunosuppressive activity. The mode of action of azathioprine has not yet been fully elucidated. The assumed mechanisms of action of the drug are taken into account: the release of 6-mercaptopurine, which acts as a purine antimetabolite; optionally blocking the -SH groups by alkylation; inhibition of nucleic acid biosynthesis at multiple stages, resulting in blocking the proliferation of cells involved in the immune response; DNA damage due to the incorporation of purine purine anions into its molecule. Azathioprine quickly breaks down to 6-mercaptopurine and a methylnitroimidazole derivative. 6-Mercaptopurine readily crosses cell membranes into the cells, where it converts to the thio-anions of purine bases, including thio-inosinic acid, which is the main active nucleotide. 6-Mercaptopurine is mainly excreted in the form of thiourea acid. The activity of the methylnitroimidazole derivative has not been precisely determined. Due to the mechanism of action of azathioprine, the therapeutic effect of the drug reveals itself only after weeks or months of treatment. Azathioprine is well absorbed in the upper gastrointestinal tract. After oral administration of labeled azathioprine³⁵The maximum radioactivity in plasma occurs between 1 and 2 hours. Azathioprine is excreted primarily in the urine, in the form of 6-thiourea acid, only a small part of the administered dose is excreted in the urine in unchanged form.

Hypersensitivity to azathioprine, other ingredients of the preparation or to 6-mercaptopurine. The treatment should not be initiated in pregnant patients or those planning pregnancy in the near future without a careful assessment of the benefits and risks of treatment.

The drug should only be used if it is possible to adequately monitor the toxic effects of the preparation throughout the treatment period. Patients should be advised to immediately consult a physician if any signs of infection, bleeding without known causes, bleeding or other symptoms of myelosuppression occur. Patients with congenital deficiency of the thiopurine methyltransferase (TPMT) enzyme may be more sensitive to the myelopressive action of azathioprine and susceptible to bone marrow depression shortly after starting treatment. A possible relationship has been reported between reduced TPMT activity and secondary leukemias and myelodyplasion in patients taking 6-mercaptopurine (the active metabolite of azathioprine) together with other cytotoxic agents. Caution should be used in patients with renal and / or hepatic failure (if there is evidence of hematopoietic toxicity, the dose should be further reduced). Incomplete data indicate that the drug is not effective in patients deficient in hypoxanthine-guanine phosphoribosyltransferase (eg with Lesch-Nyhana syndrome), due to disturbed metabolism, it is not recommended to use the preparation in these patients. In both men and women who underwent kidney transplantation due to chronic heart failure and therefore treated with the preparation, an increase in fertility was observed. In patients treated with immunosuppressive therapy, there is an increased risk of developing non-Hodgkin's lymphomas (non-Hodgkin's) and other cancers, especially skin cancers (melanomas and non-melanoma), sarcomas (Kaposiand non-Kaposi) and cervical cancerin situ. Patients receiving several immunosuppressants are exposed to increased immunosuppression, therefore the lowest therapeutic doses should be used. In patients with an increased risk of developing skin cancer, exposure to UV radiation and sunlight should be minimized (patients should be advised to wear UV protection clothing and use photoprotective creams containing strong anti-UV filters). Because the administration of immunosuppressive agents may exacerbate the clinical course of varicella zoster virus infection, it must be ensured that the patient has had VZV infection before starting immunosuppressive therapy. After possible exposure to VZV, passive immunization should be considered by administering an immunoglobulin. If the patient is infected with VZV, appropriate treatment should be used. PML, an opportunistic infection caused by the JC virus, has been reported in patients receiving azathioprine with other immunosuppressive agents. Immunosuppressive therapy should be withheld at the first signs of PML and appropriate assessment should be made to establish the diagnosis. Due to the lactose content, the drug should not be used in patients with rare hereditary galactose intolerance, Lapp lactase deficiency or malabsorption of glucose-galactose.

Do not start treatment with pregnant women or those planning pregnancy in the near future without a careful assessment of the benefits and risks of treatment. There have been reports of premature births and births of newborns with low birth weight by mothers taking the preparation, especially in combination with glucocorticoids. Autonomic spontaneous abortions have also been observed in situations where the mother or father was taking azathioprine. In pregnant women receiving azathioprine, the drug and its metabolites are detected at low concentrations in the fetus and amniotic fluid. In some newborns whose mothers took azathioprine throughout their pregnancy, leucopenia and / or thrombocytopenia have been reported. Special attention should be paid to controlling blood count parameters during pregnancy. In women treated with azathioprine, the presence of 6-mercaptopurine in colostrum and milk was demonstrated. It is not recommended that mothers receiving azathioprine should breast-feed. If any of the partners receives azathioprine, an appropriate method of contraception should be used.

Very common: viral, fungal and bacterial infections in transplant patients receiving azathioprine in combination with other immunosuppressants, bone marrow suppression, leukopenia. Common: thrombocytopenia, nausea. Uncommon: viral, fungal and bacterial infections in the remaining patient population, anemia, hypersensitivity reactions, pancreatitis, cholestasis and hepatic dysfunction. Rare: tumors, including non-Hodgkin's non-Hodgkin's lymphomas, skin cancers (melanomas and non-melanomas), sarcomas (Kaposi and non-Kaposi), cervical cancerin situ, acute myelogenous leukemia and myelodysplasia (some of them with accompanying chromosomal changes), agranulocytosis, pancytopenia, aplastic anemia, megaloblastic anemia, hypoplasia of the erythrocyte system, life-threatening liver injury (histological changes included: vascular sinus enlargement, type changespeliosis hepatis, veno-occlusive disease and nodular liver regeneration, alopecia. Very rare: cases of PML associated with JC virus after application of azathioprine in combination with other immunosuppressants, Stevens-Johnson syndrome and toxic necrotic epidermal separation, reversible interstitial pneumonitis, colitis and diverticulitis, intestinal perforation in transplant patients, severe diarrhea patients with ulcerative enterocolitis. In both women and men treated with the preparation, chromosomal abnormalities have been demonstrated, it is difficult to establish a relationship between the use of the drug and these abnormalities. In patients treated with Imuran alone or in combination with other immunosuppressants, in particular glucocorticosteroids, severe or unusual course of VZV infections and other infectious agents have been reported.In particular, bone marrow suppression occurs in patients predisposed to toxic bone marrow damage, such as persons with deficiency of thiopurine methyltransferase (TPMT), with renal or hepatic impairment, and in patients who have not reduced azathioprine while co-administering allopurinol. Few cases of several clinical syndromes have been reported after administration of azathioprine, which appear to be due to idiosyncratic reactions. Clinical symptoms include: general malaise, dizziness, nausea, vomiting, diarrhea, fever, chills, skin eruptions, rash, vasculitis, muscle and joint pain, decreases in blood pressure, kidney problems, liver dysfunction and cholestasis (drug should be discontinued immediately), fatal cases in which other serious comorbidities have contributed to the death of the patient have been reported very rarely.

Orally. If the patient is unable to take the medicine orally, azathioprine can be used intravenously. The injection should be discontinued as soon as oral administration is possible. When establishing a detailed treatment regimen, use appropriate professional literature. Transplant indications in adults and children: depending on the approved immunosuppressive regimen, the dose may be up to 5 mg / kg on the first day. daily orally. A maintenance dose in the range of 1-4 mg / kg is recommended. daily, the dose should be adjusted depending on the patient's clinical condition and hematological tolerance. Due to the risk of transplant rejection, treatment should be continued indefinitely, even if only small doses are needed. In other indications, the usual starting dose in adults and children is 1-3 mg / kg. daily, the dose should be adjusted within the given range, depending on the clinical response (which may occur only after weeks or months of treatment) and hematological tolerance. After a clear therapeutic effect, reduce the maintenance dose to the smallest possible dose, if the patient does not improve within 3 months of treatment, discontinue the drug. The daily maintenance doses can range from less than 1 mg / kg. up to 3 mg / kg
Elderly patients and patients with renal insufficiency and / or liver should be treated with doses in the lower range of the recommended posology. Overweight children may require higher doses from the recommended dose range, and therefore strict monitoring of response to treatment is recommended. The tablets should be administered at least 1 hour before or 3 h after eating or drinking milk.