Azathioprine (Azathioprinum)

Pharmacodynamics Pharmacokinetics Indications Carefully Contraindications Dosing and Administration Side effects
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Clinical and pharmacological group: & nbsp

Immunosuppressive drugs

Included in the formulation
  • Azathioprine
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    MOSHIMFARM PREPARATES them. N.А.Semashko, OJSC     Russia
    • Pharmacodynamics:

    Immunosuppressive action includes greater inhibition of delayed type hypersensitivity and cellular cytotoxicity than the production of antibodies. Inhibits the metabolism of purines and can suppress the synthesis of DNA, RNA and protein; can also affect cellular metabolism and inhibit mitosis. The mechanism of the effect of azathioprine in rheumatoid arthritis and other autoimmune processes is not known, but it is supposed to be associated with immunosuppression. Reduces the need for glucocorticoids in combination therapy.

    Pharmacological effects:

    - immunosuppressive (clinical effects may persist for a long time after drug withdrawal);

    - antirheumatic (a means transforming the disease): the onset of action in 6-8 weeks;

    - anti-inflammatory (with intestinal and SLE): the onset of action after 4-8 weeks.

    Pharmacokinetics:

    Absorption from the gastrointestinal tract is high. Relationship with plasma proteins 30% (low). Biotransformation is mainly up to 6-mercaptopurine and 6-thioinosinic acid (active metabolites). Further metabolism occurs in the liver (mainly xanthine oxidase) and erythrocytes, the ratio of which varies in different patients. Elimination of bile, kidney (1-2% in the form of unchanged substance).Partially removed during hemodialysis.

    Indications:

    - prevention of rejection reaction of the kidney, heart, liver, pancreas homomancer (as an additional tool);

    - Rheumatoid arthritis (severe, active, erosive, with no effect of standard therapy);

    - inflammatory diseases of the colon (Crohn's disease, ulcerative colitis);

    - biliary liver cirrhosis;

    - systemic dermatomyositis;

    - glomerulonephritis;

    - chronic active hepatitis;

    - systemic lupus erythematosus;

    - lupus nephritis;

    - myasthenia gravis;

    - pseudohypertrophic myopathy;

    - nephrotic syndrome;

    - pemphigus;

    - pemphigoid;

    - nodular periarteritis;

    - idiopathic thrombocytopenic purpura;

    - gangrenous pyoderma;

    - psoriasis;

    - psoriatic arthritis;

    - Reiter's syndrome;

    - radiation dermatitis;

    - multiple sclerosis.

    ICD-10
    Contraindications:Individual intolerance.
    Carefully:

    It is prescribed with caution in chicken pox, including those who were in recent contact with sick chicken pox, shingles, gout, impaired liver function, infectious diseases, pancreatitis, renal dysfunction,severe insufficiency of xanthine oxidase, as well as patients who had previously received cytotoxic or radiation therapy.

    Pregnancy and lactation:Contraindicated during pregnancy and the period of breastfeeding.
    Dosing and Administration:

    Prevention of homotransfer rejection reaction: initial dose - inside 3-5 mg / kg (120 mg / m2) per day for 1-3 days before and during surgery. Then the dose is reduced to maintenance - inward or intravenously 1-3 mg / kg per day (or 45 mg / m2 per day when taken orally). If there are symptoms of rejection of the transplanted organ, the dose is again raised to 4 mg / kg per day.

    Rheumatoid arthritis, biliary cirrhosis, systemic dermatomyositis, glomerulonephritis, chronic active hepatitis, systemic lupus erythematosus. Nephrotic syndrome, pemphigus, pemphigoid, myasthenia gravis and inflammatory bowel disease: an initial dose of 1 mg / kg per day, increases with an increment of 500 μg (0.5 mg) / kg per day after 6-8 weeks, then, if necessary , - every 4 weeks before reaching the maximum dose (2.5 mg / kg per day).

    Nodular periarteritis, acquired hemolytic anemia, idiopathic thrombocytopenic purpura: inside 1,5-2,0 mg / kg per day in 2-4 reception. Duration is set individually.

    Psoriasis: inside 0.05 g 3-4 times a day. The course of treatment is 14-48 days.

    Side effects:

    Blood System: myelosuppression in patients after kidney transplantation, with development of graft rejection reaction, leukopenia, megaloblastic anemia, thrombocytopenia, delayed myelosuppression and hemolytic anemia. As well as increased activity of ALT, AST, AFP, amylase and bilirubin in blood plasma, a decrease in albumin concentration in the blood plasma, an increase in the volume of blood cells (a sign of macrocytosis).

    Gastrointestinal tract: loss of appetite, nausea, vomiting, gastric and duodenal ulceration, intestinal bleeding, necrosis and intestinal perforation (in patients who undergone organ transplantation), ulceration of the mucous membrane of the oral cavity and lips, gastrointestinal hypersensitivity reaction. And also hepatitis, pancreatitis,

    Respiratory system: pneumonitis.

    Urinary system: acute renal failure.

    Skin: alopecia.

    Reproductive system: in mice in a dose exceeding therapeutic for a person 10 times, causes transient disorders of spermatogenesis, decreased viability and the number of spermatozoa; in a dose of 5 mg / kg reduces the percentage ratio of prolific matings in animals.

    Carcinogenicity / mutagenicity: carcinogenic in animals, increases the risk of developing malignant tumors (especially skin cancer and reticular cell lymphomas in patients who underwent kidney transplantation, as well as acute leukemia and some solid tumors in patients with rheumatoid arthritis). The risk of developing malignant neoplasms in patients who underwent kidney transplantation is higher than in rheumatoid arthritis. The risk also increases with the prior use of alkylating agents. Azathioprine mutagenic in animals and causes chromosomal abnormalities in humans (reversible when drug is withdrawn).

    Allergic reactions: hypersensitivity reactions (usually develop within 1 week of therapy and more, reversible after the withdrawal of azathioprine, with the resumption of admission may develop more severe, even lethal, hypersensitivity reactions), in rare cases, skin rashes.

    Others: with rheumatoid arthritis, the risk of hematological and tumor side effects is less, since azathioprine appoint in low doses.

    Overdose:No data.
    Interaction:

    When interacting with allopurinol inhibition of xanthine oxidase, can significantly increase the efficacy and toxicity of azathioprine. Combination should be avoided, especially in renal pathology, due to a significant risk of accumulation of 6-mercaptopurine (azathioprine metabolite) and its toxicity in the development of graft rejection. If combination is required, it is recommended to reduce the dose of azathioprine by 25-33%, carefully monitor the patient's condition and dose adjustment, depending on the response to therapy and the presence of signs of toxicity.

    In view of immunosuppression with the use of azathioprine, a weakened immune response to the introduction of killed vaccines may be observed. It is necessary to observe the interval between the end of treatment and immunization (depending on the severity of immunosuppression, the type of vaccine and other factors - from 3 months to 1 year).

    Use of live vaccines during treatment with azathioprine should be avoided (violation of the immune response, increased probability of side effects), and also within 3 months - 1 year after the end of treatment (depending on the severity of immunosuppression, type of vaccine and other factors).Patients with remission of leukemia should not be given live viral vaccines for at least 3 months after the end of chemotherapy. Immunization with live oral polio vaccine should be postponed to persons directly in contact with the patient.

    The activity of warfarin may decrease when combined with azathioprine, it may be necessary to increase its dose.

    There is an increased risk of infection and development of tumors when taking the drug with other immunosuppressants (mercaptopurine, chlorambucil, ciclosporin, cyclophosphamide).

    The risk of anemia and leukopenia may increase with concomitant use with ACE inhibitors.

    Myelo-depressants that exhibit predictable dose-dependent myelotoxicity: abacavir, azathioprine, aldesleukin, alemtuzumab, altretamine, amphotericin B (with systemic application), amphotericin B liposomal, anastrozole, busulfan, valganciclovir, species of arabineρ (with systemic use in high doses), vinblastine, vincristine, vinorelbine, ganciclovir, gemcitabine, hydroxyurea, dacarbazine, dactinomycin, daunorubicin, didanosine, doxorubicin, docetaxel, zidovudine, zoledronic acid, idarubicin, imatinib, interferon-alpha, irinotecan, ifosfamide, capecitabine, carboplatin, carmustine (with systemic application), clozapine, colchicine, lamivudine, lomustine, melphalan, mercaptopurine, methotrexate, mitoxantrone, mitomycin, sodium iodide, sodium phosphate, oxaliplatinum, paclitaxel, plikamycin, procarbazine, pegasgas, strontium chloride, streptozocin, temozolomide, teniposide, thioguanine, thiotepa, topotecan, fludarabine, flucytosine, fluorouracil (with systemic application), chlorambucil, chloramphenicol, cyclophosphamide, cisplatin, cytarabine, epirubicin, etoposide or radiotherapy in combination with azathioprine may cause increased myelotoxicity. With the concurrent or sequential use of two or more myelo-depressants, including radiation therapy, or their treatment in an anamnesis, a dose reduction of azathioprine on the basis of a blood picture may be required.

    It is possible to enhance the myelotoxic effect of azathioprine in parallel with co-trimoxazole.

    Possible rejection of the graft with parallel application of rifampicin.

    Azathioprine reduces the severity of muscle relaxation caused by nondepolarizing muscle relaxants, enhances neuromuscular blockade caused by suxamethonium.

    Means that have unpredictable, dose-independent myelotoxicity in some cases: alemtuzumab, amidopyrine, tricyclic antidepressants, antithyroid drugs, valproic acid, derivatives of hydantoin and succinimide (anticonvulsants), dapsone, gold compounds, ACE inhibitors, carbamazepine, clozapine, levamisole, loxapine, maprotiline, mirtazapine, NSAIDs (especially phenylbutazone), penicillamine, pentamidine, pimozide, primidon, Primarch, procainamide, propafenone, pyrimethamine (in high doses), pseudoephedrine, peginterferon alfa-2b, rituximab, sulfamethoxazole, sulfonamides (with systemic application), sulfasalazine, derivatives of sulfonylureas (antidiabetics), temozolomide, ticlopidine, thioxanthenes, trastuzumab, trimethoprim, felbamate, phenothiazines, flecainideρ, sodium foscarnet, chloramphenicol, cetirizine, epirubicin with parallel or sequential use with azathioprine may cause increased leukopenia and / or thrombocytopenia. You may need to reduce the dose of azathioprine on the basis of a picture of blood.

    Mixing with alkaline solutions, especially when heated, can lead to the decomposition of azathioprine with the formation of 6-mercaptopurine. A similar process is possible in the presence of compounds containing sulfhydryl groups (cysteine, glutathione, hydrogen sulphide).

    Special instructions:

    During the first 8 weeks of treatment, it is necessary to monitor the blood picture weekly, after 2 months - 1-2 times in 30 days.

    It is necessary to regularly monitor the activity of serum hepatic transaminases, alkaline phosphatase and bilirubin.

    In case of violations of kidney and / or liver function, it is recommended to reduce the dose of the drug (1/4 of the average dose).

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