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Azathioprine is metabolized to 6-mercaptopurine (6-MP). Activation of 6-mercaptopurine occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites.

The cytotoxic and immunosuppressive effects of azathioprine is mediated via the induction of lymphocyte apoptosis by the incorporation of its active metabolites, 6-thioguanine nucleotides into DNA. (It is a nonspecific purine synthesis inhibitor . It interferes with DNA and RNA synthesis so that it may reduce both cell-mediated and humoral immune responses)


  • Azathioprine is indicated as an adjunct for the prevention of rejection in renal homotransplantation.
  • Azathioprine is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms. Azathioprine is restricted to patients with severe, active and erosive disease not responsive to conventional management including rest, acetylsalicylic acid or other non-steroidal drugs, or with disease-modifying antirheumatic drugs (DMARD’s).

[edit] DOSAGE

  • Renal Homotransplantation: The dose of Azathioprine required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. Azathioprine is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of Azathioprine should not be increased to toxic levels because of threatened rejection. Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal.
  • Rheumatoid Arthritis: Azathioprineis usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg/day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks can be considered refractory. Azathioprinemay be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities.
    Maintenance therapy should be at the lowest effective dose, and the dose given can be lowered decrementally with changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant. The optimum duration of maintenance Azathioprine has not been determined. Azathioprine can be discontinued abruptly, but delayed effects are possible


  • Azathioprine should not be given to patients who have shown hypersensitivity to the drug.
  • Azathioprine should not be used for treating rheumatoid arthritis in pregnant women.
  • Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of malignancy if treated with Azathioprine.

[edit] Warnings and PRECAUTIONS

  • Malignancy: Chronic immunosuppression with this purine antimetabolite increases risk of malignancy in humans, in particular lymphoma and skin cancer. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. Physicians should inform patients of the risk of malignancy with Azathioprine.

  • Bone marrow suppression: Severe leukopenia, thrombocytopenia, anemias including macrocytic and/or pancytopenia may occur in patients being treated with Azathioprine. Severe bone marrow suppression may also occur. Patients with intermediate thiopurine S-methyl transferase (TPMT) activity may be at an increased risk of myelotoxicity if receiving conventional doses of Azathioprine. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of Azathioprine.
    TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing Azathioprine toxicity.

    Hematologic toxicities are dose related and may be more severe in renal transplant patients whose homograft is undergoing rejection. It is suggested that patients on Azathioprine have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in, or persistently low leukocyte count, or other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore, the dose should not be increased intentionally to lower the white blood cell count.
  • Serious infections: Serious infections are a constant hazard for patients receiving chronic immunosuppression, especially for homograft recipients. Fungal, viral, bacterial, and protozoal infections may be fatal and should be treated vigorously. Reduction of azathioprine dosage and/or use of other drugs should be considered
  • A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has been reported. These symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity most often develop within the first several weeks of therapy with Azathioprine and are reversible upon discontinuation of the drug. The reaction can recur within hours after rechallenge with a single dose of Azathioprine.


  • Allopurinol: One of the pathways for inactivation of azathioprine is inhibited by Allopurinol. Patients receiving Azathioprine and Allopurinol concomitantly should have a dose reduction of Azathioprine, to approximately 1/3 to 1/4 the usual dose. It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving Azathioprine and Allopurinol because both Thiopurine S-methyltransferase (TPMT) and Xanthine oxidase (XO) inactivation pathways are affected.
  • Agents Affecting Myelopoesis: Drugs which may affect leukocyte production, including co-trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients.
  • ACE inhibitors: The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia.
  • Warfarin: Azathioprine may inhibit the anticoagulant effect of warfarin.
  • Ribavirin: The use of ribavirin for hepatitis C in patients receiving azathioprine has been reported to induce severe pancytopenia and may increase the risk of azathioprine-related myelotoxicity. Inosine monophosphate dehydrogenase (IMDH) is required for one of the metabolic pathways of azathioprine. Ribavirin is known to inhibit IMDH, thereby leading to accumulation of an azathioprine metabolite, 6-methylthioionosine monophosphate (6MTITP), which is associated with myelotoxicity (neutropenia, thrombocytopenia, and anemia). Patients receiving azathioprine with ribavirin should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage or other therapy changes are necessary


  • Pregnancy Category D (US). Azathioprine can cause fetal harm when administered to a pregnant woman. Azathioprine should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of Azathioprine in pregnant patients should be avoided.
  • Nursing Mothers: The use of Azathioprine in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels both transplacentally and in breast milk. Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.


The principal and potentially serious toxic effects of Azathioprine are hematologic (Bone marrow suppression: Leukopenia and/or thrombocytopenia) and gastrointestinal (Nausea and vomiting). The risks of secondary infection and malignancy are also significant. The frequency and severity of adverse reactions depend on the dose and duration of Azathioprine as well as on the patient’s underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing Azathioprine for rheumatoid arthritis.

Hepatotoxicity: Hepatotoxicity has been uncommon (less than 1%) in rheumatoid arthritis patients. Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption. Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity

Infections: Infections (i.e. viral, fungal and bacterial) occur very commonly in transplant patients receiving azathioprine in combination with other immunosuppressants and uncommonly in other patient populations.