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Imuran

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Imuran

Side Effects
Interactions

SIDE EFFECTS

The principal and potentially serious toxic effects of IMURAN are hematologic and gastrointestinal. The risks of secondary infection and malignancy are also significant (see WARNINGS). The frequency and severity of adverse reactions depend on the dose and duration of IMURAN 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 IMURAN for rheumatoid arthritis. The relative incidences in clinical studies are summarized below:

Toxicity Renal Homograft Rheumatoid Arthritis
Leukopenia (any degree) > 50% 28%
   < 2500 cells/mm³ 16% 5.30%
  Infections 20% < 1%
Neoplasia *
  Lymphoma 0.50%  
  Others 2.80%  
* Data on the rate and risk of neoplasia among persons with rheumatoid arthritis treated with azathioprine are limited. The incidence of lymphoproliferative disease in patients with RA appears to be significantly higher than that in the general population. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg per day) was 1.8 cases per 1000 patient-years of follow-up, compared with 0.8 cases per 1000 patient-years of follow-up in those not receiving azathioprine. However, the proportion of the increased risk attributable to the azathioprine dosage or to other therapies (i.e., alkylating agents) received by patients treated with azathioprine cannot be determined.

Hematologic

Leukopenia and/or thrombocytopenia are dose-dependent and may occur late in the course of therapy with IMURAN. Dose reduction or temporary withdrawal may result in reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection in renal homotransplantation is 30 to 60 times that in rheumatoid arthritis. Anemias, including macrocytic anemia, and/or bleeding have been reported.

TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for non-functional alleles) who are at increased risk for severe, life-threatening myelosuppression from IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS and PRECAUTIONS: Laboratory Tests. Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine.6,20

Gastrointestinal

Nausea and vomiting may occur within the first few months of therapy with IMURAN, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance often can be reduced by administration of the drug in divided doses and/or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias (see PRECAUTIONS). Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis. Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin, and/or serum transaminases is known to occur following azathioprine use, primarily in allograft recipients. 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 of IMURAN. A rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving IMURAN for panuveitis.21,22,23 Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, IMURAN should be permanently withdrawn.

Others

Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, reversible interstitial pneumonitis, hepatosplenic T-cell lymphoma (see WARNINGSMalignancy), and Sweet's Syndrome (acute febrile neutrophilic dermatosis).

Read the Imuran (azathioprine) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Use with Allopurinol

One of the pathways for inactivation of azathioprine is inhibited by allopurinol. Patients receiving IMURAN and allopurinol concomitantly should have a dose reduction of IMURAN, 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 IMURAN and allopurinol because both TPMT and XO inactivation pathways are affected. See CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections.

Use with Aminosalicylates

There is in vitro evidence that aminosalicylate derivatives (e.g., sulphasalazine, mesalazine, or olsalazine) inhibit the TPMT enzyme. Concomitant use of these agents with IMURAN should be done with caution.

Use with Other Agents Affecting Myelopoesis

Drugs which may affect leukocyte production, including cotrimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients.

Use with Angiotensin-Converting Enzyme Inhibitors

The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia.

Use with Warfarin

IMURAN may inhibit the anticoagulant effect of warfarin.

Use with 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.

REFERENCES

6. Data on file, Prometheus Laboratories Inc.

20. Schutz E, Gummert J, Mohr F, Oellerich M. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant patients. Lancet. 1993; 341:436.

21. Read AE, Wiesner RH, LaBrecque DR, et al. Hepatic veno-occlusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med. 1986; 104:651-655.

22. Katzka DA, Saul SH, Jorkasky D, et al. Azathioprine and hepatic veno-occlusive disease in renal transplant patients. Gastroenterology. 1986; 90:446-454.

23. Weitz H, Gokel JM, Loeshke K, et al. Veno-occlusive disease of the liver in patients receiving immunosuppressive therapy. Virchows Arch A Pathol Anat Histol. 1982; 395:245-256.

Last reviewed on RxList: 2/18/2014
This monograph has been modified to include the generic and brand name in many instances.

Side Effects
Interactions
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