Drug Interactions between azathioprine and interferon alfa-2b / ribavirin

GENERALLY AVOID: Published case reports suggest that ribavirin may potentiate the myelotoxic effects of 6-mercaptopurine and its prodrug, azathioprine. The proposed mechanism is inhibition of inosine monophosphate dehydrogenase by ribavirin, which interferes with one of the metabolic pathways of 6-mercaptopurine and leads to accumulation of the myelotoxic metabolite 6-methylthioinosine monophosphate (6-MTIMP). Pancytopenia and bone marrow suppression have been reported in the literature to occur within 3 to 7 weeks after the concomitant administration of pegylated interferon/ribavirin and azathioprine. Myelotoxicity was reversible within 4 to 6 weeks upon withdrawal of both the hepatitis C antiviral and azathioprine treatments, and did not recur upon reintroduction of either treatment alone. Theoretically, inhibition of inosine monophosphate dehydrogenase may also reduce the pharmacologic effects of 6-mercaptopurine and azathioprine by inhibiting conversion to the active metabolite; however, this was not observed in the case reports.

MANAGEMENT: The use of ribavirin in combination with 6-mercaptopurine or azathioprine should generally be avoided if possible. Patients receiving the combination should have complete blood counts, including platelet counts, monitored weekly for the first month, twice monthly for the second and third months, then monthly or more frequently if dosage or other therapy changes are necessary. Treatment with these medications should be discontinued promptly if pancytopenia develops, and the combination should not be reintroduced following recovery.

GENERALLY AVOID: The use of azathioprine with other immunosuppressive or myelosuppressive agents may result in additive hematologic toxicities and increased risk of infections, particularly in transplant patients. Azathioprine alone may cause dose-related and potentially life-threatening bone marrow suppression, although it is usually reversible when managed promptly. Leucopenia, anemia, thrombocytopenia, and rarely, agranulocytosis, pancytopenia, and aplastic anemia have been reported. Dose-related reductions in numbers of circulating total white cells, granulocytes, and lymphocytes may also occur. Treatment with azathioprine alone or in combination with other immunosuppressants, particularly corticosteroids, has been associated with increased susceptibility to infections including severe or atypical infection and reactivation with varicella zoster virus, hepatitis B, cytomegalovirus, and other infectious agents. Very rare cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), a severely disabling and potentially fatal opportunistic viral infection of the brain, have also been reported. In addition, chronic use of azathioprine with other immunosuppressants may increase the risk of lymphoma, skin cancer, and other malignancies. Again, the risk is greatest in transplant patients, with the exception of hepatosplenic T-cell lymphoma (HSTCL), which has occurred primarily in patients with Crohn's disease or ulcerative colitis, especially adolescent and young adult males.

MANAGEMENT: Concomitant use of azathioprine with other immunosuppressive or myelosuppressive agents should be avoided whenever possible. Close clinical and laboratory monitoring for hematologic toxicity is advised if coadministration is required. Since azathioprine is considered a slow-acting drug, delayed myelosuppression may occur, and effects may persist even after the drug has been discontinued. Prompt reduction in dosage or temporary withdrawal of azathioprine may be necessary if a persistently low or rapid decline in leucocyte count occurs, or if there is other evidence of bone marrow depression.