Azathioprine - Warnings and Precautions

WARNINGS Malignancy Patients receiving immunosuppressants, including azathioprine, are at increased risk of developing lymphoma and other malignancies, particularly of the skin.

Physicians should inform patients of the risk of malignancy with azathioprine.

As usual for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet light should be limited by wearing protective clothing and using a sunscreen with a high protection factor.

Post-transplant Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors.

The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs, including azathioprine.

Therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels.

Rheumatoid Arthritis Information is available on the risk of malignancy with the use of azathioprine in rheumatoid arthritis (see ADVERSE REACTIONS ).

It has not been possible to define the precise risk of malignancy due to azathioprine.

The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients.

However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received azathioprine.

Inflammatory Bowel Disease Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with azathioprine.

These cases have had a very aggressive disease course and have been fatal.

The majority of reported cases have occurred in patients with Crohn's disease or ulcerative colitis and the majority were in adolescent and young adult males.

Some of the patients were treated with azathioprine as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis.

The safety and efficacy of azathioprine for the treatment of Crohn's disease and ulcerative colitis have not been established.

Cytopenias Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia may occur in patients being treated with azathioprine.

Severe bone marrow suppression may also occur.

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.

TPMT or NUDT15 Deficiency Patients with thiopurine S-methyl transferase (TPMT) or nucleotide diphosphatase (NUDT15) deficiency may be at an increased risk of severe and life-threatening myelotoxicity if receiving conventional doses of azathioprine (see CLINICAL PHARMACOLOGY ).

Death associated with pancytopenia has been reported in patients with absent TPMT activity receiving azathioprine.

In patients with severe myelosuppression, consider evaluation for TPMT and NUDT15 deficiency (see PRECAUTIONS: Laboratory Tests ).