Malignancy: Patients receiving immunosuppressants, including AZASAN, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with AZASAN. 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 AZASAN. 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 AZASAN in rheumatoid arthritis (see ADVERSE REACTIONS). It has not been possible to define the precise risk of malignancy due to AZASAN. 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 AZASAN. 

  
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 AZASAN. 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 AZASAN as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis. The safety and efficacy of AZASAN 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 AZASAN. 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 AZASAN 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) and nucleotide diphosphatase (NUDT15) deficiency may be at an increased risk of severe and life-threatening myelotoxicity if receiving conventional doses of AZASAN (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). Consider alternative therapy in patients with homozygous TPMT or NUDT15 deficiency and reduced dosages in patients with heterozygous deficiency (see DOSAGE AND ADMINISTRATION). 

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Serious Infections: Patients receiving immunosuppressants, including AZASAN, are at increased risk for bacterial, viral, fungal, protozoal, and opportunistic infections, including reactivation of latent infections. These infections may lead to serious, including fatal outcomes. 

  
Progressive Multifocal Leukoencephalopathy: Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), sometimes fatal, have been reported in patients treated with immunosuppressants, including AZASAN. Risk factors for PML include treatment with immunosuppressant therapies and impairment of immune function. Consider the diagnosis of PML in any patient presenting with new-onset neurological manifestations and consider consultation with a neurologist as clinically indicated. Consider reducing the amount of immunosuppression in patients who develop PML. In transplant patients, consider the risk that the reduced immunosuppression represents to the graft. 

  
Effect on Sperm in Animals: AZASAN has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose; 1 a reduced percentage of fertile matings occurred when animals received 5 mg/kg. 2

  
Pregnancy: AZASAN can cause fetal harm when administered to a pregnant woman. AZASAN should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of AZASAN in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women. 3

AZASAN is teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies. 2

Postmarketing cases of intrahepatic cholestasis of pregnancy (ICP) have been reported in women treated with azathioprine during pregnancy. ICP symptoms and evaluated bile acid levels improved following azathioprine discontinuation. Discontinue AZASAN if ICP develops in a pregnant woman.

Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on AZASAN. In a detailed case report, 4 documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy. At 10 weeks most features were normalized. DeWitte et al reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily. 5 There have been two published reports of abnormal physical findings. Williamson and Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy. 6 Tallent et al described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus. The father was on long-term azathioprine therapy. 7

Benefit versus risk must be weighed carefully before use of AZASAN in patients of reproductive potential. There are no adequate and well-controlled studies in pregnant women. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant.