added benefit or unexpected adverse effects. the use of azasan with these agents cannot be recommended.

. 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 ). . 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 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.

k 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 per 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. azasan may 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 azasan has not been determined. azasan can be discontinued abruptly, but delayed effects are possible. patients with tpmt and/or nudt deficiency: consider testing for tpmt and nudt15 deficiency in patients who experience severe bone marrow toxicities. early drug discontinutation may be considered in patients with abnormal cbc results that do ot respond to dose reduction (see clinical pharmacology , warnings:cytopenias , and precautions:laboratory tests ). homozygous deficiency in either tpmt or nudt15: because of the risk of increased toxicity, consider alternative therapies for patients who are known to have tpmt or nudt15 deficiency (see clinical pharmacology , warnings:cytopenias , and precautions:laboratory tests ). heterozygous deficiency in tpmt and/or nudt15 : because of the risk of increased toxicity, dosage reduction is recommended in patients known to have heterozygous deficiency of tpmt or nudt15. patients who are heterozygous for both tpmt and nudt15 deficiency may require more substandial dosage reductions (see clinical pharmacology , warnings:cytopenias , and precautions:laboratory tests ). use in renal dysfunction: relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of azasan or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses. procedures for proper handling and disposal of this immunosuppressive antimetabolite drug should be considered. several guidelines on this subject have been published 15-21 .there is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.

igher 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 azasan. 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. patients with low or absent tpmt or nudt15 activity are at increased risk for severe, life-threatening myelosuppression from azasan. (see clinical pharmacology , warnings:cytopenias , and precautions : laboratory tests , dosage and administration ). gastrointestinal: nausea and vomiting may occur within the first few months of therapy with azasan, 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 azasan. a rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azasan has been described in transplant patients and in one patient receiving azasan for panuveitis. 11, 12, 13 periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. if hepatic veno-occlusive disease is clinically suspected, azasan 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 warnings - malignancy ), and sweet's syndrome (acute febrile neutrophilic dermatosis). to report suspected advers reactions, contact salix pharmaceuticals at 1-800-321-4576 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours. 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 cytotoxicity of azathioprine is due, in part, to the incorporation of 6-tgn into dna. 6-mp undergoes two major inactivation routes. one is thiol methylation, which is catalyzed by the enzyme thiopurine s-methyltransferase (tpmt), to form the inactive metabolite methyl-6-mp (6-memp). another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (xo) to form 6-thiouric acid. the nucleotide diphosphatase (nudt15) enzyme is involved in conversion of the 6-tgns to inactive 6-tg monophosphates. tpmt activity correlates inversely with 6-tgn levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities. genetic polymorphisms influence tpmt and nudt15 activity. several published studies indicate that patients with reduced tpmt or nudt15 activity receiving usual doses of 6-mp or azathioprine, accumulate excessive cellular concentrations of active 6-tgns, and are at higher risk for severe myelosupression. because of the risk of toxicity, patients with tpmt or nudt15 deficiency require alternative therapy or dose modification (see dosage and administration ). approximately 0.3% (1:300) of patients of european or african ancestry have two loss-of-function alleles of the tpmt gene and have little or no tpmt activity (homozygous deficient or poor metabolizers), and approximately 10% of patients have one loss-of-function tpmt allele leading to intermediate tpmt activity (heterozygous deficient or intermediate metabolizers). the tpmt*2, tpmt*3a, and tpmt*3c alleles account for about 95% of individuals with reduced levels of tpmt activity. nudt15 deficiency is detected in <1% of patients of european or african ancestry. among patients of east asian ancestry (i.e., chinese, japanese, vietnamese), 2% have two loss-of-function alleles of the nudt15 gene, and approximately 21% have one loss-of-function allele. the p.r139c variant of nudt15 (present on the *2 and *3 alleles) is the most commonly observed, but other less common loss-of-function nudt15 alleles have been observed. inhibition of xanthine oxidase (xo) may cause increased plasma concentrations of azathioprine or its metabolites leading to toxicity (see precautions: drug interactions ). proportions of metabolites are different in individual patients, and this presumably accounts for variable magnitude and duration of drug effects. renal clearance is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function. homograft survival: the use of azathioprine for inhibition of renal homograft rejection is well established, the mechanism(s) for this action are somewhat obscure. the drug suppresses hypersensitivities of the cellmediated type and causes variable alterations in antibody production. suppression of t-cell effects, including ablation of t-cell suppression, is dependent on the temporal relationship to antigenic stimulus or engraftment. this agent has little effect on established graft rejections or secondary responses. alterations in specific immune responses or immunologic functions in transplant recipients are difficult to relate specifically to immunosuppression by azathioprine. these patients have subnormal responses to vaccines, low numbers of t-cells, and abnormal phagocytosis by peripheral blood cells, but their mitogenic responses, serum immunoglobulins, and secondary antibody responses are usually normal. immunoinflammatory response: azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. for example, the severity of adjuvant arthritis is reduced by azathioprine. the mechanisms whereby azathioprine affects autoimmune diseases are not known. azathioprine is immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses. in the rat model of adjuvant arthritis, azathioprine has been shown to inhibit the lymph node hyperplasia, which precedes the onset of the signs of the disease. both the immunosuppressive and therapeutic effects in animal models are dose-related. azathioprine is considered a slow-acting drug and effects may persist after the drug has been discontinued.