FDA label 22396b4a-bf68-4789-8293-21882aa3916d

WARNING : Chronic immunosuppression with this purine antimetabolite increases risk of neoplasia in humans. Physicians using this drug should be very familiar with this risk as well as with the mutagenic potential to both men and women and with possible hematologic toxicities. See WARNINGS .

WARNINGS Severe leukopenia, thrombocytopenia, macrocytic anemia, and/or pancytopenia may occur in patients being treated with azathioprine. Severe bone marrow suppression may also occur. Patients with intermediate thiopurine S-methyl transferase (TPMT) activity may be at an increased risk of myelotoxicity if receiving conventional doses of azathioprine. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of azathioprine. TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing azathioprine toxicity 2-9 (see PRECAUTIONS : Laboratory Tests ). 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. Serious infections are a constant hazard for patients receiving chronic immunosuppression, especially for homograft recipients. Fungal, viral, bacterial, and protozoal infections may be fatal and should be treated vigorously. Reduction of azathioprine dosage and/or use of other drugs should be considered. Azathioprine is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient’s risk of neoplasia . 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. The degree of immunosuppression is determined, not only by the immunosuppressive regimen, but also by a number of other patient factors. The number of immunosuppressive agents may not necessarily increase the risk of post-transplant lymphomas. However, transplant patients who receive multiple immunosuppressive agents may be at risk for over-immunosuppression; therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels. Information is available on the spontaneous neoplasia risk in rheumatoid arthritis, and on neoplasia following immunosuppressive therapy of other autoimmune diseases. It has not been possible to define the precise risk of neoplasia 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. Data on neoplasia in patients receiving azathioprine can be found under ADVERSE REACTIONS . Azathioprine 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; 10 a reduced percentage of fertile matings occurred when animals received 5 mg/kg. 11 Pregnancy Pregnancy Category D Azathioprine can cause fetal harm when administered to a pregnant woman. Azathioprine should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of azathioprine in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women. 12 Azathioprine 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. 11 Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on azathioprine. In a detailed case report, 13 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. 14 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. 15 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. 16 Benefit versus risk must be weighed carefully before use of azathioprine 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.

ADVERSE REACTIONS The principal and potentially serious toxic effects of azathioprine are hematologic and gastrointestinal. The risks of secondary infection and neoplasia are also significant (see WARNINGS ). The frequency and severity of adverse reactions depend on the dose and duration of azathioprine 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 azathioprine for rheumatoid arthritis. The relative incidences in clinical studies are summarized below: Toxicity Renal Homograft Rheumatoid Arthritis Leukopenia (any degree) >50% 28% <2500 cells/mm 3 16% 5.3% Infections 20% <1% Neoplasia Lymphoma Others 0.5% 2.8% 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. 12 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 azathioprine. 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. Macrocytic anemia and/or bleeding have been reported. TPMT genotyping or phenotyping can help identify patients with low or absent TPMT activity (homozygous for nonfunctional alleles) who are at increased risk for severe, life-threatening myelosuppression from azathioprine (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 azathioprine, 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 azathioprine. 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 azathioprine 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, azathioprine 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, and reversible interstitial pneumonitis and hepatosplenic T-cell lymphoma.

<table><col/><col/><col/><tbody><tr><td align="center" valign="top" styleCode=" Botrule Toprule Rrule "> Toxicity</td><td align="center" valign="top" styleCode=" Botrule Rrule "> Renal Homograft</td><td align="center" valign="top" styleCode=" Botrule "> Rheumatoid Arthritis</td></tr><tr><td valign="top" styleCode=" Botrule Rrule "> Leukopenia (any degree)</td><td align="center" valign="top" styleCode=" Botrule Rrule "> &gt;50%</td><td align="center" valign="top" styleCode=" Botrule "> 28%</td></tr><tr><td valign="top" styleCode=" Botrule Rrule "> &lt;2500 cells/mm³</td><td align="center" valign="top" styleCode=" Botrule Rrule "> 16%</td><td align="center" valign="top" styleCode=" Botrule "> 5.3%</td></tr><tr><td valign="top" styleCode=" Botrule Rrule "> Infections</td><td align="center" valign="top" styleCode=" Botrule Rrule "> 20%</td><td align="center" valign="top" styleCode=" Botrule "> &lt;1%</td></tr><tr><td valign="top" styleCode=" Botrule Rrule "> Neoplasia Lymphoma Others</td><td align="center" valign="top" styleCode=" Rrule "> 0.5% 2.8%</td><td align="center" valign="top" styleCode=" Botrule "> <footnote ID="FOOT_870">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.¹² 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.</footnote></td></tr></tbody></table>