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Patients receiving immunosuppressants, including IMURAN, are at increased risk of developing lymphoma and other malignancies, particularly of the skin. Physicians should inform patients of the risk of malignancy with IMURAN. 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.
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 IMURAN. Therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels.
Information is available on the risk of malignancy with the use of IMURAN in rheumatoid arthritis (see ADVERSE REACTIONS). It has not been possible to define the precise risk of malignancy due to IMURAN. 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 IMURAN.
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 IMURAN. 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 IMURAN as monotherapy and some had received concomitant treatment with a TNFα blocker at or prior to diagnosis. The safety and efficacy of IMURAN for the treatment of Crohn's disease and ulcerative colitis have not been established.
Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia may occur in patients being treated with IMURAN. 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 IMURAN. Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of IMURAN. TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing IMURAN 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 IMURAN 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.
Effect on Sperm in Animals
IMURAN 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 Category D. IMURAN can cause fetal harm when administered to a pregnant woman. IMURAN should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of IMURAN in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women.12
Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on IMURAN. 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 IMURAN 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.
A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has been reported. These symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity most often develop within the first several weeks of therapy with IMURAN and are reversible upon discontinuation of the drug. The reaction can recur within hours after re-challenge with a single dose of IMURAN.
Complete Blood Count (CBC) Monitoring
Patients on IMURAN should 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.
It is recommended that consideration be given to either genotype or phenotype patients for TPMT. Phenotyping and genotyping methods are commercially available. The most common non-functional alleles associated with reduced levels of TPMT activity are TPMT*2, TPMT*3A and TPMT*3C. Patients with two nonfunctional alleles (homozygous) have low or absent TPMT activity and those with one non-functional allele (heterozygous) have intermediate activity. Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. TPMT testing may also be considered in patients with abnormal CBC results that do not respond to dose reduction. Early drug discontinuation in these patients is advisable. TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections.
Carcinogenesis, Mutagenesis, Impairment of Fertility
See WARNINGS section.
Pregnancy Category D. See WARNINGS section.
Nursing Mothers: The use of IMURAN in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk.17, 18, 19 Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Safety and efficacy of azathioprine in pediatric patients have not been established.
2. Weinshilboum R. Thiopurine pharmacogenetics: clinical and molecular studies of thiopurine methyltransferase. Drug Metab Dispos. 2001;29:601-605.
3. McLeod HL, Siva C. The thiopurine S-methyltransferase gene locus -- implications for clinical pharmacogenomics. Pharmacogenomics. 2002;3:89-98.
4. Anstey A, Lennard L, Mayou SC, et al. Pancytopenia related to azathioprine – an enzyme deficiency caused by a common genetic polymorphism: a review. JR Soc Med. 1992; 85:752-756.
5. Stolk JN, Beorbooms AM, de Abreu RA, et al. Reduced thiopurine methyltransferase activity and development of side effects of azathioprine treatment in patients with rheumatoid arthritis. Arthritis Rheum. 1998; 41:18581866.
6. Data on file, Prometheus Laboratories Inc.
7. Yates CR, Krynetski EY, Loennechen T, et al. Molecular diagnosis of thiopurine S-methyltransferase deficiency: genetic basis for azathioprine and mercaptopurine intolerance. Ann Intern Med. 1997; 126:608-614.
8. Black AJ, McLeod HL, Capell HA, et al. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann Intern Med. 1998; 129:716-718.
9. Clunie GP, Lennard L. Relevance of thiopurine methyltransferase status in rheumatology patients receiving azathioprine. Rheumatology. 2004; 43:13-18.
10. Clark JM. The mutagenicity of azathioprine in mice, Drosophila melanogaster, and Neurospora crassa. Mutat Res. 1975; 28:87-99.
11. Data on file, Prometheus Laboratories Inc.
12. Tagatz GE, Simmons RL. Pregnancy after renal transplantation. Ann Intern Med. 1975; 82:113-114. Editorial Notes.
13. Cote' CJ, Meuwissen HJ, Pickering RJ. Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy. J Pediatr. 1974; 85:324-328.
14. DeWitte DB, Buick MK, Cyran SE, et al. Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone. J Pediatr. 1984; 105:625-628.
15. Williamson RA, Karp LE. Azathioprine teratogenicity: review of the literature and case report. Obstet Gynecol. 1981; 58:247-250.
16. Tallent MB, Simmons RL, Najarian JS. Birth defects in child of male recipient of kidney transplant. JAMA. 1970; 211: 1854-1855.
17. Data on file, Prometheus Laboratories Inc.
18. Saarikoski S, Seppälä M. Immunosuppression during pregnancy: transmission of azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gynecol. 1973; 115:1100-1106.
19. Coulam CB, Moyer TP, Jiang NS, et al. Breast-feeding after renal transplantation. Transplant Proc. 1982; 14: 605-609.
Last reviewed on RxList: 6/6/2011
This monograph has been modified to include the generic and brand name in many instances.
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