The oral LD50s for single doses of AZASAN® (azathioprine) in mice and rats are 2500 mg/kg and 400 mg/kg, respectively. Very large doses of this antimetabolite may lead to marrow hypoplasia, bleeding, infection, and death. About 30% of AZASAN® (azathioprine) is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis.24 A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg azathioprine. The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, SGOT, and bilirubin returned to normal 6 days after the overdose.
AZASAN® (azathioprine) should not be given to patients who have shown hypersensitivity to the drug.
AZASAN® (azathioprine) should not be used for treating rheumatoid arthritis in pregnant women.
Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, or others) may have a prohibitive risk of neoplasia if treated with AZASAN® (azathioprine).
REFERENCES
24. Schusziarra V, Ziekursch V, Schlamp R, et al. Pharmacokinetics of azathioprine under haemodialysis. Int J Clin Pharmacol Biopharm. 1976; 14:298-302.
The principal and potentially serious toxic effects of AZASAN® (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 AZASAN® (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 AZASAN® (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 | 316% | 5.3% |
| Infections | 20% | < 1% |
| Neoplasia | * | |
| Lymphoma | 0.5% | |
| Others | 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. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg/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. | ||
Leukopenia and/or thrombocytopenia are dose dependent and may occur late in the course of therapy with AZASAN® (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 AZASAN®. 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
GastrointestinalNausea and vomiting may occur within the first few months of therapy with AZASAN® (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 AZASAN® (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, AZASAN® (azathioprine) should be permanently withdrawn.
OthersAdditional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, and reversible interstitial pneumonitis.
REFERENCES
6. Data on file, Prometheus Laboratories Inc.
20. Schutz E, Gummert J, Mohr F, Oellerich M. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant patients. Lancet. 1993; 341:436.
21. Read AE, Wiesner RH, LaBrecque DR, et al. Hepatic venoocclusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med. 1986; 104:651-655.
22. Katzka DA, Saul SH, Jorkasky D, et al. Azathioprine and hepatic veno-occlusive disease in renal transplant patients. Gastroenterology. 1986; 90:446-454.
23. Weitz H, Gokel JM, Loeshke K, et al. Veno-occlusive disease of the liver in patients receiving immunosuppressive therapy. Virchows Arch A Pathol Anat Histol. 1982; 395:245-256.
AZASAN® (azathioprine) is indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms.
Renal HomotransplantationAZASAN® (azathioprine) is indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti B-cell alloantigen antibody, and other variables. The effect of azathioprine on these variables has not been tested in controlled trials.
Rheumatoid ArthritisAZASAN® (azathioprine) is indicated for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms. Aspirin, non-steroidal anti-inflammatory drugs and/or low dose glucocorticoids may be continued during treatment with AZASAN®. The combined use of azathioprine with disease modifying anti-rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of AZASAN® (azathioprine) with these agents cannot be recommended.
AZASAN® (azathioprine) can cause fetal harm when administered to a pregnant woman. AZASAN® (azathioprine) should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of AZASAN® (azathioprine) in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women.12
AZASAN® (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 AZASAN® (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 AZASAN® (azathioprine) in patients of reproductive potential. There are no adequate and wellcontrolled 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.
PRECAUTIONSAZASAN® (azathioprine) Tablets, USP are available in:
75 mg, triangle-shaped, yellow, scored tablets,
100 count bottles (NDC 65649-231-41)
15 count samples (NDC 65649-231-51)
100 mg, diamond-shaped, yellow, scored tablets,
100 count bottles (NDC 65649-241-41)
15 count samples (NDC 65649-241-51)
Store at 20° to 25°C (68° to 77° F)
Store in a dry place and protect from light.
Dispense in a tight, light-resistant container as defined in the USP.
REFERENCES
25. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety; Clinical Center Pharmacy Department and Cancer Nursing Services, National Institute of Health; 1992. US Dept of Health and Human Services. Public Health Service Publication NIH 92-2621.
26. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985; 253:1590-1592.
27. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.
28. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983; 1:426-428.
29. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J for Clinicians. 1983; 33:258-263.
30. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049.
31. Yodaiken RE, Bennett D. OSHA Work-Practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm, 1996; 43:1193-1204.
Manufactured by: AAIPharma Inc., Wilmington, NC 28405. Manufactured for: Morrisville, NC 27560.
Severe leukopenia, thrombocytopenia, macrocytic anemia, and/or pancytopenia may occur in patients being treated with AZASAN® (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 AZASAN® (azathioprine). Patients with low or absent TPMT activity are at an increased risk of developing severe, life-threatening myelotoxicity if receiving conventional doses of AZASAN® (azathioprine). TPMT genotyping or phenotyping can help identify patients who are at an increased risk for developing AZASAN® (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 AZASAN® (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.
AZASAN® (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 posttransplant 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 AZASAN® (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 AZASAN® (azathioprine) can be found under ADVERSE REACTIONS.
AZASAN® (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 DAZASAN® (azathioprine) can cause fetal harm when administered to a pregnant woman. AZASAN® (azathioprine) should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of AZASAN® (azathioprine) in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women.12
AZASAN® (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 AZASAN® (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 AZASAN® (azathioprine) in patients of reproductive potential. There are no adequate and wellcontrolled 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.
PRECAUTIONS GeneralA 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 AZASAN® (azathioprine) and are reversible upon discontinuation of the drug. The reaction can recur within hours after rechallenge with a single dose of AZASAN® (azathioprine).
Laboratory Tests Complete Blood Count (CBC) MonitoringPatients on AZASAN® (azathioprine) 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.
TPMT TestingIt 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 non-functional 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 AZASAN®. See CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections.
Carcinogenesis, Mutagenesis, Impairment of FertilitySee WARNINGS section.
Pregnancy Teratogenic EffectsPregnancy Category D. See WARNINGS section.
Nursing MothersThe use of AZASAN® 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.
Pediatric UseSafety and efficacy of azathioprine in pediatric patients have not been established.
REFERENCES
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; 41:1858-1866.
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.
TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING INPATIENTS RECEIVING AZASAN® (azathioprine). TPMT genotyping or phenotyping can be used to identify patients with absent or reduced TPMT activity. Patients with low or absent TPMT activity are at an increased risk of developing severe, lifethreatening myelotoxicity from AZASAN® (azathioprine) if conventional doses are given. Physicians may consider alternative therapies for patients who have low or absent TPMT activity (homozygous for non-functional alleles). AZASAN® (azathioprine) should be administered with caution to patients having one non-functional allele (heterozygous) who are at risk for reduced TPMT activity that may lead to toxicity if conventional doses are given. Dosage reduction is recommended in patients with reduced TPMT activity. Early drug discontinuation may be considered in patients with abnormal CBC results that do not respond to dose reduction.
Renal HomotransplantationThe dose of AZASAN® (azathioprine) required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. AZASAN® (azathioprine) is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. AZASAN® (azathioprine) is often initiated with the intravenous administration of the sodium salt, with subsequent use of tablets (at the same dose level) after the postoperative period. Intravenous administration of the sodium salt is indicated only in patients unable to tolerate oral medications. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of AZASAN® (azathioprine) should not be increased to toxic levels because of threatened rejection. Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal.
Rheumatoid ArthritisAZASAN® (azathioprine) is usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50 to 100 mg) given as a single dose or on a twice daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week 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/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® (azathioprine) 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® (azathioprine) has not been determined. AZASAN® (azathioprine) can be discontinued abruptly, but delayed effects are possible.
Use in Renal DysfunctionRelatively oliguric patients, especially those with tubular necrosis in the immediate post-cadaveric transplant period, may have delayed clearance of AZASAN® (azathioprine) 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.25-31 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate.
The principal and potentially serious toxic effects of AZASAN® (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 AZASAN® (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 AZASAN® (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 | 316% | 5.3% |
| Infections | 20% | < 1% |
| Neoplasia | * | |
| Lymphoma | 0.5% | |
| Others | 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. In one completed study, the rate of lymphoproliferative disease in RA patients receiving higher than recommended doses of azathioprine (5 mg/kg/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. | ||
Leukopenia and/or thrombocytopenia are dose dependent and may occur late in the course of therapy with AZASAN® (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 AZASAN®. 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
GastrointestinalNausea and vomiting may occur within the first few months of therapy with AZASAN® (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 AZASAN® (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, AZASAN® (azathioprine) should be permanently withdrawn.
OthersAdditional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance, and reversible interstitial pneumonitis.
REFERENCES
6. Data on file, Prometheus Laboratories Inc.
20. Schutz E, Gummert J, Mohr F, Oellerich M. Azathioprine-induced myelosuppression in thiopurine methyltransferase deficient heart transplant patients. Lancet. 1993; 341:436.
21. Read AE, Wiesner RH, LaBrecque DR, et al. Hepatic venoocclusive disease associated with renal transplantation and azathioprine therapy. Ann Intern Med. 1986; 104:651-655.
22. Katzka DA, Saul SH, Jorkasky D, et al. Azathioprine and hepatic veno-occlusive disease in renal transplant patients. Gastroenterology. 1986; 90:446-454.
23. Weitz H, Gokel JM, Loeshke K, et al. Veno-occlusive disease of the liver in patients receiving immunosuppressive therapy. Virchows Arch A Pathol Anat Histol. 1982; 395:245-256.
DRUG INTERACTIONS Use with AllopurinolOne of the pathways for inactivation of azathioprine is inhibited by allopurinol. Patients receiving AZASAN® (azathioprine) and allopurinol concomitantly should have a dose reduction of AZASAN® (azathioprine) , to approximately 1/3 to 1/4 the usual dose. It is recommended that a further dose reduction or alternative therapies be considered for patients with low or absent TPMT activity receiving AZASAN® (azathioprine) and allopurinol because both TPMT and XO inactivation pathways are affected. See CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections.
Use with AminosalicylatesThere is in vitro evidence that aminosalicylate derivatives (e.g., sulphasalazine, mesalazine, or olsalazine) inhibit the TPMT enzyme. Concomitant use of these agents with AZASAN® (azathioprine) should be done with caution.
Use with Other Agents Affecting MyelopoesisDrugs which may affect leukocyte production, including co-trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients.
Use with Angiotensin-Converting Enzyme InhibitorsThe use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia.
Use with WarfarinAZASAN® (azathioprine) may inhibit the anticoagulant effect of warfarin.
