IMURAN (azathioprine), an immunosuppressive antimetabolite, is available in tablet form for oral administration and 100-mg vials for intravenous injection. Each scored tablet contains 50 mg azathioprine and the inactive ingredients lactose, magnesium stearate, potato starch, povidone, and stearic acid. Each 100-mg vial contains azathioprine, as the sodium salt, equivalent to 100 mg azathioprine sterile lyophilized material and sodium hydroxide to adjust pH.

Azathioprine is chemically 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. The structural formula of azathioprine is:

It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound.

Azathioprine is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. The sodium salt of azathioprine is sufficiently soluble to make a 10mg/mL water solution which is stable for 24 hours at 59° to 77°F (15° to 25°C). Azathioprine is stable in solution at neutral or acid pH but hydrolysis to mercaptopurine occurs in excess sodium hydroxide (0.1N), especially on warming. Conversion to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine, glutathione, and hydrogen sulfide.

Last updated on RxList: 8/4/2008

IMURAN 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 Homotransplantation: IMURAN 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 IMURAN on these variables has not been tested in controlled trials.

Rheumatoid Arthritis: IMURAN 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 IMURAN. The combined use of IMURAN with disease modifying anti­rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of IMURAN with these agents cannot be recommended.

TPMT TESTING CANNOT SUBSTITUTE FOR COMPLETE BLOOD COUNT (CBC) MONITORING IN PATIENTS RECEIVING IMURAN. 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, life-threatening myelotoxicity from IMURAN if conventional doses are given. Physicians may consider alternative therapies for patients who have low or absent TPMT activity (homozygous for non­ functional alleles). IMURAN 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 Homotransplantation: The dose of IMURAN 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. IMURAN is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. IMURAN 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 IMURAN 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 Arthritis: IMURAN 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 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. IMURAN 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 IMURAN has not been determined. IMURAN can be discontinued abruptly, but delayed effects are possible.

Use in Renal Dysfunction: Relatively oliguric patients, especially those with tubular necrosis in the immediate postcadaveric transplant period, may have delayed clearance of IMURAN or its metabolites, may be particularly sensitive to this drug, and are usually given lower doses.

Parenteral Administration: Add 10 mL of Sterile Water for Injection, and swirl until a clear solution results. This solution, equivalent to 100 mg azathioprine, is for intravenous use only; it has a pH of approximately 9.6, and it should be used within 24 hours. Further dilution into sterile saline or dextrose is usually made for infusion; the final volume depends on time for the infusion, usually 30 to 60 minutes, but as short as 5 minutes and as long as 8 hours for the daily dose.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

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.

50 mg overlapping circle-shaped, yellow to off-white, scored tablets imprinted with "IMURAN" and "50" on each tablet; bottle of 100 (NDC 65483-590-10).

Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light.

20-mL vial, each containing the equivalent of 100 mg azathioprine (as the sodium salt) (NDC 65483-551-01).

Store at 15° to 25°C (59° to 77°F) and protect from light.

The sterile, lyophilized sodium salt is yellow, and should be dissolved in Sterile Water for Injection (see DOSAGE AND ADMINISTRATION: Parenteral Administration).

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: DSM Pharmaceuticals, Inc. Greenville, NC 27834 for Prometheus Laboratories Inc. San Diego, CA 92121. FDA Rev date: 07/09/08

Last updated on RxList: 8/4/2008

The principal and potentially serious toxic effects of IMURAN 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 IMURAN 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 IMURAN for rheumatoid arthritis. The relative incidences in clinical studies are summarized below:

Toxicity	Renal Homograft	Rheumatoid Arthritis
Leukopenia (any degree)	>50%	28%
<2500 cells/mm3	16%	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 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 IMURAN. 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 non-functional alleles) who are at increased risk for severe, life-threatening myelosuppression from IMURAN. 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 IMURAN, 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 IMURAN. 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 IMURAN 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, IMURAN 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 and hepatosplenic T-cell lymphoma.

Use with Allopurinol: One of the pathways for inactivation of azathioprine is inhibited by allopurinol. Patients receiving IMURAN and allopurinol concomitantly should have a dose reduction of IMURAN, 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 IMURAN and allopurinol because both TPMT and XO inactivation pathways are affected. See CLINICAL PHARMACOLOGY, WARNINGS, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections.

Use with Aminosalicylates: There is in vitro evidence that aminosalicylate derivatives (e.g., sulphasalazine, mesalazine, or olsalazine) inhibit the TPMT enzyme. Concomitant use of these agents with IMURAN should be done with caution.

Use with Other Agents Affecting Myelopoesis: Drugs which may affect leukocyte production, including co­trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients.

Use with Angiotensin-Converting Enzyme Inhibitors: The use of angiotensin-converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia. Use with Warfarin: IMURAN may inhibit the anticoagulant effect of warfarin.

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 veno-occlusive 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.

Last updated on RxList: 8/4/2008

Severe leukopenia, thrombocytopenia, 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.

IMURAN 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 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 azathioprine. Data on neoplasia in patients receiving IMURAN can be found under ADVERSE REACTIONS.

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: 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

IMURAN 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 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.

General: 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.

Carcinogenesis, Mutagenesis, Impairment of Fertility: See WARNINGS section.

Pregnancy: Teratogenic Effects: 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.

Pediatric Use: Safety 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.

Last updated on RxList: 8/4/2008

The oral LD50s for single doses of IMURAN 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 IMURAN 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 IMURAN. 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.

IMURAN should not be given to patients who have shown hypersensitivity to the drug. IMURAN 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 IMURAN.

REFERENCES

24. Schusziarra V, Ziekursch V, Schlamp R, et al. Pharmacokinetics of azathioprine under haemodialysis. Int J Clin Pharmacol Biopharm. 1976; 14:298-302.

Last updated on RxList: 8/4/2008

Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral ³⁵S-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all ³⁵S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine. Usual doses produce blood levels of azathioprine, and of mercaptopurine derived from it, which are low ( < 1 mcg/mL). Blood levels are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable. See OVERDOSAGE.

Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized 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 (See Metabolism Scheme in Figure 1). The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN into DNA.

6-MP undergoes two major inactivation routes (Figure 1). One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). TPMT activity is controlled by a genetic polymorphism.^1,2,3 For Caucasians and African Americans, approximately 10% of the population inherit one non-functional TPMT allele (heterozygous) conferring intermediate TPMT activity, and 0.3% inherit two TPMT non-functional alleles (homozygous) for low or absent TPMT activity. Non-functional alleles are less common in Asians. 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, leaving TPMT methylation as the only inactivation pathway. Patients with intermediate TPMT activity may be at 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.^4-9 TPMT genotyping or phenotyping (red blood cell TPMT activity) can help identify patients who are at an increased risk for developing IMURAN toxicity.^{2, 3, 7, 8, 9} Accurate phenotyping (red blood cell TPMT activity) results are not possible in patients who have received recent blood transfusions. See WARNINGS, PRECAUTIONS: DRUG INTERACTIONS, PRECAUTIONS: Laboratory Tests and ADVERSE REACTIONS sections.

Figure 1. Metabolism pathway of azathioprine: competing pathways result in inactivation by TPMT or XO, or incorporation of cytotoxic nucleotides into DNA.

GMPS: Guanosine monophosphate synthetase; HGPRT: Hypoxanthine-guanine-phosphoribosyl-transferase; IMPD: Inosine monophosphate dehydrogenase; MeMP: Methylmercaptopurine; MeMPN: Methylmercaptopurine nucleotide; TGN: Thioguanine nucleotides; TIMP: Thioinosine monophosphate; TPMT: Thiopurine S-methyltransferase; TU Thiouric acid; XO: Xanthine oxidase) (Adapted from Pharmacogenomics 2002; 3:89-98; and Cancer Res 2001; 61:5810-5816.)

Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The inhibition of xanthine oxidase in patients receiving allopurinol (ZYLOPRIM®) is the basis for the azathioprine dosage reduction required in these patients (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 cell-mediated 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.

REFERENCES

1. Lennard L. The clinical pharmacology of 6-mercaptopurine. Eur J Clin Pharmacol. 1992;43:329-339.

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.

Last updated on RxList: 8/4/2008

Patients being started on IMURAN should be informed of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician. They should be informed of the danger of infection while receiving IMURAN and asked to report signs and symptoms of infection to their physician. Careful dosage instructions should be given to the patient, especially when IMURAN is being administered in the presence of impaired renal function or concomitantly with allopurinol (see DRUG INTERACTIONS subsection and DOSAGE AND ADMINISTRATION). Patients should be advised of the potential risks of the use of IMURAN during pregnancy and during the nursing period. The increased risk of neoplasia following therapy with IMURAN should be explained to the patient.

Laboratory Tests: 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.

TPMT Testing: 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 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 IMURAN. See CLINICAL PHARMACOLOGY, WARNINGS, ADVERSE REACTIONS and DOSAGE AND ADMINISTRATION sections.

Last updated on RxList: 8/4/2008

IMPORTANT NOTE: This is a summary and does not contain all possible information about this product. For complete information about this product or your specific health needs, ask your health care professional. Always seek the advice of your health care professional if you have any questions about this product or your medical condition. This information is not intended as individual medical advice and does not substitute for the knowledge and judgment of your health care professional. This information does not contain any assurances that this product is safe, effective, or appropriate for you.

AZATHIOPRINE - ORAL

(aze-uh-THIGH-oh-preen)

COMMON BRAND NAME(S): Imuran

WARNING: Long-term use of azathioprine may increase your risk of developing certain types of cancer (e.g., skin cancer, lymphoma). You must be closely monitored by your doctor during treatment and regularly afterwards if your doctor stops treatment with this medication. Azathioprine may also cause serious (rarely fatal) blood disorders (decreased bone marrow function leading to anemia, low number of white blood cells and platelets). It can lower your body's ability to fight an infection. The risk of these side effects is higher in patients receiving this medication to prevent kidney transplant rejection than in patients treated for rheumatoid arthritis. To reduce the risk of side effects, use this medication at the lowest effective dose. Keep all medical and laboratory appointments.

Tell your doctor immediately if you develop any of the following: unusual skin changes, change in the appearance/size of moles, unusual growths/lumps, swollen glands, unexplained weight loss, night sweats, unexplained itching, signs of infection (e.g., fever, persistent sore throat), easy bruising/bleeding, or unusual tiredness.

USES: Azathioprine is used with other medications to prevent rejection of a kidney transplant. It works by weakening your body's defense system (immune system) to help your body accept the new kidney as if it were your own. This medication belongs to a class of drugs known as immunosuppressants.

Azathioprine is also used to treat patients with severe rheumatoid arthritis who have not responded to other medications (e.g., nonsteroidal anti-inflammatory drugs/NSAIDs such as ibuprofen). Rheumatoid arthritis is thought to be caused by the immune system attacking the joints. Early treatment of rheumatoid arthritis with more aggressive therapy such as azathioprine helps to reduce further joint damage and to preserve joint function.

OTHER USES: This section contains uses of this drug that are not listed in the approved professional labeling for the drug but that may be prescribed by your health care professional. Use this drug for a condition that is listed in this section only if it has been so prescribed by your health care professional.

This medication may also be used to prevent rejection of other transplanted organs, to treat a certain type of bowel condition (Crohn's disease) that is not responsive to usual treatment, and to treat other immune system problems (autoimmune diseases) as determined by your doctor.

HOW TO USE: Take this medication by mouth, usually once or twice daily as directed by your doctor. Azathioprine should be taken with food to reduce stomach upset. Dosage is based on your medical condition, weight, and response to therapy. For the treatment of rheumatoid arthritis, the manufacturer recommends that you do not take more than 2.5 milligrams per kilogram per day.

Do not increase your dose or take this medication more often without your doctor's approval. Your condition will not improve any faster and the risk of serious side effects may be increased. Also do not stop taking this medication without your doctor's approval.

Use this medication regularly in order to get the most benefit from it. Remember to use it at the same time(s) each day.

For arthritis, it may take up to 2 months of continued use to notice relief of symptoms. Inform your doctor if your condition does not improve after 3 months of treatment.

Since this drug can be absorbed through the skin, women who are pregnant or who may become pregnant should not handle or break the tablets of this medication.

SIDE EFFECTS: See also Warning section.

Remember that your doctor has prescribed this medication because he or she has judged that the benefit to you is greater than the risk of side effects. Many people using this medication do not have serious side effects.

You may experience stomach/intestinal symptoms such as nausea, vomiting, diarrhea, or loss of appetite. If these effects persist or worsen, notify your doctor immediately. These symptoms may be reduced by taking the medication after meals. Talk to your doctor or pharmacist about other dosing advice that may also help with these symptoms.

Although unlikely, more severe stomach/intestinal symptoms (e.g., severe nausea/vomiting/diarrhea, stomach/abdominal pain) may occur as part of a very serious allergic reaction. Seek immediate medical attention if you have severe stomach/intestinal symptoms or other symptoms of a serious allergic reaction which may include: fever, shaking chills, rash, itching, swelling, severe dizziness, trouble breathing, cough, new or worsening joint/muscle aches, dark urine.

Tell your doctor immediately if any of these unlikely but serious side effects occur: weakness, muscle loss, vision changes, hair loss, cold/numbness in the fingers, mouth sores, difficult/painful swallowing, greasy stools.

Seek immediate medical attention if any of these rare but very serious side effects occur: yellowing eyes/skin, swelling/extra fluid around the abdomen, vomit that contains blood or looks like coffee grounds, black stools.

This is not a complete list of possible side effects. If you notice other effects not listed above, contact your doctor or pharmacist.

Contact your doctor for medical advice about side effects. The following numbers do not provide medical advice, but in the US you may report side effects to the Food and Drug Administration (FDA) at 1-800-FDA-1088. In Canada, you may call Health Canada at 1-866-234-2345.

PRECAUTIONS: Before taking azathioprine, tell your doctor or pharmacist if you are allergic to it, or if you have any other allergies.

Before using this medication, tell your doctor or pharmacist your medical history, especially of: kidney disease, liver disease, blood disorders, decreased bone marrow function, cancer, active infections, certain enzyme disorder (TPMT deficiency).

Do not have immunizations/vaccinations without the consent of your doctor, and avoid contact with people who have recently received polio vaccine by mouth or flu vaccine inhaled through the nose.

Since this medication can increase your risk of developing serious infections, wash your hands well to prevent the spread of infections. Avoid contact with people who have illnesses that may spread to others (e.g., flu, chickenpox).

Use caution with sharp objects like safety razors or nail cutters, and avoid activities such as contact sports to lower the chance of getting cut, bruised, or injured.

Kidney function declines as you grow older. This medication is removed by the kidneys. Therefore, the elderly may be more sensitive to the effects of this drug.

This medication is not recommended for use during pregnancy. It may harm an unborn baby. Consult your doctor for more details. It is recommended that men and women use two effective forms of birth control (e.g., condoms, birth control pill) while taking this medication. However, this medication can decrease the effectiveness of intrauterine devices (IUDs). This can result in pregnancy. Talk to your doctor about other effective birth control choices.

This medication passes into breast milk and may have undesirable effects on a nursing infant. Therefore, breast-feeding while using this drug is not recommended. Consult your doctor before breast-feeding.

DRUG INTERACTIONS: Your healthcare professionals (e.g., doctor or pharmacist) may already be aware of any possible drug interactions and may be monitoring you for it. Do not start, stop, or change the dosage of any medicine before checking with them first.

This drug should not be used with the following medications because very serious interactions may occur: past or present use of alkylating-type cancer drugs (e.g., chlorambucil, cyclophosphamide, melphalan), mercaptopurine, natalizumab.

If you are currently using or have used any of these medications listed above, tell your doctor or pharmacist before starting azathioprine.

Before using this medication, tell your doctor or pharmacist of all prescription and nonprescription/herbal products you may use, especially of: ACE inhibitors (e.g., benazepril, lisinopril), allopurinol, aminosalicylates (e.g., olsalazine, sulfasalazine), "blood thinners" (e.g., enoxaparin, heparin, warfarin), drugs affecting the bone marrow (e.g., trimethoprim/sulfamethoxazole, cancer chemotherapy drugs).

This document does not contain all possible interactions. Therefore, before using this product, tell your doctor or pharmacist of all the products you use. Keep a list of all your medications with you, and share the list with your doctor and pharmacist.

OVERDOSE: If overdose is suspected, contact your local poison control center or emergency room immediately. US residents can call the US national poison hotline at 1-800-222-1222. Canadian residents should call their local poison control center directly.

NOTES: Do not share this medication with others.

Laboratory and/or medical tests (e.g., complete blood count, liver and kidney function) should be performed periodically to monitor your progress or check for side effects. Consult your doctor for more details.

If you have had an organ transplant, it is recommended that you attend a transplant education class or support group. Learn the signs of organ rejection such as a feeling of being ill, fever, or tenderness around the transplanted organ. Signs of a failing kidney transplant include a decrease in the amount of urine, swelling of the arms/legs/face, trouble breathing, or increase in blood pressure. Seek immediate medical attention if these symptoms occur.

MISSED DOSE: Unless your doctor directs you otherwise, if you take this drug once daily and miss a dose, take it as soon as you remember unless it is almost time for the next dose. If it is near the time of the next dose, skip the missed dose and resume your usual dosing schedule. Do not double the dose to catch up.

If you take more than one dose a day and miss a dose, take it as soon as you remember. If it is almost time for the next dose, take both doses together, then resume your usual dosing schedule. If you miss more than one dose, contact your doctor. You may need to have your dosing schedule adjusted.

STORAGE: Store at room temperature between 59-77 degrees F (15-25 degrees C) away from light and moisture. Do not store in the bathroom. Keep all medicines away from children and pets.

Do not flush medications down the toilet or pour them into a drain unless instructed to do so. Properly discard this product when it is expired or no longer needed. Consult your pharmacist or local waste disposal company for more details about how to safely discard your product.

MEDICAL ALERT: Your condition can cause complications in a medical emergency. For enrollment information call MedicAlert at 1-800-854-1166 (USA) or 1-800-668-1507 (Canada).

Information last revised July 2008 Copyright(c) 2008 First DataBank, Inc.