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 anti-rheumatic 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.

PROMETHEUS LABORATORIES INC. Manufactured by DSM Pharmaceuticals, Inc. Greenville, NC 27834 for Prometheus Laboratories Inc. San Diego, CA 92121. FDA Rev date: 7/26/2005

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