Imuran - Drug Monograph

Introduction

Imuran (azathioprine) is an immunosuppressive medication belonging to the antimetabolite class. First approved by the FDA in 1968, it remains a cornerstone therapy in transplant medicine and autoimmune disease management. As a prodrug of 6-mercaptopurine, Imuran interferes with purine synthesis and cellular replication, leading to its immunosuppressive effects.

Mechanism of Action

Imuran is metabolized to 6-mercaptopurine (6-MP), which is subsequently converted to active thioinosinic acid metabolites. These metabolites incorporate into DNA and RNA, inhibiting purine synthesis and interfering with nucleic acid metabolism. The drug primarily affects rapidly dividing cells, including lymphocytes, resulting in:

• Inhibition of T-cell and B-cell proliferation
• Reduced antibody production
• Suppression of cell-mediated immune responses
• Decreased inflammatory responses

Indications

• Renal transplantation: Prevention of rejection as adjunctive therapy
• Rheumatoid arthritis: Active disease unresponsive to conventional therapy

• Inflammatory bowel disease (Crohn's disease and ulcerative colitis)
• Autoimmune hepatitis
• Systemic lupus erythematosus
• Myasthenia gravis
• Vasculitis syndromes
• Dermatological conditions (pemphigus vulgaris, severe psoriasis)

Dosage and Administration

• Renal transplantation: 3-5 mg/kg/day initially, then maintenance dose of 1-3 mg/kg/day
• Rheumatoid arthritis: Initial dose 1 mg/kg/day (50-100 mg), increased by 0.5 mg/kg/day at 4-8 week intervals to maximum 2.5 mg/kg/day

• Oral formulation: Tablets (50 mg, 75 mg, 100 mg)
• Should be administered with food to minimize gastrointestinal upset
• Dosing adjustments required based on thiopurine methyltransferase (TPMT) activity

• Renal impairment: Reduce dose by 30-50% if CrCl <50 mL/min
• Hepatic impairment: Use with caution; consider dose reduction
• Elderly: Increased susceptibility to myelosuppression; lower initial doses recommended
• Pediatrics: Safety established in pediatric transplant patients

Pharmacokinetics

• Conversion to 6-mercaptopurine (non-enzymatic)
• Metabolism by xanthine oxidase (inhibited by allopurinol)
• Metabolism by thiopurine methyltransferase (TPMT) - genetic polymorphism affects activity

Contraindications

• Hypersensitivity to azathioprine or any component
• Pregnancy (unless benefits outweigh risks)
• Patients with TPMT deficiency (homozygous)
• Concurrent administration with live vaccines
• Patients with known serious infections

Warnings and Precautions

1. Severe myelosuppression: May lead to serious infections and bleeding 2. Malignancy risk: Increased risk of lymphoma and other malignancies 3. Immunosuppression: Increased susceptibility to infection

• Regular hematologic monitoring required
• Hepatotoxicity: Monitor liver enzymes regularly
• Pancreatitis: Discontinue if clinical symptoms develop
• Secondary infections: Monitor for opportunistic infections
• Vaccination: Avoid live vaccines during therapy

Drug Interactions

• Allopurinol/febuxostat: Potentiates toxicity (inhibit xanthine oxidase); reduce azathioprine dose by 65-75%
• Warfarin: May decrease anticoagulant effect
• Angiotensin-converting enzyme inhibitors: Increased risk of anemia
• Myelosuppressive agents: Additive bone marrow suppression
• Tumor necrosis factor inhibitors: Increased immunosuppression

• Aminosalicylates: May inhibit TPMT activity
• Ribavirin: Potential additive hematologic toxicity

Adverse Effects

• Nausea/vomiting (15-25%)
• Leukopenia (15-28%)
• Infection (15-20%)
• Mild hepatic enzyme elevations (10-15%)

• Severe bone marrow suppression (2-5%)
• Hepatotoxicity (2-4%)
• Pancreatitis (1-3%)
• Malignancies (long-term use)
• Hypersensitivity reactions
• Opportunistic infections

Monitoring Parameters

• Complete blood count with differential
• Liver function tests
• TPMT genotyping or phenotyping
• Renal function
• Pregnancy test if applicable

• Weekly CBC for first month, then monthly for 3 months, then every 3 months
• Liver enzymes monthly for first 3 months, then every 3 months
• Signs of infection
• Nutritional status
• Skin examinations for malignancy screening

• 6-thioguanine nucleotide levels in selected cases
• TPMT activity in cases of toxicity or inadequate response

Patient Education

• Take exactly as prescribed; do not adjust dose without medical supervision
• Report signs of infection (fever, sore throat, chills) immediately
• Report unusual bleeding or bruising
• Avoid contact with people who have infections
• Use effective contraception during treatment
• Avoid live vaccines
• Regular blood tests are essential for safety
• Report nausea, vomiting, abdominal pain, or dark urine
• Sun protection important due to increased skin cancer risk
• Inform all healthcare providers about Imuran use

References

1. Package Insert: Imuran (azathioprine) [Prescribing Information]. Prometheus Laboratories Inc.; 2021. 2. Relling MV, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes. Clin Pharmacol Ther. 2019;105(5):1095-1105. 3. Sahasranaman S, et al. Clinical pharmacology and pharmacogenetics of thiopurines. Eur J Clin Pharmacol. 2008;64(8):753-767. 4. Weinshilboum RM, Sladek SL. Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am J Hum Genet. 1980;32(5):651-662. 5. American College of Rheumatology. Guidelines for the Management of Rheumatoid Arthritis. Arthritis Care Res. 2021;73(7):924-939. 6. Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group. KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant. 2009;9 Suppl 3:S1-S155. 7. Terdiman JP, et al. American Gastroenterological Association Institute Guideline on the Use of Thiopurines, Methotrexate, and Anti-TNF-α Biologic Drugs for the Induction and Maintenance of Remission in Inflammatory Crohn's Disease. Gastroenterology. 2013;145(6):1459-1463.