What is the recommended workup for a patient being considered for azathioprine therapy?

Workup for Azathioprine

Pre-Treatment Laboratory Assessment

Before initiating azathioprine, you must check thiopurine methyltransferase (TPMT) activity or genotype, complete blood count (CBC) with platelets, and liver function tests (LFTs). 1, 2, 3

Essential Pre-Treatment Tests

• TPMT testing (activity or genotyping) is mandatory before starting azathioprine to identify patients at high risk for life-threatening myelosuppression 1, 2, 3

  • Very low or absent TPMT activity is an absolute contraindication to azathioprine due to severe pancytopenia risk 1, 3
  • Intermediate TPMT activity requires dose reduction to 1-1.5 mg/kg/day 4
  • High TPMT activity allows dosing at the higher end of the therapeutic range 1
  • Note that TPMT testing cannot substitute for ongoing CBC monitoring 3

• Baseline CBC with differential and platelet count to establish pre-treatment hematologic parameters 1, 2, 3

• Baseline liver function tests including transaminases (ALT, AST), alkaline phosphatase, and bilirubin 1, 2, 3

Additional Pre-Treatment Considerations

• Consider NUDT15 genotyping in patients who develop severe myelosuppression, as this represents another genetic pathway for azathioprine toxicity 3

• Hepatitis B and C screening (HBsAg, anti-HBc, HCV antibody) should be performed before initiating immunosuppression 2

• Varicella zoster virus (VZV) serology in patients with uncertain chickenpox history, as live vaccines are contraindicated once treatment begins 1, 2

• Pregnancy test in women of childbearing potential, as azathioprine is contraindicated in pregnancy except when benefits outweigh risks 1

Monitoring Schedule During Treatment

Monitor CBC and LFTs weekly for the first 4 weeks, then continue weekly until maintenance dose is achieved, followed by at least every 3 months indefinitely. 1, 2, 4, 3

Intensive Monitoring Phase (First 4 Weeks)

• Weekly CBC with differential and platelet count 1, 2, 3
• Weekly liver function tests 1, 2
• This intensive monitoring identifies early toxicity when it is most likely to occur 1

Dose Escalation Phase

• Continue weekly monitoring until the maintenance dose is achieved 2, 4
• Return to weekly monitoring following any dose increase 2
• The FDA label specifically emphasizes weekly monitoring during the first month, then twice monthly for months 2-3 3

Maintenance Phase

• Reduce to monthly monitoring for months 2-3 after achieving stable dosing 3
• Minimum of every 3 months once stable on a fixed maintenance dose for the duration of therapy 1, 2
• More frequent monitoring may be needed if dose adjustments occur or if the patient is on multiple immunosuppressants 2

Specific Laboratory Parameters to Monitor

Hematologic Monitoring

• White blood cell count and differential - leucopenia is the most common hematological adverse event 2
• Platelet count - thrombocytopenia below 50 × 10⁹/L requires immediate withdrawal and hematology consultation 1
• Neutrophil count - absolute neutrophil count below 1.0 × 10⁹/L requires immediate withdrawal and hematology consultation 1
• Hemoglobin - anemia can occur but is less common than leucopenia 2
• Mean corpuscular volume (MCV) - macrocytosis is a common finding that can be used to assess patient compliance 2

Hepatic Monitoring

• Transaminases (ALT, AST) to detect hepatotoxicity, which can present as either cholestatic or hepatocellular patterns 1, 2, 5
• Bilirubin as an indicator of hepatotoxicity 2
• Alkaline phosphatase 2
• Azathioprine-induced hepatotoxicity is uncommon but more frequent in patients with advanced liver disease 1

Critical Drug Interactions Requiring Pre-Treatment Assessment

Screen for allopurinol or febuxostat use before prescribing azathioprine, as concomitant use requires dose reduction to 25-33% of usual dose or is contraindicated. 1, 3

• Allopurinol inhibits xanthine oxidase and prolongs azathioprine action, causing severe toxicity - reduce azathioprine to approximately 1/3 to 1/4 usual dose if combination is unavoidable 1, 3
• Febuxostat - concomitant use is not recommended 3
• Sulfasalazine and other aminosalicylates inhibit TPMT activity and may potentiate toxicity - use with caution 1
• Ribavirin induces severe pancytopenia and increases myelotoxicity risk - requires weekly CBC monitoring if combination is necessary 3
• ACE inhibitors have been reported to induce severe leucopenia in patients on azathioprine 1
• Warfarin - azathioprine may impair anticoagulant effect 1

Patient Education and Safety Instructions

Patients must be counseled to report immediately any signs of infection, unexplained bruising or bleeding, jaundice, or severe abdominal pain. 1

Warning Signs Requiring Immediate Medical Attention

• Infection symptoms: fever, chills, sore throat, cough, burning with urination, wounds with redness/discharge 1, 2
• Bone marrow suppression: unexplained bruising, bleeding, or petechiae 1, 2
• Hepatotoxicity: jaundice, dark urine, right upper quadrant pain 1
• Pancreatitis: sudden onset severe abdominal pain with or without vomiting - check serum amylase urgently 1
• Hypersensitivity: flu-like symptoms that may represent azathioprine hypersensitivity syndrome 1

Infection Prevention

• Varicella zoster exposure: patients who have not had chickenpox should seek immediate attention if exposed for consideration of zoster immune globulin 1
• Live vaccines are contraindicated during azathioprine therapy 1, 4
• Household members should receive inactive (not live) polio vaccine due to orofecal transmission risk 1

Reproductive Counseling

• Pregnancy should be avoided during treatment - adequate contraception is mandatory 1
• Breastfeeding is not recommended as azathioprine metabolites are transferred in breast milk 3

Common Pitfalls and How to Avoid Them

• Starting azathioprine without TPMT testing - this is the single most important error to avoid, as TPMT-deficient patients can develop fatal pancytopenia 1, 3
• Inadequate monitoring frequency - the highest risk period is the first 4 weeks, requiring weekly monitoring 1, 3
• Missing drug interactions - always screen for allopurinol, febuxostat, and aminosalicylates before prescribing 3
• Delaying azathioprine withdrawal when toxicity occurs - immediate discontinuation is required for significant myelosuppression or hepatotoxicity 1, 5
• Assuming TPMT testing eliminates the need for monitoring - even with normal TPMT, regular CBC monitoring is mandatory as other toxicity pathways exist 3