Reintroduction of Azathioprine After Elevated Liver Enzymes
After a 2-week break due to elevated ALT and AST, azathioprine should be reintroduced at 50 mg/day, with sequential increases every 2-3 days if no reaction occurs, while monitoring liver function tests weekly until a stable maintenance dose is achieved. 1, 2
Initial Reintroduction Protocol
- After liver enzymes have normalized following a 2-week break, azathioprine should be reintroduced at a low dose of 50 mg/day 1, 3
- If no reaction occurs after 2-3 days, the dose can be increased sequentially 2, 1
- Maintain each dose level for 2-3 days before considering further increases 2, 1
- Target a final maintenance dose that is lower than the previous dose that caused hepatotoxicity 1
- Take medication with or shortly after food to reduce gastrointestinal side effects 3
- Consider splitting the daily dose if gastrointestinal symptoms occur 3
Monitoring During Reintroduction
- Monitor liver function tests (ALT/AST) weekly during the reintroduction phase 2, 3
- Continue weekly monitoring until a stable maintenance dose is achieved 2, 3
- After achieving a stable maintenance dose, reduce monitoring frequency to once every 2 weeks for the first 2 months 2
- Eventually transition to monitoring every 1-3 months for the duration of therapy 2, 3
When to Stop Therapy Again
- Stop azathioprine immediately if ALT/AST rises to 5 times the upper limit of normal 2, 1
- Consider stopping if ALT/AST rises to 3 times the upper limit of normal 2, 1
- Any elevation in bilirubin (≥2× ULN) along with elevated transaminases warrants immediate discontinuation 1
- Monitor for clinical symptoms such as fever, malaise, vomiting, jaundice, or unexplained deterioration 2, 1
Special Considerations
- If hepatotoxicity recurs despite dose reduction, consider alternative immunosuppressive agents 1
- Patients with intermediate or low TPMT activity are at increased risk for toxicity and may require lower doses 2, 3
- Avoid concomitant use with allopurinol, which can increase azathioprine toxicity 2
- Consider a repeat liver biopsy if azathioprine hepatotoxicity is suspected, particularly if associated with high blood levels of 6-methylmercaptopurine metabolites 1
Long-term Management
- After successful reintroduction, maintain the highest tolerated dose that does not cause liver enzyme elevation 3, 1
- For rheumatoid arthritis patients, the FDA recommends maintenance therapy at the lowest effective dose 4
- Dose adjustments should be made in increments of 0.5 mg/kg or approximately 25 mg daily every 4 weeks 4
- Continue regular monitoring of liver function tests every 1-3 months for the duration of therapy 2, 3
Hepatotoxicity with azathioprine can occur rapidly, with some cases showing elevated liver enzymes within days of initiating therapy 5. This underscores the importance of careful monitoring during reintroduction, especially in the first few weeks.