Management of Leflunomide-Induced Hepatotoxicity
For patients taking leflunomide who develop elevated liver enzymes, temporarily hold leflunomide for ALT >3 times the upper limit of normal (ULN) and consider cholestyramine washout procedure for rapid drug elimination in severe cases. 1, 2
Monitoring Recommendations
Proper monitoring is essential for early detection of hepatotoxicity:
- Baseline monitoring: Complete blood count (CBC) with differential and liver function tests (LFTs) before starting leflunomide 1, 2
- Initial monitoring: Check LFTs within the first 1-2 months after starting therapy 1
- Ongoing monitoring: Monitor LFTs every 3-4 months thereafter 1
- Increased frequency: If mild elevations occur, increase monitoring to every 1-2 weeks 2
Management Algorithm for Leflunomide-Induced Hepatotoxicity
Grade 1 (ALT/AST < 3× ULN)
- Continue leflunomide with close monitoring
- Consider checking labs more frequently (1-2 times weekly) 2
- Evaluate for other causes of liver enzyme elevation
- Avoid other hepatotoxic medications
Grade 2 (ALT/AST 3-5× ULN)
- Temporarily hold leflunomide 1, 2
- Increase monitoring frequency to every 3 days 2
- Discontinue other potentially hepatotoxic medications
- If no improvement after 3-5 days, consider starting corticosteroids (0.5-1 mg/kg/day prednisone) 2
- Resume leflunomide at reduced dose (10 mg/day) once enzymes normalize 1, 3
Grade 3-4 (ALT/AST >5× ULN)
- Permanently discontinue leflunomide 2
- Implement drug elimination procedure with cholestyramine (8g three times daily for 11 days) or activated charcoal 2
- Consult hepatology
- Monitor LFTs until normalization
Special Considerations
Risk Factors for Leflunomide Hepatotoxicity
- Concomitant use of other hepatotoxic medications, especially methotrexate 2, 3
- Pre-existing liver disease 2
- First 6 months of therapy (highest risk period) 1, 4
- Genetic polymorphisms affecting drug metabolism (e.g., CYP2C9*3 allele) 5
Important Clinical Pearls
- Most cases of hepatotoxicity occur within the first 6 months of therapy 2, 4
- In clinical practice, approximately 8.9% of patients may develop grade 2-3 hepatotoxicity within the first year 4
- In most cases, liver enzyme elevations resolve with dose reduction or temporary discontinuation 4, 3
- Patients rarely show clinical signs of hepatotoxicity despite enzyme elevations 4, 3
- For patients taking both leflunomide and methotrexate, the risk of hepatotoxicity is increased, requiring more vigilant monitoring 2
Drug Elimination Procedure
If severe hepatotoxicity occurs or rapid drug elimination is needed:
- Administer cholestyramine 8g three times daily for 11 days 2
- Alternatively, activated charcoal can be used 2
- This procedure rapidly decreases plasma concentration of the active metabolite (M1) 2
By following this structured approach to monitoring and management, clinicians can effectively address leflunomide-induced hepatotoxicity while minimizing risks to patients.