Methotrexate Toxicity: Treatment and Management
The treatment of methotrexate toxicity requires immediate administration of leucovorin (folinic acid) rescue, aggressive hydration with urinary alkalinization, and consideration of glucarpidase for severe cases with delayed elimination or renal dysfunction. 1, 2
Immediate Management of Methotrexate Toxicity
First-Line Interventions
Leucovorin (folinic acid) rescue:
- Begin as promptly as possible after toxicity is identified
- Effectiveness decreases as time interval between methotrexate administration and leucovorin initiation increases 1
- Dosing: Start with high-dose leucovorin (100 mg/m²) for severe toxicity 2
- Continue until serum methotrexate levels fall below 0.05 μmol/L 2
Aggressive hydration and urinary alkalinization:
For Severe Toxicity or Delayed Elimination
- Glucarpidase (carboxypeptidase G2):
Monitoring During Treatment
Serum methotrexate levels:
- Measure at 24,48, and 72 hours after start of infusion
- Continue daily measurement until levels <0.05 μmol/L 2
- Adjust leucovorin dose based on these levels
Laboratory monitoring:
- Complete blood count (CBC)
- Serum creatinine and renal function
- Liver transaminases
- Continue monitoring until normalization 2
Management Based on Specific Toxicities
Renal Toxicity
- Methotrexate crystallizes in renal tubules causing acute kidney injury (AKI) in 2-12% of patients 3
- Management:
- Increase hydration and urinary alkalinization
- Higher doses of leucovorin
- Consider glucarpidase if significant renal dysfunction (eGFR <30 mL/min) 4
- Avoid nephrotoxic medications
Hematologic Toxicity
- Risk factors: renal insufficiency, advanced age, dosing errors, drug interactions, hypoalbuminemia 5
- Management:
- Continue leucovorin until recovery
- Consider growth factors for severe neutropenia
- Monitor for infections and provide prophylactic antibiotics if indicated
Hepatotoxicity
- More common in patients with obesity, diabetes, hyperlipidemia, and non-alcoholic fatty liver disease 5
- Management:
- Continue leucovorin
- Monitor liver function tests until normalization
- Avoid other hepatotoxic agents including alcohol, statins, and retinoids 5
Mucositis and Gastrointestinal Toxicity
- Management:
- Supportive care with oral hygiene
- Pain management
- Nutritional support
- Continue leucovorin until resolution
Special Considerations
Overdose Management
- If ingestion occurred within 1 hour, administer activated charcoal 2
- For extreme cases with very high levels, consider hemodialysis although evidence suggests it may not significantly improve elimination compared to glucarpidase 6
- The EXTRIP workgroup suggests against extracorporeal treatments when standard care is provided, especially when glucarpidase is administered 6
Prevention of Future Toxicity
- Identify risk factors: renal dysfunction, drug interactions, MTHFR gene mutations 2
- Consider folic acid supplementation (1-5 mg daily except on methotrexate day) 2
- Enhanced monitoring for patients with risk factors
- Dose adjustment based on renal function (50% reduction if eGFR 20-50 mL/min, contraindicated if <20 mL/min) 2
Common Pitfalls to Avoid
- Delaying leucovorin administration (effectiveness decreases with time)
- Inadequate hydration and urinary alkalinization
- Failure to monitor methotrexate levels and adjust leucovorin accordingly
- Concurrent administration of drugs that interact with methotrexate (salicylates, NSAIDs, penicillins, probenecid, sulfonamides) 5
- Administering leucovorin within 2 hours of glucarpidase
High-dose leucovorin as sole therapy has been shown to be effective for managing methotrexate toxicity in patients with high methotrexate levels, with tolerable morbidity and without the need for extracorporeal removal in many cases 7.