What is the treatment for methotrexate poisoning?

Treatment of Methotrexate Poisoning

Leucovorin (folinic acid) rescue is the cornerstone of treatment for methotrexate poisoning, along with aggressive hydration, urinary alkalinization, and in severe cases, glucarpidase administration. 1, 2

Immediate Management

• Assess severity based on methotrexate levels:

  • Measure serum methotrexate levels at 24,48, and 72 hours after exposure
  • Continue daily measurements until levels are <0.05 μmol/L 1

• Initiate leucovorin rescue immediately:

  • Start as soon as possible after methotrexate overdose is identified
  • Effectiveness decreases as time interval between methotrexate exposure and leucovorin initiation increases 2
  • Initial dose: 100 mg/m² IV for significant overdose 1
  • Continue leucovorin until methotrexate levels are <0.05 μmol/L 1

• Aggressive hydration and urinary alkalinization:

  • IV hydration at 3-4 L/m²/day 1
  • Maintain urinary pH >7.0 with sodium bicarbonate to prevent precipitation of methotrexate in renal tubules 1, 2

Advanced Interventions for Severe Toxicity

• Glucarpidase (carboxypeptidase G2):

  • Indicated for toxic methotrexate concentrations with delayed clearance due to impaired renal function 2
  • Rapidly reduces plasma methotrexate levels by up to 86% 1
  • Important: Do not administer leucovorin within two hours before or after glucarpidase (leucovorin is a substrate for glucarpidase) 2

• Hemodialysis considerations:

  • Consider in extreme cases with very high methotrexate levels and renal failure 2
  • Most effective when using high-flux dialyzers 2
  • Generally less effective than glucarpidase for methotrexate elimination 2

Special Considerations for Intrathecal Overdose

• For intrathecal methotrexate overdose:
  • Requires intensive systemic support
  • High-dose systemic leucovorin
  • Alkaline diuresis
  • Rapid CSF drainage and ventriculolumbar perfusion 2
  • Consider intrathecal glucarpidase administration 3

Monitoring During Treatment

• Laboratory monitoring:

  • Daily methotrexate levels until <0.05 μmol/L
  • Complete blood count
  • Serum creatinine
  • Liver transaminases 1

• Clinical monitoring:

  • Monitor for signs of myelosuppression (neutropenia, thrombocytopenia)
  • Gastrointestinal toxicity (mucositis, stomatitis)
  • Renal function deterioration 2, 4

Pitfalls and Caveats

• Do not delay leucovorin administration - efficacy decreases with time after methotrexate exposure 2
• Avoid oral leucovorin in patients with significant mucositis or vomiting; use IV route instead
• Patients with MTHFR gene mutations are at higher risk for toxicity and may require higher doses of leucovorin 1
• Methotrexate levels may rebound after glucarpidase administration due to redistribution from tissues 3
• Continue monitoring even after initial improvement, as delayed toxicity can occur

Treatment Algorithm Based on Methotrexate Level and Renal Function

1. Low methotrexate levels with normal renal function:

   • Leucovorin 15 mg IV every 6 hours
   • Hydration and urinary alkalinization
   • Continue until methotrexate levels <0.05 μmol/L 5

2. High methotrexate levels or impaired renal function:

   • Leucovorin 100 mg/m² IV initially, then adjust based on methotrexate levels
   • Aggressive hydration (3-4 L/m²/day)
   • Urinary alkalinization (maintain pH >7.0)
   • Consider glucarpidase if methotrexate levels remain high or renal function deteriorates 1, 2

3. Severe toxicity with renal failure:

   • All of the above plus
   • Glucarpidase administration
   • Consider hemodialysis with high-flux dialyzer if glucarpidase unavailable 2, 3

By following this approach, even patients with severe methotrexate toxicity can be successfully treated, though mortality remains significant in cases of severe low-dose methotrexate toxicity 5.