What is the antidote for methotrexate toxicity?

Methotrexate Toxicity Antidote

Leucovorin (folinic acid) is the primary antidote for methotrexate toxicity and should be administered as promptly as possible after recognition of toxicity or overdose, as its effectiveness decreases with delayed administration. 1

First-Line Management of Methotrexate Toxicity

Leucovorin Rescue Protocol

• Initiate leucovorin as soon as possible after methotrexate overdose or toxicity is identified 1
• Dosing depends on severity:
  • For high-dose methotrexate toxicity: Start with high-dose leucovorin (100 mg/m²) immediately 2
  • For low-dose methotrexate toxicity: 15-25 mg IV every 6 hours until clinical improvement 3
• Continue leucovorin until methotrexate levels are <0.05 μmol/L 2
• Monitor methotrexate levels at 24,48, and 72 hours after methotrexate administration to guide leucovorin dosing 2

Supportive Measures

• Aggressive hydration (3-4 L/m²/day) to enhance renal clearance 2
• Urinary alkalinization to maintain urine pH >7.0 to prevent precipitation of methotrexate in renal tubules 1
• Daily monitoring of complete blood count, liver function, and renal function until normalization 2

Second-Line Interventions for Severe Toxicity

Glucarpidase (Carboxypeptidase G2)

• Consider for patients with:
  • Significantly delayed methotrexate elimination
  • Renal insufficiency
  • Extremely high methotrexate levels
• Rapidly reduces plasma methotrexate levels by up to 86% 2
• Important note: Do not administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for glucarpidase 1

Hemodialysis

• Consider when glucarpidase is unavailable or in extreme cases 4
• Most effective with high-flux dialyzers 1
• Note: Traditional hemodialysis and peritoneal dialysis have limited effectiveness in methotrexate removal 1

Special Considerations

Intrathecal Methotrexate Overdose

• Requires intensive systemic support:
  • High-dose systemic leucovorin
  • Alkaline diuresis
  • Rapid CSF drainage
  • Ventriculolumbar perfusion 1
• Consider intrathecal glucarpidase for direct removal from CSF 1

Oral Methotrexate Overdose

• For recent ingestion (within 1 hour): Consider activated charcoal 2
• Common scenario: Accidental daily administration instead of weekly dosing 1
• Monitor for: Myelosuppression, mucositis, gastrointestinal ulceration, and renal dysfunction 1

Monitoring During Treatment

• Methotrexate levels: Continue daily measurement until <0.05 μmol/L 2
• CBC, liver enzymes, and renal function: Monitor until normalization 2
• Clinical assessment: Evaluate for signs of mucositis, myelosuppression, and other toxicities at each visit 5

Pitfalls and Caveats

• Timing is critical: The effectiveness of leucovorin decreases as time interval between methotrexate administration and leucovorin initiation increases 1
• Do not underdose leucovorin: Inadequate leucovorin dosing may result in persistent toxicity 6
• Folic acid is not a substitute for leucovorin in acute methotrexate toxicity 7
• Patients with MTHFR gene mutations are at higher risk for toxicity and may require more aggressive intervention 2

By following this approach, methotrexate toxicity can be effectively managed with prompt recognition and appropriate intervention, significantly reducing morbidity and mortality associated with this potentially life-threatening condition.