Leucovorin Dosing for Methotrexate Toxicity
For methotrexate toxicity, leucovorin (folinic acid) should be administered at an initial dose of up to 100 mg/m² intravenously if methotrexate levels are unknown, and continued every 6 hours until methotrexate levels are <0.05 μmol/L. 1
Dosing Based on Methotrexate Level and Clinical Scenario
High-Dose Methotrexate Toxicity
- Normal methotrexate elimination: 15 mg PO, IM, or IV every 6 hours for 60 hours (10 doses starting 24 hours after methotrexate infusion) 2
- Delayed late methotrexate elimination (serum level >0.2 μmol/L at 72 hours or >0.05 μmol/L at 96 hours): Continue 15 mg every 6 hours until methotrexate level is <0.05 μmol/L 2
- Delayed early methotrexate elimination and/or acute renal injury (serum level ≥50 μmol/L at 24 hours or ≥5 μmol/L at 48 hours, OR ≥100% increase in serum creatinine): 150 mg IV every 3 hours until methotrexate level is <1 μmol/L, then 15 mg IV every 3 hours until level is <0.05 μmol/L 2
Low-Dose Methotrexate Toxicity
- For overdose or toxicity from low-dose methotrexate (≤50 mg/week), 15 mg IV every 6 hours is generally effective 3
- In cases of severe toxicity with myelosuppression (WBC ≤2×10⁹/L or platelets ≤50×10⁹/L), research shows no significant difference in outcomes between 15 mg and 25 mg every 6 hours 3
Additional Supportive Measures
Hydration and Urinary Alkalinization
- Aggressive intravenous hydration (3-4 L/m²/day) 1
- Urinary alkalinization to maintain pH >7.0 1
- Continue until methotrexate levels are <0.05 μmol/L 2
Monitoring
- Daily complete blood count and renal function tests 1
- Serum methotrexate levels (if available) 2
- Close observation for signs of infection 1
Additional Interventions for Severe Cases
- Consider glucarpidase for toxic methotrexate concentrations with delayed clearance due to renal insufficiency 1
- Consider G-CSF for severe myelosuppression 1
- For patients with acute kidney injury, continue hydration and urinary alkalinization until renal function normalizes 2
Special Considerations
- Leucovorin should never be administered intrathecally 2
- For patients with inadvertent daily instead of weekly dosing, immediate leucovorin rescue is critical 3
- Patients with hypoalbuminemia are at higher risk of mortality from methotrexate toxicity 3
- For patients with methotrexate-induced pancytopenia, leucovorin rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy 2
The evidence clearly supports prompt initiation of leucovorin rescue therapy, with dosing based on methotrexate levels and clinical presentation. Early intervention with appropriate leucovorin dosing significantly reduces mortality and morbidity associated with methotrexate toxicity.