Leucovorin Dosing for Methotrexate Toxicity in a 60 kg Patient
For a 60 kg patient recovering from methotrexate toxicity, administer leucovorin 10 mg/m² (approximately 18 mg for a typical adult body surface area of 1.8 m²) intravenously every 6 hours until the serum methotrexate level falls below 10⁻⁸ M (0.01 micromolar). 1
Initial Dosing Algorithm
Start leucovorin immediately upon recognition of toxicity, ideally within 24 hours of the last methotrexate dose, as efficacy decreases dramatically with time and becomes doubtful after 24 hours 2
The FDA-approved initial dose is leucovorin 10 mg/m² IV, IM, or PO every 6 hours for inadvertent methotrexate overdosage or impaired elimination 1
For a 60 kg patient with typical body surface area of approximately 1.7-1.8 m², this translates to approximately 17-18 mg per dose 1
In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin must be administered parenterally (IV or IM), not orally 1
Dose Escalation Based on Methotrexate Levels
If the 24-hour serum creatinine has increased 50% over baseline OR if the 24-hour methotrexate level is >5 × 10⁻⁶ M OR the 48-hour level is >9 × 10⁻⁷ M, escalate to leucovorin 100 mg/m² IV every 3 hours until the methotrexate level falls below 10⁻⁸ M 1
For severe delayed elimination (methotrexate level ≥50 micromolar at 24 hours or ≥5 micromolar at 48 hours), use 150 mg IV every 3 hours until methotrexate level is <1 micromolar, then reduce to 15 mg IV every 3 hours until level is <0.05 micromolar 1
When methotrexate levels are unknown at presentation, guidelines recommend starting with up to 100 mg/m² IV as the initial dose 2
Duration of Therapy
Continue leucovorin until the serum methotrexate level is below 10⁻⁸ M (0.01 micromolar) 1
For delayed late methotrexate elimination (level remaining >0.2 micromolar at 72 hours and >0.05 micromolar at 96 hours), continue 15 mg IV every 6 hours until the methotrexate level is <0.05 micromolar 1
Monitor serum creatinine and methotrexate levels at 24-hour intervals to guide dose adjustments 1
Essential Supportive Measures
Provide aggressive IV hydration (3 L/day) and urinary alkalinization with sodium bicarbonate to maintain urine pH ≥7.0 2, 1
The bicarbonate dose should be adjusted to maintain urine pH at 7.0 or greater 1
Admit patients to hospital for monitoring and surveillance for sepsis, as methotrexate overdose carries high mortality risk 2
Administration Considerations
Do not administer leucovorin intrathecally 1
Due to calcium content, inject no more than 160 mg of leucovorin per minute intravenously (16 mL of 10 mg/mL solution per minute) 1
Do not mix leucovorin in the same infusion as 5-fluorouracil, as this may lead to precipitate formation 1
Evidence on Dose Comparisons
A 2023 randomized controlled trial comparing 15 mg versus 25 mg leucovorin every 6 hours in severe low-dose methotrexate toxicity found no significant difference in 30-day mortality (42% vs 47%, p=0.74) or hematological recovery between doses 3
High-dose leucovorin as sole therapy (ranging 0.24 to 8 g/day) successfully rescued patients with severe methotrexate toxicity (levels 102-940 micromolar at 24 hours) without need for extracorporeal removal, though significant but tolerable myelosuppression occurred 4
Critical Pitfalls to Avoid
Do not delay leucovorin administration waiting for methotrexate levels, as early treatment may be life-saving 2
Do not confuse routine folic acid supplementation (1-5 mg daily) with leucovorin rescue therapy—these are entirely different interventions for different clinical scenarios 5
Do not use oral leucovorin if the patient has mucositis, nausea, vomiting, or any gastrointestinal toxicity 1
Recognize that serum albumin is a predictor of survival in severe methotrexate toxicity, with lower albumin associated with higher mortality 3