What is the recommended leucovorin (folinic acid) dose for treating low-dose methotrexate toxicity?

Leucovorin Dosing for Low-Dose Methotrexate Toxicity

For low-dose methotrexate toxicity, leucovorin (folinic acid) should be administered at a dose of 10 mg/m² intravenously or orally every 6 hours until serum methotrexate levels are less than 10⁻⁸ M or until clinical toxicity resolves. 1

Dosing Considerations

Standard Dosing Protocol

• Initial dose: 10 mg/m² (approximately 15 mg for adults)
• Route: IV preferred for severe toxicity; oral for mild cases
• Frequency: Every 6 hours
• Duration: Until methotrexate levels are less than 10⁻⁸ M or until clinical toxicity resolves

Dose Adjustments Based on Severity

• For severe toxicity (elevated serum creatinine or high methotrexate levels):
  • If 24-hour serum creatinine has increased 50% over baseline
  • If 24-hour methotrexate level is greater than 5 × 10⁻⁶ M
  • If 48-hour methotrexate level is greater than 9 × 10⁻⁷ M
  • Increase dose to 100 mg/m² IV every 3 hours until methotrexate level is less than 10⁻⁸ M 2

Administration Considerations

• Oral administration is limited to doses of 25 mg or less due to saturable absorption 2
• For doses greater than 25 mg, parenteral administration is required 2
• Leucovorin rescue should begin as soon as possible after an inadvertent overdose and within 24 hours of methotrexate administration 2
• The effectiveness of leucovorin decreases as the time interval between methotrexate administration and leucovorin treatment increases 1

Supportive Measures

• Maintain hydration (3 L/day) 2
• Urinary alkalinization with sodium bicarbonate to maintain urine pH at 7.0 or greater 2
• Monitor fluid and electrolyte status closely 2
• Continue hydration and urinary alkalinization until serum methotrexate level falls below 0.05 micromolar and renal function normalizes 2

Monitoring Parameters

• Serum creatinine and methotrexate levels at 24-hour intervals 2
• Complete blood count to monitor for hematologic recovery 3
• Assessment of mucositis 3

Clinical Considerations

• A recent randomized controlled trial comparing 15 mg vs. 25 mg leucovorin doses every 6 hours showed no significant difference in survival or time to hematological recovery between the two doses 3
• Low serum albumin is a predictor of poor outcomes in methotrexate toxicity 3
• Severe low-dose methotrexate toxicity carries significant mortality despite leucovorin rescue 3

Common Pitfalls to Avoid

1. Delaying leucovorin administration beyond 24 hours after methotrexate exposure significantly reduces its effectiveness 1
2. Inadequate hydration and urinary alkalinization can lead to methotrexate precipitation in renal tubules 1
3. Using oral leucovorin for doses greater than 25 mg (use IV route instead) 2
4. Discontinuing leucovorin too early before methotrexate levels have adequately decreased 2
5. Failing to recognize inadvertent methotrexate overdose (e.g., daily instead of weekly dosing) 1