When should leucovorin (folinic acid) be started in a patient with inadvertent methotrexate toxicity and does the last dose of methotrexate matter?

Timing of Leucovorin in Inadvertent Methotrexate Toxicity

Leucovorin must be started as soon as possible after recognizing inadvertent methotrexate toxicity—ideally within hours of the last dose—because effectiveness decreases dramatically as time passes, with doubtful efficacy if initiated later than 24 hours after the last methotrexate dose. 1, 2

Critical Time-Dependent Efficacy

The timing of leucovorin initiation relative to the last methotrexate dose is absolutely critical for patient survival:

• Leucovorin is most effective when initiated within a few hours of the last methotrexate dose 1
• Efficacy becomes doubtful if leucovorin is started more than 24 hours after the last methotrexate dose 1
• As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases 2
• Early treatment may be life-saving, particularly given the high mortality risk associated with methotrexate overdose 1

Immediate Management Algorithm

Step 1: Recognize Toxicity and Start Leucovorin Immediately

Do not wait for laboratory confirmation or methotrexate levels before starting leucovorin if inadvertent overdose is suspected 1, 2

• If ≥1 mg/kg methotrexate was ingested within 1 hour, give activated charcoal first 1
• Start leucovorin (folinic acid/calcium folinate) as soon as possible after recognition 1, 2
• Initial dose: up to 100 mg/m² IV if methotrexate level is unknown 1
• For inadvertent overdose: 10 mg/m² IV/IM/PO every 6 hours until methotrexate level <10⁻⁸ M (0.01 micromolar) 3

Step 2: Measure Methotrexate Levels

• Obtain serum methotrexate level at least 4 hours after ingestion 1
• Measure serum creatinine and methotrexate levels at 24-hour intervals 3
• Continue monitoring until methotrexate level <0.05 micromolar 1

Step 3: Adjust Leucovorin Dosing Based on Levels

For delayed early methotrexate elimination (levels ≥50 micromolar at 24 hours or ≥5 micromolar at 48 hours):

• Increase to 150 mg IV every 3 hours until methotrexate level <1 micromolar 3
• Then 15 mg IV every 3 hours until methotrexate level <0.05 micromolar 3

For delayed late methotrexate elimination (level >0.2 micromolar at 72 hours):

• Continue 15 mg IV/PO/IM every 6 hours until methotrexate level <0.05 micromolar 3

Step 4: Supportive Measures

• Admit to hospital for monitoring 1
• Aggressive IV hydration (3 L/day) 1, 3
• Urinary alkalinization with sodium bicarbonate to maintain urine pH ≥7.0 to prevent methotrexate precipitation in renal tubules 1, 3
• Monitor for sepsis, as there is high mortality risk with methotrexate overdose 1

Route of Administration Considerations

If gastrointestinal toxicity, nausea, or vomiting is present, leucovorin must be administered parenterally (IV or IM), not orally 1, 3

• Never administer leucovorin intrathecally 3
• Due to calcium content, inject no more than 160 mg leucovorin per minute IV (16 mL of 10 mg/mL solution per minute) 3

Duration of Treatment

Continue leucovorin until both of the following are met:

• Methotrexate levels <0.05 micromolar 1
• Hematological abnormalities have returned to normal and mucosal ulceration has healed 1

Common Pitfall: The "Daily Instead of Weekly" Error

The most common inadvertent overdose scenario involves patients taking methotrexate daily instead of weekly 1, 4. In these cases:

• Patients may have received 7 times the intended dose over one week
• Symptoms (mucositis, fever, diarrhea, erythema, ulceration) may take 6-23 days to manifest 1
• Start leucovorin immediately upon recognition, even if the last dose was several days ago—some benefit may still occur 2, 3
• Mortality in severe low-dose methotrexate toxicity can reach 42-47% despite leucovorin treatment 4

Leucovorin Dosing: Standard vs. High-Dose

Recent evidence shows no significant survival difference between 15 mg vs. 25 mg leucovorin every 6 hours in severe low-dose methotrexate toxicity 4. Therefore:

• Standard dose of 15 mg every 6 hours is appropriate for most cases 4
• Escalate to higher doses (150 mg every 3 hours) only for delayed early elimination with very high methotrexate levels 3

Additional Rescue Measures for Severe Cases

• Filgrastim (G-CSF) 5 mcg/kg/day subcutaneously for toxic bone marrow suppression to accelerate myeloid recovery 1
• Glucarpidase may be considered for toxic methotrexate concentrations with delayed clearance due to renal impairment, but do not give leucovorin within 2 hours before or after glucarpidase (leucovorin is a substrate for glucarpidase) 2
• High-dose leucovorin with supportive care alone (without glucarpidase) can successfully manage many cases of methotrexate-induced acute kidney injury 5