Is Leucovorin (folinic acid) effective in treating oral methotrexate toxicity in a patient who has taken a double dose?

Yes, Leucovorin (Folinic Acid) is Effective for Oral Methotrexate Toxicity

Leucovorin should be administered as promptly as possible for oral methotrexate overdose, as it is the indicated antidote that can be life-saving, with efficacy decreasing dramatically as time passes after methotrexate ingestion. 1, 2

Critical Time-Dependent Administration

The effectiveness of leucovorin is directly tied to how quickly it is initiated:

• Leucovorin is most effective when started within a few hours of the last methotrexate dose 3
• Efficacy decreases dramatically as time passes, becoming doubtful if initiated later than 24 hours after the last methotrexate dose 3
• Early treatment with leucovorin may be life-saving, particularly given the high mortality risk associated with methotrexate overdose 3
• The FDA label explicitly states: "As the time interval between methotrexate administration and leucovorin initiation increases, the effectiveness of leucovorin in counteracting toxicity decreases" 1, 2

Immediate Management for Double Dose Overdose

For a patient who has taken a double dose of oral methotrexate, implement the following algorithm:

If Recognized Within 1 Hour:

• Give activated charcoal first if ≥1 mg/kg methotrexate was ingested 3
• Start leucovorin as soon as possible after recognition 3

Initial Leucovorin Dosing:

• Initial dose: up to 100 mg/m² IV if methotrexate level is unknown 3
• For oral overdoses, leucovorin at a dose equal to or greater than the possible ingestion should be given as soon as possible 4
• Higher doses of leucovorin may be used as rescue therapy for significant methotrexate toxicities 5

Route of Administration:

• Intravenous leucovorin should be administered as promptly as possible for accidental overdosages 1
• Oral leucovorin can be used, but IV is preferred for more reliable absorption in overdose situations 1
• Never administer leucovorin intrathecally—it may be harmful or fatal 1

Supportive Management

Beyond leucovorin administration, the following measures are essential:

• Admit patients to hospital for monitoring 3
• Aggressive IV hydration (3 L/day) 3
• Urinary alkalinization with sodium bicarbonate to maintain urine pH ≥7.0 to prevent methotrexate precipitation in renal tubules 3, 2
• Monitor for sepsis, as there is high mortality risk with methotrexate overdose 3

Monitoring Requirements

Essential monitoring to guide leucovorin therapy:

• Monitoring of serum methotrexate concentration is essential in determining the optimal dose and duration of treatment with leucovorin 1, 2
• Monitor complete blood count, liver function tests, and renal function tests regularly 5
• Continue leucovorin until methotrexate levels are safe and cellular function is restored 6

Mechanism of Leucovorin Rescue

Why leucovorin works for methotrexate toxicity:

• Leucovorin (folinic acid) bypasses the methotrexate-induced dihydrofolate reductase inhibition 6
• It replenishes folate stores depleted by methotrexate, allowing cells to resume normal DNA synthesis 7
• Leucovorin is highly beneficial in preventing myelosuppression, gastric toxicity, and neurotoxic effects after methotrexate therapy 8

Important Distinctions: Leucovorin vs. Folic Acid

Do not confuse routine folic acid supplementation with leucovorin rescue therapy:

• Leucovorin (folinic acid) is the antidote for methotrexate overdose and should be administered immediately in overdose situations 7
• Regular folic acid supplementation (1-5 mg daily) is for prevention of toxicity in patients on chronic methotrexate therapy, not for acute overdose 5, 7
• Folinic acid should only be used for methotrexate toxicity, not routine supplementation 9

Additional Rescue Measures for Severe Cases

If toxicity develops despite leucovorin:

• Filgrastim (G-CSF) 5 mcg/kg/day subcutaneously may be used for toxic bone marrow suppression to accelerate myeloid recovery 3
• Glucarpidase is indicated for toxic methotrexate concentrations in patients with delayed methotrexate clearance due to impaired renal function 2, 8
• If glucarpidase is used, do not administer leucovorin within two hours before or after a dose of glucarpidase because leucovorin is a substrate for glucarpidase 2

Common Pitfalls to Avoid

Critical errors that can compromise treatment:

• Do not delay leucovorin administration while waiting for methotrexate levels—start immediately based on clinical suspicion 3, 1
• Do not use regular folic acid instead of leucovorin for acute overdose—leucovorin is the appropriate antidote 7, 9
• Do not give leucovorin intrathecally under any circumstances 1
• Do not underestimate the severity—even "double dose" oral methotrexate can cause life-threatening toxicity, particularly with repeated dosing over multiple days 6

Expected Clinical Course with Leucovorin Treatment

What to expect when leucovorin is given appropriately:

• In a documented pediatric case with methotrexate levels 10 times greater than toxic threshold, treatment with leucovorin rescue resulted in an unremarkable clinical course with only mild liver enzyme elevation that resolved without sequelae 4
• High-dose leucovorin as sole therapy (without hemodialysis) has been shown effective for severe methotrexate intoxication with tolerable morbidity, though neutropenia, thrombocytopenia, and mucositis may still occur 10