What is the administration protocol for Inj Leucovorin (folinic acid) in a patient with methotrexate toxicity?

Leucovorin Administration for Methotrexate Toxicity

Administer leucovorin (folinic acid) 15 mg IV, IM, or PO every 6 hours immediately upon recognition of methotrexate toxicity, as efficacy diminishes dramatically with time and becomes doubtful if initiated later than 24 hours after the last methotrexate dose. 1, 2

Immediate Dosing Protocol

Standard Rescue Dosing

• Start leucovorin at 15 mg (approximately 10 mg/m²) every 6 hours for 10 doses, beginning 24 hours after the start of high-dose methotrexate infusion 3
• For suspected toxicity or delayed elimination, initiate leucovorin immediately—do not wait for laboratory confirmation 1, 2
• Continue leucovorin until serum methotrexate level falls below 0.05 micromolar (5 × 10⁻⁸ M) 3

Route of Administration

• In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin MUST be administered parenterally (IV or IM), never orally 3
• Never administer leucovorin intrathecally 3

Dose Escalation for Severe Toxicity

Escalation Criteria and Dosing

If methotrexate levels remain dangerously elevated or severe clinical toxicity develops, escalate leucovorin to 100-150 mg/m² IV every 3 hours until methotrexate level falls below 1 micromolar, then reduce to 15 mg every 3 hours until level is below 0.05 micromolar 3, 2

Specific escalation triggers include: 3

• Serum methotrexate ≥50 micromolar at 24 hours
• Serum methotrexate ≥5 micromolar at 48 hours
• 100% or greater increase in serum creatinine at 24 hours after methotrexate
• Methotrexate level remaining above 0.2 micromolar at 72 hours

Essential Supportive Measures

Hydration and Alkalinization

• Aggressive IV hydration at 3 L/day or 125 mL/m²/hr is mandatory 1
• Urinary alkalinization with sodium bicarbonate to maintain urine pH ≥7.0 until methotrexate level <0.05 micromolar 1, 3
• These measures prevent methotrexate precipitation in renal tubules 2

Monitoring Requirements

• Measure serum creatinine and methotrexate levels at least once daily, more frequently in complicated cases 1, 3
• Monitor complete blood count with differential daily to detect worsening cytopenias 2
• Continue monitoring until methotrexate level is below 0.05 micromolar and clinical recovery occurs 3

Management of Specific Toxicity Scenarios

Inadvertent Overdose (Oral)

• If ≥1 mg/kg methotrexate ingested within 1 hour, administer activated charcoal first, then start leucovorin immediately 2, 4
• Initial leucovorin dose: up to 100 mg/m² IV if methotrexate level is unknown 2
• Hospital admission is required for monitoring and sepsis surveillance due to high mortality risk 1, 2

Severe Bone Marrow Suppression

• Administer filgrastim (G-CSF) 5 mcg/kg/day subcutaneously for toxic bone marrow suppression to accelerate myeloid recovery 1, 2, 4
• Monitor closely for sepsis, as myelosuppression accounts for the majority of methotrexate-associated fatalities 4

Intrathecal Methotrexate Toxicity

• For accidental intrathecal overdose, oral leucovorin 10 mg may be administered twice daily beginning on the day of treatment and continuing for 3 days to mitigate systemic toxicity 5
• Leucovorin does not cross the blood-brain barrier in sufficient amounts to interfere with CSF methotrexate effect 5

Context-Specific Regimens

Low-Risk Gestational Trophoblastic Neoplasia

• Leucovorin 15 mg orally 30 hours after each methotrexate injection 1

High-Risk Gestational Trophoblastic Neoplasia

• Leucovorin 15 mg IV/PO every 12 hours for 4 doses, starting 24 hours after methotrexate infusion 1

Rheumatoid Arthritis/Inflammatory Conditions

• For prevention of toxicity with low-dose weekly methotrexate: folic acid 1-5 mg daily (except on methotrexate day) or leucovorin 10 mg twice daily for 3 days after methotrexate 5
• For established toxicity: leucovorin 15 mg every 6 hours until recovery 2

Critical Pitfalls to Avoid

Timing Errors

• Delaying leucovorin administration is the most critical error—efficacy is doubtful if initiated >24 hours after last methotrexate dose 1, 2, 4
• Early intervention (within 24 hours) is associated with significantly better outcomes and reduced mortality 6

Drug Confusion

• Never confuse folic acid with folinic acid (leucovorin)—only leucovorin bypasses methotrexate's metabolic block and serves as an effective antidote 2, 4
• Folic acid is for prevention; leucovorin is for treatment of acute toxicity 2

Glucarpidase Interaction

• If glucarpidase is used for severe toxicity, do not administer leucovorin within 2 hours before or after glucarpidase, as leucovorin is a substrate for glucarpidase 7, 6
• Glucarpidase rapidly reduces plasma methotrexate by 98.7% within 15 minutes but also depletes reduced folates 6

Inadequate Dose Escalation

• Inadequate initial increase in leucovorin dosing after glucarpidase or in severe toxicity is associated with grade 4-5 toxicity and death 6
• Presence of grade 4 toxicity before intervention requires immediate dose escalation to 100-150 mg/m² every 3 hours 3, 6

High-Risk Patient Factors Requiring Enhanced Vigilance

Patients with the following require lower thresholds for leucovorin escalation: 2, 4

• Renal insufficiency (85% of methotrexate is renally excreted)
• Advanced age (>50-70 years)
• Hypoalbuminemia
• Third-space fluid collections (pleural effusions, ascites)
• Concurrent nephrotoxic drugs (NSAIDs, trimethoprim-sulfamethoxazole)