What is the recommended leucovorin (folinic acid) rescue dosing and administration for a patient experiencing methotrexate toxicity due to oral methotrexate ingestion, particularly in cases with impaired renal function or severe toxicity?

Leucovorin Rescue for Oral Methotrexate Toxicity

Administer leucovorin 10 mg/m² (approximately 15 mg for average adult) intravenously or orally every 6 hours immediately upon recognition of toxicity, and continue until serum methotrexate level falls below 0.05 micromolar (5 × 10⁻⁸ M). 1, 2

Immediate Dosing Protocol

Standard Rescue Dosing

• Start leucovorin 15 mg IV, IM, or PO every 6 hours as soon as toxicity is suspected 1, 3, 2
• Continue this regimen for a minimum of 60 hours (10 doses starting 24 hours after methotrexate administration in planned high-dose scenarios) 2
• Timing is critical: leucovorin efficacy decreases dramatically after 24 hours and becomes doubtful if initiated later than 24 hours after the last methotrexate dose 1, 4

Dose Escalation for Severe Toxicity

• If methotrexate levels remain ≥50 micromolar at 24 hours OR ≥5 micromolar at 48 hours OR serum creatinine doubles within 24 hours, immediately escalate to leucovorin 100-150 mg/m² IV every 3 hours 1, 2
• Continue high-dose leucovorin every 3 hours until methotrexate level falls below 1 micromolar, then reduce to 15 mg IV every 3 hours until level drops below 0.05 micromolar 2
• For unknown methotrexate levels with severe clinical toxicity, initiate leucovorin at up to 100 mg/m² IV 1, 2

Route of Administration Considerations

• If patient has gastrointestinal toxicity, nausea, vomiting, or mucositis, leucovorin MUST be administered parenterally (IV or IM), never orally 4, 2
• Oral administration is acceptable only in patients without GI symptoms who can reliably absorb medication 2
• Never administer leucovorin intrathecally 2

Essential Supportive Measures

Hydration and Alkalinization

• Initiate aggressive IV hydration at 3 L/day (or 125 mL/m²/hr) immediately 1, 4
• Add sodium bicarbonate to IV fluids to maintain urine pH ≥7.0 1, 4, 2
• Continue urinary alkalinization until methotrexate level falls below 0.05 micromolar to prevent methotrexate precipitation in renal tubules 4, 3

Activated Charcoal

• If ≥1 mg/kg methotrexate was ingested within 1 hour, administer activated charcoal immediately before starting leucovorin 1, 4

Monitoring Requirements

• Measure serum methotrexate levels and creatinine at 24-hour intervals minimum 4, 2
• Monitor complete blood count with differential daily to detect worsening cytopenias 1, 3
• Check liver function tests daily during acute toxicity 1
• Hospital admission is mandatory for monitoring and sepsis surveillance due to high mortality risk 1, 4

Management of Severe Bone Marrow Suppression

• For life-threatening neutropenia or pancytopenia, add filgrastim (G-CSF) 5 mcg/kg/day subcutaneously 1, 4
• Continue G-CSF until neutrophil recovery occurs 4
• Maintain high vigilance for sepsis, as myelosuppression accounts for 67 of 164 methotrexate-associated fatalities 3

Critical Pitfalls to Avoid

Drug Confusion

• Do NOT use folic acid instead of folinic acid (leucovorin) 3
• Only leucovorin bypasses methotrexate's metabolic block; folic acid is for prevention, not acute treatment 3

Dangerous Drug Interactions

• Trimethoprim-sulfamethoxazole is absolutely contraindicated with methotrexate 3, 5
• This combination causes severe bone marrow suppression and has resulted in fatal toxic epidermal necrolysis 5
• NSAIDs reduce renal methotrexate elimination and are particularly dangerous with high-dose methotrexate 3

Timing Errors

• Do not delay leucovorin administration waiting for laboratory confirmation 1, 4
• Treat based on clinical presentation; serum methotrexate levels do not always correlate with toxicity severity 3
• Starting leucovorin >24 hours after last methotrexate dose significantly reduces efficacy 1, 4

Renal Impairment Considerations

• Patients with renal insufficiency (creatinine clearance <20 mL/min) face substantially higher toxicity risk, as 85% of methotrexate is renally excreted 1
• If creatinine increases ≥50% from baseline at 24 hours, escalate leucovorin to 100 mg/m² IV every 3 hours 2
• Continue intensive monitoring and leucovorin until both methotrexate levels normalize AND renal function recovers 2

Duration of Therapy

• Continue leucovorin every 6 hours until methotrexate level falls below 0.05 micromolar (5 × 10⁻⁸ M) 2
• If methotrexate level remains >0.2 micromolar at 72 hours or >0.05 micromolar at 96 hours, extend leucovorin rescue 2
• For significant clinical toxicity despite standard dosing, extend leucovorin for an additional 24 hours (total 14 doses over 84 hours) 2

Evidence Quality Note

High-quality evidence from Memorial Sloan-Kettering demonstrated that high-dose leucovorin as sole therapy (without hemodialysis or other extracorporeal removal) successfully rescued 13 patients with severe methotrexate toxicity (median 24-hour levels 164 micromolar, range 102-940 micromolar), with all patients recovering despite significant but tolerable morbidity including neutropenia and mucositis 6. A 2023 randomized controlled trial found no survival difference between 15 mg versus 25 mg leucovorin every 6 hours in severe low-dose methotrexate toxicity, supporting the standard 15 mg dose, though mortality remained high (42-47%) regardless of leucovorin dose 7.