What are the doses of leucovorin (folinic acid) and sodium bicarbonate for managing methotrexate-induced toxicity?

Leucovorin and Sodium Bicarbonate Dosing for Methotrexate Toxicity

For inadvertent methotrexate overdose or severe toxicity, administer leucovorin 10-100 mg/m² IV every 6 hours (depending on methotrexate levels) along with aggressive IV hydration at 3 L/day and urinary alkalinization using sodium bicarbonate to maintain urine pH ≥7.0. 1, 2

Leucovorin Dosing Algorithm

Immediate Management (Inadvertent Overdose)

• Start leucovorin as soon as possible after recognition of overdose—efficacy decreases dramatically after 24 hours from the last methotrexate dose 1
• Initial dose: 10 mg/m² IV every 6 hours if methotrexate level is unknown 2
• If methotrexate level is known to be elevated: up to 100 mg/m² IV may be required 1
• Continue until serum methotrexate level falls below 10⁻⁸ M (0.01 micromolar) 2

High-Dose Methotrexate Rescue Protocol

• Standard rescue: 15 mg (approximately 10 mg/m²) IV/IM/PO every 6 hours for 10 doses starting 24 hours after methotrexate infusion begins 2
• If gastrointestinal toxicity, nausea, or vomiting present, administer parenterally only 2

Dose Escalation Based on Methotrexate Levels

For delayed early elimination or acute renal injury:

• Methotrexate level ≥50 micromolar at 24 hours OR ≥5 micromolar at 48 hours
• Serum creatinine increased ≥100% at 24 hours
• Escalate to 150 mg IV every 3 hours until methotrexate <1 micromolar, then 15 mg IV every 3 hours until <0.05 micromolar 2

For delayed late elimination:

• Methotrexate level >0.2 micromolar at 72 hours or >0.05 micromolar at 96 hours
• Continue 15 mg IV/PO every 6 hours until methotrexate <0.05 micromolar 2

Critical Dosing Considerations

• Maximum IV infusion rate: 160 mg leucovorin per minute (due to calcium content) 2
• For doses >10 mg/m², reconstitute with Sterile Water for Injection only (not bacteriostatic water with benzyl alcohol) and use immediately 2
• Never administer leucovorin intrathecally—this is explicitly contraindicated 2, 3

Sodium Bicarbonate Protocol

Urinary Alkalinization Strategy

• Goal: Maintain urine pH ≥7.0 throughout methotrexate elimination 1, 2, 3
• Administer sodium bicarbonate either orally or incorporated into IV hydration solution 3
• Continue alkalinization until methotrexate level <0.05 micromolar 2

Hydration Requirements

• 3 liters per day (or 125 mL/m²/hr) of IV fluids 1, 3
• For high-dose methotrexate protocols: 1,000 mL/m² over 6 hours prior to methotrexate, then continue at 125 mL/m²/hr during infusion and for 2 days after completion 3
• If creatinine rises >1.25 times baseline, increase hydration to 200 mL/m²/hr 4

Fluid Composition

• 0.45% sodium chloride with 5% dextrose
• 7.5% sodium bicarbonate (50 mmol/L)
• Potassium chloride (20 mmol/L) 4

Monitoring Requirements

• Measure serum creatinine and methotrexate levels at least daily until methotrexate <0.05 micromolar 2, 3
• Check urine pH at baseline, 24 hours, and 48 hours 4
• Monitor for sepsis—high mortality risk with methotrexate overdose 1

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 is licensed for plasma methotrexate levels >1 μmol/L in patients with compromised renal function and delayed elimination 5
• Acute intermittent hemodialysis with high-flux dialyzer may be beneficial in severe cases with renal failure 3

Common Pitfalls to Avoid

• Do not delay leucovorin administration—waiting for methotrexate levels wastes critical time; start empirically 1
• Do not confuse routine folic acid supplementation (1-5 mg daily for prevention) with leucovorin rescue therapy (much higher doses for acute toxicity) 1, 6
• Do not use oral leucovorin if patient has mucositis, nausea, or vomiting—switch to parenteral route 2
• Do not stop leucovorin prematurely—continue until documented methotrexate level <0.05 micromolar, which may take 7-17 days in severe cases 7

Evidence Quality Note

High-dose leucovorin as sole therapy (without hemodialysis) has been shown effective even for severe intoxication with methotrexate levels up to 940 micromol/L at 24 hours, though with significant but tolerable morbidity including neutropenia and mucositis 7. However, mortality in severe low-dose methotrexate toxicity remains substantial (42-47%) even with leucovorin rescue, with serum albumin being the only predictor of survival 8.