What is the recommended dosing for Leucovorin (folinic acid)?

Leucovorin Dosing

Leucovorin dosing depends critically on the clinical indication: for colorectal cancer chemotherapy regimens, use 400 mg/m² IV over 2 hours on day 1 every 2 weeks; for methotrexate rescue after high-dose therapy, start with 15 mg IV/IM/PO every 6 hours beginning 24 hours after methotrexate infusion, adjusting based on methotrexate levels and renal function. 1, 2

Colorectal Cancer Chemotherapy Regimens

Standard FOLFOX and FOLFIRI protocols require leucovorin 400 mg/m² IV infused over 2 hours on day 1, repeated every 2 weeks. 1, 3, 4 This dose applies whether leucovorin is combined with oxaliplatin (mFOLFOX6), irinotecan (FOLFIRI), or when adding targeted agents like bevacizumab, cetuximab, or panitumumab. 1, 3

Critical Dosing Equivalency

• Levoleucovorin 200 mg/m² equals standard leucovorin 400 mg/m² because levoleucovorin contains only the active L-isomer. 1, 3, 2
• Never confuse these formulations—using the wrong dose could result in either underdosing (ineffective therapy) or overdosing (increased toxicity). 3

Alternative Colorectal Cancer Regimens

For the Roswell-Park regimen, leucovorin 500 mg/m² IV over 2 hours is given on days 1,8,15,22,29, and 36, repeated every 8 weeks. 1 The simplified biweekly regimen (sLV5FU2) uses the same 400 mg/m² dose as FOLFOX/FOLFIRI. 1

Methotrexate Rescue Dosing

Standard High-Dose Methotrexate Protocol

For methotrexate doses of 12-15 g/m², begin leucovorin rescue at 15 mg (approximately 10 mg/m²) IV/IM/PO every 6 hours for 10 doses, starting 24 hours after the beginning of methotrexate infusion. 2 If gastrointestinal toxicity, nausea, or vomiting occurs, administer leucovorin parenterally rather than orally. 2

Dose Adjustments Based on Methotrexate Levels

Continue leucovorin and urinary alkalinization until serum methotrexate falls below 0.05 micromolar (5 x 10⁻⁸ M). 2 Adjust dosing according to this algorithm:

• Normal elimination (methotrexate ~10 micromolar at 24h, ~1 micromolar at 48h, <0.2 micromolar at 72h): Continue 15 mg every 6 hours for 60 hours total. 2

• Delayed late elimination (methotrexate >0.2 micromolar at 72h or >0.05 micromolar at 96h): Continue 15 mg every 6 hours until methotrexate <0.05 micromolar. 2

• Delayed early elimination or acute renal injury (methotrexate ≥50 micromolar at 24h OR ≥5 micromolar at 48h OR serum creatinine doubles): Escalate to 150 mg IV every 3 hours until methotrexate <1 micromolar, then 15 mg IV every 3 hours until <0.05 micromolar. 2

Critical Monitoring Requirements

Monitor serum creatinine and methotrexate levels at least daily during rescue therapy. 2 Patients with delayed elimination require aggressive hydration, urinary alkalinization to pH ≥7.0, and close monitoring of fluid and electrolyte status. 2 These patients are at high risk for reversible renal failure. 2

Rescue Dose Calculation for Critical Cases

When methotrexate elimination is severely delayed, leucovorin rescue dose (mg) = 10 × methotrexate concentration (mg/L) × 0.76 × body weight (kg). 5 This tenfold excess over total body methotrexate is necessary to achieve effective rescue in critical situations. 5

Low-Dose Methotrexate Toxicity

For severe toxicity from chronic low-dose methotrexate (≤50 mg/week), leucovorin 15-25 mg IV every 6 hours is standard, though evidence shows no survival difference between these doses. 6 The 15 mg dose appears adequate for most cases. 6

Congenital Toxoplasmosis

For treatment of congenital toxoplasmosis in infants receiving pyrimethamine and sulfadiazine, leucovorin 10 mg PO three times weekly prevents hematologic toxicity. 1 This supplementation continues throughout the 12-month treatment course. 1

Trimetrexate Rescue

When trimetrexate glucuronate is used for Pneumocystis pneumonia, leucovorin 20 mg/m² every 6 hours for 24 days is required (continuing 3 days beyond the 21-day trimetrexate course). 1

Critical Safety Considerations

• Never administer leucovorin intrathecally—this can be fatal. 2
• Limit chemotherapy orders to 24-hour units (e.g., write "1200 mg/m²/day" not "2400 mg/m² over 48 hours") to minimize medication errors. 1, 3
• Check for drug interactions that impair methotrexate elimination (NSAIDs, proton pump inhibitors, penicillins) before initiating rescue. 2
• In colorectal cancer regimens, administer 5-FU and leucovorin separately to avoid precipitate formation. 2