What are the indications, dosing regimens, contraindications, and alternatives for leucovorin (folinic acid) when used for methotrexate (MTX) rescue, to reduce toxicity from 5‑fluorouracil (5‑FU) or capecitabine chemotherapy, and to treat folate deficiency?

Leucovorin (Folinic Acid): Indications, Dosing, and Clinical Use

Primary Indications

Leucovorin has four FDA-approved indications: methotrexate rescue after high-dose therapy, treatment of inadvertent methotrexate overdose, treatment of megaloblastic anemia when oral therapy is not feasible, and combination with 5-fluorouracil for advanced colorectal cancer. 1

1. Methotrexate Rescue After High-Dose Therapy

For high-dose methotrexate (12-15 g/m²), leucovorin 15 mg (approximately 10 mg/m²) should be administered every 6 hours for 10 doses starting 24 hours after the beginning of methotrexate infusion. 1

• Continue leucovorin until the methotrexate level falls below 0.05 micromolar (5 × 10⁻⁸ M) 1
• If gastrointestinal toxicity, nausea, or vomiting occurs, administer leucovorin parenterally rather than orally 1
• Never administer leucovorin intrathecally 1

Dose escalation protocol based on methotrexate elimination:

• Normal elimination (methotrexate ~10 micromolar at 24h, ~1 micromolar at 48h, <0.2 micromolar at 72h): Continue standard 15 mg every 6 hours for 60 hours 1
• Delayed late elimination (methotrexate >0.2 micromolar at 72h or >0.05 micromolar at 96h): Continue 15 mg every 6 hours until level <0.05 micromolar 1
• Delayed early elimination or acute renal injury (methotrexate ≥50 micromolar at 24h or ≥5 micromolar at 48h, OR ≥100% increase in serum creatinine): Escalate to 150 mg IV every 3 hours until methotrexate <1 micromolar, then 15 mg IV every 3 hours until <0.05 micromolar 1

2. Inadvertent Methotrexate Overdose or Toxicity

Leucovorin must be administered immediately upon recognition of methotrexate toxicity, as efficacy diminishes dramatically after 24 hours and becomes doubtful if initiated later than 24 hours after the last methotrexate dose. 2, 3

Initial dosing for suspected overdose:

• Administer up to 100 mg/m² IV if methotrexate level is unknown 2
• Standard rescue dose: 15 mg IV or orally every 6 hours until toxicity resolves 3
• For severe toxicity: Escalate to 100 mg/m² IV every 3 hours until methotrexate level falls below 10⁻⁸ M 2

Critical supportive measures:

• Aggressive IV hydration (3 L/day) 2
• Urinary alkalinization with sodium bicarbonate to maintain urine pH ≥7.0 2, 1
• If recent ingestion (≥1 mg/kg within 1 hour), administer activated charcoal first 2
• Monitor complete blood count, renal function, and liver function tests daily 2
• For severe neutropenia (<1×10⁹/L), consider filgrastim (G-CSF) 5 mcg/kg/day subcutaneously 2

A recent 2023 randomized controlled trial found no significant difference in survival or hematological recovery between 15 mg and 25 mg leucovorin doses given every 6 hours for severe low-dose methotrexate toxicity, with 30-day mortality of 42-47% in both groups. 4 This suggests the standard 15 mg dose is adequate for most cases of low-dose methotrexate toxicity.

3. Prevention of Low-Dose Methotrexate Toxicity

All patients on weekly methotrexate should receive folic acid supplementation (1-5 mg daily except on methotrexate day, or 5 mg weekly) to prevent gastrointestinal, hepatic, and hematologic toxicity. 5, 3

For patients experiencing minor toxicities despite folic acid:

• Leucovorin 10 mg orally twice daily for 3 days after methotrexate may be used as an alternative to folic acid 2
• This approach is particularly useful for patients with persistent stomatitis or gastrointestinal symptoms 2

Critical distinction: Only leucovorin (folinic acid) bypasses methotrexate's metabolic block and serves as an effective antidote for acute toxicity; folic acid is for prevention only, not treatment of established toxicity. 3

4. Combination with 5-Fluorouracil for Colorectal Cancer

Leucovorin enhances 5-FU cytotoxicity by stabilizing the binding of fluorodeoxyuridylic acid to thymidylate synthase. 6

Standard regimens:

• FOLFOX/FOLFIRI: Leucovorin 400 mg/m² IV over 2 hours on day 1, followed by 5-FU 400 mg/m² IV bolus, then 1200 mg/m²/day × 2 days continuous infusion, repeated every 2 weeks 5, 6
• Simplified biweekly (sLV5FU2): Leucovorin 400 mg/m² IV over 2 hours on day 1, followed by 5-FU bolus 400 mg/m² and continuous infusion, repeated every 2 weeks 5, 6
• Roswell Park regimen: Leucovorin 500 mg/m² IV over 2 hours followed by 5-FU 500 mg/m² IV bolus, days 1,8,15,22,29, and 36, repeated every 8 weeks 5

Low-dose leucovorin (20 mg/m²) is therapeutically equivalent to high-dose leucovorin (200-500 mg/m²) when combined with bolus 5-FU. 6

Levoleucovorin (the active L-isomer) 200 mg/m² is equivalent to standard leucovorin 400 mg/m², representing a cost-effective alternative. 5, 6

Critical administration note: Leucovorin should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form. 1 Administer separately. 5

5. Treatment of Megaloblastic Anemia Due to Folate Deficiency

Leucovorin is indicated for megaloblastic anemia when oral therapy is not feasible. 1

• This indication is reserved for patients unable to take oral folic acid due to severe gastrointestinal dysfunction, malabsorption, or critical illness 1
• Once oral intake is possible, transition to oral folic acid (1-5 mg daily) is preferred 3

Contraindications and Critical Warnings

Absolute contraindications:

• Intrathecal administration is absolutely contraindicated 2, 1
• Pernicious anemia or other megaloblastic anemias due to vitamin B12 deficiency (leucovorin may mask hematologic manifestations while allowing neurologic damage to progress) 1

High-risk drug interactions:

• Trimethoprim-sulfamethoxazole is absolutely contraindicated with methotrexate due to severe bone marrow suppression risk 3
• NSAIDs reduce renal elimination of methotrexate, particularly dangerous with any dose 5, 3
• Other high-risk interactions include salicylates, sulfonamides, penicillins, and probenecid 3

Alternatives to Leucovorin

For colorectal cancer treatment:

• Oral capecitabine (a fluoropyrimidine prodrug) does not require leucovorin co-administration and has demonstrated equivalent efficacy to 5-FU/leucovorin in multiple trials. 6
• CAPOX (capecitabine plus oxaliplatin) is equivalent to FOLFOX in activity and safety 6

For methotrexate toxicity prevention:

• Folic acid 1-5 mg daily (except on methotrexate day) is the standard preventive measure 5, 3
• Oral folic acid at doses of 25-125 mg/m² can elevate the same plasma metabolites as leucovorin (5-methyltetrahydrofolate, 5,10-methylenetetrahydrofolate, tetrahydrofolate, and 10-formyltetrahydrofolate), though metabolites accumulate more slowly and persist longer than with leucovorin 7

For severe methotrexate toxicity with delayed elimination:

• Carboxypeptidase G2 (glucarpidase) should be obtained from the National Institutes of Health on a compassionate-use basis for cases where plasma methotrexate levels remain elevated despite standard measures 3

Route of Administration Considerations

Oral versus parenteral leucovorin:

• After oral administration, almost all folate in serum and urine is in the form of 5-methyltetrahydrofolic acid, with peak serum levels at 3 hours 8
• After parenteral administration, nearly one-third of folate is in the form of folinic acid and the remainder as 5-methyltetrahydrofolic acid, with peak levels at 30 minutes 8
• For methotrexate rescue, parenteral administration is preferred when gastrointestinal toxicity is present 1
• Oral administration may be acceptable for low-dose methotrexate rescue in patients without gastrointestinal symptoms 2, 8

Common Pitfalls to Avoid

• Delaying leucovorin administration: Efficacy is doubtful if initiated >24 hours after last methotrexate dose 2, 3
• Confusing folic acid with folinic acid (leucovorin): Only leucovorin bypasses methotrexate's metabolic block for acute toxicity treatment 3
• Assuming low serum methotrexate levels exclude toxicity: Treat based on clinical presentation, not solely on levels 3
• Mixing leucovorin with 5-FU in the same infusion: This causes precipitate formation 5, 1
• Limiting chemotherapy orders to >24-hour units: Always order as 1200 mg/m²/day, NOT 2400 mg/m² over 48 hours, to minimize medication errors 5, 6