Dosage / Administration

For methotrexate poisoning: Efficacy depends on early administration of leucovorin. Leucovorin is available in oral, intramuscular (IM), or intravenous (IV) formulations, but IV is the preferred route of administration.

Dosage should be based on methotrexate level, if known, and renal function.

• Methotrexate level unknown – A dose equal to or greater than the dose of methotrexate should be given intravenously. Dosage of leucovorin ranges from 10-25 mg/m² every 6 hours, but doses of 1000 mg/m² have been given. Most cases are treated with 100 mg/m² (about 150 mg) over 15-30 minutes followed by 10 mg/m² (15 mg) every 6 hours for 5 days or until the serum methotrexate level is below 0.05 µmol/L or undetectable.
• Elevated methotrexate level or elevated serum creatinine – Serum methotrexate of ≥ 50 µmol/L at 24 hours or ≥5 µmol/L at 48 hours after administration or a ≥ 100% increase in serum creatinine at 24 hours after methotrexate administration (eg, an increase from 0.5 to ≥1 mg/dL). Give leucovorin 150 mg IV every 3 hours until methotrexate is < 1 µmol/L; then 15 mg IV every 3 hours until methotrexate is < 0.05 µmol/L.
• If the 24-hour serum creatinine increases 100% in the first 24 hours after methotrexate, or if the 24-hour methotrexate level reaches or exceeds 50 µmol/L, or if the 48-hour methotrexate level reaches or exceeds 5 µmol/L, increase the leucovorin dose to 150 mg IV every 3 hours until the methotrexate level is less than 1 µmol/L. Then give a dose of 15 mg IV every 3 hours until the methotrexate level is less than 0.01 µmol/L, or is undetectable.
• Methanol poisoning for adults and children – Give 1 mg/kg (up to 50-70 mg) IV every 4 hours for the first 24 hours. Then give oral folic acid 50-70 mg every 4-6 hours until methanol levels are undetectable.

Indications

• As an antidote for folic acid antagonists (eg, methotrexate, trimethoprim, and pyrimethamine). Supratherapeutic methotrexate ingestion usually occurs in the context of accidental daily dosing of methotrexate, rather than usual weekly dosing.
• Methanol poisoning – Leucovorin is the preferred form of folic acid to enhance the breakdown of formic acid.

Contraindications

• No known contraindications.
• US Food and Drug Administration (FDA) Category C (indeterminate).

Monitoring
Serum methotrexate levels are closely monitored in patients with methotrexate toxicity; however, it is inappropriate to wait for methotrexate levels before starting treatment with leucovorin.

Adverse Effects

• Anaphylaxis (rare).
• Seizures (rare).
• Hypercalcemia with rapid administration (> 160 mg/min) and a very high dose.

Toxicity
None.

Mechanism of Action
Folinic acid (leucovorin) is a functional form of folic acid and is essential for DNA / RNA synthesis. Methotrexate inhibits the dihydrofolate reductase enzyme required for reduction of folic acid to folinic acid.

Administration of folinic acid bypasses this inhibition and restores DNA / RNA synthesis.

In methanol poisoning, leucovorin enhances the elimination of formate, which is produced from methanol.