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  1. Pharmacology. Leucovorin (folinic acid or citrovorum factor) is a metabolically functional form of folic acid. Unlike folic acid, leucovorin does not require reduction by dihydrofolate reductase, and therefore it can participate directly in the one-carbon transfer reactions necessary for purine biosynthesis and cellular DNA and RNA production. In animal models of methanol intoxication, replacement of a deficiency of leucovorin and folic acid can reduce morbidity and mortality because these agents catalyze the oxidation of the highly toxic metabolite formic acid to nontoxic products. However, there is no evidence that their administration in the absence of a deficiency is effective.

  2. Indications

    1. Folic acid antagonists (eg, methotrexate, trimethoprim, and pyrimethamine). Note: Leucovorin treatment is essential because cells are incapable of using folic acid owing to inhibition of dihydrofolate reductase.

    2. Methanol poisoning. Leucovorin is an alternative to folic acid.

  3. Contraindications. No known contraindications.

  4. Adverse effects

    1. Allergic reactions as a result of prior sensitization have been reported.

    2. Hypercalcemia from the calcium salt may occur (limit infusion rate to 160 mg/min in adults).

    3. Use in pregnancy. FDA Category C (indeterminate). This does not preclude its acute, short-term use in a seriously symptomatic patient (See Introduction in Section III).

  5. Drug or laboratory interactions. Leucovorin bypasses the antifolate effect of methotrexate.

  6. Dosage and method of administration

    1. Methotrexate poisoning. Note: Efficacy depends on early administration. Leucovorin should be given within 1 hour of poisoning, if possible; do not wait for methotrexate levels to initiate therapy. The drug should be given intravenously. The most effective dose and duration of treatment are uncertain.

      1. Methotrexate level unknown. Administer intravenously a dose equal to or greater than the dose of methotrexate. Leucovorin doses typically range from 10 to 25 mg/m2 every 6 hours, but doses of up to 1000 mg/m2 have been used. Most serious cases are treated with 100 mg/m2 (or about 150 mg in an average-size adult) IV over 15–30 minutes followed by 10 mg/m2 (or ˜15 mg) IV every 6 hours for at least 3 days, or until the serum methotrexate level falls below 0.01 mcmol/L or is undetectable.

      2. Elevated methotrexate level or elevated serum creatinine

        1. If the 24-hour serum creatinine increases 50% in the first 24 hours after methotrexate or if the 24-hour methotrexate level exceeds 5 mcmol/L or if the 48-hour methotrexate level exceeds 0.9 mcmol/L, increase the leucovorin dose to 100 mg/m2 intravenously every 3 hours until the methotrexate level is less than 0.01 mcmol/L or is undetectable.

        2. 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 mcmol/L or if the 48-hour methotrexate level reaches or exceeds 5 mcmol/L, increase the leucovorin dose to 150 mg intravenously every 3 hours until the methotrexate level is less than 1 mcmol/L. Then give a dose of 15 mg intravenously every 3 hours until the methotrexate level is less than 0.01 mcmol/L or is undetectable.

    2. Other folic acid antagonists. Administer 5–15 mg/day IM, IV, or PO ...

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