DESCRIPTION

Folic acid is a water-soluble, essential vitamin used in the treatment of methanol or methotrexate poisoning and proposed for the treatment of ethylene glycol poisoning.

FORMS AND USES

Folic Acid

• Oral. It is available alone or in combination with other vitamins. It is also available in foods such as leafy vegetables, yeast, and liver in the form of reduced polyglutamates.
• Parenteral. Folic acid (sodium folate, Folvite) is available in 5 and 10 mg/ml in 10-ml vials.

Folinic Acid (Leucovorin, Citrovorum Factor, Wellcovorin)

• Oral. The 5-mg tablet contains 5 mg of leucovorin and inactive ingredients (cornstarch, di-basic calcium phosphate, magnesium stearate, and pregelatinized starch). The 15-mg tablet contains 15 mg of leucovorin and inactive ingredients (lactose, magnesium stearate, microcrystalline cellulose, pregelatinized starch, and sodium starch glycolate).
• Parenteral. Solution contains leucovorin (as the calcium salt) 10 mg/ml. Inactive ingredients include 80 mg of sodium chloride per vial and sodium hydroxide or hydrochloric acid to adjust the pH to 8.1. The dry product has no preservatives. It should be diluted with bacteriostatic water for injection (USP), which contains benzyl alcohol, or with sterile water for injection (USP).

MECHANISM OF ACTION

• Folic acid is actively transported into cells and converted to its biologically active form, tetrahydrofolate, by a two-step enzymatic reduction involving dihydrofolate reductase.
• Tetrahydrofolate has several biologically active forms that are cofactors in biochemical reactions and synthesis of DNA and RNA precursors and several amino acids.
• In methanol poisoning, the administration of folic acid or leucovorin enhances the metabolism and elimination of formic acid, the toxic end-product of methanol metabolism to carbon dioxide and water.
• In ethylene glycol poisoning, a minor metabolic pathway may produce formic acid.
  • Theoretically, administration of folic acid or leucovorin will enhance the elimination of formic acid.
  • The clinical usefulness of folate in this scenario has not been tested.
• Methotrexate is a folate analog and a potent inhibitor of dihydrofolate reductase.
  • Administration of leucovorin bypasses the inhibited dihydrofolate reductase system, displaces methotrexate from dihydrofolate reductase, competes with methotrexate for intercellular transport, and increases efflux of methotrexate from the cell.

DRUG AND DISEASE INTERACTIONS

• Death from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving leucovorin and fluorouracil.
• Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin, and primidone.

PREGNANCY AND LACTATION

• US FDA Pregnancy Category C. Studies have shown that the drug exerts animal teratogenic or embryocidal effects, but there are no controlled studies in women, or no studies are available in either animals or women.
• It is unknown whether leucovorin is excreted in human milk.

Section Outline:

• DESCRIPTION
• FORMS AND USES
  • Folic Acid
  • Folinic Acid (Leucovorin, Citrovorum Factor, Wellcovorin)
• MECHANISM OF ACTION
• DRUG AND DISEASE INTERACTIONS
• PREGNANCY AND LACTATION

• Methanol poisoning. Folic acid or leucovorin may be used. Patients treated with fomepizole or ethanol should also receive folic acid or leucovorin.
• Ethylene glycol poisoning. Although the use of leucovorin has theoretical application, it is not routinely recommended.
• Methotrexate overdose. Typically, this involves patients in whom an inadvertent, iatrogenic overdose is discovered after methotrexate administration. Leucovorin (not folic acid) is the only effective treatment.

There are no known contraindications.

ADVERSE EFFECTS

• Rare allergic reactions to folic acid preparations include erythema, rash, itching, malaise, and wheezing.
• Gastrointestinal effects, anorexia, nausea, and abdominal distention, may occur.
• CNS effects, including altered sleep patterns, difficulty in concentrating, irritability, depression, and confusion, have been reported rarely in patients receiving 15 mg of folic acid daily for 1 month. Minimal daily intake is estimated to be 0.1 to 0.2 mg, and usual dietary intake is 0.5 to 1.0 mg/day.
• Decreased serum vitamin B₁₂ concentrations may occur in patients receiving prolonged folic acid therapy.
• Because of the benzyl alcohol contained in certain diluents, when doses greater than 10 mg/m² are administered, leucovorin calcium should be reconstituted with sterile water instead and used immediately.
• Because of the calcium content of the leucovorin solution, no more than 160 mg per minute (16 ml/min) of leucovorin should be injected intravenously.

Leucovorin is preferred to folic acid for all indications.

METHANOL POISONING

• Leucovorin. A dose of 1 to 2 mg/kg is administered intravenously every 4 to 6 hours until methanol is eliminated and acidosis resolves. If hemodialysis is indicated, a dose of leucovorin should be administered at the completion of dialysis.
• Folic acid. A dose of 50 to 75 mg is administered intravenously every 4 to 6 hours until methanol is eliminated and acidosis resolves.

METHOTREXATE TOXICITY

• Folic acid is not an effective antidote.
• Intravenous leucovorin is administered immediately in a dose equal to or greater than the ingested dose of methotrexate.
  • The dose is repeated every 6 hours until methotrexate level is less than 10^-8 molar.
  • If the methotrexate dose is unknown, 10 mg/m² of leucovorin is administered every 6 hours until the methotrexate level is less than 10^-8 molar.
  • The duration of leucovorin therapy typically ranges from 12 to 72 hours.
  • The pediatric dose for an unknown methotrexate dose is 10 mg/m².
• Serum creatinine and methotrexate levels should be determined at 24-hour intervals.
  • If serum creatinine has increased 50% over baseline, if the 24-hour methotrexate level is greater than 5 × 10^-6 molar, or if the 48-hour level is greater than 9 × 10^-7 molar, intravenous leucovorin dosage should be increased to 100 mg/m² every 6 hours until the methotrexate level is less than 10^-7 molar at 24 hours or 10^-8 molar at any time.
  • If the 24-hour methotrexate level is greater than 5 × 10^-5 molar or if the 48-hour level is greater than 9 × 10^-6 molar, the intravenous leucovorin dose should be increased to 1,000 mg/m² every 6 hours until the methotrexate level is less than 10^-7 molar at 24 hours or 10^-8 molar at any time.

Section Outline:

• METHANOL POISONING
• METHOTREXATE TOXICITY

• Intravenous administration is preferred, especially if gastrointestinal symptoms are present or if more than 50 mg is to be given, because intestinal cellular transport mechanisms for leucovorin become saturated at this amount.
• Because both folic acid and leucovorin are highly water soluble and will be removed during hemodialysis, an additional dose of folic acid or leucovorin should be administered following dialysis.
• Folic acid should not be substituted for leucovorin in methotrexate overdose.

Poisoning by liver preparations and other antianemic agents.

See Also: SECTION IV, Antineoplastic Medications, Ethylene Glycol, and Methanol chapters.

RECOMMENDED READING

Howland MA. Folic acid and leucovorin (folinic acid). In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al., eds. Goldfrank's toxicologic emergencies, 6th ed. Norwalk, CT: Appleton & Lange, 1998.

Jacobsen D, McMartin K. Methanol and ethylene glycol poisonings—mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol 1986;1:309-334.

Osterloh JD, Pond SM, Grady S, et al. Serum formate concentrations in methanol intoxication as a criterion for hemodialysis. Ann Intern Med 1986;104:200-203.

Author: Luke Yip

Reviewer: Rivka S. Horowitz