Action

Counteracts therapeutic and toxic effects of folic acid antagonists; may enhance therapeutic and toxic effects of fluoropyrimidines used in cancer therapy. Also supplements folic acid in folic acid deficiency.

Availability

Injection (expressed as base): 10 mg/vial, 50 mg/vial, 100 mg/vial, 200 mg/vial, 350 mg/vial, 500 mg/vial

Injection, preservative-free (expressed as base): 10 mg/vial, 50 mg/vial, 200 mg/vial, 350 mg/vial, 500 mg/vial

Tablets: 5 mg, 15 mg, 25 mg

Indications and dosages

➣ Leucovorin rescue after high-dose methotrexate therapy

Adults: 15 mg (approximately 10 mg/m²) P.O., I.M., or I.V. q 6 hours, starting 24 hours after methotrexate infusion begins and continuing until serum methotrexate level drops below 10^-8 M. If 24-hour serum creatinine level rises 50% over baseline or if 24-hour methotrexate level exceeds 5 × 10^-6 M or 48-hour level exceeds 9 × 10^-7 M, increase leucovorin dosage to 100 mg/m² I.V. q 3 hours and continue hydration and urinary alkalization until methotrexate level drops below 10^-8 M.

➣ To reduce toxicity and counteract effects of impaired methotrexate elimination or inadvertent overdose of folic acid antagonist

Adults: 15 mg (roughly 10 mg/m²) I.M., I.V., or P.O. q 6 hours until serum methotrexate level drops below 10^-8 M. If 24-hour serum creatinine level rises 50% over baseline or if 24-hour methotrexate level exceeds 5 × 10^-6 M or 48-hour level exceeds 9 × 10^-7 M, increase leucovorin dosage to 100 mg/m² I.V. q 3 hours and continue hydration and urinary alkalization until methotrexate level drops below 10^-8 M.

➣ Advanced colorectal cancer

Adults: Usually given in one of the following regimens: 200 mg/m² slow I.V. injection over at least 3 minutes, followed by I.V. injection of 5-fluorouracil (5-FU); or 20 mg/m² I.V. injection, followed by I.V. injection of 5-FU. Treatment is repeated daily for 5 days, and may then be repeated at 28-day intervals for two courses and then at 4- to 5-week intervals, as prescribed.

➣ Megaloblastic anemia secondary to folic acid deficiency

Adults: Up to 1 mg I.M. daily

Dosage adjustment

• In leucovorin rescue after high-dose methotrexate therapy: delayed early or late methotrexate elimination (serum methotrexate level still above 0.2 µM at 72 hours and above 0.05 µM [5 × 10^-8] at 96 hours after administration)

• Evidence of acute renal injury

Contraindications

• Treatment of pernicious anemia and other megaloblastic anemias caused by vitamin B₁₂ deficiency

Precautions

Use cautiously in:

• anemia (when vitamin B₁₂ deficiency has been ruled out)

• patients receiving 5-FU concomitantly

• pregnant or breastfeeding patients

• children.

Administration

See Recheck leucovorin dosage in current published protocols before giving as methotrexate rescue.

• Give parenterally in patients with GI toxicity, nausea, or vomiting.

• Reconstitute leucovorin injection with sterile or bacteriostatic water for injection containing benzyl alcohol. (When giving with 5-FU for colorectal cancer in dosages above 10 mg/m², reconstitute only with sterile water for injection.)

See Don't mix leucovorin injection with 5-FU, because precipitation will occur.

See Give I.V. leucovorin slowly (no faster than 160 mg/minute) because of calcium content. Large doses may be infused over 1 to 6 hours as directed.

See Don't give intrathecally; drug may be harmful or fatal by this route.

• Be aware that P.O. dosages above 25 mg are not recommended.

Adverse reactions

Skin: urticaria

Other: allergic sensitization reactions, anaphylactoid reactions

Interactions

Drug-drug. 5-FU: enhanced fluorouracil toxicity

Methotrexate, other folic acid antagonists: negated therapeutic and toxic effects of these drugs

Phenobarbital, phenytoin, primidone: negated anticonvulsant effect, increased frequency of seizures in susceptible children

Patient monitoring

See Monitor serum creatinine and methotrexate levels every 24 hours.

See Monitor closely for adverse reactions. Continue leucovorin therapy, hydration, and urinary alkalization until serum methotrexate level drops below 10^-8 M.

See Monitor CBC with white cell differential and platelet count before leucovorin/5-FU therapy starts. Repeat weekly during first two courses and then once each cycle at anticipated white blood cell nadir.

• Check electrolyte levels and liver function tests before each treatment for first three cycles. Thereafter, check before every other cycle.

• Assess for adequate hydration when giving with 5-FU or high-dose methotrexate.

• Watch for hypersensitivity reactions, especially anaphylactoid reactions.

Patient teaching

• Teach patient about drug and protocol.

See Stress importance of taking leucovorin as prescribed with high-dose methotrexate therapy. Emphasize that it's not just a vitamin.

• Tell patient to immediately report signs or symptoms of allergic reaction, such as hives.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs mentioned above.