citrovorum factor

citrovorum factor

n.

See folinic acid.

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citrovorum factor.

See folinic acid.

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citrovorum factor

see folinic acid.

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leucovorin calcium (citrovorum factor, folinic acid)

Lederfolin (UK), Refolinon (UK), Sodiofolin (UK)

Pharmacologic class: Water-soluble vitamin

Therapeutic class: Vitamin, antidote to folic acid antagonist, antianemic, antineoplastic adjunct

Pregnancy risk category C

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

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

Route	Onset	Peak	Duration
P.O.	20-30 min	60 to 90 min	3-6 hr
I.V.	<5 min	Unknown	3-6 hr
I.M.	10-20 min	35 to 60 min	3-6 hr

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

☞ Monitor serum creatinine and methotrexate levels every 24 hours.
☞ Monitor closely for adverse reactions. Continue leucovorin therapy, hydration, and urinary alkalization until serum methotrexate level drops below 10^-8 M.
☞ 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.
☞ 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.