• Minimizes hematologic effects of high-dose methotrexate therapy (leucovorin rescue).
• Advanced colorectal carcinoma (with 5-fluorouracil).
• Management of overdoses/prevention of toxicity from folic acid antagonists (pyrimethamine, trimethoprim).
• Folic acid deficiency (megaloblastic anemia) unresponsive to oral replacement.

Contraindicated in:

• Hypersensitivity
• Pedi: Preparations containing benzyl alcohol should not be used in neonates.

Use Cautiously in:

• Undiagnosed anemia (may mask the progression of pernicious anemia)
• Ascites
• Renal failure
• Dehydration
• Pleural effusions
• Urine pH <7
• OB: Safety not established in pregnancy
• Lactation: Safety not established in breastfeeding.

Hemat: thrombocytosis.
Misc: allergic reactions (rash, urticaria, wheezing).

Drug-Drug:

• May ↓ anticonvulsant effect of barbiturates, phenytoin, or primidone.
• High doses of the liquid contain significant alcohol and may cause ↑ CNS depression when used with CNS depressants.
• Concurrent use with trimethoprim/sulfamethoxazole may result in ↓ anti-infective efficacy and poor therapeutic outcome when used to treat Pneumocystis jirovecii pneumonia in patients with HIV.
• May ↑ therapeutic effects and toxicity of fluorouracil; therapy may be combined for this purpose.

(Generic available)

• Tablets: 5 mg; 10 mg; 15 mg; 25 mg;
• Powder for injection: 50 mg/vial; 100 mg/vial; 200 mg/vial; 350 mg/vial; 500 mg/vial;
• Solution for injection (preservative-free): 10 mg/mL;

High-Dose Methotrexate — Leucovorin Rescue. Must start within 24 hr of methotrexate.

• PO, IM, IV (Adults and Children): Normal methotrexate elimination: 10 mg/m² every 6 hr (1st dose IV/IM, then change to PO) until methotrexate level is <5 × 10^–8 M (0.05 micromolar). Larger doses/longer duration may be required in patients with aciduria, ascites, dehydration, renal impairment, GI obstruction, pleural/peritoneal effusions. Dose of leucovorin should be determined on the basis of plasma methotrexate levels.

Advanced Colorectal Cancer

• IV (Adults): 200 mg/m² followed by 5-fluorouracil 370 mg/m² or leucovorin 20 mg/m² is followed by 5-fluorouracil 425 mg/m². Regimen is given daily for 5 days every 4–5 wk.

Prevention of Hematologic Toxicity from Pyrimethamine

• PO, IV (Adults and Children): 5–15 mg/day.

Inadvertent Overdose of Folic Acid Antagonists

• IM, IV (Adults and Children): Methotrexate–large doses: 75 mg IV followed by 12 mg IM every 6 hr for 4 doses; methotrexate–average doses: 6–12 mg IM every 6 hr for 4 doses; other folic acid antagonists: amount equal in mg to folic acid antagonist.

Megaloblastic Anemia

• PO, IM, IV (Adults and Children): Up to 1 mg/day (up to 6 mg/day for dihydrofolate reductase deficiency).

• The reduced form of folic acid that serves as a cofactor in the synthesis of DNA and RNA.

• Reversal of toxic effects of folic acid antagonists.
• Reversal of folic acid deficiency.

Therapeutic Classification: antidotes (for methotrexate), vitamins

Pharmacologic Classification: folic acid analogues

Absorption: Well absorbed (38%) following PO administration. ↓ bioavailability with larger doses. Oral absorption is saturated at doses >25 mg. Well absorbed following IM administration. IV administration results in complete bioavailability.

Distribution: Widely distributed to tissues. Concentrates in the CNS and liver.

Metabolism/Excretion: Extensively converted to tetrahydrofolic derivatives, including 5-methyltetrahydrofolate, a major storage form.

Half-life: 3.5 hr.

(serum folate concentrations)

• Explain purpose of medication to patient. Emphasize need to take exactly as ordered. Advise patient to contact health care professional if a dose is missed.
• Advise females of reproductive potential to notify health care professional if pregnancy is planned or suspected, or if breastfeeding.
• Leucovorin Rescue: Instruct patient to drink at least 3 liters of fluid each day during leucovorin rescue.
• Folic Acid Deficiency: Encourage patient to eat a diet high in folic acid (meat proteins; bran; dried beans; and green, leafy vegetables).

loo-koe-VOR-in