leucovorin calcium

REMS

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.

Contraind./Precautions ⬆ ⬇

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.

Adv. Reactions/Side Effects ⬆ ⬇

Hemat: thrombocytosis

Misc: allergic reactions (rash, urticaria, wheezing)

Interactions ⬆ ⬇

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.

Availability ⬆ ⬇

(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

Route/Dosage ⬆ ⬇

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).

Action ⬆ ⬇

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

Therapeutic effects:

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

Classifications ⬆ ⬇

Therapeutic Classification: antidotes (for methotrexate), vitamins

Pharmacologic Classification: folic acid analogues

Pharmacokinetics ⬆ ⬇

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.

Time/Action Profile ⬆ ⬇

(serum folate concentrations)

ROUTE	ONSET	PEAK	DURATION
PO	20–30 min	unknown	3–6 hr
IM	10–20 min	unknown	3–6 hr
IV	<5 min	unknown	3–6 hr

Patient/Family Teaching ⬆ ⬇

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.
Rep: 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).

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Indications ⬇