Levoleucovorin Calcium

Toxicity Associated with Folic Acid Antagonists

IV rescue therapy after high-dose methotrexate therapy (to control the duration of exposure of sensitive cells to methotrexate) for treatment of osteosarcoma (designated an orphan drug by FDA for this use).1 2 3 6 17

Antidote to diminish the toxicity and counteract the effects of unintentional overdosage of methotrexate (e.g., resulting from impaired elimination) and other folic acid antagonists (designated an orphan drug by FDA for this use).1 6 17

Colorectal Cancer

In combination with fluorouracil for the palliative treatment of advanced-stage colorectal cancer.1 10002

Has been studied for treatment of advanced-stage colorectal cancer in combination with fluorouracil and other agents (i.e., irinotecan, oxaliplatin)†.10003 10004 10005 10006 However, use in such combination regimens not fully established.19

Other Uses

Manufacturer states that levoleucovorin should not be used for the treatment of pernicious anemia and megaloblastic anemias secondary to lack of vitamin B12; such use may alleviate hematologic manifestations while allowing neurologic complications to progress.1

Absorption

Bioavailability

Peak serum concentrations of active metabolite 5-methyltetrahydrofolic acid (5-methyl-THF) attained in an average 0.9 hours.1

Equipotent doses of IV levoleucovorin and IV racemic leucovorin result in similar systemic exposures to the l-isomer of leucovorin and to 5-methyl-THF.1 10011 10012

Distribution

Extent

Levoleucovorin is actively and passively transported across cell membranes.1

Small amounts of 5-methyl-THF distributed into CSF.1

Elimination

Metabolism

Metabolized to 5-methyl-THF, the primary circulating form of active reduced folate.1 7 8 10 Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by folylpolyglutamate synthetase.1

Elimination Route

Excreted in urine as unchanged drug and metabolites.10 17

Half-life

5.1 and 6.8 hours for THF and 5-methyl-THF, respectively.1

Storage

Parenteral

25°C (may be exposed to 15–30°C).1 Protect from light.1

Following reconstitution or further dilution in 0.9% sodium chloride injection, solutions may be stored up to 12 hours at room temperature.1

Following dilution in 5% dextrose injection, solutions may be stored for up to 4 hours at room temperature.1

2–8°C.1 Protect from light.1

Following dilution in 0.9% sodium chloride injection or 5% dextrose injection, solutions may be stored for up to 4 hours at room temperature.1

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

• The pharmacologically active levorotatory (l) isomer of racemic d,l-leucovorin.1 2 3 4 5 7 10 Constitutes approximately 50% of racemic leucovorin;1 2 3 5 7 8 10 17 exerts effects at half the dose of racemic leucovorin.4

• A reduced derivative of folic acid; does not require reduction by dihydrofolate reductase to participate in reactions utilizing folates.1

• Counteracts the therapeutic and toxic effects (e.g., hematologic toxicity) of folic acid antagonists (e.g., methotrexate);1 2 no effect on other established toxicities of methotrexate resulting from drug and/or metabolite precipitation in kidneys (e.g., nephrotoxicity).1

• Enhances therapeutic and toxic effects of fluoropyrimidines (e.g., fluorouracil) by stabilizing binding of fluorouracil metabolite (5-fluoro-2′-deoxyuridine 5′-monophosphate [FdUMP]) to thymidylate synthase (enzyme responsible for DNA repair and replication), thus enhancing inhibition of this enzyme.1