Leucovorin (folinic acid, also known as Citrovorum factor) is a reduced folate derivative that serves as an antidote to folic acid antagonists and as a chemotherapy modulator.
It does not require reduction by dihydrofolate reductase to participate in folate-dependent reactions.
It acts like folic acid in many tissues but bypasses steps blocked by antifolates such as methotrexate.
Leucovorin is the 5‑formyl derivative of tetrahydrofolate that can enter one‑carbon pathways without DHFR‑mediated reduction.
Leucovorin (folinic acid, calcium folinate) is the reduced, active form of folate used primarily as a “rescue” agent with high‑dose methotrexate and as a modulator of 5‑fluorouracil, as well as in select folate‑responsive anemias and rare neurometabolic conditions.
Mechanism of Action
Leucovorin has dual and opposing mechanisms depending on the clinical context. When used as methotrexate rescue, it counteracts the therapeutic and toxic effects of folic acid antagonists by bypassing dihydrofolate reductase inhibition and replenishing reduced folate pools.
Conversely, when combined with 5-fluorouracil (5-FU), leucovorin enhances both therapeutic and toxic effects by converting to 5,10-methylenetetrahydrofolate, which stabilizes the binding of fluorodeoxyuridylic acid to thymidylate synthase, thereby potentiating enzyme inhibition.
The FDA-approved indications for leucovorin include:
Methotrexate rescue after high-dose methotrexate therapy in osteosarcoma
Diminishing toxicity from impaired methotrexate elimination or inadvertent overdosage of folic acid antagonists
Megaloblastic anemia due to folic acid deficiency when oral therapy is not feasible
Advanced colorectal cancer in combination with 5-fluorouracil to prolong survival
Dosing Regimens
Methotrexate Rescue (High-Dose): 15 mg (approximately 10 mg/m²) IV/IM/PO every 6 hours for 10 doses, starting 24 hours after the beginning of methotrexate infusion.
Serum methotrexate and creatinine levels should be monitored at least daily.
Impaired Methotrexate Elimination/Overdosage: 10 mg/m² IV/IM/PO every 6 hours until serum methotrexate level is less than 10⁻⁸ M.
If the 24-hour serum creatinine increases by 50% or methotrexate levels remain elevated, increase to 100 mg/m² IV every 3 hours until methotrexate level is less than 10⁻⁸ M.
Colorectal Cancer (with 5-FU): Two common regimens include 200 mg/m² IV over 2 hours followed by 5-FU, or 20 mg/m² IV followed by 5-FU, repeated every 2 weeks.
Leucovorin doses are not adjusted for toxicity, but 5-FU doses are adjusted based on patient tolerance.
Megaloblastic Anemia: Up to 1 mg daily. Doses greater than 1 mg/day have no additional efficacy.
Leucovorin is never administered intrathecally – this may be harmful or fatal.
Leucovorin should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.
In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin should be administered parenterally rather than orally.
Doses greater than 25 mg should be given IV due to saturable oral absorption.
Elderly and debilitated patients receiving leucovorin with 5-FU are at greater risk for severe gastrointestinal toxicity.
Concomitant use with trimethoprim-sulfamethoxazole for Pneumocystis pneumonia in HIV patients was associated with increased treatment failure.
Rescue after high‑dose methotrexate or methotrexate overdose to limit myelosuppression, mucositis, nephrotoxicity, and other toxicities.
Modulation of 5‑fluorouracil in colorectal cancer regimens to enhance binding of FdUMP to thymidylate synthase and improve antitumor effect.
Treatment or prevention of certain megaloblastic anemias when folic acid cannot be used or absorbed, with the caveat that B12 deficiency must be excluded first.
Dosing and administration
Routes: oral, IV, or IM; IV preferred in significant methotrexate toxicity, vomiting, or malabsorption.
Methotrexate rescue: typically started 24 hours after methotrexate infusion and continued q6h with dose and duration guided by MTX levels and renal function; delays beyond ~40 hours markedly increase risk of irreversible toxicity.
With 5‑FU: given IV in various schedules (e.g., bolus 5‑FU plus leucovorin or infusional regimens), allowing lower 5‑FU dosing due to potentiation.
Treating folate‑deficiency megaloblastic anemia with leucovorin alone can mask and worsen neurologic complications of unrecognized B12 deficiency; B12 must be ruled out first.
Concomitant use during Pneumocystis jirovecii pneumonia treatment with TMP‑SMX has been associated with higher failure and morbidity rates: Adverse effects are usually related to the underlying chemotherapy (e.g., 5‑FU) but can include GI upset and rarely hypersensitivity.
Leucovorin is a prescription reduced folate used in cerebral folate deficiency and other rare folate transport/metabolism disorders, often associated with FRAAs or FOLR1 variants.