Leucovorin Calcium
5-formyl tetrahydrofolic acid
Also known as: Citrovorum factor · 5-formyl tetrahydrofolate · citrovorin · folidan · FTHF · NSC-3590 · calcium folinate · calcifolin · calfonat · folinic acid calcium salt
Reviewed by the VetSheet Veterinary TeamUpdated Apr 5, 2026Evidence-based veterinary reference
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Dosing by species
🌎 NA — North America🌍 EU — Europe
Dogs
| Indication | Dose | Route | Frequency | Duration | Region |
|---|---|---|---|---|---|
| Folate deficiency associated with pyrimethamine use | 5-15 mg (total dose) PO or parenterally once daily | PO/Parenteral | q24h | — | 🌎 NA |
| Methotrexate overdose | 25-200 mg/m2 parenterally every 6 hours until methotrexate levels are less than 1 X 10 -8 M | Parenteral | q6h | Until methotrexate levels are < 1 X 10^-8 M | 🌎 NA |
- Methotrexate overdose: Most effective if given within 48 hours of overdose. Dose is dependent on serum methotrexate concentration.
Cats
| Indication | Dose | Route | Frequency | Duration | Region |
|---|---|---|---|---|---|
| Folate deficiency associated with pyrimethamine use | 5-15 mg (total dose) PO or parenterally once daily | PO/Parenteral | q24h | — | 🌎 NA |
| Bone marrow suppression associated with pyrimethamine or trimethoprim/sulfa | 5 mg once daily | Not specified | q24h | — | 🌎 NA |
| To prevent bone marrow toxicity associated with pyrimethamine | 1 mg/kg once daily | Not specified | q24h | — | 🌎 NA |
| Methotrexate overdose | 25-200 mg/m2 parenterally every 6 hours until methotrexate levels are less than 1 X 10 -8 M | Parenteral | q6h | Until methotrexate levels are < 1 X 10^-8 M | 🌎 NA |
- Methotrexate overdose: Most effective if given within 48 hours of overdose.
Horses
| Indication | Dose | Route | Frequency | Duration | Region |
|---|---|---|---|---|---|
| Macrocytic anemia and neutropenia associated with pyrimethamine and/or trimethoprim (especially in pregnant mares) | 0.1-0.3 mg/kg PO once daily | PO | q24h | — | 🌎 NA |
- Macrocytic anemia and neutropenia associated with pyrimethamine and/or trimethoprim (especially in pregnant mares): A more practical approach would be to ensure that the horse receives green hay or pasture (high tetrahydrofolate levels in green roughage).
Doses are a clinical reference for licensed veterinary professionals. Always confirm against the current label and the individual patient.
Overview
Leucovorin calcium (also known as folinic acid or citrovorum factor) is a reduced folic acid derivative primarily used in veterinary medicine as a rescue agent or antidote.
- Primary Indication: It is used to reverse or prevent hematologic toxicity (such as bone marrow suppression, macrocytic anemia, and neutropenia) associated with dihydrofolate reductase inhibitors (e.g., pyrimethamine, trimethoprim, or ormetoprim).
- Methotrexate Rescue: While routinely used in human medicine as a rescue agent for high-dose methotrexate chemotherapy, it is rarely used for this purpose in veterinary medicine, except in cases of accidental methotrexate overdose.
- Clinical Pearl: Unlike standard folic acid, leucovorin does not require the enzyme dihydrofolate reductase to become biologically active. This allows it to bypass the enzymatic blockade caused by folic acid antagonists, directly supplying the necessary folates for cellular function.
Mechanism of action
Leucovorin is a reduced form of folic acid that acts as a direct coenzyme in cellular metabolism.
- Bypassing DHFR: It does not require conversion by dihydrofolate reductase (DHFR) to become biologically active.
- Active Metabolite: It is converted in the body to active reduced forms, predominantly 5-methyltetrahydrofolate (5-methyl THF).
- DNA Synthesis: These reduced folates act as coenzymes in the synthesis of purine and pyrimidine nucleotides → essential for DNA synthesis and the maintenance of normal erythropoiesis (red blood cell production).
- Enzyme Inhibition: Leucovorin inhibits thymidylate synthase by stabilizing the binding of fluorodeoxyuridylic acid to the enzyme. This mechanism potentiates both the antineoplastic activity and the toxicity of fluorouracil (5-FU).
Safety & warnings
Contraindications
- Known intolerance or hypersensitivity to leucovorin
Adverse effects
- Gastrointestinal effects (noted in humans with oral administration)
- Seizures (very rare, noted in humans)
- Hypersensitivity reactions (very rare, noted in humans)
Precautions
Use with extreme caution in patients receiving systemic fluorouracil. Because of its calcium content, large intravenous doses should be given slowly and not bolused. In humans, folinic acid therapy may mask the signs associated with cobalamin (B-12) deficiency in megaloblastic anemias. When reconstituting powder with bacteriostatic water (which contains benzyl alcohol), avoid use in neonates or very small animals.
Drug interactions
Large doses of leucovorin may reduce the antiseizure efficacy of these agents.
Leucovorin may increase both the antineoplastic efficacy and toxicity of 5-FU.
Leucovorin may reduce their efficacy somewhat; however, protozoa cannot utilize leucovorin, preserving the antimicrobial effect against them.
Monitoring
- Complete Blood Count (CBC)
- Methotrexate serum levels (if used for methotrexate overdoses; may require contacting a local human hospital)
Pharmacokinetics
Half-life
Absorption
In humans, oral bioavailability is dose-dependent (97% at 25 mg, decreasing to 37% at 100 mg). IM bioavailability is similar to IV. Peak levels of active reduced folates occur 1.7-2.4 hours after oral dosing, and about 10 minutes after IV administration.
Distribution
Apparent volume of distribution for both L- and D-forms is about 0.6 L/kg in dogs. About 50% of oral body stores of reduced folates are found in the liver.
Metabolism
Extensively metabolized to active reduced forms, predominantly 5-methyltetrahydrofolate (5-methyl THF).
Elimination
Excreted into the urine, primarily as 10-formyl-THF or 5,10-methyl-THF.
Overdose
Except in situations where drug interactions are possible (e.g., with fluorouracil or antiseizure medications), an inadvertent overdose is unlikely to be of clinical concern.
Available products
Formulations
- Oral tablets
- Injection solution
- Powder for injection
Human-labeled
- Leucovorin Calcium Oral Tablets: 5 mg, 15 mg, & 25 mg
- Leucovorin Calcium Injection Solution: 10 mg/mL in 5 mg single dose vials
- Leucovorin Calcium Powder for Injection: 50 mg, 100 mg, 200 mg & 350 mg in vials
Regulatory status
No regulatory data for: 🇺🇸 US · 🇪🇺 EU · 🇬🇧 UK · 🇭🇰 HK · 🇹🇼 TW · 🇯🇵 JP · 🇰🇷 KR · 🇦🇺 AU
Storage & stability
Tablets and powder for injection should be stored below 40°C (preferably between 15-30°C) in a well-closed container and protected from light. Injection solution should be refrigerated between 2-8°C and protected from light. Reconstituted solutions made with sterile water should be used immediately; those made with bacteriostatic water are stable up to 7 days. IV solutions in LRS, Ringer's, or 0.9% NaCl are stable up to 24 hours at room temperature. Not compatible with fluorouracil solutions.
Client information
Important: If this medication is being used to treat methotrexate toxicity, it should only be administered in an inpatient hospital setting under strict veterinary supervision.
- Administration: Oral leucovorin may be given with or without meals.
- Strict Adherence: It is critical to follow the exact dosage schedule prescribed by your veterinarian. Missing doses can compromise the treatment or prevention of severe blood cell abnormalities (hematologic toxicity).
- Missed Doses: If you miss a dose, contact your veterinarian for instructions. Do not double up on doses without professional guidance.
VetSheet drug reference is intended for licensed veterinary professionals as a clinical decision-support aid, not a substitute for professional judgement or the manufacturer’s current label.