LEUCOVORIN CALCIUM
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LEUCOVORIN CALCIUM (LEUCOVORIN CALCIUM).
Leucovorin calcium is a reduced form of folic acid that serves as a cofactor in nucleic acid synthesis. It is converted to tetrahydrofolate (THF), which is essential for purine and pyrimidine biosynthesis. It bypasses dihydrofolate reductase (DHFR), allowing continued DNA synthesis in the presence of methotrexate or other DHFR inhibitors.
| Metabolism | Primarily hepatic and intracellular metabolism to active folate forms (e.g., 5-methyltetrahydrofolate). |
| Excretion | Primarily excreted in urine as inactive metabolites (80-90%) and unchanged drug (<5%). Fecal excretion accounts for 5-10% via biliary elimination of metabolites. |
| Half-life | Leucovorin (5-formyltetrahydrofolate) has a terminal half-life of approximately 6.2 hours for the active [6S]-isomer and 31-33 hours for the inactive [6R]-isomer. The active metabolite, 5-methyltetrahydrofolate, has a half-life of about 3.5 hours. Clinical context: Half-life is dose-dependent and prolonged in renal impairment. |
| Protein binding | Leucovorin is approximately 15-20% bound to plasma proteins, primarily albumin. The active metabolite 5-methyltetrahydrofolate has higher binding (30-40% to albumin). |
| Volume of Distribution | Volume of distribution is 0.4-0.8 L/kg, indicating distribution into total body water. Clinical meaning: Leucovorin distributes widely to tissues including liver and kidneys; does not readily cross intact blood-brain barrier. |
| Bioavailability | Oral: 90-100% absorbed (saturable at high doses). Intramuscular: 100% bioavailability. Intravenous: 100%. |
| Onset of Action | Intravenous: Rapid, within 5-10 minutes. Oral: 30-60 minutes for detectable serum levels. Intramuscular: 20-30 minutes. Clinical effect (rescue from methotrexate toxicity) occurs within 1-2 hours of administration. |
| Duration of Action | Duration of folate rescue effect is approximately 24-48 hours, depending on dose and methotrexate levels. Plasma concentrations of reduced folates decline to baseline within 24 hours after a single IV dose. |
| Molecular Weight | 511.46 Da (as calcium pentahydrate) |
15 mg orally, intramuscularly, or intravenously every 6 hours for 5 to 7 doses; for rescue after high-dose methotrexate: 10 mg/m2 every 6 hours until serum methotrexate level <5×10^-8 M; for advanced colorectal cancer: 200 mg/m2 IV over 2 hours with 5-fluorouracil 370 mg/m2 IV bolus on days 1-5 every 28 days.
| Dosage form | INJECTABLE |
| Renal impairment | No specific dose adjustment recommended; use with caution in severe renal impairment (CrCl <20 mL/min) as methotrexate clearance is impaired; monitor methotrexate levels and adjust leucovorin dose accordingly. |
| Liver impairment | No specific Child-Pugh based adjustments; use with caution in severe hepatic impairment due to potential for altered folate metabolism; monitor for toxicity. |
| Pediatric use | For methotrexate rescue: 15 mg/m2 orally or intravenously every 6 hours for 5 to 7 doses; or 10 mg/m2 every 6 hours until serum methotrexate level <5×10^-8 M. For advanced colorectal cancer: 200 mg/m2 IV over 2 hours with 5-fluorouracil; dose adjustment based on body surface area. |
| Geriatric use | No specific age-related dose adjustments; use standard adult dosing with caution due to increased risk of renal and hepatic impairment; monitor methotrexate levels and adjust leucovorin dose as needed. |
| 1st trimester | Leucovorin calcium is generally considered safe during the first trimester when used at recommended doses. It is a form of folate, essential for fetal neural tube development. No teratogenic effects have been reported in human studies, but avoid excessive doses. |
| 2nd trimester | Safe during the second trimester when used at therapeutic doses. Monitor for maternal hypersensitivity, and consider that high doses may potentially cause fetal harm; however, no specific risks have been documented. |
| 3rd trimester | Considered safe in the third trimester at usual doses. No fetal toxicity reported, but use only if clearly needed, as high doses may interfere with maternal-fetal metabolism. |
Clinical note
Comprehensive clinical and safety monograph for LEUCOVORIN CALCIUM (LEUCOVORIN CALCIUM).
| Placental transfer | Leucovorin calcium readily crosses the placenta. It is a stable reduced folate that is transported via folate receptors and carriers. Adequate amounts reach the fetal circulation, which is beneficial for prophylaxis of neural tube defects. |
■ FDA Black Box Warning
Because of the potential danger of intrathecal administration (which can be fatal), leucovorin calcium should not be given intrathecally. Also, accidental overdose of folic acid (including leucovorin) may obscure pernicious anemia and lead to irreversible neurological damage.
| Serious Effects |
Hypersensitivity to leucovorin or any component of the formulationPernicious anemia or other megaloblastic anemias due to vitamin B12 deficiency (use may mask B12 deficiency and cause neurological progression)
| Precautions | Monitor for severe allergic reactions, including anaphylaxis., Caution in patients with pernicious anemia or other vitamin B12 deficiencies as it may mask hematologic signs while neurologic symptoms progress., Leucovorin enhances the toxicity of 5-fluorouracil, especially in elderly patients; careful monitoring required., Should not be administered intrathecally due to risk of severe adverse reactions or death., Use with caution in patients with seizures or epilepsy. |
| Food/Dietary | No significant food interactions reported. However, because leucovorin is often used with methotrexate, patients should avoid alcohol (increases hepatotoxicity) and maintain adequate hydration. |
Loading safety data…
| Breastfeeding |
| Leucovorin is minimally excreted into breast milk. It is a reduced folate and is naturally present in breast milk. The infant would receive negligible doses, and no adverse effects are expected. However, caution is advised with high maternal doses, as there are limited data. The American Academy of Pediatrics considers it compatible with breastfeeding. |
| Lactation Rating | L1 (Safe) |
| Teratogenic Risk | Leucovorin is a folate analog and is not teratogenic at therapeutic doses. Data from animal studies and human pregnancies show no increased risk of major birth defects. However, high doses may interfere with folate metabolism, but no specific adverse fetal effects have been documented. Use during pregnancy is considered low risk. |
| Fetal Monitoring | No specific fetal monitoring is required. Monitor maternal complete blood count and serum methotrexate levels if used as rescue therapy. For high-dose therapy, monitor renal function and fluid balance. |
| Fertility Effects | Leucovorin does not have known direct effects on fertility. It may be used to reduce methotrexate toxicity, which can affect fertility indirectly by protecting normal cells. |
| Clinical Pearls | Leucovorin calcium is used as a rescue agent after high-dose methotrexate therapy to prevent myelosuppression and mucositis. It must be initiated within 24 hours of methotrexate administration. Monitor serum methotrexate levels and renal function during rescue. Also used to enhance the efficacy of 5-fluorouracil in colorectal cancer by stabilizing the 5-FU-thymidylate synthase complex. |
| Patient Advice | Take leucovorin exactly as prescribed; do not miss doses. · If you miss a dose, contact your healthcare provider immediately. · Report any signs of allergic reaction (rash, hives, swelling, difficulty breathing). · You may need frequent blood tests to monitor methotrexate levels and kidney function. · Avoid alcohol and limit caffeine intake as they may worsen side effects. · Use effective contraception during treatment and for at least 1 month after the last dose. |