LEUCOVORIN CALCIUM PRESERVATIVE FREE
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LEUCOVORIN CALCIUM PRESERVATIVE FREE (LEUCOVORIN CALCIUM PRESERVATIVE FREE).
Leucovorin is a reduced form of folic acid that bypasses dihydrofolate reductase inhibition, providing a source of tetrahydrofolate for DNA synthesis and repair. It rescues normal cells from methotrexate toxicity by replenishing reduced folate pools.
| Metabolism | Leucovorin is rapidly converted to active folate metabolites (e.g., 5-methyltetrahydrofolate) mainly in the liver and intestinal mucosa via dihydrofolate reductase and other enzymes. |
| Excretion | Renal excretion of calcium folinate (leucovorin) and its active metabolite, 5-methyltetrahydrofolate (5-MTHF), accounts for approximately 80-90% of elimination; fecal excretion is minimal. Approximately 50% of an administered dose is excreted unchanged in urine within 24 hours. |
| Half-life | The terminal elimination half-life of calcium folinate is approximately 6-7 hours. The active metabolite, 5-MTHF, has a terminal half-life of about 11-12 hours. This longer half-life supports prolonged plasma levels required for rescue therapy following high-dose methotrexate. |
| Protein binding | Calcium folinate is approximately 30-50% bound to plasma proteins, primarily albumin. The active metabolite 5-MTHF exhibits similar binding characteristics. |
| Volume of Distribution | Volume of distribution is approximately 0.3-0.5 L/kg, indicating distribution mainly in extracellular fluid. This is consistent with its hydrophilic nature and limited tissue penetration except in cells with active folate transporters. |
| Bioavailability | Oral bioavailability is dose-dependent and ranges from 60-80% for doses up to 50 mg, but decreases at higher doses due to saturable transport. Intramuscular bioavailability is nearly 100%. Intravenous bioavailability is 100%. |
| Onset of Action | Intravenous: Immediate onset, with peak plasma levels achieved within minutes. Intramuscular: Onset within 10-15 minutes. Oral: Onset occurs within 30 minutes to 2 hours, with peak plasma concentrations in 1-2 hours. |
| Duration of Action | Intravenous: Duration of therapeutic effect is approximately 4-6 hours, though dosing is typically repeated based on methotrexate levels. Oral: Duration is variable, with effects lasting 6-8 hours. For rescue, it is administered every 6 hours. |
For rescue after high-dose methotrexate: 10 mg/m2 orally, intravenously, or intramuscularly every 6 hours for 10 doses. For advanced colorectal cancer: 200 mg/m2 intravenously over 2 hours daily for 5 days every 3 weeks (with 5-FU).
| Dosage form | SOLUTION |
| Renal impairment | For methotrexate rescue: CrCl 10-50 mL/min: reduce leucovorin dose by 50%; CrCl <10 mL/min: avoid use. No specific adjustment for other indications. |
| Liver impairment | No specific adjustment; use with caution in severe hepatic impairment. |
| Pediatric use | For methotrexate rescue: 10 mg/m2 orally, IV, or IM every 6 hours for 10 doses starting 24 hours after methotrexate. For osteosarcoma: 15 mg/m2 orally or IV every 6 hours for 10 doses. |
| Geriatric use | No specific dose adjustment. Use standard dosing; monitor renal function due to age-related decline. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LEUCOVORIN CALCIUM PRESERVATIVE FREE (LEUCOVORIN CALCIUM PRESERVATIVE FREE).
| Breastfeeding | Leucovorin is excreted into breast milk in low amounts; M/P ratio not established. Considered compatible with breastfeeding due to its role as a vitamin derivative. |
| Teratogenic Risk | Leucovorin calcium is a metabolite of folic acid and is not associated with teratogenic risk. First trimester: no evidence of fetal harm; second trimester: no evidence; third trimester: no evidence. Folic acid supplementation is protective against neural tube defects. |
■ FDA Black Box Warning
None
| Serious Effects |
["History of severe hypersensitivity to leucovorin or any component","Pernicious anemia or other megaloblastic anemias due to vitamin B12 deficiency (unless used as rescue therapy)"]
| Precautions | ["May precipitate seizures in patients with epilepsy, especially when used with folate antagonists","Use caution in patients with pernicious anemia or vitamin B12 deficiency, as it may mask hematologic signs while neurologic damage progresses","Allergic reactions including anaphylaxis have been reported","Avoid intrathecal administration; contains preservative-free formulation for intravenous use"] |
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| Fetal Monitoring |
| Monitor maternal complete blood count (CBC) and renal function; fetal ultrasound if used with methotrexate in oncology protocols. |
| Fertility Effects | No known adverse effects on fertility. Used to mitigate methotrexate-induced fertility impairment. |