LEVOLEUCOVORIN CALCIUM
Clinical safety rating: caution
Comprehensive clinical and safety monograph for LEVOLEUCOVORIN CALCIUM (LEVOLEUCOVORIN CALCIUM).
Levoleucovorin calcium is the calcium salt of the pharmacologically active L-isomer of folinic acid. It serves as a reduced folate cofactor that bypasses dihydrofolate reductase inhibition by methotrexate, thereby restoring nucleotide synthesis and rescuing normal cells from methotrexate toxicity. It also enhances the efficacy of 5-fluorouracil by stabilizing the binding of fluorodeoxyuridine monophosphate to thymidylate synthase.
| Metabolism | Levoleucovorin is rapidly converted to the active metabolite 5-methyltetrahydrofolate (5-MTHF) via dihydrofolate reductase (DHFR) and other folate-dependent enzymes. Metabolism occurs primarily in the liver and intestinal mucosa. |
| Excretion | Primarily renal (80-90% as unchanged drug and metabolites, including 5-methyltetrahydrofolate); small amount biliary/fecal (<10%). |
| Half-life | Terminal half-life of levoleucovorin is 5.1-6.8 hours; active metabolite (5-methyltetrahydrofolate) half-life 4.5-6.2 hours. Context: Leucovorin rescue requires monitoring to avoid toxicity. |
| Protein binding | ~15% (primarily albumin). |
| Volume of Distribution | 0.44-0.82 L/kg; distributes widely including into CSF (10-20% of plasma). |
| Bioavailability | Oral: 75-95% (dose-dependent; higher bioavailability at lower doses). |
| Onset of Action | IV: Immediate (within minutes); Oral: 30-60 minutes. |
| Duration of Action | IV: 3-6 hours (plasma folate levels); Oral: 6-12 hours. Clinical note: Dosing interval based on methotrexate levels. |
Adult: 7.5 mg/m2 intravenously or orally every 6 hours for 4 doses beginning 72 hours after starting high-dose methotrexate, or as 5 mg orally every 6 hours for 8 doses after low-dose methotrexate.
| Dosage form | SOLUTION |
| Renal impairment | For GFR 10-50 mL/min: reduce dose by 50%; for GFR <10 mL/min: avoid use due to risk of methotrexate toxicity. |
| Liver impairment | No specific dose adjustment based on Child-Pugh; use with caution in severe hepatic impairment. |
| Pediatric use | Children: 7.5-12 mg/m2 orally or intravenously every 6 hours for 4-8 doses starting 72 hours after methotrexate; alternatively, 5 mg orally every 6 hours for 8 doses. |
| Geriatric use | No specific dose adjustment; monitor renal function and adjust dose based on creatinine clearance as per renal adjustment guidelines. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for LEVOLEUCOVORIN CALCIUM (LEVOLEUCOVORIN CALCIUM).
| Breastfeeding | It is unknown if levoleucovorin calcium is excreted in human breast milk. Given its molecular weight (approximately 601.5 g/mol) and high water solubility, excretion is possible but likely minimal. No M/P ratio is available. Caution is advised. The developmental and health benefits of breastfeeding should be weighed against the mother's clinical need for levoleucovorin and potential adverse effects on the infant. |
| Teratogenic Risk | Levoleucovorin calcium is a reduced folate used to counteract the effects of folate antagonists. Data on its teratogenicity in pregnancy is limited. Folate deficiency is known to increase the risk of neural tube defects, but supplementation is protective. Levoleucovorin is a folate analog and is considered low risk. In animal studies, no fetal harm was observed at clinically relevant doses. However, due to the critical role of folate in embryogenesis, it should only be used if clearly needed. No specific trimester risks are documented. |
■ FDA Black Box Warning
Not applicable. Levoleucovorin calcium does not have an FDA black box warning.
| Serious Effects |
["Hypersensitivity to levoleucovorin, folinic acid, or any component of the formulation.","Pernicious anemia or other vitamin B12 deficiency megaloblastic anemias (use may mask hematologic recovery while neurologic damage progresses)."]
| Precautions | ["Caution in patients with pernicious anemia or other megaloblastic anemias due to vitamin B12 deficiency, as levoleucovorin may mask hematologic manifestations.","Administer with extreme caution in patients with known hypersensitivity to levoleucovorin or folinic acid.","May exacerbate seizures in patients with epilepsy or seizure disorders.","Monitor renal function and methotrexate levels closely when used for methotrexate rescue."] |
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| Fetal Monitoring | No specific monitoring is required for levoleucovorin use in pregnancy. Standard prenatal care should be continued. In cases of overdose with folate antagonists, monitor for signs of folate deficiency in the mother and fetus. No fetal monitoring is indicated. |
| Fertility Effects | Levoleucovorin is not known to adversely affect fertility. It is a naturally occurring folate and is essential for DNA synthesis and cell division. No impairment of fertility has been reported in animal studies or human data. It may actually be beneficial in conditions where folate deficiency is a cause of infertility. |