WELLCOVORIN
Clinical safety rating: caution
Comprehensive clinical and safety monograph for WELLCOVORIN (WELLCOVORIN).
Folinic acid (leucovorin) is a reduced form of folic acid that bypasses dihydrofolate reductase inhibition, providing cofactors for nucleotide synthesis and reversing the effects of folate antagonists such as methotrexate.
| Metabolism | Folinic acid is metabolized via reduction and methylation to active folate forms (e.g., 5-methyltetrahydrofolate) in the liver and other tissues. Involves dihydrofolate reductase and other folate-metabolizing enzymes. |
| Excretion | Primarily renal excretion as unchanged drug and metabolites; about 80-90% of a dose is excreted in urine within 24 hours, with approximately 50-70% as unchanged folinic acid and the remainder as 5-methyltetrahydrofolate and other metabolites. Fecal excretion accounts for <10%. |
| Half-life | The terminal elimination half-life of folinic acid (active reduced folate) is approximately 6-7 hours in patients with normal renal function. The pharmacologically active metabolite, 5-methyltetrahydrofolate, has a longer half-life of about 10-12 hours. In renal impairment, half-life may be prolonged. |
| Protein binding | Approximately 15% bound to plasma proteins, mainly albumin. Binding is not extensive. |
| Volume of Distribution | Volume of distribution is approximately 0.5-0.6 L/kg, indicating distribution into total body water and some tissue binding. It crosses the blood-brain barrier poorly. |
| Bioavailability | Oral bioavailability is variable: approximately 25-30% for the active isomer (l-folinic acid) due to first-pass metabolism; the racemic mixture (d,l-folinic acid) has a lower absolute bioavailability of about 30% for the active component. Intravenous and intramuscular routes provide 100% bioavailability. |
| Onset of Action | Intravenous: within 5 minutes for reversal of methotrexate toxicity. Oral: 30-60 minutes to achieve detectable serum levels, with peak effect on rescue from methotrexate occurring at 1-2 hours. |
| Duration of Action | The serum concentration of reduced folates remains above baseline for 12-24 hours after a single dose. For methotrexate rescue, repeated dosing every 6 hours for 72 hours is recommended. Leucovorin 'rescue' effect persists as long as adequate levels are maintained. |
| Molecular Weight | 601.6 |
WELLCOVORIN (levoleucovorin) is administered intravenously or intramuscularly at a dose of 7.5 mg (approximately 0.1 mg/kg) every 6 hours for 10 doses starting 24 hours after the end of methotrexate infusion. Alternatively, 15 mg orally every 6 hours for 10 doses, starting 24 hours after methotrexate infusion.
| Dosage form | SOLUTION |
| Renal impairment | No specific GFR-based dose modifications are provided in the prescribing information. However, levoleucovorin is renally eliminated, and caution is advised in patients with renal impairment. For severe renal impairment (CrCl < 10 mL/min), consider dose reduction or extended interval. Monitor methotrexate levels and adjust leucovorin dose accordingly. |
| Liver impairment | No specific dose adjustments are recommended for hepatic impairment based on Child-Pugh class. However, caution is advised in patients with significant hepatic dysfunction due to potential altered folate metabolism. |
| Pediatric use | WELLCOVORIN is not FDA approved for pediatric use. However, in pediatric patients, levoleucovorin is sometimes used at a dose of 10 mg/m² (or 0.2 mg/kg) every 6 hours for 5-7 doses, starting 24 hours after methotrexate infusion, adjusted based on methotrexate levels. Dosing should be individualized based on clinical response and methotrexate concentration. |
| Geriatric use |
| 1st trimester | Limited human data; animal studies show fetal abnormalities at high doses. Use only if clearly needed. |
| 2nd trimester | Limited human data; no known teratogenicity, but caution due to folate antagonism. |
| 3rd trimester | Limited human data; potential for fetal folate deficiency if used near term. |
Clinical note
Comprehensive clinical and safety monograph for WELLCOVORIN (WELLCOVORIN).
| Placental transfer | Active placental transfer; achieves fetal concentrations similar to maternal. |
| Breastfeeding | Excreted into breast milk in low amounts; not expected to cause adverse effects in infant if maternal folate stores are adequate. |
| Lactation Rating |
■ FDA Black Box Warning
No FDA black box warning.
| Serious Effects |
Hypersensitivity to leucovorin or any componentPernicious anemia or other megaloblastic anemias due to vitamin B12 deficiency
| Precautions | May mask pernicious anemia and other megaloblastic anemias due to vitamin B12 deficiency; caution in patients with renal impairment; hypersensitivity reactions; gastrointestinal toxicity with 5-FU combination. |
| Food/Dietary | No significant food interactions have been reported. However, maintain adequate hydration and avoid alcohol due to potential hepatotoxicity. No specific dietary restrictions are required. |
| Clinical Pearls |
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| No specific geriatric dose adjustments are recommended. Due to age-related decline in renal function, monitor renal function and methotrexate levels closely, and consider dose adjustment based on creatinine clearance. |
| L2 (Safer) |
| Teratogenic Risk | WELLCOVORIN (levoleucovorin) is a folate analog. Folate is essential for fetal development. Wellcovorin is the active enantiomer of leucovorin, which is used to counteract folic acid antagonists. Available data do not indicate an increased risk of major birth defects with therapeutic doses. However, high-dose methotrexate therapy (which Wellcovorin is used to rescue from) is teratogenic. During first trimester, folate supplementation is protective against neural tube defects. During second and third trimester, folate requirements increase. No specific fetal risks are known from Wellcovorin alone. However, the underlying condition requiring treatment may pose risks. |
| Fetal Monitoring | Monitor complete blood count, serum creatinine, and folate levels if indicated. No specific fetal monitoring required. For use in methotrexate rescue, monitor methotrexate levels. |
| Fertility Effects | No known adverse effects on human fertility. Folate is necessary for spermatogenesis and oogenesis. Wellcovorin as a folate source should not impair fertility. |
| WELLCOVORIN (levoleucovorin) is the active l-isomer of leucovorin; it does not require metabolic activation and is preferred in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. It is used to reduce the toxicity of methotrexate (MTX) and to enhance the efficacy of fluorouracil (5-FU). When used for MTX rescue, initiate 24 hours after start of MTX infusion; monitor serum MTX levels, creatinine, and urine pH. Rescue dose and duration depend on MTX levels; continue until MTX level < 0.05 μmol/L. For 5-FU modulation, administer immediately before or simultaneously with 5-FU; do not use with irinotecan due to increased diarrhea risk. |
| Patient Advice | Take this medication exactly as prescribed; do not change the dose or frequency without consulting your doctor. · This drug may be given as an injection or as an oral tablet; follow the instructions for the specific formulation you receive. · If you miss a dose, contact your healthcare provider; do not double the next dose. · Report any signs of allergic reaction (rash, hives, swelling, difficulty breathing) or severe gastrointestinal symptoms (severe diarrhea, vomiting, abdominal pain) immediately. · Drink plenty of fluids to stay hydrated, especially during chemotherapy treatment. · Avoid alcohol while taking this medication as it may increase the risk of liver toxicity. · Inform your doctor if you are pregnant, planning to become pregnant, or breastfeeding. |