{"adverse_reactions":["6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Hypersensitivity Reactions [see Warnings and Precautions ( 5.1 )]. The following adverse reactions have been identified during postapproval use of leucovorin (d,l‑leucovorin) or levoleucovorin (l‑leucovorin). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Dermatologic: Pruritus, rash. • Respiratory: Dyspnea. • Other Clinical Events: Rigors, temperature change. Safety information for the treatment of FOLR1-CFTD with oral leucovorin is limited. The available evidence is based on published case reports [see Clinical Studies ( 14.1 )] . Adverse reactions included pruritus, rash, urticaria, dyspnea, hypersensitivity reactions, rigors, and temperature change. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1‑888‑825‑5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch."],"carcinogenesis_and_mutagenesis_and_impairment_of_fertility":["13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Adequate studies to assess the potential for carcinogenicity or genotoxicity, or for adverse effects on fertility have not been conducted for leucovorin."],"clinical_pharmacology":["12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Levoleucovorin, a reduced folate and the pharmacologically active isomer of leucovorin (5-formyl-tetrahydrofolic acid), can mitigate the toxic effects of folate antagonists, including methotrexate and other agents that inhibit dihydrofolate reductase (DHFR). Inhibition of DHFR blocks the formation of tetrahydrofolate, an essential cofactor for DNA synthesis and repair. Levoleucovorin has been observed to increase levels of 5-MTHF, an active metabolite of folate, in case studies of FOLR1-CFTD [see Clinical Studies ( 14.1 )] . 12.2 Pharmacodynamics Levoleucovorin and its metabolites (5,10‑methenyltetrahydrofolate, 5,10‑methylenetetrahydrofolate, and 5‑MTHF) serve as cofactors in “one carbon” metabolism. These reactions are involved in the generation of nucleic acids and the regulation of gene expression. 12.3 Pharmacokinetics Leucovorin is a racemic mixture of (l)- or levoleucovorin and (d)- or dextroleucovorin. Following oral administration of leucovorin to healthy adults, dextroleucovorin, levoleucovorin, and 5-MTHF exposures increased in a dose proportional manner with doses up to 25 mg, but in a less than dose proportional manner with doses greater than 25 mg. Absorption Following oral administration of leucovorin in adults, the apparent bioavailability of levoleucovorin is 97% for 25 mg, 75% for 50 mg, and 37% for 100 mg, and dextroleucovorin is approximately 19% for 25 mg, 20% for 50 mg, and 7% for 100 mg. After a single oral 15 mg (7.5 mg/m 2 ) dose of WELLCOVORIN, time to peak serum folate concentration is 1.7 hours. Effect of Food: The effect of food on the pharmacokinetics of WELLCOVORIN has not been evaluated. As leucovorin is a highly soluble and well absorbed drug, and different immediate-release oral formulations of leucovorin (oral tablet and oral solution) showed relatively higher bioavailability of total folates (>95%), food is not expected to have a clinically significant effect on the pharmacokinetics of leucovorin or 5-MTHF. Crushing of leucovorin tablets and mixing with food or liquid has been reported in literature. Distribution Levoleucovorin is minimally bound to human serum albumin. The reported human serum albumin binding of 5‑MTHF ranges from 42-49%. Leucovorin is not observed in cerebrospinal fluid (CSF) and 5-MTHF is reported to accumulate in CSF in children with leukemia. Elimination After intravenous administration of leucovorin in adults, the reported mean plasma elimination half-life in the literature was 0.5-1.3 hours for levoleucovorin and 3-7 hours for 5-MTHF. Metabolism: Following administration of oral leucovorin, levoleucovorin undergoes metabolism in intestinal cells via methenyltetrahydrofolate synthetase (MTHFS) and methylenetetrahydrofolate reductase (MTHFR) to its active metabolite, 5-MTHF. 5-MTHF is the main active metabolite in plasma after oral administration of leucovorin. Excretion: Leucovorin is mainly excreted by the kidney as unchanged dextroleucovorin, levoleucovorin, or as 5‑MTHF, the metabolic product of levoleucovorin. Specific Populations Patients with Renal Impairment: The kidney is reported to contribute to the elimination of dextroleucovorin, levoleucovorin and its active metabolite, and plasma concentrations of dextroleucovorin, levoleucovorin, and 5‑MTHF may be increased in patients with renal impairment. However, clinical studies on the impact of renal impairment have not been conducted. Patients with Hepatic Impairment: The liver is reported to contribute to the metabolism of levoleucovorin, and plasma concentrations of levoleucovorin and 5‑MTHF may be increased in patients with hepatic impairment. However, clinical studies on the impact of hepatic impairment have not been conducted."],"clinical_studies":["14 CLINICAL STUDIES 14.1 Cerebral Folate Transport Deficiency with Folate Receptor 1 Genetic Variant (FOLR1-CFTD) FOLR1-CFTD is a very rare neurological syndrome. No clinical trials have been conducted to examine the efficacy and safety of leucovorin in patients with FOLR1 variants. Evidence for the efficacy and safety of leucovorin in patients with FOLR1-CFTD was derived from the published literature. Forty-six patients with FOLR1-CFTD who received leucovorin treatment via various administration routes were identified in 26 published case reports and case reviews through 2024. Thirty cases were described in more than one publication. Of the 46 patients, a total of 27 (59%) were reported as having received leucovorin only via the oral administration route. These 27 patients ranged from approximately 2 months of age to 33 years of age at treatment initiation, and 25 of the patients had dosing information. The starting oral dose ranged from 0.5 to 3 mg/kg/day, and was 2 mg/kg/day in 14 of the 25 patients. Of the 20 patients with dose escalation reported, 17 had a maximum dose ≤6 mg/kg/day (reported range: 1.7 to 8.5 mg/kg/day). Information related to duration of use of leucovorin was limited, and there was no obvious relationship between the starting or maximum oral dose with patient demographics or disease severity. In some cases, it was reported that dose increase was based on clinical review of patient response. A range of clinical improvements in various neurological symptoms following treatment with oral leucovorin was reported for 24 of the 27 patients (e.g., reduction in severity or number of seizures; improvements in motor function, communication, and/or behavior). The remaining 3 patients showed either no change or no progression of symptoms; both the observed clinical improvements and the lack of disease progression are unexpected when compared to the progressive natural history of these patients with FOLR1-CFTD. CSF 5-MTHF measurements were collected at varying, unspecified time points across patients, with timing broadly categorized as before or after treatment initiation in most cases. In the subset of 27 FOLR1-CFTD patients who received oral leucovorin only, pre-treatment 5-MTHF levels were very low (<10 nmol/L in 17 of 21 patients with observed levels) compared to reported reference ranges from 40 up to 240 nmol/L. A subset of 7 patients had CSF 5-MTHF levels measured both before and after leucovorin initiation. All 7 patients experienced an increase in CSF 5-MTHF levels following treatment initiation, with 5 achieving normalization above 40 nmol/L."],"contraindications":["4 CONTRAINDICATIONS WELLCOVORIN is contraindicated in patients with a history of hypersensitivity reaction depending on indication as described below, to leucovorin (folinic acid), levoleucovorin, folic acid, or any component of WELLCOVORIN [see Description ( 11 )] : • Folic acid antagonist or DHFR inhibitor toxicity: history of severe hypersensitivity reaction • FOLR1-CFTD: history of any hypersensitivity reaction Reactions have included anaphylactic reactions [see Warnings and Precautions ( 5.1 )] . History of hypersensitivity reaction, depending on indication, to leucovorin (folinic acid), levoleucovorin, folic acid, or any component of WELLCOVORIN: • folic acid antagonist or DHFR inhibitor toxicity: history of a severe hypersensitivity reaction • FOLR1-CFTD: history of any hypersensitivity reaction. ( 4 , 5.1 )"],"description":["11 DESCRIPTION Leucovorin is a racemic mixture of the 5‑formyl derivative of tetrahydrofolic acid. The biologically active compound of the mixture is the (-)‑ L ‑Levoisomer, known as Citrovorum factor , or (-)‑folinic acid or levoleucovorin. Leucovorin is a water soluble form of reduced folate in the folate group. The chemical name of leucovorin, a folate analog, is the calcium salt of N ‑[4‑[[(2‑amino‑5‑formyl‑1,4,5,6,7,8-hexahydro‑4‑oxo‑6‑pteridinyl)methyl] amino]benzoyl]‑ L ‑glutamic acid. The molecular formula is C 20 H 21 CaN 7 O 7 and the molecular weight is 511.51 g/mol. The structural formula of leucovorin calcium is: WELLCOVORIN (leucovorin calcium) tablets, USP are for oral administration. Each 5 mg tablet contains 5 mg of leucovorin (equivalent to 5.4 mg of leucovorin calcium), and each 25 mg tablet contains 25 mg of leucovorin (equivalent to 27.01 mg of leucovorin calcium). The 5 mg and 25 mg tablets contain the following inactive ingredients: corn starch, lactose, magnesium stearate, and povidone. Additionally, the 25 mg tablet contains FD&C Yellow Number 6 Lake. Leucovorin chemical structure"],"dosage_and_administration":["2 DOSAGE AND ADMINISTRATION • WELLCOVORIN is for oral administration only and can be taken with or without food. Crushing of leucovorin tablets and mixing with food or liquid has been reported in literature. ( 2.1 ) • Administer WELLCOVORIN as soon as possible after a folic acid antagonist or dihydrofolate reductase (DHFR) inhibitor overdose and within 24 hours of methotrexate use when there is impaired methotrexate elimination. ( 2.2 ) Recommended Dosage to Reduce Methotrexate Toxicity in Patients with Impaired Methotrexate Elimination o 10 mg/m 2 (up to 25 mg) orally every 6 hours until the serum methotrexate levels are less than 10 -8 M (0.01 micromolar). If a dosage greater than 25 mg every 6 hours is needed, an injectable formulation of leucovorin should be administered parenterally. ( 2.2 ) Recommended Dosage to Reduce the Toxicity of Folic Acid Antagonists or DHFR Inhibitors in Patients Following an Overdosage o 5 mg to 15 mg per day. ( 2.2 ) • For patients with impaired methotrexate elimination and following a methotrexate overdose, administer intravenous fluids (3 L/day) and alkalinize the urine to maintain the urine pH at 7.0 or greater. ( 2.2 ) Recommended Dosage to Treat FOLR1-CFTD • Initiate oral WELLCOVORIN as follows based on body weight: o Less than 40 kg: 1 to 2 mg/kg/day and adjust to the maximum recommended dosage of 8.5 mg/kg/day. ( 2.3 ) o 40 kg or more: 1 to 2 mg/kg/day and adjust to the maximum recommended dosage of 330 mg/day. ( 2.3 ) • Administer the total daily dosage once daily or in divided doses up to 6 times per day. ( 2.3 ) • Single doses of 25 mg or less are preferred; do not administer more than 75 mg as a single dose. ( 2.3 ) 2.1 Important Administration Instructions Each indication has a different method for calculating the dosage (i.e., fixed dosage, body surface area‑based dosage, or body weight‑based dosage). Ensure that the correct method for calculating the dosage is used [see Dosage and Administration ( 2.2 , 2.3 )] . WELLCOVORIN is for oral administration only and can be taken with or without food [see Clinical Pharmacology ( 12.3 )] . Crushing of leucovorin tablets and mixing with food or liquid (e.g., water, breastmilk, infant formula) has been reported in literature. If administering via this method, administer immediately after mixing. 2.2 Recommended Dosage to Reduce the Toxicity of Methotrexate in Patients with Impaired Methotrexate Elimination or to Reduce the Toxicity of Folic Acid Antagonists or Dihydrofolate Reductase Inhibitors Following Overdose Administer WELLCOVORIN as soon as possible after a folic acid antagonist or DHFR inhibitor overdose and within 24 hours of methotrexate administration when there is impaired methotrexate elimination. The effectiveness of WELLCOVORIN decreases as the time interval between WELLCOVORIN administration and the folic acid antagonist or DHFR inhibitor increases. For patients with impaired methotrexate elimination, monitor serum methotrexate concentrations and serum creatinine to determine the recommended dosage and duration of WELLCOVORIN. For patients with impaired methotrexate elimination and in patients following a methotrexate overdose, administer intravenous fluids (3 Liters per day) and alkalinize the urine to maintain a urine pH of 7.0 or greater. The recommended WELLCOVORIN dosage to reduce methotrexate toxicity in patients with impaired methotrexate elimination: o 10 mg/m 2 (up to 25 mg) orally every 6 hours until the serum methotrexate levels are less than 10 -8 M (0.01 micromolar). o When a dosage greater than 25 mg every 6 hours is needed for this use, WELLCOVORIN is not recommended because this dosage and the formulation may be inadequate to treat significant methotrexate toxicity, resulting in possible methotrexate toxicity fatalities. Refer to the prescribing information for leucovorin injection for dosage recommendations. o If the 24-hour serum creatinine has increased 50% over baseline or if the 24-hour methotrexate level is greater than 5 x 10 -6 M or the 48-hour level is greater than 9 x 10 -7 M, higher doses of leucovorin are needed; discontinue oral administration of WELLCOVORIN and administer leucovorin intravenously or intramuscularly. Refer to the prescribing information for leucovorin injection for the appropriate dosage and duration. o In patients who experience non-oliguric renal failure, continue leucovorin, hydration and alkalinization of the urine (pH of 7.0 or greater) until the methotrexate level is 0.05 micromolar. o Extend the duration of WELLCOVORIN administration for an additional 24 hours in subsequent courses of methotrexate in patients who experience significant methotrexate toxicities, impaired methotrexate elimination including third-space fluid accumulation and inadequate hydration, or renal impairment. The recommended WELLCOVORIN dosage to reduce the toxicity of folic acid antagonists or DHFR inhibitors (trimethoprim or pyrimethamine) following an overdose: o 5 mg to 15 mg orally once daily. 2.3 Recommended Dosage for Cerebral Folate Transport Deficiency with Folate Receptor 1 Genetic Variant The recommended oral dosage of WELLCOVORIN for patients with FOLR1-CFTD is based on the patient’s weight (see Table 1 ). Adjust dosage based on clinical response [see Clinical Studies ( 14.1 )] . Table 1. Recommended WELLCOVORIN Dosage for Patients with FOLR1-CFTD Patient Weight Initial Total Daily Dosage a Maximum Total Daily Dosage a Frequency of Administration b a Round doses to the nearest tablet strength or combination of strengths. b Bioavailability is reduced with individual leucovorin doses above 25 mg in adults [see Clinical Pharmacology ( 12.3 )] . Less than 40 kg 1 to 2 mg/kg/day 8.5 mg/kg/day Administer the total daily dosage once daily or in divided doses up to 6 times per day. Single doses of 25 mg or less are preferred; do not administer more than 75 mg as a single dose. 40 kg or more 1 to 2 mg/kg/day 330 mg/day"],"dosage_and_administration_table":["
Patient Weight
Initial Total Daily Dosagea
Maximum Total Daily Dosagea
Frequency of Administrationb
a Round doses to the nearest tablet strength or combination of strengths.
b Bioavailability is reduced with individual leucovorin doses above 25 mg in adults [see Clinical Pharmacology (12.3)].
Less than 40 kg
1 to 2 mg/kg/day
8.5 mg/kg/day
Administer the total daily dosage once daily or in divided doses up to 6 times per day. Single doses of 25 mg or less are preferred; do not administer more than 75 mg as a single dose.
"],"set_id":"6fc53cb8-739d-4c0d-b928-5103abcb4f73","spl_product_data_elements":["Wellcovorin Leucovorin LEUCOVORIN CALCIUM LEUCOVORIN STARCH, CORN LACTOSE, UNSPECIFIED FORM MAGNESIUM STEARATE POVIDONE, UNSPECIFIED off-white WELLCOVORIN;5 Wellcovorin Leucovorin LEUCOVORIN CALCIUM LEUCOVORIN STARCH, CORN LACTOSE, UNSPECIFIED FORM MAGNESIUM STEARATE POVIDONE, UNSPECIFIED FD&C YELLOW NO. 6 ALUMINUM LAKE peach WELLCOVORIN;25"],"storage_and_handling":["16.2 Storage and Handling Store at 15°C to 25°C (59°F to 77°F). Protect from light and moisture."],"use_in_specific_populations":["8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Available data on the intermittent use of leucovorin for the treatment of folic acid antagonist or DHFR inhibitor toxicity during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. There are no adequate data on the use of leucovorin for the treatment of FOLR1-CFTD in pregnant women. Adequate animal reproductive and developmental studies have not been conducted with leucovorin. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Risks with Concomitant Use of WELLCOVORIN and Chemotherapy Drugs administered in combination with WELLCOVORIN may cause fetal harm. Refer to the Prescribing Information for the chemotherapy administered in combination with WELLCOVORIN for additional information, as appropriate. 8.2 Lactation Risk Summary There are no data on the presence of leucovorin in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WELLCOVORIN and any potential adverse effects on the breastfed infant from leucovorin or from the underlying maternal condition. Refer to the Prescribing Information for chemotherapy administered in combination with WELLCOVORIN for breastfeeding recommendations, as appropriate. 8.4 Pediatric Use WELLCOVORIN is indicated for the treatment of cerebral folate transport deficiency in pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD) [see Clinical Studies ( 14.1 )] . The safety and effectiveness of WELLCOVORIN have not been established to reduce the toxicity of methotrexate in pediatric patients with impaired methotrexate elimination or in pediatric patients to reduce the toxicity of folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose. Folic acid in large amounts may counteract the antiepileptic effect of phenobarbital, phenytoin, and primidone, and increase the frequency of seizures in susceptible pediatric patients [see Drug Interactions ( 7.1 )] . 8.5 Geriatric Use There is insufficient information in patients 65 years of age and older on the use of WELLCOVORIN to reduce the toxicity of methotrexate, other folic acid antagonists, or DHFR inhibitors, and there is no information on the use of WELLCOVORIN to treat FOLR1-CFTD in patients 65 years of age and older to determine whether they respond differently from younger patients [see Clinical Studies ( 14.1 )] ."],"version":"1","warnings_and_cautions":["5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Withhold or permanently discontinue WELLCOVORIN based on severity and indication. ( 4 , 5.1 ) 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylactic reactions and urticaria, have been reported following the administration of leucovorin. WELLCOVORIN is contraindicated for the treatment of folic acid antagonist or DHFR inhibitor toxicity in patients with a history of a severe hypersensitivity reaction and for the treatment of FOLR1-CFTD in patients with a history of any hypersensitivity reaction to leucovorin, levoleucovorin, folic acid, or any component of WELLCOVORIN [see Contraindications ( 4 )] . Withhold or permanently discontinue WELLCOVORIN based on the severity of hypersensitivity."]}