Leucovorin Calcium 5 mg Tablet, 100-count — NDC 69315-184-01 (Billing 69315-0184-01)

12 CLINICAL PHARMACOLOGY

12.1Mechanism 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) ] .

12.2Pharmacodynamics 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.

12.3Pharmacokinetics 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 leucovorin, time to peak serum folate concentration is 1.7 hours. Effect of Food: The effect of food on the pharmacokinetics of leucovorin 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.

12.1Mechanism 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) ] .

12.3Pharmacokinetics 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 leucovorin, time to peak serum folate concentration is 1.7 hours. Effect of Food: The effect of food on the pharmacokinetics of leucovorin 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.

12.2Pharmacodynamics 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.

14 CLINICAL STUDIES

14.1Cerebral 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.

14.1Cerebral 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 r… [Excerpted — this section continues on DailyMed.]

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, 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.