Leucovorin Calcium

Indications and Usage ( 1.2 ) 03/2026 Dosage and Administration ( 2.1 , 2.3 ) 03/2026 Contraindications ( 4 ) 03/2026 Warnings and Precautions ( 5.1 ) 03/2026

1 INDICATIONS AND USAGE Leucovorin is a folate analog indicated: To reduce the toxicity of: Methotrexate in adult patients with impaired methotrexate elimination, and Folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose in adult patients. (1.1) For the treatment of cerebral folate transport deficiency in adult and pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD). (1.2) Limitations of Use Leucovorin is not recommended for use in patients with a deficiency of methenyltetrahydrofolate synthetase (MTHFS) because MTHFS is a primary enzyme in the metabolism of leucovorin to 5-methenyltetrahydrofolate. (1.2) Limitations of Use Leucovorin is not indicated for the treatment of pernicious anemia or other megaloblastic anemias, due to the lack of vitamin B12, because of the risk of progression of neurologic manifestations despite hematologic remission. (1.3) 1.1 Reduction of Toxicity of Folic Acid Antagonists or Dihydrofolate Reductase Inhibitors Leucovorin is indicated to reduce the toxicity of: Methotrexate in adult patients with impaired methotrexate elimination, and Folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose in adult patients. 1.2 Cerebral Folate Transport Deficiency with Folate Receptor 1 Genetic Variant Leucovorin is indicated for the treatment of cerebral folate transport deficiency in adult and pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD). Limitations of Use Leucovorin is not recommended for use in patients with a deficiency of methenyltetrahydrofolate synthetase (MTHFS) because MTHFS is a primary enzyme in the metabolism of leucovorin to 5-methenyltetrahydrofolate (5-MTHF) [see Clinical Pharmacology (12.3) ]. 1.3 Limitations of Use Leucovorin is not indicated for the treatment of pernicious anemia or other megaloblastic anemias, due to the lack of vitamin B12, because of the risk of progression of neurologic manifestations despite hematologic remission.

1.1 Reduction of Toxicity of Folic Acid Antagonists or Dihydrofolate Reductase Inhibitors Leucovorin is indicated to reduce the toxicity of: Methotrexate in adult patients with impaired methotrexate elimination, and Folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose in adult patients.

1.2 Cerebral Folate Transport Deficiency with Folate Receptor 1 Genetic Variant Leucovorin is indicated for the treatment of cerebral folate transport deficiency in adult and pediatric patients who have a confirmed variant in the folate receptor 1 gene (FOLR1-CFTD). Limitations of Use Leucovorin is not recommended for use in patients with a deficiency of methenyltetrahydrofolate synthetase (MTHFS) because MTHFS is a primary enzyme in the metabolism of leucovorin to 5-methenyltetrahydrofolate (5-MTHF) [see Clinical Pharmacology (12.3) ].

1.3 Limitations of Use Leucovorin is not indicated for the treatment of pernicious anemia or other megaloblastic anemias, due to the lack of vitamin B12, because of the risk of progression of neurologic manifestations despite hematologic remission.

2 DOSAGE AND ADMINISTRATION Leucovorin calcium tablets are 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 Leucovorin calcium tablets 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 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 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 leucovorin calcium tablets as follows based on body weight: 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) 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) ]. Leucovorin 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 leucovorin 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 leucovorin decreases as the time interval between leucovorin 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 leucovorin. 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 leucovorin dosage to reduce methotrexate toxicity in patients with impaired methotrexate elimination: 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). When a dosage greater than 25 mg every 6 hours is needed for this use, leucovorin 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. If the 24-hour serum creatinine has increased 50% over baseline or if the 24-hour methotrexate level is greater …

3 DOSAGE FORMS AND STRENGTHS Leucovorin calcium tablets: 5 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over "184" debossed on the other side; bottles of 30 (NDC 69315-184-03) and 100 (NDC 69315-184-01). 10 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over "185" debossed on the other side; bottles of 12 (NDC 69315-185-12) and 24 (NDC 69315-185-24). 15 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over "186" debossed on the other side; bottles of 24 (NDC 69315-186-24). 25 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over "187" debossed on the other side; bottles of 25 (NDC 69315-187-25). Tablets: 5 mg, 10 mg, 15 mg, 25 mg of leucovorin (3)

4 CONTRAINDICATIONS Leucovorin calcium tablets are 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 leucovorin calcium tablets [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 leucovorin calcium tablets: folic acid antagonist or DHFR inhibitor toxicity: history of a severe hypersensitivity reaction FOLR1-CFTD: history of any hypersensitivity reaction. ( 4 , 5.1 )

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 Hikma Pharmaceuticals USA Inc. at 1-800-962-8364 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

7 DRUG INTERACTIONS Certain Antiepileptic Drugs : Increase monitoring for seizure activity in leucovorin-treated patients taking certain concomitant antiepileptic drugs. Certain antiepileptic drugs may reduce the effectiveness of leucovorin. (7.1, 7.2) Trimethoprim-Sulfamethoxazole : Avoid concomitant use of leucovorin with trimethoprim-sulfamethoxazole. (7.1) Fluorouracil : Leucovorin may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients. (7.1) 7.1 Effects of Leucovorin on Other Drugs Certain Antiepileptic Drugs Increase monitoring for seizure activity in leucovorin-treated patients taking certain concomitant antiepileptic drugs. Folic acid in high doses may reduce the effectiveness of certain antiepileptic drugs (e.g., phenobarbital, phenytoin, and primidone) and thereby increase the frequency of seizures in susceptible patients, including pediatric patients. It is not known whether folinic acid, including leucovorin, has the same effects; however, both folic and folinic acids, including leucovorin, share some common metabolic pathways. Trimethoprim-Sulfamethoxazole Avoid concomitant use of leucovorin with trimethoprim-sulfamethoxazole. The effectiveness of trimethoprim-sulfamethoxazole can be decreased if used concomitantly with leucovorin, which was associated with increased rates of treatment failure and mortality in patients with HIV infection who receive trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jirovecii pneumonia. Fluorouracil Leucovorin may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. Concomitant granulocytopenia and fever were present in some but not all of the patients. 7.2 Effect of Other Drugs on Leucovorin Certain antiepileptic drugs may reduce folate absorption and metabolism leading to folate deficiency. As folic acid and folinic acid share common metabolic pathways, certain antiepileptic drugs may reduce the effectiveness of leucovorin.

7.1 Effects of Leucovorin on Other Drugs Certain Antiepileptic Drugs Increase monitoring for seizure activity in leucovorin-treated patients taking certain concomitant antiepileptic drugs. Folic acid in high doses may reduce the effectiveness of certain antiepileptic drugs (e.g., phenobarbital, phenytoin, and primidone) and thereby increase the frequency of seizures in susceptible patients, including pediatric patients. It is not known whether folinic acid, including leucovorin, has the same effects; however, both folic and folinic acids, including leucovorin, share some common metabolic pathways. Trimethoprim-Sulfamethoxazole Avoid concomitant use of leucovorin with trimethoprim-sulfamethoxazole. The effectiveness of trimethoprim-sulfamethoxazole can be decreased if used concomitantly with leucovorin, which was associated with increased rates of treatment failure and mortality in patients with HIV infection who receive trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jirovecii pneumonia. Fluorouracil Leucovorin may enhance the toxicity of fluorouracil. Deaths from severe enterocolitis, diarrhea, and dehydration have been reported in elderly patients receiving weekly leucovorin and fluorouracil. Concomitant granulocytopenia and fever were present in some but not all of the patients.

7.2 Effect of Other Drugs on Leucovorin Certain antiepileptic drugs may reduce folate absorption and metabolism leading to folate deficiency. As folic acid and folinic acid share common metabolic pathways, certain antiepileptic drugs may reduce the effectiveness of leucovorin.

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 Leucovorin calcium tablets and Chemotherapy Drugs administered in combination with leucovorin calcium tablets may cause fetal harm. Refer to the Prescribing Information for the chemotherapy administered in combination with leucovorin calcium tablets 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 leucovorin calcium tablets 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 leucovorin calcium tablets for breastfeeding recommendations, as appropriate. 8.4 Pediatric Use Leucovorin calcium tablets are 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 leucovorin calcium tablets 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 leucovorin calcium tablets to reduce the toxicity of methotrexate, other folic acid antagonists, or DHFR inhibitors, and there is no information on the use of leucovorin calcium tablets 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 )] .

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 )] .

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 : 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), each 10 mg tablet contains 10 mg of leucovorin (equivalent to 10.8 mg of leucovorin calcium), each 15 mg tablet contains 15 mg of leucovorin (equivalent to 16.2 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, 10 mg, 15 mg and 25 mg tablets contain the following inactive ingredients: lactose monohydrate, anhydrous lactose, microcrystalline cellulose, croscarmellose sodium, colloidal silicon dioxide, magnesium stearate. Additionally, the 15 mg and 25 mg tablets contains FD&C yellow #6. image description

10 OVERDOSAGE Consider contacting the Poison Help line (1-800-222-1222) or a medical toxicologist for overdose management recommendations.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Leucovorin Calcium Tablets, USP: 5 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over "184" debossed on the other side; bottles of 30 (NDC 69315-184-03) and 100 (NDC 69315-184-01). 10 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over "185" debossed on the other side; bottles of 12 (NDC 69315-185-12) and 24 (NDC 69315-185-24). 15 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over " 186" debossed on the other side; bottles of 24 (NDC 69315-186-24). 25 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over " 187" debossed on the other side; bottles of 25 (NDC 69315-187-25). Storage and Handling Store at 15°C to 25°C (59°F to 77°F). Protect from light and moisture.

16.1 How Supplied Leucovorin Calcium Tablets, USP: 5 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over "184" debossed on the other side; bottles of 30 (NDC 69315-184-03) and 100 (NDC 69315-184-01). 10 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over "185" debossed on the other side; bottles of 12 (NDC 69315-185-12) and 24 (NDC 69315-185-24). 15 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over " 186" debossed on the other side; bottles of 24 (NDC 69315-186-24). 25 mg tablets are supplied as a white to off-white to pale yellow, round tablet; scored on one side and "LP" over " 187" debossed on the other side; bottles of 25 (NDC 69315-187-25). Storage and Handling Store at 15°C to 25°C (59°F to 77°F). Protect from light and moisture.