LEUCOVORIN CALCIUM

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 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 leucovorin and administer leucovorin intravenously or intramuscularly. Refer to the prescribing information for leucovorin injection for the appropriate dosage and duration. 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. Extend the duration of leucovorin 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 leucovorin dosage to reduce the toxicity of folic acid antagonists or DHFR inhibitors (trimethoprim or pyrimethamine) following an overdose: 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 leucovorin 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 Leucovorin Dosage for Patients with FOLR1-CFTD Patient Weight Initial Total Daily Dosage * Maximum Total Daily Dosage Round doses to the nearest tablet strength or combination of strengths. Frequency of Administration 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 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 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 leucovorin and administer leucovorin intravenously or intramuscularly. Refer to the prescribing information for leucovorin injection for the appropriate dosage and duration. 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. Extend the duration of leucovorin 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 leucovorin dosage to reduce the toxicity of folic acid antagonists or DHFR inhibitors (trimethoprim or pyrimethamine) following an overdose: 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 leucovorin 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 Leucovorin Dosage for Patients with FOLR1-CFTD Patient Weight Initial Total Daily Dosage * Maximum Total Daily Dosage Round doses to the nearest tablet strength or combination of strengths. Frequency of Administration 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

4 CONTRAINDICATIONS Leucovorin 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 leucovorin [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)

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions : Withhold or permanently discontinue leucovorin 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. Leucovorin 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 leucovorin [see Contraindications (4) ] . Withhold or permanently discontinue leucovorin based on the severity of hypersensitivity. 5.1 Hypersensitivity Reactions Hypersensitivity reactions, including anaphylactic reactions and urticaria, have been reported following the administration of leucovorin. Leucovorin 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 leucovorin [see Contraindications (4) ] . Withhold or permanently discontinue leucovorin based on the severity of hypersensitivity.

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.

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 Leading Pharma LLC at 1-844-740-7500 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 and Chemotherapy Drugs administered in combination with leucovorin may cause fetal harm. Refer to the Prescribing Information for the chemotherapy administered in combination with leucovorin for additional information, as appropriate.