leucovorin calcium

INDICATIONS AND USAGE Leucovorin Calcium for Injection rescue is indicated after high dose methotrexate therapy in osteosarcoma. Leucovorin Calcium for Injection is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosages of folic acid antagonists. Leucovorin Calcium for Injection is indicated in the treatment of megaloblastic anemias due to folic acid deficiency when oral therapy is not feasible. Leucovorin Calcium for Injection is also indicated for use in combination with 5-fluorouracil to prolong survival in the palliative treatment of patients with advanced colorectal cancer. Leucovorin Calcium for Injection should not be mixed in the same infusion as 5-fluorouracil because a precipitate may form.

DOSAGE AND ADMINISTRATION: Advanced Colorectal Cancer Either of the following two regimens is recommended: Leucovorin is administered at 200 mg/m 2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-fluorouracil at 370 mg/m 2 by intravenous injection. Leucovorin is administered at 20 mg/m 2 by intravenous injection followed by 5-fluorouracil at 425 mg/m 2 by intravenous injection. 5-Fluorouracil and leucovorin should be administered separately to avoid the formation of a precipitate. Treatment is repeated daily for five days. This five-day treatment course may be repeated at 4 week (28-day) intervals, for 2 courses and then repeated at 4 to 5 week (28 to 35 day) intervals provided that the patient has completely recovered from the toxic effects of the prior treatment course. In subsequent treatment course, the dosage of 5-fluorouracil should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-fluorouracil should be reduced by 20% for patients who experienced moderate hematologic or gastrointestinal toxicity in the prior treatment course, and by 30% for patients who experienced severe toxicity (see PRECAUTIONS , Laboratory Tests ). For patients who experienced no toxicity in the prior treatment course, 5-fluorouracil dosage may be increased by 10%. Leucovorin dosages are not adjusted for toxicity. Several other doses and schedules of leucovorin/5-fluorouracil therapy have also been evaluated in patients with advanced colorectal cancer; some of these alternative regimens may also have efficacy in the treatment of this disease. However, further clinical research will be required to confirm the safety and effectiveness of these alternative leucovorin/5-fluorouracil treatment regimens. Leucovorin Rescue After High-Dose Methotrexate Therapy The recommendations for leucovorin rescue are based on a methotrexate dose of 12 to 15 grams/m 2 administered by intravenous infusion over 4 hours (see methotrexate package insert for full prescribing information). 4 Leucovorin rescue at a dose of 15 mg (approximately 10 mg/m 2 ) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. In the presence of gastrointestinal toxicity, nausea or vomiting, leucovorin should be administered parenterally. Do not administer leucovorin intrathecally. Serum creatinine and methotrexate levels should be determined at least once daily. Leucovorin administration, hydration, and urinary alkalization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). The leucovorin dose should be adjusted or leucovorin rescue extended based on the following guidelines: GUIDELINES FOR LEUCOVORIN DOSAGE AND ADMINISTRATION DO NOT ADMINISTER LEUCOVORIN INTRATHECALLY Clinical Situation Laboratory Findings Leucovorin Dosage and Duration Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours. 15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar. Patients who experience delayed …

CONTRAINDICATIONS Leucovorin calcium is improper therapy for pernicious anemia and other megaloblastic anemias secondary to the lack of vitamin B 12 . A hematologic remission may occur while neurologic manifestations continue to progress.

ADVERSE REACTIONS Allergic sensitization, including anaphylactoid reactions and urticaria, has been reported following administration of both oral and parenteral leucovorin. No other adverse reactions have been attributed to the use of leucovorin per se . Table 1 summarizes significant adverse events occurring in 316 patients treated with the leucovorin-5-fluorouracil combinations compared against 70 patients treated with 5-fluorouracil alone for advanced colorectal carcinoma. These data are taken from the Mayo/NCCTG large multicenter prospective trial evaluating the efficacy and safety of the combination regimen. TABLE 1 PERCENTAGE OF PATIENTS TREATED WITH LEUCOVORIN/FLUOROURACIL FOR ADVANCED COLORECTAL CARCINOMA REPORTING ADVERSE EXPERIENCES OR HOSPITALIZED FOR TOXICITY High LV = Leucovorin 200 mg/m 2 , Low LV = Leucovorin 20 mg/m 2 Any = percentage of patients reporting toxicity of any severity Grade 3+ = percentage of patients reporting toxicity of grade 3 or higher (High LV)/5-FU (N=155) (Low LV)/5-FU (N=161) 5-FU Alone (N=70) Any (%) Grade 3+ (%) Any (%) Grade 3+ (%) Any (%) Grade 3+ (%) Leukopenia 69 14 83 23 93 48 Thrombocytopenia 8 2 8 1 18 3 Infection 8 1 3 1 7 2 Nausea 74 10 80 9 60 6 Vomiting 46 8 44 9 40 7 Diarrhea 66 18 67 14 43 11 Stomatitis 75 27 84 29 59 16 Constipation 3 0 4 0 1 - Lethargy/Malaise/Fatigue 13 3 12 2 6 3 Alopecia 42 5 43 6 37 7 Dermatitis 21 2 25 1 13 - Anorexia 14 1 22 4 14 - Hospitalization for Toxicity 5% 15% 7% TABLE 2 GUIDELINES FOR LEUCOVORIN CALCIUM DOSAGE AND ADMINISTRATION DO NOT ADMINISTER LEUCOVORIN CALCIUM INTRATHECALLY Clinical Situation Laboratory Findings Leucovorin Calcium Dosage and Duration Normal Methotrexate Elimination Serum methotrexate level approximately 10 micromolar at 24 hours after administration, 1 micromolar at 48 hours, and less than 0.2 micromolar at 72 hours. 15 mg PO, IM, or IV q 6 hours for 60 hours (10 doses starting at 24 hours after start of methotrexate infusion). Delayed Late Methotrexate Elimination Serum methotrexate level remaining above 0.2 micromolar at 72 hours, and more than 0.05 micromolar at 96 hours after administration. Continue 15 mg PO, IM, or IV q 6 hours, until methotrexate level is less than 0.05 micromolar. Delayed Early Methotrexate Elimination and/or Evidence of Acute Renal Injury Serum methotrexate level of 50 micromolar or more at 24 hours, or 5 micromolar or more at 48 hours after administration, OR; a 100% or greater increase in serum creatinine level at 24 hours after methotrexate administration (e.g., an increase from 0.5 mg/dL to a level of 1 mg/dL or more). 150 mg IV q 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar. To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

Drug Interactions 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. Preliminary animal and human studies have shown that small quantities of systemically administered leucovorin calcium enter the CSF primarily as 5-methyltetrahydrofolate and, in humans, remain 1-3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. However, high doses of leucovorin calcium may reduce the efficacy of intrathecally administered methotrexate. Leucovorin calcium may enhance the toxicity of 5-fluorouracil. (See WARNINGS .)

DESCRIPTION Leucovorin is one of several active, chemically reduced derivatives of folic acid. It is useful as an antidote to drugs which act as folic acid antagonists. Also known as folinic acid, Citrovorum factor, or 5-formyl-5,6,7,8-tetrahydrofolic acid, this compound has the chemical designation of Calcium N -[ p -[[[(6 RS )-2-amino-5-formyl-5,6,7,8-tetrahydro-4-hydroxy-6-pteridinyl]methyl]amino]benzoyl]-L-glutamate (1:1). The structural formula of leucovorin calcium is: C 20 H 21 CaN 7 O 7 M.W.=511.5 Leucovorin Calcium for Injection, USP is a sterile product indicated for intramuscular (IM) or intravenous (IV) administration and is supplied in 50 mg, 100 mg, 200 mg, 350 mg, and 500 mg vials. Each 50 mg vial of Leucovorin Calcium for Injection, USP, when reconstituted with 5 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL. Each 100 mg vial of Leucovorin Calcium for Injection, USP, when reconstituted with 10 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL. Each 200 mg vial of Leucovorin Calcium for Injection, USP, when reconstituted with 20 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL. Each 350 mg vial of Leucovorin Calcium for Injection, USP, when reconstituted with 17.5 mL of sterile diluent, contains leucovorin (as the calcium salt) 20 mg/mL. Each 500 mg vial of Leucovorin Calcium for Injection, USP, when reconstituted with 50 mL of sterile diluent, contains leucovorin (as the calcium salt) 10 mg/mL. In each dosage form, one milligram of leucovorin calcium contains 0.002 mmol of leucovorin and 0.002 mmol of calcium. These lyophilized products contain no preservative. The inactive ingredient is Sodium Chloride, USP, added to adjust tonicity. The inactive ingredient is sodium chloride 40 mg/vial for the 50 mg vial, 80 mg/vial for the 100 mg vial, 80 mg/vial for the 200 mg vial, 140 mg/vial for the 350 mg vial, and 450 mg/vial for the 500 mg vial. Sodium hydroxide and/or hydrochloric acid are used to adjust the pH to approximately 8.1 during manufacture. Reconstitute with Bacteriostatic Water for Injection, USP, which contains benzyl alcohol (see WARNINGS section), or with Sterile Water for Injection, USP. structural formula

OVERDOSAGE Excessive amounts of leucovorin may nullify the chemotherapeutic effect of folic acid antagonists.

Impaired Methotrexate Elimination or Inadvertent Overdosage Leucovorin rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion (see WARNINGS ). Leucovorin calcium for injection 10 mg/m 2 should be administered IV, IM, or PO every 6 hours until the serum methotrexate level is less than 10 -8 M. In the presence of gastrointestinal toxicity, nausea, or vomiting, leucovorin calcium for injection should be administered parenterally. Do not administer leucovorin calcium for injection intrathecally. Serum creatinine and methotrexate levels should be determined at 24 hour intervals. 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, the dose of leucovorin calcium for injection should be increased to 100 mg/m 2 IV every 3 hours until the methotrexate level is less than 10 -8 M. Hydration (3 L/d) and urinary alkalinization with sodium bicarbonate solution should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater.

HOW SUPPLIED Leucovorin Calcium for Injection, USP is supplied in sterile, single use vials as follows: NDC 0143-9555-01 50 mg individually boxed vial. NDC 0143-9554-01 100 mg individually boxed vial. NDC 0143-9553-01 200 mg individually boxed vial. NDC 0143-9552-01 350 mg individually boxed vial. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Protect from light. Retain in carton until time of use. To report SUSPECTED ADVERSE REACTIONS, contact Hikma Pharmaceuticals USA, Inc. at 1-877-845-0689, or the FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . For Product Inquiry call 1-877-845-0689. Manufactured by: HIKMA FARMACÊUTICA (PORTUGAL), S.A. Estrada do Rio da Mó, 8, 8A e 8B – Fervença – 2705-906 Terrugem SNT, PORTUGAL Distributed by: Hikma Pharmaceuticals USA Inc. Berkeley Heights, NJ 07922 Revised October 2021 PIN404-WES/2