Levoleucovorin

6 ADVERSE REACTIONS Allergic reactions were reported in patients receiving Levoleucovorin injection. (6.3) Vomiting (38%), stomatitis (38%) and nausea (19%) were reported in patients receiving Levoleucovorin injection as rescue after high-dose methotrexate therapy. (6.1) The most common adverse reactions (>50%) in patients with advanced colorectal cancer receiving Levoleucovorin injection in combination with 5-FU were diarrhea, nausea and stomatitis. (6.2) To report SUSPECTED ADVERSE REACTIONS, contact Fosun Pharma USA Inc. at 1-866-611-3762 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Studies in High-Dose Methotrexate Therapy Since clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following table presents the frequency of adverse reactions which occurred during the administration of 58 courses of high-dose methotrexate 12 grams/m 2 followed by Levoleucovorin injection rescue for osteosarcoma in 16 patients age 6 to 21. Most patients received levoleucovorin injection 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Table 2 Adverse Reactions with High-Dose Methotrexate Therapy Body System/ Adverse Reactions Number (%) of Patients with Adverse Reactions (N =16) Number (%) of Courses with Adverse Reactions (N = 58) All Grade 3+ All Grade 3+ Gastrointestinal Stomatitis 6 (37.5) 1 (6.3) 10 (17.2) 1 (1.7) Vomiting 6 (37.5) 0 14 (24.1) 0 Nausea 3 (18.8) 0 3 (5.2) 0 Diarrhea 1 (6.3) 0 1 (1.7) 0 Dyspepsia 1 (6.3) 0 1 (1.7) 0 Typhlitis 1 (6.3) 1 (6.3) 1 (1.7) 1 (1.7) Respiratory Dyspnea 1 (6.3) 0 1 (1.7) 0 Skin and Appendages Dermatitis 1 (6.3) 0 1 (1.7) 0 Other Confusion 1 (6.3) 0 1 (1.7) 0 Neuropathy 1 (6.3) 0 1 (1.7) 0 Renal function abnormal 1 (6.3) 0 3 (5.2) 0 Taste perversion 1 (6.3) 0 1 (1.7) 0 Total number of patients 9 (56.3) 2 (12.5) Total number of courses 25 (43.1) 2 (3.4) The incidence of adverse reactions may be underestimated because not all patients were fully evaluable for toxicity for all cycles in the clinical trials. Leukopenia and thrombocytopenia were observed, but could not be attributed to high-dose methotrexate with levoleucovorin injection rescue because patients were receiving other myelosuppressive chemotherapy. 6.2 Clinical Studies in Combination with 5-FU in Colorectal Cancer A randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with advanced colorectal cancer failed to show superiority of a regimen of 5-FU + levoleucovorin to 5-FU + d,l -leucovorin in overall survival. Patients were randomized to 5-FU 370 mg/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or with 5-FU 370 mg/m 2 intravenously and d,l -leucovorin 200 mg/m 2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity. The following table presents the most frequent adverse reactions which occurred in patients in the 2 treatment arms. Table 3 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm Adverse Reaction Levoleucovorin/5FU n=318 d,l -Leucovorin/5FU n=307 Adverse Event N (%) Grade 1-4 Grade 3-4 Grade 1-4 Grade 3-4 Gastrointestinal Stomatitis 229 (72%) 37 (12%) 221 (72%) 44 (14%) Diarrhea 222 (70%) 61 (19%) 201 (65%) 51 (17%) Nausea 197 (62%) 25 (8%) 186 (61%) 26 (8%) Vomiting 128 (40%) 17 (5%) 114 (37%) 18 (6%) Abdominal Pain 1 45 (14%) 10 (3%) 57 (19%) 10 (3%) General Disorders Asthenia/Fatigue/Malaise 91 (29%) 15 (5%) 99 (32%) 34 (11%) Metabolism and Nutrition Anorexia/Decreased Appetite 76 (24%) 13 (4%) 77 (25%) 5 (2%) Skin Disorders Dermatitis 91 (29%) 3 (1%) 86 (28%) 4 (1%) Alopecia 83 (26%) 1 (0.3%) 87 (28%) 3 (1%) 1 Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness 6.3 Postmarketing Experience Since adverse reactions from spontaneous reports are provided voluntarily from a population of uncertain size, it is not always possible to estimate reliably their frequency or establish a causal relationship to drug exposure. Spontaneously reported adverse reactions collected by the WHO Collaborating Center for International Drug Monitoring in Uppsala Sweden have yielded seven cases where levoleucovorin was administered with a regimen of methotrexate. The events were dyspnea, pruritus, rash, temperature change and rigors. For 217 adverse reactions (108 reports) where levoleucovorin was a suspected or interacting medication, there were 40 occurrences of “possible allergic reactions.” In an analysis where calcium levoleucovorin injection was reported as the primary suspect drug and fluorouracil (FU) was reported as a concomitant medication, possible allergic reactions were reported among 47 cases (67 events).

4 CONTRAINDICATIONS Levoleucovorin injection is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. Levoleucovorin is contraindicated for patients who have had previous allergic reactions attributed to folic acid or folinic acid. (4)

11 DESCRIPTION Levoleucovorin is the levo isomeric form of racemic d,l-leucovorin , present as the calcium salt. Levoleucovorin is the pharmacologically active isomer of leucovorin [(6-S)-leucovorin]. Levoleucovorin Injection contains levoleucovorin calcium, which is one of several active, chemically reduced derivatives of folic acid. It is useful as antidote to the inhibition of dihydrofolate reductase by methotrexate. This compound has the chemical designation calcium (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl]amino]benzoyl}­L-glutamate pentahydrate.The molecular weight is 601.6 and the structural formula is: Its molecular formula is C 20 H 21 CaN 7 O 7 . 5 H 2 0. Levoleucovorin Injection is supplied as a sterile solution of either 175 mg levoleucovorin in 17.5 ml or 250 mg levoleucovorin in 25 mL. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. Sodium hydroxide is used for pH adjustment to pH 8.0 (6.5 to 8.5). Levoleucovorin-SPL-Structure

2 DOSAGE AND ADMINISTRATION Do not administer intrathecally. (2.1) Levoleucovorin injection is dosed at one-half the usual dose of racemic d,l- leucovorin. (2.1) Levoleucovorin injection Rescue After High-Dose Methotrexate Therapy Levoleucovorin injection rescue recommendations are based on a methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours. Levoleucovorin injection rescue at a dose of 7.5 mg (approximately 5 mg/m 2 ) every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. Determine serum creatinine and methotrexate levels at least once daily. Continue Levoleucovorin injection administration, hydration, and urinary alkalinization (pH of 7.0 or greater) until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). The Levoleucovorin injection dose may need to be adjusted. (2.3) Levoleucovorin Injection Administration in Combination with 5-Fluorouracil (5-FU) The following regimens have been used historically for the treatment of colorectal cancer: 1. Levoleucovorin injection is administered at 100 mg/m 2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m 2 by intravenous injection. (2.5) 2. Levoleucovorin injection is administered at 10 mg/m 2 by intravenous injection followed by 5-FU at 425 mg/m 2 by intravenous injection. (2.5) 5-FU and Levoleucovorin injection 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 courses, the dosage of 5-FU should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-FU 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. For patients who experienced no toxicity in the prior treatment course, 5-FU dosage may be increased by 10%. Levoleucovorin injection dosages are not adjusted for toxicity. (2.5) 2.1 Administration Guidelines Levoleucovorin injection is dosed at one-half the usual dose of racemic d,l -leucovorin. Levoleucovorin injection is indicated for intravenous administration only. Do not administer intrathecally. 2.2 Co-administration of Levoleucovorin injection with other agents Due to the risk of precipitation, do not co-administer Levoleucovorin injection with other agents in the same admixture. 2.3 Levoleucovorin injection Rescue After High-Dose Methotrexate Therapy The recommendations for Levoleucovorin injection rescue are based on a methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours(see methotrexate package insert for full prescribing information).Levoleucovorin injection rescue at a dose of 7.5 mg(approximately 5 mg/m 2 )every 6 hours for 10 doses starts 24 hours after the beginning of the methotrexate infusion. Serum creatinine and methotrexate levels should be determined at least once daily. Levoleucovorin injection administration, hydration, and urinary alkalinization (pH of 7.0 or greater) should be continued until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). The Levoleucovorin injection dose should be adjusted or rescue extended based on the following guidelines. Table 1 Guidelines for Levoleucovorin injection Dosage and Administration Clinical Situation Laboratory Findings Levoleucovorin injection 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 7.5 mg 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 7.5 mg 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). 75 mg IV q 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg IV q 3 hours until methotrexate level is less than 0.05 micromolar. Patients who experience delayed early methotrexate elimination are likely to develop reversible renal failure. In addition to appropriate levoleucovorin injection therapy, these patients require continuing hydration and urinary alkalinization, and close monitoring of fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. Some patients will have abnormalities in methotrexate elimination or renal function following methotrexate administration, which are significant but less severe than the abnormalities described in the table above. These abnormalities may or may not be associated with significant clinical toxicity. If significant clinical toxicity is observed, Levoleucovorin injection rescue should be extended for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of therapy. The possibility that the patient is taking other medications which interact with methotrexate (e.g., medications which may interfere with methotrexate elimination or binding to serum albumin) should always be reconsidered when laboratory abnormalities or clinical toxicities are observed. Delayed methotrexate excretion may be caused by accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration. Under such circumstances, higher doses of levoleucovorin injection or prolonged administration may be indicated. Although levoleucovorin injection may ameliorate the hematologic toxicity associated with high-dose methotrexate, levoleucovorin injection has no effect on other established toxicities of methotrexate such as the nephrotoxicity resulting from drug and/or metabolite precipitation in the kidney. 2.4 Dosing Recommendations for Inadvertent Methotrexate Overdosage Levoleucovorin injection rescue should begin as soon as possible after an inadvertent overdosage and within 24 hours of methotrexate administration when there is delayed excretion. As the time interval between antifolate administration [e.g., methotrexate] and levoleucovorin injection rescue increases, levoleucovorin injection effectiveness in counteracting toxicity may decrease. Levoleucovorin injection 7.5 mg(approximately 5 mg/m 2 ) should be administered IV every 6 hours until the serum methotrexate level is less than 10 -8 M. 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 levoleucovorin injection should be increased to 50 mg/m 2 IV every 3 hours until the methotrexate level is less than 10 -8 M. Hydration (3 L/day) and urinary alkalinization with NaHCO3 should be employed concomitantly. The bicarbonate dose should be adjusted to maintain the urine pH at 7.0 or greater. 2.5 Levoleucovorin injection Administration in Combination with 5-Fluorouracil(5-FU) The following regimens have been used historically for the treatment of colorectal cancer: Levoleucovorin injection is administered at 100 mg/m 2 by slow intravenous injection over a minimum of 3 minutes, followed by 5-FU at 370 mg/m 2 by intravenous injection. Levoleucovorin injection is administered at 10 mg/m 2 by intravenous injection followed by 5-FU at 425 mg/m 2 by intravenous injection. 5-FU and levoleucovorin injection 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 courses, the dosage of 5-FU should be adjusted based on patient tolerance of the prior treatment course. The daily dosage of 5-FU 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. For patients who experienced no toxicity in the prior treatment course, 5-FU dosage may be increased by 10%. Levoleucovorin injection dosages are not adjusted for toxicity. 2.6 Reconstitution and Infusion Instructions Levoleucovorin Injection Levoleucovorin injection contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. Levoleucovorin injection solutions may be further diluted to concentrations of 0.5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. The diluted solution using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP may be held at room temperature for not more than 4 hours. Visually inspect the diluted solution for particulate matter and discoloration, prior to administration. CAUTION: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not use if cloudiness or precipitate is observed. No more than 16 mL of levoleucovorin Injection (160 mg of levoleucovorin) should be injected intravenously per minute, because of the calcium content of the levoleucovorin solution.

1 INDICATIONS AND USAGE Levoleucovorin injection is a folate analog. Levoleucovorin injection rescue is indicated after high-dose methotrexate therapy in osteosarcoma. Levoleucovorin injection is also indicated to diminish the toxicity and counteract the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. Levoleucovorin injection is indicated for use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer. Levoleucovorin injection is a folate analog indicated for: • Rescue after high-dose methotrexate therapy in osteosarcoma. • Diminishing the toxicity and counteracting the effects of impaired methotrexate elimination and of inadvertent overdosage of folic acid antagonists. • Use in combination chemotherapy with 5-fluorouracil in the palliative treatment of patients with advanced metastatic colorectal cancer.(1) Limitations of Use Levoleucovorin injection is not approved for pernicious anemia and megaloblastic anemias. Improper use may cause a hematologic remission while neurologic manifestations continue to progress. (1.1) 1.1 Limitations of Use Levoleucovorin injection is not approved for pernicious anemia and megaloblastic anemias secondary to the lack of vitamin B 12 .Improper use may cause a hematologic remission while neurologic manifestations continue to progress.

10 OVERDOSAGE No data are available for overdosage with levoleucovorin.

7 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 children. It is not known whether folinic acid has the same effects. However, both folic and folinic acids share some common metabolic pathways. Caution should be taken when taking folinic acid in combination with anticonvulsant drugs. Preliminary human studies have shown that small quantities of systemically administered leucovorin enter the CSF, primarily as its major metabolite, 5-methyltetrahydrofolate(5-MTHFA). In humans, the CSF levels of 5-MTHFA remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. Levoleucovorin injection increases the toxicity of 5-fluorouracil [see Warnings and Precautions (5.2)]. Levoleucovorin Injection may counteract the antiepileptic effect of phenobarbital, phenytoin and primidone, and increase the frequency of seizures in susceptible patients. (7)

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.1.1 Levoleucovorin effects during high-dose methotrexate therapy Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “onecarbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. 12.1.2 Levoleucovorin effects in combination with 5-fluorouracil Levoleucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme. 12.2 Pharmacodynamics Levoleucovorin is actively and passively transported across cell membranes. In vivo, levoleucovorin is converted to 5-methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate. Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate. 12.3 Pharmacokinetics The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours. The mean terminal half-life for total-THF and (6S)-5-methyl-5,6,7,8 tetrahydrofolate was 5.1 and 6.8 hours, respectively. A pharmacokinetic study was conducted in 40 healthy subjects who received a single intravenous dose of either levoleucovorin (200 mg/m 2 ) or racemic d,l -leucovorin(400 mg/m 2 ), each administered as a 2-hour infusion in a crossover design. Results indicate that the 90% confidence interval for the geometric mean ratios for both AUC 0-inf and C max were within the standard limit of 80 to 125% for both l -leucovorin and l -5-methyl-THF. Therefore, the exposure to l -leucovorin and 5-methyl-THF(AUC 0-inf and C max )was comparable whether it was administered as levoleucovorin or as d,l -leucovorin. The geometric mean AUC 0-inf values for levoleucovorin were 30719 ng.h/mL and 31296 ng.h/mL for levoleucovorin and d,l -leucovorin, respectively. The geometric mean C max values for levoleucovorin were 10895 ng/mL and 11301 ng/ mL for levoleucovorin and d,l -leucovorin, respectively. The geometric mean AUC 0-inf values for 5-methyl-THF were 52105 ng.h/mL and 50137 ng.h/mL for levoleucovorin and d,l -leucovorin, respectively. The geometric mean C max values for 5-methyl-THF were 4930 ng/mL and 4658 ng/mL for levoleucovorin and d,l -leucovorin, respectively. Use of Levoleucovorin in combination with 5-fluorouracil A published cross study comparison showed that the mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether 5-FU (370 mg/m 2 /day IV bolus) was given in combination with levoleucovorin (250 mg/m 2 and 1000 mg/m 2 as a continuous IV infusion for 5.5 days, N=9) or in combination with d,l -leucovorin (500 mg/m 2 as a continuous IV infusion for 5.5 days, N=6).

12.1 Mechanism of Action 12.1.1 Levoleucovorin effects during high-dose methotrexate therapy Levoleucovorin is the pharmacologically active isomer of 5-formyl tetrahydrofolic acid. Levoleucovorin does not require reduction by the enzyme dihydrofolate reductase in order to participate in reactions utilizing folates as a source of “onecarbon” moieties. Administration of levoleucovorin can counteract the therapeutic and toxic effects of folic acid antagonists such as methotrexate, which act by inhibiting dihydrofolate reductase. 12.1.2 Levoleucovorin effects in combination with 5-fluorouracil Levoleucovorin can enhance the therapeutic and toxic effects of fluoropyrimidines used in cancer therapy such as 5-fluorouracil. 5-fluorouracil is metabolized to 5-fluoro-2'-deoxyuridine-5'-monophosphate (FdUMP), which binds to and inhibits thymidylate synthase (an enzyme important in DNA repair and replication). Levoleucovorin is readily converted to another reduced folate, 5,10-methylenetetrahydrofolate, which acts to stabilize the binding of FdUMP to thymidylate synthase and thereby enhances the inhibition of this enzyme.

12.2 Pharmacodynamics Levoleucovorin is actively and passively transported across cell membranes. In vivo, levoleucovorin is converted to 5-methyltetrahydrofolic acid (5-methyl-THF), the primary circulating form of active reduced folate. Levoleucovorin and 5-methyl-THF are polyglutamated intracellularly by the enzyme folylpolyglutamate synthetase. Folylpolyglutamates are active and participate in biochemical pathways that require reduced folate.

12.3 Pharmacokinetics The pharmacokinetics of levoleucovorin after intravenous administration of a 15 mg dose was studied in healthy male volunteers. After rapid intravenous administration, serum total tetrahydrofolate (total-THF) concentrations reached a mean peak of 1722 ng/mL. Serum (6S)-5-methyl-5,6,7,8-tetrahydrofolate concentrations reached a mean peak of 275 ng/mL and the mean time to peak was 0.9 hours. The mean terminal half-life for total-THF and (6S)-5-methyl-5,6,7,8 tetrahydrofolate was 5.1 and 6.8 hours, respectively. A pharmacokinetic study was conducted in 40 healthy subjects who received a single intravenous dose of either levoleucovorin (200 mg/m 2 ) or racemic d,l -leucovorin(400 mg/m 2 ), each administered as a 2-hour infusion in a crossover design. Results indicate that the 90% confidence interval for the geometric mean ratios for both AUC 0-inf and C max were within the standard limit of 80 to 125% for both l -leucovorin and l -5-methyl-THF. Therefore, the exposure to l -leucovorin and 5-methyl-THF(AUC 0-inf and C max )was comparable whether it was administered as levoleucovorin or as d,l -leucovorin. The geometric mean AUC 0-inf values for levoleucovorin were 30719 ng.h/mL and 31296 ng.h/mL for levoleucovorin and d,l -leucovorin, respectively. The geometric mean C max values for levoleucovorin were 10895 ng/mL and 11301 ng/ mL for levoleucovorin and d,l -leucovorin, respectively. The geometric mean AUC 0-inf values for 5-methyl-THF were 52105 ng.h/mL and 50137 ng.h/mL for levoleucovorin and d,l -leucovorin, respectively. The geometric mean C max values for 5-methyl-THF were 4930 ng/mL and 4658 ng/mL for levoleucovorin and d,l -leucovorin, respectively. Use of Levoleucovorin in combination with 5-fluorouracil A published cross study comparison showed that the mean dose-normalized steady-state plasma concentrations for both levoleucovorin and 5-methyl-THF were comparable whether 5-FU (370 mg/m 2 /day IV bolus) was given in combination with levoleucovorin (250 mg/m 2 and 1000 mg/m 2 as a continuous IV infusion for 5.5 days, N=9) or in combination with d,l -leucovorin (500 mg/m 2 as a continuous IV infusion for 5.5 days, N=6).

20221026

3

3 DOSAGE FORMS AND STRENGTHS Levoleucovorin Injection, 175 mg is supplied in a single-dose vial containing 17.5 mL sterile solution. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. Levoleucovorin Injection, 250 mg is supplied in a single-dose vial containing 25 mL sterile solution. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. Levoleucovorin Injection: 17.5 mL of a sterile solution containing levoleucovorin calcium pentahydrate equivalent to 175 mg Levoleucovorin and 0.83% sodium chloride. (3, 11, 16) Levoleucovorin Injection: 25 mL of a sterile solution containing levoleucovorin calcium pentahydrate equivalent to 250 mg levoleucovorin and 0.83% sodium chloride. (3, 11, 16)

Levoleucovorin Levoleucovorin SODIUM CHLORIDE SODIUM HYDROXIDE WATER LEVOLEUCOVORIN CALCIUM LEVOLEUCOVORIN Levoleucovorin Levoleucovorin SODIUM CHLORIDE SODIUM HYDROXIDE WATER LEVOLEUCOVORIN CALCIUM LEVOLEUCOVORIN

13.2 Animal Toxicology and/or Pharmacology The acute intravenous LD 50 values in adult mice and rats were 575 mg/kg (1725 mg/m 2 ) and 378 mg/kg (2268 mg/m 2 ), respectively. Signs of sedation, tremors, reduced motor activity, prostration, labored breathing, and/or convulsion were observed in these studies. Anticipated human dose for each administration is approximately 5 mg/m 2 for high-dose methotrexate therapy which represents a 3-log safety margin.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No studies have been conducted to evaluate the potential of levoleucovorin for carcinogenesis, mutagenesis and impairment of fertility. 13.2 Animal Toxicology and/or Pharmacology The acute intravenous LD 50 values in adult mice and rats were 575 mg/kg (1725 mg/m 2 ) and 378 mg/kg (2268 mg/m 2 ), respectively. Signs of sedation, tremors, reduced motor activity, prostration, labored breathing, and/or convulsion were observed in these studies. Anticipated human dose for each administration is approximately 5 mg/m 2 for high-dose methotrexate therapy which represents a 3-log safety margin.

ANDA210892

Levoleucovorin

Levoleucovorin

72266-121

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL Levoleucovorin Injection NDC Number: 72266-120-01 175 mg/17.5 mL(10 mg/mL) Container Label Levoleucovorin Injection NDC Number: 72266-120-01 175 mg/17.5 mL(10 mg/mL) Carton Label Levoleucovorin Injection NDC Number: NDC 72266-121-01 250 mg/25 mL(10 mg/mL) Container Label Levoleucovorin Injection NDC Number: NDC 72266-121-01 250 mg/25 mL(10 mg/mL) Carton Label levoleucovorin-175mg-label levoleucovorin-175mg-carton levoleucovorin-250mg-label levoleucovorin-250mg-carton

14 CLINICAL STUDIES 14.1 High-Dose Methotrexate Therapy The safety and efficacy of levoleucovorin rescue following high-dose methotrexate were evaluated in 16 patients age 6 to 21 who received 58 courses of therapy for osteogenic sarcoma. High-dose methotrexate was one component of several different combination chemotherapy regimens evaluated across several trials. Methotrexate 12 g/m 2 IV over 4 hours was administered to 13 patients, who received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 g/m 2 IV over 6 hours, followed by levoleucovorin 7.5 mg every 3 hours for 18 doses beginning 12 hours after completion of methotrexate. The mean number of levoleucovorin doses per course was 18.2 and the mean total dose per course was 350 mg. The efficacy of levoleucovorin rescue following high-dose methotrexate was based on the adverse reaction profile. [See Adverse Reactions (6)] 14.2 Combination with 5-FU in Colorectal Cancer In a randomized clinical study conducted by the Mayo Clinic and the North Central Cancer Treatment Group (Mayo/NCCTG) in patients with advanced metastatic colorectal cancer, three treatment regimens were compared: d,l -leucovorin (LV) 200 mg/m 2 and 5-fluorouracil (5-FU) 370 mg/m 2 versus LV 20 mg/m 2 and 5-FU 425 mg/m 2 versus 5-FU 500 mg/m 2 . All drugs were administered by slow intravenous infusion daily for 5 days repeated every 28 to 35 days. Response rates were 26% (p=0.04 versus 5-FU alone), 43% (p=0.001 versus 5-FU alone) and 10% for the high dose leucovorin, low dose leucovorin and 5-FU alone groups, respectively. Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.050), and 7.7 months. The low dose LV regimen gave a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose LV regimen gave a statistically significant improvement in performance status and trended toward improvement in weight gain and in relief of symptoms but these were not statistically significant. In a second Mayo/NCCTG randomized clinical study the 5-FU alone arm was replaced by a regimen of sequentially administered methotrexate (MTX), 5-FU, and LV. Response rates with LV 200 mg/m 2 and 5-FU 370 mg/m 2 versus LV 20 mg/m 2 and 5-FU 425 mg/m 2 versus sequential MTX and 5-FU and LV were respectively 31% (p≤0.01), 42% (p≤0.01), and 14%. Respective median survival times were 12.7 months (p≤0.04), 12.7 months (p≤0.01), and 8.4 months. No statistically significant difference in weight gain of more than 5% or in improvement in performance status was seen between the treatment arms. A randomized controlled trial conducted by the NCCTG in patients with advanced metastatic colorectal cancer failed to show superiority of a regimen of 5-FU + levoleucovorin to 5-FU + d,l -leucovorin in overall survival. Patients were randomized to 5-FU 370 mg/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or with 5-FU 370 mg/m 2 intravenously and d,l -leucovorin 200 mg/m 2 intravenously, both daily for 5 days. Treatment was repeated week 4 and week 8, and then every 5 weeks until disease progression or unacceptable toxicity. Levoleucovorin is dosed at one-half the usual dose of racemic d,l -leucovorin.

8.5 Geriatric Use Clinical studies of levoleucovorin injection in the treatment of osteosarcoma did not include subjects aged 65 and over to determine whether they respond differently from younger subjects. In the NCCTG clinical trial of levoleucovorin injection in combination with 5-FU in advanced colorectal cancer, adverse reactions were consistent with 5-FU related toxicity and were similar for patients age 65 and older and for patients younger than age 65.

8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from levoleucovorin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

8.4 Pediatric Use [See Clinical Studies (14)]

8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with levoleucovorin injection. It is not known whether levoleucovorin injection can cause fetal harm when administered to a pregnant woman or if it can affect reproduction capacity. Levoleucovorin injection should be given to a pregnant woman only if clearly needed.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Animal reproduction studies have not been conducted with levoleucovorin injection. It is not known whether levoleucovorin injection can cause fetal harm when administered to a pregnant woman or if it can affect reproduction capacity. Levoleucovorin injection should be given to a pregnant woman only if clearly needed. 8.3 Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from levoleucovorin, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use [See Clinical Studies (14)] 8.5 Geriatric Use Clinical studies of levoleucovorin injection in the treatment of osteosarcoma did not include subjects aged 65 and over to determine whether they respond differently from younger subjects. In the NCCTG clinical trial of levoleucovorin injection in combination with 5-FU in advanced colorectal cancer, adverse reactions were consistent with 5-FU related toxicity and were similar for patients age 65 and older and for patients younger than age 65.

16 HOW SUPPLIED/STORAGE AND HANDLING Levoleucovorin Injection, 175 mg contains 17.5 mL sterile clear pale yellow color solution in a single-dose vial. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. NDC 72266-120-01 175 mg/17.5 mL solution - carton containing one single-dose vial Levoleucovorin Injection, 250 mg contains 25 mL sterile clear pale yellow color solution in a single-dose vial. Each mL contains levoleucovorin calcium pentahydrate equivalent to 10 mg levoleucovorin and 8.3 mg sodium chloride. NDC 72266-121-01 250 mg/25 mL solution - carton containing one single-dose vial Store in refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light. Store in carton until contents are used. Trademarks are the property of their respective owners. Distributed by: Fosun Pharma USA Inc. Princeton, NJ 08540 Made in India January 2019