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1 INDICATIONS AND USAGE Levoleucovorin injection is indicated for: rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma. diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients. the treatment of adults with metastatic colorectal cancer in combination with fluorouracil. Limitations of Use: Levoleucovorin injection is not indicated for pernicious anemia and megaloblastic anemia secondary to the lack of vitamin B 12, because of the risk of progression of neurologic manifestations despite hematologic remission. Levoleucovorin injection is a folate analog indicated for: Rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma. ( 1 ) Diminishing the toxicity associated with overdosage of folic acid antagonists or impaired methotrexate elimination in adult and pediatric patients. ( 1 ) Treatment of adults with metastatic colorectal cancer in combination with fluorouracil. ( 1 ) Limitations of Use: Levoleucovorin injection is not indicated for the treatment of pernicious anemia and megaloblastic anemia secondary to lack of vitamin B 12 , because of the risk of progression of neurologic manifestations despite hematologic remission. ( 1 )
2 DOSAGE AND ADMINISTRATION For intravenous administration only. Do not administer intrathecally. ( 2.1 ) Rescue After High-Dose Methotrexate Therapy Rescue recommendations are based on methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours. Initiate rescue at a dose of 7.5 mg (approximately 5 mg/m 2 ) every 6 hours, 24 hours after the beginning of methotrexate infusion. ( 2.3 ) Continue until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). Adjust dose if necessary based on methotrexate elimination; refer to Full Prescribing Information. ( 2.3 ) Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start as soon as possible after methotrexate overdosage or within 24 hours of delayed methotrexate elimination. ( 2.4 ) Administer levoleucovorin injection 7.5 mg (approximately 5 mg/m 2 ) intravenously every 6 hours until methotrexate level is less than 5 x 10 -8 M (0.05 micromolar). ( 2.4 ) Metastatic Colorectal Cancer in Combination with Fluorouracil The following regimens have been used for the treatment of colorectal cancer: Levoleucovorin injection 100 mg/m 2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil 370 mg/m 2 once daily for 5 consecutive days. ( 2.5 ) Levoleucovorin injection 10 mg/m 2 by intravenous injection followed by fluorouracil 425 mg/m 2 once daily for 5 consecutive days. ( 2.5 ) Administer Fluorouracil and levoleucovorin injection separately to avoid the formation of precipitate. The above five-day courses may be repeated every 4 weeks for 2 courses, then every 4 to 5 weeks, if the patient has recovered from toxicity from the prior course. Do not adjust levoleucovorin injection dosage for toxicity. ( 2.5 ) 2.1 Important Use Information 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 Recommended Dosage for Rescue After High-Dose Methotrexate Therapy The recommended dosage for levoleucovorin injection is based on a methotrexate dose of 12 grams/m 2 administered by intravenous infusion over 4 hours. Twenty-four hours after starting the methotrexate infusion, initiate levoleucovorin injection at a dose of 7.5 mg (approximately 5 mg/m 2 ) as an intravenous infusion every 6 hours. Monitor serum creatinine and methotrexate levels at least once daily. Continue levoleucovorin injection administration, hydration, and urinary alkalinization (pH of 7 or greater) until the methotrexate level is below 5 x 10 -8 M (0.05 micromolar). Adjust the levoleucovorin injection dose or extend the duration as recommended in Table 1 . Table 1: Recommended Dosage for Levoleucovorin Injection based on Serum Methotrexate and Creatinine Levels Clinical Situation Laboratory Findings Recommendation 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 Administer 7.5 mg by intravenous infusion every 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.
t 72 hours Administer 7.5 mg by intravenous infusion every 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 by intravenous infusion every 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). Administer 75 mg by intravenous infusion every 3 hours until methotrexate level is less than 1 micromolar; then 7.5 mg by intravenous infusion every 3 hours until methotrexate level is less than 0.05 micromolar. * These patients are likely to develop reversible renal failure. In addition to appropriate levoleucovorin injection therapy, continue hydration and urinary alkalinization and monitor fluid and electrolyte status, until the serum methotrexate level has fallen to below 0.05 micromolar and the renal failure has resolved. Impaired Methotrexate Elimination or Renal Impairment Decreased methotrexate elimination or renal impairment which are clinically important but less severe than the abnormalities described in Table 1 can occur following methotrexate administration. If toxicity associated with methotrexate is observed, in subsequent courses extend levoleucovorin injection rescue for an additional 24 hours (total of 14 doses over 84 hours). Third-Space Fluid Collection and Other Causes of Delayed Methotrexate Elimination Accumulation in a third space fluid collection (i.e., ascites, pleural effusion), renal insufficiency, or inadequate hydration can delay methotrexate elimination. Under such circumstances, higher doses of levoleucovorin injection or prolonged administration may be indicated. 2.4 Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start levoleucovorin injection as soon as possible after an overdosage of methotrexate or within 24 hours of methotrexate administration when methotrexate elimination is impaired. As the time interval between methotrexate administration and levoleucovorin injection increases, the effectiveness of levoleucovorin injection to diminish methotrexate toxicity may decrease. Administer levoleucovorin injection 7.5 mg (approximately 5 mg/m 2 ) by intravenous infusion every 6 hours until the serum methotrexate level is less than 5 x 10 -8 M (0.05 micromolar). Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the dosage of levoleucovorin injection to 50 mg/m 2 intravenously every 3 hours and continue levoleucovorin injection at this dosage until the methotrexate level is less than 5 x 10 -8 M for the following: if serum creatinine at 24-hours increases 50% or more compared to baseline if the methotrexate level at 24-hours is greater than 5 x 10 -6 M if the methotrexate level at 48-hours is greater than 9 x 10 -7 M, Continue concomitant hydration (3 L per day) and urinary alkalinization with sodium bicarbonate. Adjust the sodium bicarbonate dose to maintain urine pH at 7 or greater. 2.5 Dosage in Combination with Fluorouracil for Metastatic Colorectal Cancer The following regimens have been used for the treatment of colorectal cancer: Levoleucovorin injection 100 mg/m 2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil at 370 mg/m 2 by intravenous injection, once daily for 5 consecutive days.
n with Fluorouracil for Metastatic Colorectal Cancer The following regimens have been used for the treatment of colorectal cancer: Levoleucovorin injection 100 mg/m 2 by intravenous injection over a minimum of 3 minutes, followed by fluorouracil at 370 mg/m 2 by intravenous injection, once daily for 5 consecutive days. Levoleucovorin injection 10 mg/m 2 by intravenous injection, followed by fluorouracil 425 mg/m 2 by intravenous injection, once daily for 5 consecutive days. Administer fluorouracil and levoleucovorin injection separately to avoid the formation of a precipitate. This five-day course may be repeated every 4 weeks for 2 courses, then every 4 to 5 weeks, if the patient has recovered from the toxicity from the prior course. Do not adjust levoleucovorin injection dosage for toxicity. Refer to fluorouracil prescribing information for information on fluorouracil dosage and dosage modifications for adverse reactions. 2.6 Preparation for Administration Levoleucovorin contains no preservative. Observe strict aseptic technique during reconstitution of the drug product. Discard unused portion. Levoleucovorin solutions may be further diluted to concentrations of 0.5 mg per mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Do not store the product diluted using 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP for more than 4 hours at room temperature. Visually inspect the diluted solution for particulate matter and discoloration prior to administration. Do not use if cloudiness or precipitate is observed. Inject no more than 16 mL of levoleucovorin injection (160 mg of levoleucovorin) intravenously per minute, because of the calcium content of the levoleucovorin solution.
2.4 Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start levoleucovorin injection as soon as possible after an overdosage of methotrexate or within 24 hours of methotrexate administration when methotrexate elimination is impaired. As the time interval between methotrexate administration and levoleucovorin injection increases, the effectiveness of levoleucovorin injection to diminish methotrexate toxicity may decrease. Administer levoleucovorin injection 7.5 mg (approximately 5 mg/m 2 ) by intravenous infusion every 6 hours until the serum methotrexate level is less than 5 x 10 -8 M (0.05 micromolar). Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the dosage of levoleucovorin injection to 50 mg/m 2 intravenously every 3 hours and continue levoleucovorin injection at this dosage until the methotrexate level is less than 5 x 10 -8 M for the following: if serum creatinine at 24-hours increases 50% or more compared to baseline if the methotrexate level at 24-hours is greater than 5 x 10 -6 M if the methotrexate level at 48-hours is greater than 9 x 10 -7 M, Continue concomitant hydration (3 L per day) and urinary alkalinization with sodium bicarbonate. Adjust the sodium bicarbonate dose to maintain urine pH at 7 or greater.
3 DOSAGE FORMS AND STRENGTHS Injection: 175 mg/17.5 mL (10 mg/mL) or 250 mg/25 mL (10 mg/mL) of levoleucovorin sterile colorless to faint yellow solution in a single-dose vial. Injection: 175 mg per 17.5 mL (10 mg per mL) or 250 mg per 25 mL (10 mg per mL) in a single-dose vial ( 3 )
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypercalcemia [see Warnings and Precautions ( 5.1 )] Increased gastrointestinal toxicities with fluorouracil [see Warnings and Precautions ( 5.2 )] The most common adverse reactions (≥20%) in patients receiving high-dose methotrexate therapy with levoleucovorin rescue are stomatitis and vomiting. ( 6.1 ) The most common adverse reactions (>50%) in patients receiving levoleucovorin in combination with fluorouracil for metastatic colorectal cancer are stomatitis, diarrhea, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Slate Run Pharmaceuticals at 1-800-341-9214 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because 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. High-Dose Methotrexate Therapy Table 2 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 rescue for osteosarcoma in 16 patients aged 6 to 21 years. Most patients received levoleucovorin 7.5 mg every 6 hours for 60 hours or longer, beginning 24 hours after completion of methotrexate administration. Table 2 Adverse Reactions with High-Dose Methotrexate Therapy Adverse Reactions Levoleucovorin n = 16 All Grades (%) Grades 3-4 (%) Gastrointestinal Stomatitis 38 6 Vomiting 38 0 Nausea 19 0 Diarrhea 6 0 Dyspepsia 6 0 Typhlitis 6 6 Respiratory Dyspnea 6 0 Skin and Appendages Dermatitis 6 0 Other Confusion 6 0 Neuropathy 6 0 Renal function abnormal 6 0 Taste perversion 6 0 Combination with Fluorouracil in Colorectal Cancer Table 3 presents the frequency of adverse reaction which occurred in 2 arms of a randomized controlled trial conducted by the North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer. The trial failed to show superior overall survival with fluorouracil + levoleucovorin compared to fluorouracil + d,l -leucovorin. Patients were randomized to fluorouracil 370 mg/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or to fluorouracil 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. Table 3 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm 1 Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness Adverse Reaction Levoleucovorin/fluorouracil n=318 d,l -Leucovorin/fluorouracil n=307 Grades 1-4 (%) Grades 3-4 (%) Grades 1-4 (%) Grades 3-4 (%) Gastrointestinal Disorders Stomatitis 72 12 72 14 Diarrhea 70 19 65 17 Nausea 62 8 61 8 Vomiting 40 5 37 6 Abdominal Pain 1 14 3 19 3 General Disorders Asthenia/Fatigue/Malaise 29 5 32 11 Skin Disorders Dermatitis 29 1 28 1 Alopecia 26 0.3 28 1 Metabolism and Nutrition Anorexia/Decreased Appetite 24 4 25 2 6.2 Postmarketing Experience The following adverse reaction have been identified during postapproval use of levoleucovorin products.
<table ID="_Reft2" width="100%"><caption>Table 2 Adverse Reactions with High-Dose Methotrexate Therapy</caption><col width="25%"/><col width="37%"/><col width="37%"/><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Adverse Reactions</content></paragraph></td><td colspan="2" align="center" styleCode="Rrule Botrule Toprule " valign="top"><paragraph><content styleCode="bold">Levoleucovorin</content> <content styleCode="bold">n = 16</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">All Grades (%)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">Grades 3-4 (%)</content></paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="bottom"><paragraph><content styleCode="bold">Gastrointestinal</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Stomatitis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>38</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>38</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspepsia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Typhlitis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Respiratory</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dyspnea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin and Appendages</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dermatitis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule "
d styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dermatitis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td colspan="3" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Other</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Confusion</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Neuropathy</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Renal function abnormal</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Taste perversion</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table>
h>0</paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Taste perversion</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0</paragraph></td></tr></tbody></table> <table ID="_Reft3" width="100%"><caption>Table 3 Adverse Reactions Occurring in ≥ 10% of Patients in Either Arm</caption><col width="34%"/><col width="21%"/><col width="16%"/><col width="17%"/><col width="11%"/><tfoot><tr><td align="left" colspan="5" styleCode="Botrule" valign="top"><sup>1</sup>Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness </td></tr></tfoot><tbody><tr><td rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Adverse Reaction</content></paragraph></td><td colspan="2" align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold">Levoleucovorin/fluorouracil</content> <content styleCode="bold">n=318</content></paragraph></td><td colspan="2" align="center" styleCode="Rrule Botrule Toprule " valign="bottom"><paragraph><content styleCode="bold"><content styleCode="italics">d,l</content>-Leucovorin/fluorouracil </content> <content styleCode="bold">n=307</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">Grades 1-4</content> <content styleCode="bold">(%)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">Grades 3-4</content></paragraph><paragraph><content styleCode="bold">(%)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">Grades 1-4</content> <content styleCode="bold">(%)</content></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph><content styleCode="bold">Grades 3-4</content> <content styleCode="bold">(%)</content></paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Gastrointestinal Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Stomatitis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>72</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>12</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>72</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>14</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Diarrhea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>70</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>65</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>17</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Nausea</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>62</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>61</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>40</paragraph></td><td align="center" styleCode="Rr
/paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>8</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Vomiting</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>40</paragraph></td><td align="center" styleCode="Rr ule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>37</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>6</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Abdominal Pain <sup>1</sup></paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>14</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>19</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>3</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">General Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Asthenia/Fatigue/Malaise</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>29</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>5</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>32</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>11</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Skin Disorders</content></paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Dermatitis</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>29</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td styleCode="Rrule Lrule Botrule " valign="top"><paragraph>Alopecia</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>26</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>0.3</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>28</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>1</paragraph></td></tr><tr><td colspan="5" styleCode="Rrule Lrule Botrule " valign="top"><paragraph><content styleCode="bold">Metabolism and Nutrition</content></paragraph></td></tr><tr><td styleCode="Rrule Botrule Lrule " valign="top"><paragraph>Anorexia/Decreased Appetite</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>24</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>4</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>25</paragraph></td><td align="center" styleCode="Rrule Botrule " valign="top"><paragraph>2</paragraph></td></tr></tbody></table>
11 DESCRIPTION Levoleucovorin is a folate analog and the pharmacologically active levo-isomer of d,l-leucovorin. The chemical name of levoleucovorin calcium is calcium (6S)-N-{4-[[(2-amino-5-formyl-1,4,5,6,7,8-hexahydro-4-oxo-6-pteridinyl)methyl] amino]benzoyl}-L-glutamate mixed hydrates. The molecular formula is C 20 H 21 CaN 7 O 7 ●nH 2 O (n = 3.2 to 5.8) and the molecular weight is 569.1 to 616.0. The molecular structure is: Levoleucovorin injection, for intravenous use is supplied as a colorless to faint yellow solution of either 175 mg levoleucovorin in 17.5 mL or 250 mg levoleucovorin in 25 mL per single-dose vial. Each mL contains 10 mg levoleucovorin (equivalent to 10.8 mg levoleucovorin calcium (as mixed hydrates)) and 8.3 mg sodium chloride. Sodium hydroxide is used for pH adjustment to pH 8.2 (6.5 to 8.5). Chemical Structure
14 CLINICAL STUDIES 14.1 Rescue after High-Dose Methotrexate Therapy in Patients with Osteosarcoma The efficacy of levoleucovorin rescue following high-dose methotrexate was evaluated in 16 patients aged 6 to 21 years 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 grams/m 2 as an intravenous infusion over 4 hours was administered to 13 patients, who received levoleucovorin 7.5 mg by intravenous infusion every 6 hours for 60 hours or longer beginning 24 hours after completion of methotrexate. Three patients received methotrexate 12.5 grams/m 2 intravenously over 6 hours, followed by levoleucovorin 7.5 mg by intravenous infusion 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 ( 6.1 )]. 14.2 Metastatic Colorectal Cancer In a randomized clinical study conducted by Mayo Clinic and North Central Cancer Treatment Group (NCCTG) in patients with metastatic colorectal cancer comparing d,l -leucovorin 200 mg/m 2 and fluorouracil 370 mg/m 2 versus d,l -leucovorin 20 mg/m 2 and fluorouracil 425 mg/m 2 versus fluorouracil 500 mg/m 2 , with all drugs administered by intravenous infusion daily for 5 days every 28 to 35 days, response rates were 26% (p=0.04 versus fluorouracil alone), 43% (p=0.001 versus fluorouracil alone) and 10%, respectively. Respective median survival times were 12.2 months (p=0.037), 12 months (p=0.050), and 7.7 months. The low dose d,l -leucovorin regimen was associated with a statistically significant improvement in weight gain of more than 5%, relief of symptoms, and improvement in performance status. The high dose d,l -leucovorin regimen was associated with 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 randomized clinical study conducted by Mayo Clinic and NCCTG, the fluorouracil alone arm was replaced by a regimen of sequentially administered methotrexate, fluorouracil, and d,l -leucovorin. Response rates with d,l -leucovorin 200 mg/m 2 and fluorouracil 370 mg/m 2 versus d,l -leucovorin 20 mg/m 2 and fluorouracil 425 mg/m 2 versus sequential methotrexate and fluorouracil and d,l -leucovorin 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. There was 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 NCCTG in patients with metastatic colorectal cancer failed to show superiority of a regimen of fluorouracil + levoleucovorin to fluorouracil + d,l -leucovorin in overall survival. Patients were randomized to fluorouracil 370 mg/m 2 intravenously and levoleucovorin 100 mg/m 2 intravenously, both daily for 5 days, or to fluorouracil 370 mg/m 2 intravenously and d,l -leucovorin 200 mg/m 2 intravenously, both daily for 5 days.
16 HOW SUPPLIED/STORAGE AND HANDLING Levoleucovorin injection is a sterile colorless to faint yellow solution in a single-dose vial available as: 175 mg/17.5 mL (10 mg/mL) solution – NDC 70436-209-80 250 mg/25 mL (10 mg/mL) solution – NDC 70436-210-80 Store in refrigerator at 2°C to 8°C (36°F to 46°F). Protect from light. Store in carton until contents are used. Manufactured by: Hainan Poly Pharm. Co., Ltd. Hainan Province, China, 571127 Distributed by: Slate Run Pharmaceuticals, LLC Columbus, Ohio 43215