KHAPZORY

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 a 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 the methotrexate infusion. ( 2.2 ) 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. ( 2.2 ) 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. ( 2.3 ) Administer KHAPZORY 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). ( 2.3 ) Metastatic Colorectal Cancer in Combination with Fluorouracil The following regimens have been used for the treatment of colorectal cancer. o KHAPZORY 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. ( 2.4 ) o KHAPZORY 10 mg/m 2 by intravenous injection followed by fluorouracil 425 mg/m 2 once daily for 5 consecutive days. ( 2.4 ) 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. ( 2.4 ) Do not adjust KHAPZORY dosage for toxicity. ( 2.4 ) 2.1 Important Use Information KHAPZORY is indicated for intravenous administration only . Do not administer intrathecally . KHAPZORY consists of levoleucovorin in the form of a disodium salt, which makes it compatible with fluorouracil. This allows KHAPZORY and fluorouracil to be combined in the same infusion bag for intravenous administration without catheter occlusion or precipitation for up to 72 hours at 20°C to 25°C (68°F to 77°F). 2.2 Recommended Dosage for Rescue After High-Dose Methotrexate Therapy The recommended dosage for KHAPZORY is based on a methotrexate dose of 12 grams/m 2 administered as intravenous infusion over 4 hours. Twenty-four hours after starting the methotrexate infusion, initiate KHAPZORY 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 KHAPZORY, 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 dose KHAPZORY or extend the duration as recommended in Table 1 . Table 1 Recommended Dosage for KHAPZORY 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. 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 KHAPZORY therapy, continue hydration and urinary alkalinization, and monitoring 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 KHAPZORY 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 KHAPZORY or prolonged administration may be indicated. 2.3 Recommended Dosage for Overdosage of Folic Acid Antagonists or Impaired Methotrexate Elimination Start KHAPZORY 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 KHAPZORY increases, the effectiveness of KHAPZORY to diminish methotrexate toxicity may decrease. Administer KHAPZORY 7.5 mg (approximately 5 mg/m 2 ) as an 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 KHAPZORY to 50 mg/m 2 intravenously every 3 hours and continue KHAPZORY at this dosage until the methotrexate level is less than 5 x 10 -8 M for the following: • if the 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 bicarbonate dose to maintain urine pH at 7 or greater. 2.4 Dosage in Combination with Fluorouracil for Metastatic Colorectal Cancer The following regimens have been used for the treatment of colorectal cancer: • KHAPZORY 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 • KHAPZORY at 10 mg/m 2 by intravenous injection, followed by fluorouracil at 425 mg/m 2 ,by intravenous injection once daily for 5 consecutive days 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 toxicity from the prior course. Do not adjust KHAPZORY dosage for toxicity. Refer to fluorouracil prescribing information for information on fluorouracil dosage and dosage modifications for adverse reactions. 2.5 Preparation Reconstitution Reconstitute 175 mg KHAPZORY vial with 3.6 mL of 0.9% Sodium Chloride Injection, USP, to a concentration of 50 mg/mL. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. The reconstituted solution should be clear, colorless to slight yellow and free of visible particles. Discard the reconstituted solution with visible particulate matter or discoloration. If not used immediately, store the reconstituted solution for up to 12 hours at room temperature at 20°C to 25°C (68°F to 77°F). Protect from light. Dilution Withdraw the required volume of the reconstituted solution from the vial and dilute with 0.9% Sodium Chloride for Injection, USP or 5% Dextrose Injection, USP to a final concentration of 0.5 mg/mL to 5 mg/mL. Discard any unused portion remaining in the single-dose vial(s). Store the diluted solution for up to 12 hours at room temperature at 20°C to 25°C (68°F to 77°F) if not used immediately. Protect from light. Visually inspect the diluted solution for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.

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1 INDICATIONS AND USAGE KHAPZORY is indicated for: rescue after high-dose methotrexate therapy in adult and pediatric patients with osteosarcoma.