VYKOURA

2 DOSAGE AND ADMINISTRATION VYKOURA is indicated for intravenous or intramuscular administration. Do not administer intrathecally. ( 2.1 ) Rescue After High-Dose Methotrexate Therapy : Rescue recommendations are based on methotrexate dose of 12 to 15 grams/m 2 administered by intravenous infusion over 4 hours. Initiate rescue at a dose of 15 mg (approximately 10 mg/m 2 ) every 6 hours beginning 24 hours after the beginning of methotrexate infusion. ( 2.2 ) Continue until the methotrexate level is below 0.05 micromolar (5 x 10 -8 M). Adjust dose, if necessary, based on methotrexate elimination. ( 2.2 ) Reducing the Toxicity of Methotrexate in Patients with Impaired Methotrexate Elimination or Following an Overdosage of Folic Acid Antagonists or DHFR Inhibitors : Start as soon as possible after methotrexate overdosage or within 24 hours of delayed methotrexate elimination. ( 2.3 ) Administer VYKOURA 10 mg/m 2 intravenously or intramuscularly every 6 hours until methotrexate level is less than 0.01 micromolar (1 x 10 -8 M). ( 2.3 ) Metastatic Colorectal Cancer in Combination with Fluorouracil : 20 mg/m 2 to 500 mg/m 2 based on specific combination regimen. Administer VYKOURA before fluorouracil. ( 2.4 ) Do not mix VYKOURA with other drugs or administer other drugs through the same intravenous line. ( 2.4 ). Megaloblastic Anemia Due to Folic Acid Deficiency: Up to 1 mg/day administered intravenously until adequate hematologic response is achieved. 2.1 Important Administration Information VYKOURA is indicated for intravenous (IV) and intramuscular (IM) administration. Do not administer intrathecally. VYKOURA may be harmful or fatal if given intrathecally. Do NOT mix VYKOURA with other drugs or administer other drugs through the same intravenous line. A precipitate may form if VYKOURA is mixed with fluorouracil. Due to the calcium content of VYKOURA, do NOT exceed the maximum infusion rate of 160 mg/minute to avoid hypercalcemia . [See Warnings and Precautions (5.2) ] 2.2 Recommended Dosage for Rescue After High-Dose Methotrexate Therapy The recommended dosage for VYKOURA is based on serum methotrexate levels obtained 24 hours following the methotrexate infusion (refer to the methotrexate prescribing information). Table 1 describes the VYKOURA regimen in patients who receive a dose of 12-15 grams/m 2 of methotrexate. Consult institutional guidelines for additional dosing information as appropriate. Begin VYKOURA twenty-four hours after starting the methotrexate infusion. As the time interval between methotrexate administration and VYKOURA increases, the effectiveness of VYKOURA to diminish methotrexate toxicity may decrease. VYKOURA may be administered intravenously or intramuscularly [see Dosage and Administration (2.6) ] . Monitor serum creatinine and methotrexate levels at least once daily. Administer intravenous fluids (3 Liters per day) and alkalinize the urine to a pH of 7 or greater until the methotrexate level is below 0.05 micromolar (5 x 10 -8 M). Table 1 Recommended Dosage for VYKOURA After High-Dose Methotrexate Based on Serum Methotrexate and Serum Creatinine Levels * These patients are likely to develop reversible renal failure. In addition to appropriate VYKOURA 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. Clinical Situation Laboratory Findings Recommended Dosage 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 intravenously or intramuscularly every 6 hours for 60 hours for a total of 10 doses. Begin VYKOURA 24 hours after the 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 intravenously or intramuscularly 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). 150 mg intravenously or intramuscularly every 3 hours, until methotrexate level is less than 1 micromolar; then 15 mg intravenously or intramuscularly every 3 hours until methotrexate level is less than 0.05 micromolar. Extend VYKOURA rescue for an additional 24 hours (total of 14 doses over 84 hours) in subsequent courses of methotrexate in patients with: Impaired methotrexate elimination including third-space fluid accumulation and inadequate hydration Renal impairment 2.3 Recommended Dosage to Reduce Toxicity of Folic Acid Antagonists or Dihydrofolate Reductase (DHFR) Inhibitors or for Impaired Methotrexate Elimination Start VYKOURA as soon as possible after an inadvertent overdosage of methotrexate or within 24 hours of methotrexate administration when methotrexate elimination is impaired. As the time interval between methotrexate administration and VYKOURA increases, the effectiveness of VYKOURA to diminish methotrexate toxicity may decrease. Administer VYKOURA 10 mg/m 2 intravenously or intramuscularly every 6 hours until the serum methotrexate level is less than 0.01 micromolar (1 x 10 -8 M). Monitor serum creatinine and methotrexate levels at least every 24 hours. Increase the dosage of VYKOURA to 100 mg/m 2 intravenously every 3 hours if serum creatinine at 24-hours increases 50% or more compared to baseline the methotrexate level at 24-hours is greater than 5 micromolar (5 x 10 -6 M) the methotrexate level at 48-hours is greater than 0.9 micromolar (9 x 10 -7 M) Continue VYKOURA at the same dosage until the methotrexate level is less than 0.01 micromolar (1 x 10 -8 M). Continue intravenous fluids (3 L per day) and sodium bicarbonate. Adjust the sodium bicarbonate dose to maintain urine pH at 7.0 or greater. 2.4 Recommended Dosage in Combination with Fluorouracil for Advanced Colorectal Cancer Administer VYKOURA intravenously prior to fluorouracil. Dosage of VYKOURA in combination with fluorouracil varies by regimen and ranges from 20 mg/m 2 to 500 mg/m 2 . Consult institutional guidelines for recommended dosing, dosing frequency, and duration of therapy. Refer to the Prescribing Information for fluorouracil and other drugs used in combination with VYKOURA for additional information on management of adverse reactions. 2.5 Recommended Dosage for Megaloblastic Anemia Due to Folic Acid Deficiency Up to 1 mg daily administered intravenously until adequate hematologic response is achieved. There is no evidence that doses greater than 1 mg/day have greater efficacy than those of 1 mg; additionally, loss of folate in urine becomes roughly logarithmic as the amount administered exceeds 1 mg. 2.6 Preparation and Administration Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. For Intravenous Injection Preparation Select the appropriate number of vial(s) based on the prescribed dose. Withdraw the calculated dose into a sterile syringe and administer immediately. Discard partially used or empty vials as VYKOURA does not contain any preservatives. Administration Administer VYKOURA slowly. Do not exceed an intravenous administration rate of 160 mg per minute (16 mL per minute) to avoid hypercalcemia [see Warnings and Precautions (5.2) ] . For Intramuscular Injection Preparation Select the appropriate number of vial(s) based on the prescribed dose. Withdraw the calculated dose into a sterile syringe and administer immediately. Discard partially used or empty vials as VYKOURA does not contain any preservatives. Administration Administer the prescribed dose of VYKOURA by intramuscular injection using standard aseptic technique.

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1 INDICATIONS AND USAGE VYKOURA is indicated for: 1.1 Rescue after high-dose methotrexate (MTX) therapy in adult and pediatric patients.