VYKOURA

1 INDICATIONS AND USAGE VYKOURA is indicated for: 1.1 Rescue after high-dose methotrexate (MTX) therapy in adult and pediatric patients. 1.2 Reducing the toxicity of: Methotrexate in adult and pediatric patients with impaired methotrexate elimination or Folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose in adult and pediatric patients. 1.3 Treatment of megaloblastic anemias due to folic acid deficiency in adult and pediatric patients when oral therapy is not feasible. 1.4 Treatment of patients with metastatic colorectal cancer in combination with fluorouracil. Limitations of Use VYKOURA 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. VYKOURA is a folate analog indicated for: Rescue after high-dose methotrexate therapy in adult and pediatric patients. ( 1.1 ) Reducing the toxicity of methotrexate in adult and pediatric patients with impaired methotrexate elimination or folic acid antagonists or dihydrofolate reductase (DHFR) inhibitors following an overdose in adult and pediatric patients. ( 1.2 ) Treatment of megaloblastic anemias due to folic acid deficiency in adult and pediatric patients when oral therapy is not feasible. ( 1.3 ) Treatment of patients with metastatic colorectal cancer in combination with 5-fluorouracil. ( 1.4 ) Limitations of Use : VYKOURA 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. ( 1.3 )

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.

4 CONTRAINDICATIONS VYKOURA is contraindicated in patients who have had a severe hypersensitivity reaction to leucovorin (folinic acid), levoleucovorin, or folic acid [see Warnings and Precautions (5.1) ]. Reactions have included anaphylactic reactions. VYKOURA is contraindicated in patients who have had a severe hypersensitivity reaction to leucovorin (folinic acid), levoleucovorin, or folic acid. ( 4 )

5 WARNINGS AND PRECAUTIONS Hypersensitivity : Hypersensitivity reactions, including anaphylactic reactions and urticaria can occur. Withhold or permanently discontinue VYKOURA based on the severity of hypersensitivity. ( 5.1 ) Hypercalcemia : Due to calcium content, inject no more than 16 mL (160 mg) of VYKOURA intravenously per minute. ( 5.2 ) Risk of Administration Errors : Do not administer VYKOURA intrathecally. ( 5.3 ) 5.1 Hypersensitivity Hypersensitivity reactions, including anaphylactic reactions and urticaria, have been reported following the administration of leucovorin. VYKOURA is contraindicated in patients who have had a severe hypersensitivity reaction to leucovorin, levoleucovorin, or folic acid [see Contraindications (4) ]. Withhold or permanently discontinue VYKOURA based on the severity of hypersensitivity. 5.2 Hypercalcemia Because of the calcium content of the VYKOURA, do not administer more than 160 mg of VYKOURA intravenously per minute [see Dosing and Administration (2.6) ] . 5.3 Risk of Administration Errors In the treatment of accidental overdosages of intrathecally administered folic acid antagonists, do not administer VYKOURA intrathecally. VYKOURA MAY BE HARMFUL OR FATAL IF GIVEN INTRATHECALLY.

7 DRUG INTERACTIONS 7.1 Effects of Other Drugs on VYKOURA Glucarpidase Administer VYKOURA at least 2 hours before or 2 hours after the glucarpidase dose when administering concomitantly. Glucarpidase can decrease leucovorin concentrations, which may decrease the effect of leucovorin rescue. 7.2 Effects of VYKOURA on Other Drugs Certain Antiepileptic Drugs Increase monitoring for seizure activity in patients taking certain concomitant antiepileptic drugs. Folic acid in high doses may reduce the effectiveness of certain antiepileptic drugs (e.g., phenobarbital, phenytoin, and primidone) and thereby increase the frequency of seizures. It is not known whether folinic acid, including VYKOURA, has the same effects; however, both folic and folinic acids, including VYKOURA share some common metabolic pathways. Trimethoprim-Sulfamethoxazole Avoid concomitant use of VYKOURA with trimethoprim-sulfamethoxazole . The effectiveness of trimethoprim-sulfamethoxazole can be decreased if used concomitantly with VYKOURA which was associated with increased rates of treatment failure and mortality in patients with HIV infection who receive trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jirovecii pneumonia.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypersensitivity [see Warnings and Precautions (5.1) ] Hypercalcemia [see Warnings and Precautions (5.2) ] The most common adverse reactions (≥20%) in patients receiving high-dose methotrexate therapy with leucovorin rescue are stomatitis and vomiting. ( 6.1 ) The most common adverse reactions (>50%) in patients receiving leucovorin in combination with fluorouracil for metastatic colorectal cancer are stomatitis, diarrhea, and nausea. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avyxa Pharma, LLC at 1-888-520-0954 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 clinical practice. Table 2 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 2: Percentage of Patients Treated with Leucovorin and 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%

8.1 Pregnancy Risk Summary Available data on the use of leucovorin during pregnancy have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. Adequate animal reproduction studies have not been conducted with leucovorin. Agents administered in combination with VYKOURA may cause fetal harm. Refer to the Prescribing Information for agents administered in combination with VYKOURA for additional information, as appropriate. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.