KHAPZORY

Levoleucovorin is a folate analog and the pharmacologically active levo-isomer of d,l- leucovorin. The chemical name is (2S)-2-[[4-[[(6S)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6- yl] methylamino] benzoyl] amino] pentanedioate. The molecular formula is C 20 H 23 N 7 O 7 and the molecular weight is 473.45. The molecular structure is: Levoleucovorin is a slightly hygroscopic, crystalline, yellow powder which is soluble in water when pH is at or above 8. KHAPZORY 175 mg is a sterile lyophilized powder consisting of 175 mg levoleucovorin, 29.6 mg sodium hydroxide, and 105 mg mannitol in each vial. Additional sodium hydroxide and/or hydrochloric acid may be used to adjust the pH during manufacture. It is intended for intravenous administration after reconstitution with 3.6 mL of sterile 0.9% Sodium Chloride Injection, USP. Levoleucovorin Chemical Structure

KHAPZORY 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 adult and pediatric patients. The treatment of adults with metastatic colorectal cancer in combination with fluorouracil. Limitations of Use KHAPZORY is not indicated for pernicious anemia and megaloblastic anemia secondary to lack the of vitamin B 12 because of the risk of progression of neurologic manifestations despite hematologic remission. KHAPZORY is a folate analog indicated for: Rescue after high-dose methotrexate therapy in adults 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 KHAPZORY is not indicated for pernicious anemia and megaloblastic anemia secondary to lack of vitamin B12 because of the risk of progression of neurologic manifestations despite hematologic remission.( 1 )

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 . 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 Reconstitute the 175 mg vial contents with 3.6 mL of 0.9% Sodium Chloride Injection, USP, to obtain a clear, colorless to yellowish solution (resultant concentration 50 mg per mL levoleucovorin). Reconstitution with a sodium chloride solution with preservatives (e.g., benzyl alcohol) has not been studied. Do not store reconstituted solution for more than 12 hours at room temperature. Protect from light. Dilute reconstituted solution immediately (if possible), to concentrations of 0.5 mg/mL to 5 mg/mL in 0.9% Sodium Chloride Injection, USP or 5% Dextrose Injection, USP. Do not store the diluted reconstituted solution for more than 12 hours at room temperature. Protect from light. Visually inspect the product for particulate matter and discoloration prior to administration. Discard if particulate matter or discoloration is observed.

KHAPZORY is contraindicated in patients who have had severe hypersensitivity to leucovorin products, folic acid, or folinic acid [see Adverse Reactions ( 6.2 )] . Patients who have had severe hypersensitivity reactions to leucovorin products, folic acid, or folinic acid. ( 4 )

The following clinical significant adverse reactions are described elsewhere in the labeling: • Increased gastrointestinal toxicities with fluorouracil [see Warnings and Precautions ( 5.1 )] 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 Acrotech Biopharma Inc at 1-888-292-9617 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 (%) Grade 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 reactions 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 Adverse Reactions 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* 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 *Includes abdominal pain, upper abdominal pain, lower abdominal pain, and abdominal tenderness 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of levoleucovorin products. Because these adverse reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following have been reported: • Dermatologic : pruritus, rash • Respiratory : dyspnea • Other Clinical Events : temperature change, rigors, allergic reactions

7.1 Effects of Leucovorin Products on Other Drugs Antiepileptic Drugs 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. Monitor patients taking folinic acid in combination with antiepileptic drugs. Fluorouracil Leucovorin products increase the toxicity of fluorouracil. Do not initiate or continue therapy with Fusilev and fluorouracil in patients with symptoms of gastrointestinal toxicity until those symptoms have resolved. Monitor patients with diarrhea until the diarrhea has resolved, as rapid deterioration leading to death can occur [see Warnings and Precautions ( 5.2 )] . Trimethoprim-Sulfamethoxazole The concomitant use of d, l -leucovorin with trimethoprim-sulfamethoxazole for the acute treatment of Pneumocystis jiroveci pneumonia in patients with HIV infection was associated with increased rates of treatment failure and morbidity in a placebo-controlled study [see Warnings and Precautions ( 5 )] .