UDENYCA

1 INDICATIONS AND USAGE UDENYCA is a leukocyte growth factor indicated to Decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. ( 1.1 ) Increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome). ( 1.2 ) Limitations of Use UDENYCA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. 1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy UDENYCA is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia [see Clinical Studies ( 14.1 )] . Limitations of Use UDENYCA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. 1.2 Patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome UDENYCA is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation [see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.2 )] .

2 DOSAGE AND ADMINISTRATION Patients with cancer receiving myelosuppressive chemotherapy 6 mg administered subcutaneously once per chemotherapy cycle. ( 2.1 ) Do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy. ( 2.1 ) Use weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1 . ( 2.3 ) Patients acutely exposed to myelosuppressive doses of radiation Two doses, 6 mg each, administered subcutaneously one week apart. Administer the first dose as soon as possible after suspected or confirmed exposure to myelosuppressive doses of radiation, and a second dose one week after. ( 2.2 ) Use weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1 . ( 2.3 ) 2.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy The recommended dosage of UDENYCA is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. For dosing in pediatric patients weighing less than 45 kg, refer to Table 1 . Do not administer UDENYCA between 14 days before and 24 hours after administration of cytotoxic chemotherapy. 2.2 Patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome The recommended dose of UDENYCA is two doses, 6 mg each, administered subcutaneously one week apart. For dosing in pediatric patients weighing less than 45 kg, refer to Table 1 . Administer the first dose as soon as possible after suspected or confirmed exposure to radiation levels greater than 2 gray (Gy). Administer the second dose one week after the first dose. Obtain a baseline complete blood count (CBC). Do not delay administration of UDENYCA if a CBC is not readily available. Estimate a patient’s absorbed radiation dose (i.e., level of radiation exposure) based on information from public health authorities, biodosimetry if available, or clinical findings such as time to onset of vomiting or lymphocyte depletion kinetics. 2.3 Administration UDENYCA is administered subcutaneously via a single-dose prefilled autoinjector, a single-dose prefilled syringe for manual use or for use with the on-body injector (OBI) for UDENYCA, which is co-packaged with a single dose prefilled syringe for OBI. Use of the OBI for UDENYCA is not recommended for patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome. Use of the OBI has not been studied in pediatric patients. Prior to use‚ remove the carton from the refrigerator and allow UDENYCA to reach room temperature for a minimum of 30 minutes. Discard any UDENYCA left at room temperature for greater than 48 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer UDENYCA if discoloration or particulates are observed. The needle cap on the prefilled syringe and prefilled autoinjector is not made with natural rubber latex. Pediatric Patients Weighing Less than 45 kg The UDENYCA prefilled syringe is not designed to allow for direct administration of doses less than 0.6 mL (6 mg). The syringe does not bear graduation marks which are necessary to accurately measure doses of UDENYCA less than 0.6 mL (6 mg) for direct administration to patients. Thus, the direct administration to patients requiring dosing of less than 0.6 mL (6 mg) is not recommended due to the potential for dosing errors. Refer to Table 1 . Table 1. Dosing of UDENYCA for pediatric patients weighing less than 45 kg Body Weight UDENYCA Dose Volume to Administer Less than 10 kg For pediatric patients weighing less than 10 kg, administer 0.1 mg/kg (0.01 mL/kg) of UDENYCA See below See below 10 - 20 kg 1.5 mg 0.15 mL 21 - 30 kg 2.5 mg 0.25 mL 31 - 44 kg 4 mg 0.4 mL The UDENYCA prefilled autoinjector is not suitable for use in pediatric patients weighing less than 45 kg. The UDENYCA prefilled autoinjector delivers the entire contents (6 mg in 0.6 mL) in a single injection and is not adjustable. 2.4 Advice to Give …

5 WARNINGS AND PRECAUTIONS Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture ( 5.1 ) Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue UDENYCA in patients with ARDS. ( 5.2 ) Serious allergic reactions, including anaphylaxis: Permanently discontinue UDENYCA in patients with serious allergic reactions. ( 5.3 ) The on-body injector for UDENYCA uses acrylic adhesives. For patients who have reactions to acrylic adhesives, use of this product may result in a significant reaction. ( 5.4 ) Fatal sickle cell crises: Discontinue UDENYCA if sickle cell crisis occurs. ( 5.5 ) Glomerulonephritis: Evaluate and consider dose-reduction or interruption of UDENYCA if causality is likely. ( 5.6 ) Thrombocytopenia: Monitor platelet count ( 5.8 ) Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using UDENYCA in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. ( 5.11 ) Potential device failures: Instruct patients to notify their healthcare provider if they suspect the on-body injector may not have performed as intended. ( 5.12 ) 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of pegfilgrastim products. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving UDENYCA. 5.2 Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving pegfilgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving UDENYCA for ARDS. Discontinue UDENYCA in patients with ARDS. 5.3 Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving pegfilgrastim products. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue UDENYCA in patients with serious allergic reactions. Do not administer UDENYCA to patients with a history of serious allergic reactions to pegfilgrastim products or filgrastim products. 5.4 Allergies to Acrylics The on-body injector (OBI) for UDENYCA uses acrylic adhesive. For patients who have reactions to acrylic adhesives, use of this product may result in a significant reaction. 5.5 Use in Patients with Sickle Cell Disorders Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving pegfilgrastim products. Discontinue UDENYCA if sickle cell crisis occurs. 5.6 Glomerulonephritis Glomerulonephritis has occurred in patients receiving pegfilgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of pegfilgrastim products. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of UDENYCA. 5.7 Leukocytosis White blood cell (WBC) counts of 100 x 10 9 /L or greater have been observed in patients receiving pegfilgrastim products. Monitoring of complete blood count (CBC) during UDENYCA therapy is recommended. 5.8 Thrombocytopenia Thrombocytopenia has been reported in patients receiving pegfilgrastim products. Monitor platelet counts. 5.9 Capillary Leak Syndrome Capillary leak syndrome has been reported after G-CSF administration, including pegfilgrastim products, and is characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closel…

4 CONTRAINDICATIONS UDENYCA is contraindicated in patients with a history of serious allergic reactions to pegfilgrastim products or filgrastim products. Reactions have included anaphylaxis [see Warnings and Precautions ( 5.3 )] . Patients with a history of serious allergic reaction to human granulocyte colony-stimulating factors such as pegfilgrastim products or filgrastim products. ( 4 )

8.1 Pregnancy Risk Summary Although available data with UDENYCA or pegfilgrastim product use in pregnant women are insufficient to establish whether there is a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes, there are available data from published studies in pregnant women exposed to filgrastim products. These studies have not established an association of filgrastim product use during pregnancy with major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal studies, no evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). In pregnant rabbits, increased embryo lethality and spontaneous abortions occurred at 4 times the maximum recommended human dose simultaneously with signs of maternal toxicity (see Data ). The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively. Data Animal Data Pregnant rabbits were dosed with pegfilgrastim subcutaneously every other day during the period of organogenesis. At cumulative doses ranging from the approximate human dose to approximately 4 times the recommended human dose (based on body surface area), the treated rabbits exhibited decreased maternal food consumption, maternal weight loss, as well as reduced fetal body weights and delayed ossification of the fetal skull; however, no structural anomalies were observed in the offspring from either study. Increased incidences of post-implantation losses and spontaneous abortions (more than half the pregnancies) were observed at cumulative doses approximately 4 times the recommended human dose, which were not seen when pregnant rabbits were exposed to the recommended human dose. Three studies were conducted in pregnant rats dosed with pegfilgrastim at cumulative doses up to approximately 10 times the recommended human dose at the following stages of gestation: during the period of organogenesis, from mating through the first half of pregnancy, and from the first trimester through delivery and lactation. No evidence of fetal loss or structural malformations was observed in any study. Cumulative doses equivalent to approximately 3 and 10 times the recommended human dose resulted in transient evidence of wavy ribs in fetuses of treated mothers (detected at the end of gestation but no longer present in pups evaluated at the end of lactation).

8.2 Lactation Risk Summary There are no data on the presence of pegfilgrastim products in human milk, the effects on the breastfed child, or the effects on milk production. Other filgrastim products are secreted poorly into breast milk, and filgrastim products are not absorbed orally by neonates. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for UDENYCA and any potential adverse effects on the breastfed child from UDENYCA or from the underlying maternal condition.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: Splenic Rupture [see Warnings and Precautions ( 5.1 )] Acute Respiratory Distress Syndrome [see Warnings and Precautions ( 5.2 )] Serious Allergic Reactions [see Warnings and Precautions ( 5.3 )] Allergies to Acrylics [see Warnings and Precautions ( 5.4 )] Use in Patients with Sickle Cell Disorders [see Warnings and Precautions ( 5.5 )] Glomerulonephritis [see Warnings and Precautions ( 5.6 )] Leukocytosis [see Warnings and Precautions ( 5.7 )] Thrombocytopenia [see Warnings and Precautions ( 5.8 )] Capillary Leak Syndrome [see Warnings and Precautions ( 5.9 )] Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions ( 5.10 )] Myelodysplastic syndrome [see Warnings and Precautions ( 5.11 )] Acute myeloid leukemia [see Warnings and Precautions ( 5.11 )] Aortitis [see Warnings and Precautions ( 5.13 )] Most common adverse reactions (≥ 5% difference in incidence compared to placebo) are bone pain and pain in extremity. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Accord BioPharma at 1-866-941-7875 or FDA at 1-800-FDA-1088 (1-800-332-1088) 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pegfilgrastim clinical trials safety data are based upon 932 patients receiving pegfilgrastim in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received pegfilgrastim after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. The following adverse reaction data in Table 2 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m 2 every 21 days (Study 3). A total of 928 patients were randomized to receive either 6 mg pegfilgrastim (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and <1% Asian, Native American or other. The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfilgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity. Table 2. Adverse Reactions with ≥ 5% Higher Incidence in pegfilgrastim Patients Compared to Placebo in Study 3 Body System Adverse Reaction Placebo (N = 461) pegfilgrastim 6 mg SC on Day 2 (N = 467) Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9% Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 10 9 /L was observed in less than 1% of 932 patients with non-myeloid malignancies receiving pegfilgrastim. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of pegfilgrastim or of other pegfilgrastim products. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic b…