Efbemalenograstim Alfa-Vuxw

1. INDICATIONS AND USAGE RYZNEUTA is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adult patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Limitations of Use RYZNEUTA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. RYZNEUTA is a leukocyte growth factor indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in adult patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. ( 1 ) Limitations of Use RYZNEUTA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. ( 1 )

2. DOSAGE AND ADMINISTRATION Recommended Dose: 20 mg administered subcutaneously once per chemotherapy cycle. ( 2.1 ) Administer approximately 24 hours after cytotoxic chemotherapy. Do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy. ( 2.1 ) 2.1 Recommended Dosage The recommended dosage of RYZNEUTA is a single subcutaneous injection of 20 mg administered once per chemotherapy cycle at least 24 hours after cytotoxic chemotherapy. Do not administer RYZNEUTA within 14 days before and <24 hours after administration of cytotoxic chemotherapy. 2.2 Administration RYZNEUTA is administered subcutaneously via a single-dose prefilled syringe by a healthcare professional. Prior to use‚ remove the carton from the refrigerator (keeping the prefilled syringe inside the carton) for a minimum of 30 minutes to allow the product to reach room temperature. Discard any product 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 RYZNEUTA if discoloration or particulates are observed. Caution: This product contains natural rubber latex which may cause allergic reactions. The needle cap on the prefilled syringe contains natural rubber; people with latex allergies should not administer this product. The RYZNEUTA prefilled syringe does not bear graduation marks and is intended only to deliver the entire contents of the syringe (20 mg/mL) for direct administration to adult patients. Administer injection by pinching the skin and holding. Inject into the abdomen, the back or side of the upper arms, or the thighs. Rotate injection sites. Do not inject into scar tissue or areas that are reddened, inflamed, or swollen. If injecting into the abdomen, avoid a 2-inch diameter circle around the navel. Once the entire dose has been injected, the needle safety device will be triggered, pulling the needle automatically from the skin, and into the barrel; the entire needle will be covered by the needle guard.

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 )] Sickle Cell Crisis in Patients with Sickle Cell Disorders [see Warnings and Precautions ( 5.4 )] Glomerulonephritis [see Warnings and Precautions ( 5.5 )] Leukocytosis [see Warnings and Precautions ( 5.6 )] Thrombocytopenia [see Warnings and Precautions ( 5.7 )] Capillary Leak Syndrome [see Warnings and Precautions ( 5.8 )] Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions ( 5.9 )] Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer [see Warnings and Precautions ( 5.10 )] Aortitis [see Warnings and Precautions ( 5.11 )] Most common adverse reactions (≥10%) were nausea, anemia, and thrombocytopenia. ( 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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The following adverse reaction data are based on two studies [see Clinical Studies ( 14 )]. The first was a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving doxorubicin 60 mg/m 2 and docetaxel 75 mg/m 2 every 21 days (Study GC-627-04). A total of 122 female patients were randomized to receive either 20 mg RYZNEUTA (n=83) or placebo (n=39) in chemotherapy cycle 1; all patients received RYZNEUTA in cycles 2-4. The second was a randomized, open-label, active-controlled study in patients with stage I to III invasive breast cancer receiving docetaxel 75 mg/m 2 and cyclophosphamide 600 mg/m 2 (Study GC-627-05). A total of 393 patients were randomized to receive either 20 mg RYZNEUTA (n=197) or pegfilgrastim (n=196) in chemotherapy cycles 1 through 4. In Study GC-627-04, the most common adverse reactions (≥10%) in the RYZNEUTA arm through cycle 1 were nausea, anemia, and thrombocytopenia (see Table 1). Other adverse reactions reported by ≥ 20% of RYZNEUTA-treated Patients with Breast Cancer Receiving Myelosuppressive Chemotherapy in Study GC-627-05 were fatigue and bone pain. Table 1. Adverse Reactions Adverse reactions that occurred in ≥10% of Ryzneuta-treated patients and ≥5% more than placebo-treated patients. in Study GC-627-04 in RYZNEUTA-treated Patients with Breast Cancer Receiving Myelosuppressive Chemotherapy Through Cycle 1 Adverse Reactions Ryzneuta (n=83) Placebo (n=39) Nausea 42 (51) 15 (39) Anemia 12 (15) 4 (10) Thrombocytopenia 10 (12) 1 (3)

12.3 Pharmacokinetics The pharmacokinetics of efbemalenograstim alfa-vuxw was studied in female patients with breast cancer and healthy male subjects. Efbemalenograstim alfa-vuxw exhibited nonlinear and time-dependent pharmacokinetics over the dose range of 30 to 360 μg/kg. At the approved recommended dose in healthy subjects, the mean (%CV) C max was 1202 ng/mL (56%), and the AUC 0-inf was 76357 h*ng/mL (65%). At the approved recommended dose in patients with breast cancer, the geometric mean (CV%) Cmax was 1085 ng/mL (92%) in Cycle 1 and 525 ng/mL (163%) in Cycle 3; the geometric mean (CV%) AUC 0-inf was 54858 h*ng/mL (110%) in Cycle 1 and 26217 h*ng/mL (167%) in Cycle 3. Absorption The median t max of efbemalenograstim alfa-vuxw administered as 80 to 320 μg/kg in female patients with breast cancer receiving EC chemotherapy ranged from 24 hours to 48 hours in Cycle 1 and 9 to 30 hours in Cycle 3. The median t max of efbemalenograstim alfa-vuxw administered as 240 to 320 μg/kg in female participants with breast cancer receiving TAC chemotherapy was 36 hours in Cycle 1 and ranged from 24 to 30 hours in Cycle 3. Distribution The geometric mean (CV%) apparent volume of distribution of efbemalenograstim alfa-vuxw was 18.8 L (257%) in Cycle 1 and 40.7 L (387%) in Cycle 3 in female patients with breast cancer. Elimination The geometric mean (CV%) apparent clearance of efbemalenograstim alfa-vuxw was 0.36 L/h (110%) in Cycle 1 and 0.76 L/h (167%) in Cycle 3. The geometric mean (CV%) elimination half-life of efbemalenograstim alfa-vuxw was 35.6 h (108%) in Cycle 1 and 36.9 h (120%) in Cycle 3. Neutrophil receptor binding is an important component of the clearance of efbemalenograstim alfa-vuxw, and serum clearance is directly related to the number of neutrophils. Metabolism Efbemalenograstim alfa-vuxw is expected to be metabolized into small peptides by catabolic pathways. Specific Populations No clinically significant differences were observed based on age (20 to 83 years) or body weight (40 to 137 kg) [see Use in Specific Populations ( 8.5 )]. The impact of sex, race/ethnicity, renal impairment, hepatic impairment, and pregnancy on the pharmacokinetics of efbemalenograstim alfa-vuxw are unknown.