RYZNEUTA

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.

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.

3. DOSAGE FORMS AND STRENGTHS Injection: 20 mg/mL clear, colorless, preservative-free solution in a single-dose prefilled syringe. Injection: 20 mg/mL solution in a single-dose prefilled syringe. ( 3 )

4. CONTRAINDICATIONS RYZNEUTA is contraindicated in patients with a history of serious allergic reactions to granulocyte stimulating factors such as efbemalenograstim alfa-vuxw, pegfilgrastim, or filgrastim products [see Warnings and Precautions ( 5.3 )] . Patients with a history of serious allergic reactions to granulocyte stimulating factors such as efbemalenograstim alfa-vuxw, pegfilgrastim, or filgrastim products. ( 4 )

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)

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 cyclophosphami …

8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Although available data with RYZNEUTA 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 other human G-CSF products. These studies have not established an association of G-CSF 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 and rabbits that received cumulative doses of efbemalenograstim alfa-vuxw approximately 2.6 and 0.7 times, respectively, the recommended human dose (based on body surface area). 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 Three studies were conducted in pregnant rats dosed with efbemalenograstim alfa-vuxw at cumulative doses up to approximately 2.6 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. Growth and learning were also unaffected. Pregnant rabbits were dosed with efbemalenograstim alfa-vuxw every other day during organogenesis at cumulative doses up to 0.7 times the recommended human dose showed no signs of fetal loss or structural malformations. Maternal toxicity (decreased weight gain or weight loss and/or death) was observed when higher cumulative doses of efbemalenograstim alfa-vuxw were used in an early dose-ranging study in rabbits. 8.2 Lactation Risk Summary There are no data on the presence of efbemalenograstim alfa-vuxw or its metabolite in either human or animal milk, the effects on the breastfed child, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for efbemalenograstim alfa-vuxw and any potential adverse effects on the breastfed child from efbemalenograstim alfa-vuxw or from the underlying maternal condition. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of RYZNEUTA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience with RYZNEUTA has not identified differences in responses between the elderly and younger patients.

12.1 Mechanism of Action Efbemalenograstim alfa-vuxw is a colony-stimulating factor that acts on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.

11. DESCRIPTION Efbemalenograstim alfa-vuxw, a leukocyte growth factor, is a 413 amino acid recombinant fusion protein consisting of human G-CSF, a 16 amino-acid linker, and the Fc portion of human IgG2. In solution, efbemalenograstim alfa-vuxw forms covalently-linked dimers (disulfide bonds between Fc moieties), resulting in an immunoglobulin-like structure. The dimer is a water-soluble, glycosylated protein with a molecular weight of approximately 93.4 kilodaltons (kDa), of which 89.5 kDa is attributed to amino acids (protein sequence) and the remainder is from glycosylation. Efbemalenograstim alfa-vuxw is obtained from genetically-engineered strain of Chinese hamster ovary (CHO) cells grown in a serum-free medium. RYZNEUTA (efbemalenograstim alfa-vuxw) injection is supplied in 1 mL prefilled single-dose syringes for manual subcutaneous injection. The prefilled syringe does not bear graduation marks and is designed to deliver the entire contents of the syringe (20 mg/mL). Each syringe contains 20 mg efbemalenograstim alfa-vuxw in a sterile, clear, colorless, preservative-free solution (pH 5.2) containing acetate (0.6 mg), EDTA (0.29 mg), polysorbate 20 (0.1 mg), sodium (0.23 mg), and sorbitol (50 mg) in Water for Injection, USP.

10. OVERDOSAGE Overdosage of RYZNEUTA may result in leukocytosis and bone pain. In the event of overdose, general supportive measures should be instituted, as necessary. Monitor the patient for adverse reactions [see Adverse Reactions ( 6 )] .

16. HOW SUPPLIED/STORAGE AND HANDLING RYZNEUTA (efbemalenograstim alfa-vuxw) injection is a clear, colorless, preservative-free solution supplied in a prefilled single-dose syringe with a 27-gauge, 1/2-inch needle and an UltraSafe PassiveTM Needle Guard, containing 20 mg of efbemalenograstim alfa-vuxw. Caution: This product contains natural rubber latex which may cause allergic reactions. The needle cap of the prefilled syringe contains natural rubber; persons with latex allergies should not administer this product. RYZNEUTA is provided in a dispensing pack containing one 20 mg/mL prefilled syringe (NDC 72893-016-02). 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. Store refrigerated at 2°C to 8°C (36°F to 46°F) in the carton to protect from light. Do not shake. Discard syringes stored at room temperature for more than 48 hours. Do not freeze. Discard syringe if frozen.