RYZNEUTA

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 Evive Biotechnology Singapore Pte. Ltd. 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/m2 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)

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 )

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.

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.

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 )

5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of recombinant human granulocyte colony-stimulating factor (rhG CSF) products, such as RYZNEUTA. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving RYZNEUTA.

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 )] .

12. CLINICAL PHARMACOLOGY 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. 12.2 Pharmacodynamics Over the tested dose range of 30 to 360 μg/kg in healthy adult males, neutrophils generally increased in a dose-dependent manner; however, the effect on neutrophils plateaued at the top two doses of 240 and 360 μg/kg. In patients with breast cancer given EC chemotherapy, in cycle 1, median ANC peaked on Day 4 (about 24 hours after efbemalenograstim alfa-vuxw administration) for the 240 and 320 μg/kg doses, declined to nadir on Days 8–9, and then recovered to a count of 2.0 × 10 9 /L and higher by Day 11. The ANC levels in cycles 2, 3, and 4 tended to be higher than those observed in cycle 1. In patients with breast cancer given TAC chemotherapy, in cycle 1, median ANC peaked on Day 3 (about 24 hours after efbemalenograstim alfa-vuxw administration) in cycle 1 and 3, reached nadir on Day 8, and recovered to 2.0 x 10 9 /L on Days 9 and 10 for the 320 μg/kg and 240 μg/kg doses, respectively. Mean ANC nadir was higher with 320 μg/kg compared to 240 μg/kg in both cycle 1 (0.75 x 10 9 /L and 0.29 x 10 9 /L, respectively), and cycle 3 (1.19 x 10 9 /L and 0.57 x 10 9 /L, respectively). 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 tmax 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. 12.6 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 efbemalenograstim alfa-vuxw or of other efbemalenograstim alfa products. During the 3-month treatment period and 6-month follow-up in studies GC-627-04, GC-627-05 and SP11631, 20/438 (4.6%) RYZNEUTA-treated subjects developed treatment-emergent anti-drug antibodies to efbemalenograstim alfa-vuxw (3/121, 17/197 and 0/120, respectively). A dditionally, 16/438 (3.7%) of RYZNUETA-treated subjects developed treatment-emergent antibodies to G-CSF (1/121, 15/197 and 0/120, respectively). None of these patients who were positive for antibodies to efbemalenograstim alfa-vuxw or G-CSF had evidence of neutralizing antibodies using a cell-based bioassay, and there was no evidence of altered pharmacokinetics or allergic-type reactions. In Study GC-627-05, the incidence of antibodies to G-CSF was similar in patients treated with RYZNEUTA (15/197, 7.6%) and pegfilgrastim (13/195, 6.7%). None of these patients had evidence of neutralizing antibodies to G-CSF based on a cell-based bioassay and clinical observations, including absolute neutrophil counts.

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.

12.2 Pharmacodynamics Over the tested dose range of 30 to 360 μg/kg in healthy adult males, neutrophils generally increased in a dose-dependent manner; however, the effect on neutrophils plateaued at the top two doses of 240 and 360 μg/kg. In patients with breast cancer given EC chemotherapy, in cycle 1, median ANC peaked on Day 4 (about 24 hours after efbemalenograstim alfa-vuxw administration) for the 240 and 320 μg/kg doses, declined to nadir on Days 8–9, and then recovered to a count of 2.0 × 10 9 /L and higher by Day 11. The ANC levels in cycles 2, 3, and 4 tended to be higher than those observed in cycle 1. In patients with breast cancer given TAC chemotherapy, in cycle 1, median ANC peaked on Day 3 (about 24 hours after efbemalenograstim alfa-vuxw administration) in cycle 1 and 3, reached nadir on Day 8, and recovered to 2.0 x 10 9 /L on Days 9 and 10 for the 320 μg/kg and 240 μg/kg doses, respectively. Mean ANC nadir was higher with 320 μg/kg compared to 240 μg/kg in both cycle 1 (0.75 x 10 9 /L and 0.29 x 10 9 /L, respectively), and cycle 3 (1.19 x 10 9 /L and 0.57 x 10 9 /L, respectively).

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 tmax 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.

20231123

2

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 )

RYZNEUTA efbemalenograstim alfa-vuxw EFBEMALENOGRASTIM ALFA EFBEMALENOGRASTIM ALFA ACETATE ION EDETIC ACID POLYSORBATE 20 SODIUM SORBITOL WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenesis studies have been conducted with efbemalenograstim alfa-vuxw. Efbemalenograstim alfa did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 2.2 times higher than the recommended human dose (based on body surface area).

13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenesis studies have been conducted with efbemalenograstim alfa-vuxw. Efbemalenograstim alfa did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 2.2 times higher than the recommended human dose (based on body surface area).

BLA761134

RYZNEUTA

efbemalenograstim alfa-vuxw

73491-627

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

RYZNEUTA (efbemalenograstim alfa-vuxw) Injection 20 mg/mL For Subcutaneous Use Only Single-dose Prefilled Syringe EVIVE BIOTECHNOLOGY SINGAPORE PTE. LTD 301878 Exp. LOT label-barrel

17. PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information) Advise patients of the following risks and potential risks with RYZNEUTA: Rupture or enlargement of the spleen may occur. Symptoms include left upper quadrant abdominal pain or left shoulder pain. Advise patients to report pain in these areas to their healthcare provider immediately [see Warnings and Precautions ( 5.1 )] . Dyspnea, with or without fever, progressing to acute respiratory distress syndrome, may occur. Advise patients to report dyspnea to their healthcare provider immediately [see Warnings and Precautions ( 5.2 )] . Serious allergic reactions may occur, which may be signaled by rash, facial edema, wheezing, dyspnea, hypotension, or tachycardia. Advise patients to seek immediate medical attention if signs or symptoms of hypersensitivity reaction occur [see Warnings and Precautions ( 5.3 )] . In patients with sickle cell disease, sickle cell crisis and death have occurred with use of human granulocyte colony-stimulating factors. Discuss potential risks and benefits for patients with sickle cell disease prior to the administration of RYZNEUTA [see Warnings and Precautions ( 5.4 )] . Glomerulonephritis may occur. Symptoms include swelling of the face or ankles, dark colored urine or blood in the urine, or a decrease in urine production. Advise patients to report signs or symptoms of glomerulonephritis to their healthcare provider immediately [see Warnings and Precautions ( 5.5 )] . Capillary leak syndrome may occur. Symptoms include hypotension and edema. Advise patients to report signs and symptoms of capillary leak syndrome to their healthcare provider immediately [see Warnings and Precautions ( 5.9 )] . There may be an increased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with breast and lung cancer who receive RYZNEUTA in conjunction with chemotherapy and/or radiation therapy. Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding. Advise patients to report to their physician signs and symptoms of MDS/AML [see Warnings and Precautions ( 5.9 )] . Aortitis may occur. Symptoms may include fever, abdominal pain, malaise, back pain, and increased inflammatory markers. Advise patients to report signs and symptoms of aortitis to their physician immediately [see Warnings and Precautions ( 5.11 )] . RYZNEUTA ® (efbemalenograstim alfa-vuxw) Manufactured by: EVIVE BIOTECHNOLOGY SINGAPORE PTE. LTD. Singapore, 189720 U.S. License No 2248 © 2023 Evive Biotechnology Singapore PTE. LTD. For more information, go to www.ryzneuta.com or call 1-888-292-9617

14. CLINICAL STUDIES The efficacy of RYZNEUTA to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs was evaluated in two randomized, controlled studies. Study GC-627-04 [NCT02872103] was a randomized, double-blind, placebo-controlled study that employed doxorubicin 60 mg/m2 and docetaxel 75 mg/m 2 administered every 21 days for up to 4 cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 122 patients were randomized to receive a single subcutaneous injection of RYZNEUTA (20 mg) or placebo on day 2 of chemotherapy cycle 1. All patients received RYZNEUTA (20 mg) on day 2 of chemotherapy cycles 2 – 4. The patients were 30 to 69 years of age and all female. The race was 99% Caucasian, and 1% Black. The ethnicity was 2% Hispanic or Latino. Efficacy was based upon the mean duration of severe (Grade 4) neutropenia in cycle 1 which was lower for RYZNEUTA-treated patients as compared to placebo-treated patients (LS mean: 1.4 days versus 4.3 days, respectively, p<0.001 [95% CI: 2.4, 3.5]). The incidence of febrile neutropenia (defined as temperature ≥38.3℃, or >38.0℃ sustained for at least 1 hour, and ANC < 0.5 × 109/L) was also lower for RYZNEUTA-treated patients compared to placebo-treated patients in cycle 1 (4.8% versus 25.6%, respectively, p=0.0016; 20.8% difference [95% CI: 1.8%, 38.8%]. Study GC-627-05 [NCT03252431] was a randomized, active-controlled study that compared RYZNEUTA to pegfilgrastim. Study GC-627-05 employed docetaxel 75 mg/m 2 and cyclophosphamide 600 mg/m 2 administered every 21 days for up to 4 cycles for the treatment of non-metastatic breast cancer. In this study, 393 patients were randomized to receive a single subcutaneous injection of RYZNEUTA (20 mg) or pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle. The patients were 26 to 83 years of age and all female and Caucasian. The ethnicity was 0.3% Hispanic or Latino. The study demonstrated that the mean days of severe (Grade 4) neutropenia of RYZNEUTA-treated patients did not exceed that of pegfilgrastim-treated patients by more than 0.6 days in cycle 1 of chemotherapy. The mean days of severe neutropenia in cycle 1 were 0.2 days in both the RYZNEUTA and pegfilgrastim arms (difference in means 0.0 days [95% CI -0.1, 0.1]). Subgroup analyses of treatment effect were not useful due to small subgroup sizes.

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.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

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. 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.

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 Passive™ 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 73491-627-01). 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° to 8°C (36° 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.