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.

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.

5.2 Acute Respiratory Distress Syndrome

Acute respiratory distress syndrome (ARDS) can occur in patients receiving rhG-CSF products, such as RYZNEUTA. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving RYZNEUTA for ARDS. Discontinue RYZNEUTA in patients with ARDS.

5.3 Serious Allergic Reactions

Serious allergic reactions, including anaphylaxis, can occur in patients receiving rhG-CSF products, such as RYZNEUTA. Permanently discontinue RYZNEUTA in patients with serious allergic reactions. RYZNEUTA is contraindicated in patients with a history of serious allergic reactions to RYZNEUTA or other rhG-CSF products such as pegfilgrastim, eflapegrastim or filgrastim products.

5.4 Sickle Cell Crisis in Patients with Sickle Cell Disorders

Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving rhG-CSF products, such as RYZNEUTA. Discontinue RYZNEUTA if sickle cell crisis occurs.

5.5 Glomerulonephritis

Glomerulonephritis has occurred in patients receiving rhG-CSF 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 rhG-CSF. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of RYZNEUTA.

5.6 Leukocytosis

White blood cell (WBC) counts of 100 × 10 9/L or greater have been observed in patients receiving rhG-CSF products. Monitor complete blood count (CBC) during RYZNEUTA therapy. Discontinue RYZNEUTA treatment if WBC count of 100 × 10 9/L or greater occurs.

5.7 Thrombocytopenia

Thrombocytopenia has been reported in patients receiving rhG-CSF products. Thrombocytopenia occurred in 11% of RYZNEUTA-treated patients. One patient (0.4%) experienced severe thrombocytopenia. Monitor platelet counts.

5.8 Capillary Leak Syndrome

Capillary leak syndrome has been reported after administration of rhG-CSF products and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency and severity, and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.9 Potential for Tumor Growth Stimulatory Effects on Malignant Cells

The granulocyte colony-stimulating factor (G-CSF) receptor through which RYZNEUTA acts has been found on tumor cell lines. The possibility that RYZNEUTA acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which RYZNEUTA is not approved, cannot be excluded.

5.10 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer

MDS and AML have been associated with the use of rhG-CSF products in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer. Monitor patients for signs and symptoms of MDS/AML in these settings.

5.11 Aortitis

Aortitis has been reported in patients receiving rhG-CSF products. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue RYZNEUTA if aortitis is suspected.

5.12 Nuclear Imaging

Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone imaging results.

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 2every 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 2and 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.

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.

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 maxwas 1202 ng/mL (56%), and the AUC 0-infwas 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-infwas 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 maxof 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). Additionally, 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.

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).