STIMUFEND

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 )] Use 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 [see Warnings and Precautions ( 5.10 )] Acute myeloid leukemia [see Warnings and Precautions ( 5.10 )] Aortitis [see Warnings and Precautions ( 5.11 )] 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 Fresenius Kabi USA, LLC at 1-800-551-7176 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. 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 As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other pegfilgrastim products may be misleading. 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 breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of pegfilgrastim products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Splenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions ( 5.1 )] Acute respiratory distress syndrome (ARDS) [see Warnings and Precautions ( 5.2 )] Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema, and flushing [see Warnings and Precautions ( 5.3 )] Sickle cell crisis [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 )] Injection site reactions Sweet's syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitis Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions ( 5.10 )] Aortitis [see Warnings and Precautions ( 5.11 )] Alveolar hemorrhage

4 CONTRAINDICATIONS Stimufend 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 reactions to human granulocyte colony-stimulating factors such as pegfilgrastim products or filgrastim products. ( 4 )

11 DESCRIPTION Pegfilgrastim-fpgk is a covalent conjugate of recombinant methionyl human G-CSF and monomethoxypolyethylene glycol. Recombinant methionyl human G-CSF is a water-soluble 175 amino acid protein with a molecular weight of approximately 19 kilodaltons (kD). Recombinant methionyl human G-CSF is obtained from the bacterial fermentation of a strain of E coli transformed with a genetically engineered plasmid containing the human G-CSF gene. To produce pegfilgrastim-fpgk, a 20 kD monomethoxypolyethylene glycol molecule is covalently bound to the N-terminal methionyl residue of recombinant methionyl human G-CSF. The average molecular weight of pegfilgrastim-fpgk is approximately 39 kD. Stimufend (pegfilgrastim-fpgk) injection is supplied in 0.6 mL pre-filled syringes for manual subcutaneous injection. The pre-filled syringe does not bear graduation marks and is designed to deliver the entire contents of the syringe (6 mg/0.6 mL). The delivered 0.6 mL dose from the prefilled syringe contains 6 mg pegfilgrastim-fpgk (based on protein weight) in a sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.35 mg), polysorbate 20 (0.02 mg), sodium (0.02 mg), and sorbitol (30 mg) in Water for Injection, USP.

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 Stimufend 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 Stimufend 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 Stimufend 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 Stimufend 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 Stimufend is administered subcutaneously via a single-dose prefilled syringe for manual use. Prior to use, remove the carton from the refrigerator and allow the Stimufend prefilled syringe to reach room temperature for a minimum of 30 minutes. Discard any prefilled syringe left at room temperature for greater than 72 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Stimufend if discoloration or particulates are observed. The needle cap on the pre-filled syringes contains dry natural rubber (derived from latex); persons with latex allergies should not administer these products. Pediatric Patients weighing less than 45 kg The Stimufend pre-filled 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 Stimufend 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 Stimufend for Pediatric Patients Weighing Less Than 45 kg *For pediatric patients weighing less than 10 kg, administer 0.1 mg/kg (0.01 mL/kg) of Stimufend. Body Weight Stimufend Dose Volume to Administer Less than 10 kg * 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

1 INDICATIONS AND USAGE Stimufend 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 Stimufend is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. 1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy Stimufend 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 Stimufend 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 Stimufend 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 )].

10 OVERDOSAGE Overdosage of pegfilgrastim products may result in leukocytosis and bone pain. Events of edema, dyspnea, and pleural effusion have been reported in a single patient who administered pegfilgrastim on 8 consecutive days in error. In the event of overdose, the patient should be monitored for adverse reactions [see Adverse Reactions ( 6 )] .

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Pegfilgrastim products are colony-stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation. 12.2 Pharmacodynamics Animal data and clinical data in humans suggest a correlation between pegfilgrastim products' exposure and the duration of severe neutropenia as a predictor of efficacy. Selection of the dosing regimen of Stimufend is based on reducing the duration of severe neutropenia. 12.3 Pharmacokinetics The pharmacokinetics of pegfilgrastim was studied in 379 patients with cancer. The pharmacokinetics of pegfilgrastim was nonlinear, and clearance decreased with increases in dose. Neutrophil receptor binding is an important component of the clearance of pegfilgrastim, and serum clearance is directly related to the number of neutrophils. In addition to numbers of neutrophils, body weight appeared to be a factor. Patients with higher body weights experienced higher systemic exposure to pegfilgrastim after receiving a dose normalized for body weight. A large variability in the pharmacokinetics of pegfilgrastim was observed. The half-life of pegfilgrastim ranged from 15 to 80 hours after subcutaneous injection. Specific Populations No gender-related differences were observed in the pharmacokinetics of pegfilgrastim, and no differences were observed in the pharmacokinetics of geriatric patients (³ 65 years of age) compared with younger patients (< 65 years of age) [see Use in Specific Populations ( 8.5 )] . Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. Pediatric Patients with Cancer Receiving Myelosuppressive Chemotherapy The pharmacokinetics and safety of pegfilgrastim were studied in 37 pediatric patients with sarcoma in Study 4 [see Clinical Studies ( 14.1 )] . The mean (± standard deviation [SD]) systemic exposure (AUC 0-inf ) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11), 22.0 (± 13.1) mcg · hr/mL in the 6 to 11 years age group (n = 10), and 29.3 (± 23.2) mcg · hr/mL in the 12 to 21 years age group (n = 13). The terminal elimination half- lives of the corresponding age groups were 30.1 (± 38.2) hours, 20.2 (± 11.3) hours, and 21.2 (± 16.0) hours, respectively. Patients Acutely Exposed to Myelosuppressive Doses of Radiation The pharmacokinetics of pegfilgrastim products is not available in patients acutely exposed to myelosuppressive doses of radiation. Based on limited pharmacokinetic data in irradiated non-human primates, the area under the concentration-time curve (AUC), reflecting the exposure to pegfilgrastim in non-human primates following a 300 mcg/kg dose of pegfilgrastim, appears to be greater than in humans receiving a 6 mg dose. Results from population modeling and simulation indicate that two 6 mg doses of pegfilgrastim administered one week apart in adults result in clinically relevant effects on duration of grade 3 and 4 neutropenia. In addition, weight-based dosing in pediatric patients weighing less than 45 kg [see Dosage and Administration, Section 2.3 , Table 1 ] provides exposures comparable to those in adults receiving two 6 mg doses one week apart.

12.1 Mechanism of Action Pegfilgrastim products are colony-stimulating factors that act on hematopoietic cells by binding to specific cell surface receptors, thereby stimulating proliferation, differentiation, commitment, and end cell functional activation.

12.2 Pharmacodynamics Animal data and clinical data in humans suggest a correlation between pegfilgrastim products' exposure and the duration of severe neutropenia as a predictor of efficacy. Selection of the dosing regimen of Stimufend is based on reducing the duration of severe neutropenia.

12.3 Pharmacokinetics The pharmacokinetics of pegfilgrastim was studied in 379 patients with cancer. The pharmacokinetics of pegfilgrastim was nonlinear, and clearance decreased with increases in dose. Neutrophil receptor binding is an important component of the clearance of pegfilgrastim, and serum clearance is directly related to the number of neutrophils. In addition to numbers of neutrophils, body weight appeared to be a factor. Patients with higher body weights experienced higher systemic exposure to pegfilgrastim after receiving a dose normalized for body weight. A large variability in the pharmacokinetics of pegfilgrastim was observed. The half-life of pegfilgrastim ranged from 15 to 80 hours after subcutaneous injection. Specific Populations No gender-related differences were observed in the pharmacokinetics of pegfilgrastim, and no differences were observed in the pharmacokinetics of geriatric patients (³ 65 years of age) compared with younger patients (< 65 years of age) [see Use in Specific Populations ( 8.5 )] . Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. Pediatric Patients with Cancer Receiving Myelosuppressive Chemotherapy The pharmacokinetics and safety of pegfilgrastim were studied in 37 pediatric patients with sarcoma in Study 4 [see Clinical Studies ( 14.1 )] . The mean (± standard deviation [SD]) systemic exposure (AUC 0-inf ) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11), 22.0 (± 13.1) mcg · hr/mL in the 6 to 11 years age group (n = 10), and 29.3 (± 23.2) mcg · hr/mL in the 12 to 21 years age group (n = 13). The terminal elimination half- lives of the corresponding age groups were 30.1 (± 38.2) hours, 20.2 (± 11.3) hours, and 21.2 (± 16.0) hours, respectively. Patients Acutely Exposed to Myelosuppressive Doses of Radiation The pharmacokinetics of pegfilgrastim products is not available in patients acutely exposed to myelosuppressive doses of radiation. Based on limited pharmacokinetic data in irradiated non-human primates, the area under the concentration-time curve (AUC), reflecting the exposure to pegfilgrastim in non-human primates following a 300 mcg/kg dose of pegfilgrastim, appears to be greater than in humans receiving a 6 mg dose. Results from population modeling and simulation indicate that two 6 mg doses of pegfilgrastim administered one week apart in adults result in clinically relevant effects on duration of grade 3 and 4 neutropenia. In addition, weight-based dosing in pediatric patients weighing less than 45 kg [see Dosage and Administration, Section 2.3 , Table 1 ] provides exposures comparable to those in adults receiving two 6 mg doses one week apart.

20231024

4

3 DOSAGE FORMS AND STRENGTHS Stimufend is a clear, colorless, preservative-free solution available as: Injection: 6 mg/0.6 mL in a single-dose pre-filled syringe for manual use only. Injection: 6 mg/0.6 mL solution in a single-dose pre-filled syringe for manual use only. ( 3 )

STIMUFEND pegflilgrastim-fpgk PEGFILGRASTIM PEGFILGRASTIM ACETATE ION POLYSORBATE 20 SODIUM SORBITOL WATER

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenesis studies have been performed with pegfilgrastim products. Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 6 to 9 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 performed with pegfilgrastim products. Pegfilgrastim did not affect reproductive performance or fertility in male or female rats at cumulative weekly doses approximately 6 to 9 times higher than the recommended human dose (based on body surface area).

BLA761173

STIMUFEND

pegflilgrastim-fpgk

65219-371

HUMAN PRESCRIPTION DRUG

SUBCUTANEOUS

PACKAGE LABEL – PRINCIPAL DISPLAY – STIMUFEND –One 0.6 mL Single-Dose Prefilled Syringe CARTON PANEL Stimufend pegfilgrastim-fpgk Injection 6 mg/0.6 mL NDC 65219-371-10 Rx Only Pegylated Recombinant Methionyl Human Granulocyte Colony-Stimulating Factor (PEG-r-methHuG-CSF) derived from E Coli For Subcutaneous Use Only 1 single-dose pre-filled syringe This product contains Dry Natural Rubber Sterile Solution-No Preservative PACKAGE LABEL – PRINCIPAL DISPLAY – STIMUFEND –One 0.6 mL Single-Dose Prefilled Syringe CARTON PANEL

Indications and Usage, Patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome ( 1.2 ) 9/2023 Dosage and Administration, Patients with Hematopoietic Subsyndrome of Acute radiation Syndrome ( 2.2 ) 9/2023

17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Patient Information and Instructions for Use). Advise patients of the following risks and potential risks with Stimufend: Splenic rupture and splenomegaly Acute Respiratory Distress Syndrome Serious allergic reactions Sickle cell crisis Glomerulonephritis Increased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with breast and lung cancer who receive Stimufend in conjunction with chemotherapy and/or radiation therapy Capillary Leak Syndrome Aortitis Advise patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome) that efficacy studies of pegfilgrastim products for this indication could not be conducted in humans for ethical and feasibility reasons and that, therefore, approval of this use was based on efficacy studies conducted in animals [see Clinical Studies ( 14.2 )] . Instruct patients who self-administer Stimufend using the single-dose pre-filled syringe of the: Importance of following the Instructions for Use (see Instructions for Use). Dangers of reusing syringes. Importance of following local requirements for proper disposal of used syringes. Manufactured by: Fresenius Kabi USA, LLC Lake Zurich, Illinois 60047 U.S. License No. 2146 Product of Italy

Instructions for Use STIMUFEND® (STIM-yu-fend) (pegfilgrastim-fpgk) Injection, for subcutaneous use Single-Dose Prefilled Syringe Guide to parts After Use (Clear needle guard locked in place) Important: The needle is covered by a gray needle cap before use. Important: Read the Patient Information for important information you need to know about STIMUFEND before using these Instructions for Use. Before you use a STIMUFEND prefilled syringe, read this important information. Storing the prefilled syringe Store STIMUFEND in the refrigerator between 36°F and 46°F (2°C to 8°C). Do not freeze. Throw away (dispose of) STIMUFEND that has been frozen. Keep the prefilled syringe in the original carton to protect from light or physical damage. Take the prefilled syringe out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection. Throw away (dispose of) any STIMUFEND that has been left at room temperature, 68°F to 77°F (20°C to 25°C), for more than 72 hours. Keep the STIMUFEND prefilled syringe out of the reach of children. Using the prefilled syringe It is important that you do not try to give the injection unless you or your caregiver has received training from your healthcare provider. Make sure the name STIMUFEND appears on the carton and prefilled syringe label. Check the carton and prefilled syringe label to make sure the dose strength is 6 mg/0.6 mL. You should not inject a dose of STIMUFEND to children weighing less than 45 kg from a STIMUFEND prefilled syringe. A dose less than 0.6 mL (6 mg) cannot be accurately measured using the STIMUFEND prefilled syringe. Do not use a prefilled syringe after the expiration date on the label. Do not shake the prefilled syringe. Do not remove the gray needle cap from the prefilled syringe until you are ready to inject. Do not use the prefilled syringe if the carton is open or damaged. Do not use a prefilled syringe if it has been dropped on a hard surface. The prefilled syringe may be broken even if you cannot see the break. Use a new prefilled syringe. The gray needle cap on the prefilled syringe contains dry natural rubber (made from latex). Tell your healthcare provider if you are allergic to latex. You should not give STIMUFEND using the prefilled syringe if you have latex allergies. The prefilled syringe has a clear needle guard that automatically activates to cover the needle after the injection is given. Do not use a prefilled syringe if the clear needle guard has been activated. Use another prefilled syringe that has not been activated and is ready to use. Call your healthcare provider if you have any questions. Step 1: Prepare 1.1 Remove the prefilled syringe carton from the refrigerator. Remove the syringe tray from the carton. On a clean, well-lit surface, place the syringe tray at room temperature for 30 minutes before you give an injection. Do not use the prefilled syringe if the carton is damaged. Do not try to warm the prefilled syringe by using a heat source such as hot water or microwave. Do not leave the prefilled syringe in direct sunlight. Do not shake the prefilled syringe. Open the tray by peeling away the cover. Grab the clear needle guard to remove the prefilled syringe from the tray (see Figure C ). For safety reasons: Do not grab the plunger rod. Do not grab the gray needle cap. 1.2 Inspect the medicine and prefilled syringe. Make sure the medicine in the prefilled syringe is clear and colorless. Do not use the prefilled syringe if: The needle safety guard is activated (see Figure D ). The medicine is cloudy or discolored, or contains flakes or particles (see Figure E ). Any part appears cracked or broken. The prefilled syringe has been dropped. The gray needle cap is missing or not securely attached (see Figure E ). The expiration date printed on the label has passed (see Figure E ). In all cases use a new syringe and call your healthcare provider. 1.3 Gather all materials needed for the injection (see Figure F ). Wash your hands thoroughly with soap and water. On a clean, well-lit work surface, place the: Prefilled syringe Alcohol wipe Cotton ball or gauze pad Adhesive bandage Sharps disposal container Step 2: Get ready 2.1 Prepare and clean the injection site(s). You can use: Stomach area (abdomen) except for a 2 -inch area away from the navel (belly button) (see Figure G ) Thigh (see Figure G ) Back area of the upper arm (only if someone else is giving you the injection) (See Figure H ) Upper outer area of the buttocks (only if someone else is giving you the injection) (see Figure H ) Clean the injection site with an alcohol wipe (see Figure I ). Let the skin dry. Do not touch this area again before injecting. If you want to use the same injection site, make sure it is not the same spot on the injection site you used for a previous injection. Do not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks. 2.2 Hold the prefilled syringe by the clear needle guard. Carefully pull the gray needle cap straight off and away from the body (see Figure J ). Do not remove the gray needle cap from the prefilled syringe until you are ready to inject. Do not twist or bend the gray needle cap. Do not hold the prefilled syringe by the plunger rod. Do not put the gray needle cap back onto the prefilled syringe. Important: Throw the gray needle cap into the sharps disposal container (see Figure K ). Step 3: Subcutaneous (under the skin) injection 3.1 Pinch the injection site to create a firm surface (see Figure L ). Important: Keep skin pinched while injecting. 3.2 Hold the pinch. Insert the needle into the skin at 45 to 90 degrees (see Figure M ). 3.3 Using slow and constant pressure, push the plunger rod until it reaches the bottom (see Figure N ). The plunger rod must be pushed down fully to ensure the full dose has been injected (see Figure O ). Do not remove the needle from the skin when the plunger reaches the end and proceed with next step. Step 4: Finish 4.1 Slowly release your thumb upward. This will allow the needle to move up into the clear needle guard and cover the entire needle (see Figure P ). Do not try to recap the needle as it could lead to needle stick injury. Important: When you remove the syringe, if it looks like the medicine is still in the syringe barrel, this means you have not received a full dose. Call your healthcare provider right away. 4.2 Discard (throw away) your prefilled syringe. Put the used prefilled syringe in a FDA-cleared sharps disposal container right away after use (see Figure Q ). Do not throw away (dispose of) the prefilled syringe in your household trash. If you do not have a FDA-cleared sharps disposal container, you may use a household container that is: made of a heavy-duty plastic, can be closed with a tight-fitting, puncture-resistant lid, without sharps being able to come out, upright and stable during use, leak-resistant, and properly labeled to warn of hazardous waste inside the container. When your sharps disposal container is almost full, you will need to follow your community guidelines for the right way to dispose of your sharps disposal container. There may be state or local laws about how you should throw away used needles and syringes. For more information about safe sharps disposal, and for specific information about sharps disposal in the state that you live in, go to the FDA's website at: http://www.fda.gov/safesharpsdisposal Do not reuse the prefilled syringe. Do not recycle the prefilled syringe or sharps disposal container or throw them in the household trash. Important : Always keep the sharps disposal container out of the reach of children. 4.3 Examine the injection site. If there is blood, press a cotton ball or gauze pad on the injection site. Do not rub the injection site. Apply an adhesive bandage if needed (see Figure R ). This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured by: Fresenius Kabi USA, LLC Lake Zurich, Illinois 60047 U.S. License No. 2146 Issued: 09/2022 Figure A Figure B Figure C Figure D Figure E Figure F Figures G and H Figure I Figure J Figure K Figure L Figure M Figures N and O Figure P Figure Q Figure R Fresenius Kabi Logo

14 CLINICAL STUDIES 14.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy Pegfilgrastim was evaluated in three randomized, double-blind, controlled studies. Studies 1 and 2 were active-controlled studies that employed doxorubicin 60 mg/m 2 and docetaxel 75 mg/m 2 administered every 21 days for up to 4 cycles for the treatment of metastatic breast cancer. Study 1 investigated the utility of a fixed dose of pegfilgrastim. Study 2 employed a weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in a 100% incidence of severe neutropenia (ANC < 0.5 x 10 9 /L) with a mean duration of 5 to 7 days and a 30% to 40% incidence of febrile neutropenia. Based on the correlation between the duration of severe neutropenia and the incidence of febrile neutropenia found in studies with filgrastim, duration of severe neutropenia was chosen as the primary endpoint in both studies, and the efficacy of pegfilgrastim was demonstrated by establishing comparability to filgrastim-treated patients in the mean days of severe neutropenia. In Study 1, 157 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) on day 2 of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (100 mcg/kg) on day 2 or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 2 of each chemotherapy cycle. Both studies met the major efficacy outcome measure of demonstrating that the mean days of severe neutropenia of pegfilgrastim-treated patients did not exceed that of filgrastim-treated patients by more than 1 day in cycle 1 of chemotherapy. The mean days of cycle 1 severe neutropenia in Study 1 were 1.8 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.2 (95% CI - 0.2, 0.6)] and in Study 2 were 1.7 days in the pegfilgrastim arm compared to 1.6 days in the filgrastim arm [difference in means 0.1 (95% CI - 0.2, 0.4)]. A secondary endpoint in both studies was days of severe neutropenia in cycles 2 through 4 with results similar to those for cycle 1. Study 3 was a randomized, double-blind, placebo-controlled study that employed docetaxel 100 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, 928 patients were randomized to receive a single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day 2 of each chemotherapy cycle. Study 3 met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature ≥ 38.2°C and ANC ≤ 0.5 x 10 9 /L) was lower for pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, p < 0.001). The incidence of hospitalizations (1% versus 14%) and IV anti-infective use (2% versus 10%) for the treatment of febrile neutropenia was also lower in the pegfilgrastim-treated patients compared to the placebo-treated patients. Study 4 was a multicenter, randomized, open-label study to evaluate the efficacy, safety, and pharmacokinetics [see Clinical Pharmacology ( 12.3 )] of pegfilgrastim in pediatric and young adult patients with sarcoma. Patients with sarcoma receiving chemotherapy age 0 to 21 years were eligible. Patients were randomized to receive subcutaneous pegfilgrastim as a single-dose of 100 mcg/kg (n = 37) or subcutaneous filgrastim at a dose 5 mcg/kg/day (n = 6) following myelosuppressive chemotherapy. Recovery of neutrophil counts was similar in the pegfilgrastim and filgrastim groups. The most common adverse reaction reported was bone pain. 14.2 Patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome Efficacy studies of pegfilgrastim products could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Approval of this indication was based on efficacy studies conducted in animals and data supporting pegfilgrastim's effect on severe neutropenia in patients with cancer receiving myelosuppressive chemotherapy [see Dosage and Administration ( 2.1 )]. The recommended dose of Stimufend is two doses, 6 mg each, administered one week apart for humans exposed to myelosuppressive doses of radiation. For pediatric patients weighing less than 45 kg, dosing of Stimufend is weight-based and is provided in Table 1 [see Dosage and Administration ( 2.3 )] . This dosing regimen is based on population modeling and simulation analyses. The exposure associated with this dosing regimen is expected to provide sufficient pharmacodynamic activity to treat humans exposed to myelosuppressive doses of radiation [see Clinical Pharmacology ( 12.3 )] . The safety of pegfilgrastim at a dose of 6 mg has been assessed on the basis of clinical experience in patients with cancer receiving myelosuppressive chemotherapy. The efficacy of pegfilgrastim for the acute radiation syndrome setting was studied in a randomized, placebo-controlled non-human primate model of radiation injury. Rhesus macaques were randomized to either a control (n = 23) or treated (n = 23) cohort. On study day 0, animals (n = 6 to 8 per irradiation day) were exposed to total body irradiation (TBI) of 7.50 ± 0.15 Gy delivered at 0.8 ± 0.03 Gy/min, representing a dose that would be lethal in 50% of animals by 60 days of follow-up (LD50/60). Animals were administered subcutaneous injections of a blinded treatment (control article [5% dextrose in water] or pegfilgrastim [300-319 mcg/kg/day]) on study day 1 and on study day 8. The primary endpoint was survival. Animals received medical management consisting of intravenous fluids, antibiotics, blood transfusions, and other support as required. Pegfilgrastim significantly (at 0.0014 level of significance) increased 60-day survival in irradiated non-human primates: 91% survival (21/23) in the pegfilgrastim group compared to 48% survival (11/23) in the control group.

8.5 Geriatric Use Of the 932 patients with cancer who received pegfilgrastim in clinical studies, 139 (15%) were aged 65 and over, and 18 (2%) were aged 75 and over. No overall differences in safety or effectiveness were observed between patients aged 65 and older and younger patients.

8.4 Pediatric Use The safety and effectiveness of Stimufend have been established in pediatric patients. No overall differences in safety were identified between adult and pediatric patients based on postmarketing surveillance and review of the scientific literature. Use of Stimufend in pediatric patients for chemotherapy-induced neutropenia is based on Stimufend's approval as a biosimilar to pegfilgrastim and evidence from adequate and well-controlled studies of pegfilgrastim in adults with additional pharmacokinetic and safety data of pegfilgrastim in pediatric patients with sarcoma [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.1 )] . The use of Stimufend to increase survival in pediatric patients acutely exposed to myelosuppressive doses of radiation is based on Stimufend's approval as a biosimilar to pegfilgrastim, evidence from efficacy studies of pegfilgrastim conducted in animals, and clinical data supporting the use of pegfilgrastim in patients with cancer receiving myelosuppressive chemotherapy. Efficacy studies of pegfilgrastim products could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Results from population modeling and simulation indicate that two weight-based doses of pegfilgrastim ( Table 1 ) administered one week apart provide pediatric patients weighing less than 45 kg with exposures comparable to that of adults receiving two 6 mg doses one week apart [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )].

8.1 Pregnancy Risk Summary Although available data with Stimufend 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 embryolethality 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary Although available data with Stimufend 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 embryolethality 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 Stimufend and any potential adverse effects on the breastfed child from Stimufend or from the underlying maternal condition. 8.4 Pediatric Use The safety and effectiveness of Stimufend have been established in pediatric patients. No overall differences in safety were identified between adult and pediatric patients based on postmarketing surveillance and review of the scientific literature. Use of Stimufend in pediatric patients for chemotherapy-induced neutropenia is based on Stimufend's approval as a biosimilar to pegfilgrastim and evidence from adequate and well-controlled studies of pegfilgrastim in adults with additional pharmacokinetic and safety data of pegfilgrastim in pediatric patients with sarcoma [see Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.1 )] . The use of Stimufend to increase survival in pediatric patients acutely exposed to myelosuppressive doses of radiation is based on Stimufend's approval as a biosimilar to pegfilgrastim, evidence from efficacy studies of pegfilgrastim conducted in animals, and clinical data supporting the use of pegfilgrastim in patients with cancer receiving myelosuppressive chemotherapy. Efficacy studies of pegfilgrastim products could not be conducted in humans with acute radiation syndrome for ethical and feasibility reasons. Results from population modeling and simulation indicate that two weight-based doses of pegfilgrastim ( Table 1 ) administered one week apart provide pediatric patients weighing less than 45 kg with exposures comparable to that of adults receiving two 6 mg doses one week apart [see Dosage and Administration ( 2.3 ), Clinical Pharmacology ( 12.3 ) and Clinical Studies ( 14.2 )]. 8.5 Geriatric Use Of the 932 patients with cancer who received pegfilgrastim in clinical studies, 139 (15%) were aged 65 and over, and 18 (2%) were aged 75 and over. No overall differences in safety or effectiveness were observed between patients aged 65 and older and younger patients.

16 HOW SUPPLIED/STORAGE AND HANDLING Stimufend single-dose prefilled syringe for manual use Stimufend (pegfilgrastim-fpgk) injection is a clear, colorless, preservative-free solution supplied in a pre-filled single-dose syringe for manual use containing 6 mg pegfilgrastim-fpgk, supplied with a 27-gauge, 1/2-inch needle with a Safe'n'Sound ® passive Needle Guard. The needle cap of the pre-filled syringe contains natural rubber (a derivative of latex). Stimufend is provided in a dispensing pack containing one sterile 6 mg/0.6 mL pre-filled syringe (NDC 65219-371-10). Stimufend pre-filled syringe does not bear graduation marks and is intended only to deliver the entire contents of the syringe (6 mg/0.6 mL) for direct administration. Use of the pre-filled syringe is not recommended for direct administration for pediatric patients weighing less than 45 kg who require doses that are less than the full contents of the syringe. Store refrigerated between 36°F to 46°F (2°C to 8°C) in the carton to protect from light. Do not shake. Discard syringes stored at room temperature for more than 72 hours. Do not freeze. Discard syringe if frozen.