CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

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 to times higher than the recommended human dose (based on body surface area).

ADVERSE REACTIONS SECTION.

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)] 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 Pfizer Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.Biosimilar means that the biological product is approved based on data demonstrating that it is highly similar to an FDA-approved biological product, known as reference product, and that there are no clinically meaningful differences between the biosimilar product and the reference product.Biosimilarity of NYVEPRIA has been demonstrated for the condition(s) of use (e.g., indication(s), dosing regimen(s)), strength(s), dosage form(s), and route(s) of administration described in its Full Prescribing Information.. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 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 single 100 mcg/kg (n 259) or single mg (n 546) dose per chemotherapy cycle over cycles.The following adverse reaction data in Table are from randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days (Study 3). total of 928 patients were randomized to receive either 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 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 3Body System Adverse ReactionPlacebo(N 461)Pegfilgrastim mg SC on Day 2(N 467)Musculoskeletal and connective tissue disorders Bone pain26%31% Pain in extremity4%9%. LeukocytosisIn clinical studies, leukocytosis (WBC counts >100 109/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.. 6.2Immunogenicity. 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 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 patients had evidence of neutralizing antibodies detected using cell-based bioassay.. 6.3Postmarketing Experience. The following adverse reactions have been identified during post-approval use of pegfilgrastim products. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to reliably estimate their frequency or establish 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 reactionsSweets syndrome (acute febrile neutrophilic dermatosis), cutaneous vasculitisMyelodysplastic 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. 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. Sweets 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.

CLINICAL PHARMACOLOGY SECTION.

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 correlation between pegfilgrastim products exposure and the duration of severe neutropenia as predictor of efficacy. Selection of the dosing regimen of NYVEPRIA 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 factor. Patients with higher body weights experienced higher systemic exposure to pegfilgrastim after receiving dose normalized for body weight. large variability in the pharmacokinetics of pegfilgrastim was observed. The half-life of pegfilgrastim ranged from 15 to 80 hours after subcutaneous injection. Specific PopulationsNo gender-related differences were observed in the pharmacokinetics of pegfilgrastim, and no differences were observed in the pharmacokinetics of geriatric patients (>=65 years of age) compared with younger patients (<65 years of age) [see Use in Specific Populations (8.5)].. Renal ImpairmentIn 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 ChemotherapyThe pharmacokinetics and safety of pegfilgrastim were studied in 37 pediatric patients with sarcoma in Study [see Clinical Studies (14)]. The mean (+- standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 47.9 (+- 22.5) mcghr/mL in the youngest age group (0 to years, = 11), 22.0 (+- 13.1) mcghr/mL in the to 11 years age group (n 10), and 29.3 (+- 23.2) mcghr/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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Pegfilgrastim was evaluated in three randomized, double-blind, controlled studies. Studies and were active-controlled studies that employed doxorubicin 60 mg/m2 and docetaxel 75 mg/m2 administered every 21 days for up to cycles for the treatment of metastatic breast cancer. Study investigated the utility of fixed dose of pegfilgrastim. Study employed weight-adjusted dose. In the absence of growth factor support, similar chemotherapy regimens have been reported to result in 100% incidence of severe neutropenia (ANC <0.5 109/L) with mean duration of to days and 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 single subcutaneous injection of pegfilgrastim (6 mg) on day of each chemotherapy cycle or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day of each chemotherapy cycle. In Study 2, 310 patients were randomized to receive single subcutaneous injection of pegfilgrastim (100 mcg/kg) on day or daily subcutaneous filgrastim (5 mcg/kg/day) beginning on day 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 day in cycle of chemotherapy. The mean days of cycle severe neutropenia in Study 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 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 through with results similar to those for cycle 1.Study was randomized, double-blind, placebo-controlled study that employed docetaxel 100 mg/m2 administered every 21 days for up to cycles for the treatment of metastatic or non-metastatic breast cancer. In this study, 928 patients were randomized to receive single subcutaneous injection of pegfilgrastim (6 mg) or placebo on day of each chemotherapy cycle. Study met the major trial outcome measure of demonstrating that the incidence of febrile neutropenia (defined as temperature >=38.2C and ANC <=0.5 109/L) was lower for pegfilgrastim-treated patients as compared to placebo-treated patients (1% versus 17%, respectively, < 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 was 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 to 21 years were eligible. Patients were randomized to receive subcutaneous pegfilgrastim as single dose of 100 mcg/kg (n 37) or subcutaneous filgrastim at dose 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.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. NYVEPRIA is contraindicated in patients with history of serious allergic reactions to pegfilgrastim products or filgrastim products. Reactions have included anaphylaxis [see Warnings and Precautions (5.3)].. Patients with history of serious allergic reactions to human granulocyte colony-stimulating factors such as pegfilgrastim products or filgrastim products. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Pegfilgrastim-apgf is covalent conjugate of recombinant methionyl human G-CSF and monomethoxypolyethylene glycol. Recombinant methionyl human G-CSF is water-soluble 175 amino acid protein with molecular weight of approximately 19 kilodaltons (kD). Recombinant methionyl human G-CSF is obtained from the bacterial fermentation of strain of E. coli transformed with genetically engineered plasmid containing the human G-CSF gene. To produce pegfilgrastim-apgf, 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-apgf is approximately 39 kD.NYVEPRIA for manual subcutaneous injection is supplied in 0.6 mL prefilled syringes. The prefilled 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 for manual subcutaneous injection contains mg pegfilgrastim-apgf (based on protein weight) in sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.35 mg), polysorbate 20 (0.02 mg), sodium (0.01 mg), and sorbitol (30 mg) in Water for Injection, USP.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Patients with cancer receiving myelosuppressive chemotherapy6 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. (2.2). 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. (2.2). 2.1Patients with Cancer Receiving Myelosuppressive Chemotherapy. The recommended dosage of NYVEPRIA is single subcutaneous injection of mg administered once per chemotherapy cycle. For dosing in pediatric patients weighing less than 45 kg, refer to Table 1. Do not administer NYVEPRIA between 14 days before and 24 hours after administration of cytotoxic chemotherapy.. 2.2Administration. NYVEPRIA is administered subcutaneously via single-dose prefilled syringe for manual use.Prior to use, remove the carton from the refrigerator and allow the NYVEPRIA prefilled syringe to reach room temperature for minimum of 30 minutes. Discard any prefilled syringe left at room temperature for greater than 15 days.Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. NYVEPRIA is supplied as clear and colorless solution. Do not administer NYVEPRIA if discoloration or particulates are observed.The NYVEPRIA syringe plunger stopper and needle cover are not made with natural rubber latex.. Pediatric Patients Weighing Less than 45 kgThe NYVEPRIA prefilled 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 NYVEPRIA 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 NYVEPRIA for Pediatric Patients Weighing Less than 45 kgBody WeightNYVEPRIA DoseVolume to AdministerLess than 10 kgFor pediatric patients weighing less than 10 kg, administer 0.1 mg/kg (0.01 mL/kg) of NYVEPRIA. See below See below 10 20 kg1.5 mg0.15 mL21 30 kg2.5 mg0.25 mL31 44 kg4 mg0.4 mL.

DOSAGE FORMS & STRENGTHS SECTION.

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

GERIATRIC USE SECTION.

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.

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. NYVEPRIA (pegfilgrastim-apgf) injection is clear, colorless solution supplied in prefilled single-dose syringe for manual use containing mg pegfilgrastim-apgf, supplied with 27-gauge 1/2-inch needle and BD UltraSafe Plus(TM) Passive Needle Guard.The NYVEPRIA syringe plunger stopper and needle cover are not made with natural rubber latex.NYVEPRIA is provided in dispensing pack containing one sterile mg/0.6 mL prefilled syringe (NDC 0069-0324-01).NYVEPRIA prefilled 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 prefilled 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 36F to 46F (2C to 8C) in the carton to protect from light. Do not shake. Discard syringes stored at room temperature for more than 15 days. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard syringe if frozen more than once.

IMMUNOGENICITY.

6.2Immunogenicity. 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 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 patients had evidence of neutralizing antibodies detected using cell-based bioassay.

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. NYVEPRIA 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 clinically significant incidence of febrile neutropenia [see Clinical Studies (14)].. NYVEPRIA is 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 clinically significant incidence of febrile neutropenia. (1)Limitations of UseNYVEPRIA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. (1). Limitations of UseNYVEPRIA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

INFORMATION FOR PATIENTS SECTION.

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 NYVEPRIA:Splenic rupture and splenomegalyAcute Respiratory Distress SyndromeSerious allergic reactionsSickle cell crisisGlomerulonephritisIncreased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with breast and lung cancer who receive pegfilgrastim products in conjunction with chemotherapy and/or radiation therapyCapillary Leak SyndromeAortitisInstruct patients who self-administer NYVEPRIA using the single-dose prefilled syringe of the:Importance of following the Instructions for Use.Dangers of reusing syringes.Importance of following local requirements for proper disposal of used syringes.This products labeling may have been updated. For the most recent prescribing information, please visit www.pfizer.com.. 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 pegfilgrastim products in conjunction with chemotherapy and/or radiation therapy. Capillary Leak Syndrome. Aortitis. Importance of following the Instructions for Use.. Dangers of reusing syringes.. Importance of following local requirements for proper disposal of used syringes.

INSTRUCTIONS FOR USE SECTION.

Instructions for UseNYVEPRIA (Nigh-VEP ree-ah)(pegfilgrastim-apgf)Injection, for subcutaneous useSingle-Dose Prefilled SyringeGuide to partsBefore useAfter useImportant: The needle is covered by the needle cover before use.ImportantRead the Patient Information for important information that you need to know about NYVEPRIA before using these Instructions for Use.Before you use NYVEPRIA prefilled syringe, read this important information.Storing the prefilled syringeStore NYVEPRIA in the refrigerator between 36F to 46F (2C to 8C).Do not freeze. If NYVEPRIA is accidentally frozen, allow the prefilled syringe to thaw in the refrigerator before injecting.Do not use NYVEPRIA prefilled syringe that has been frozen more than time. Use new NYVEPRIA prefilled syringe.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 NYVEPRIA that has been left at room temperature, 68F to 77F (20C to 25C), for more than 15 days. Keep the NYVEPRIA prefilled syringe out of the reach of children.Using the prefilled syringeIt 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 NYVEPRIA appears on the carton and prefilled syringe label.Check the carton and prefilled syringe label to make sure the dose strength is mg/0.6 mL.You should not inject dose of NYVEPRIA to children weighing less than 45 kg from NYVEPRIA prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the NYVEPRIA prefilled syringe.Do not use prefilled syringe after the expiration date on the label.Do not shake the prefilled syringe.Do not remove the needle cover 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 prefilled syringe if it has been dropped on hard surface. The prefilled syringe may be broken even if you cannot see the break. Use new prefilled syringe.The prefilled syringe has needle guard that automatically activates to cover the needle after the injection is given. Do not use prefilled syringe if the 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: PrepareA. Remove the prefilled syringe carton from the refrigerator.Remove the inner carton containing the prefilled syringe from the outer carton by peeling away the cover. On clean, well-lit surface, place the inner carton containing the prefilled syringe at room temperature for 30 minutes before you give an injection. Do not use the prefilled syringe if the inner carton containing the prefilled syringe is damaged.Do not try to warm the prefilled syringe by using 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 inner carton containing the prefilled syringe by peeling away the cover. Grab the needle guard to remove the prefilled syringe from the inner carton containing the prefilled syringe.For safety reasons: Do not grab the plunger rod.Do not grab the needle cover. B. 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 medicine is cloudy or discolored, or contains flakes or particles.Any part appears cracked or broken.The prefilled syringe has been dropped.The needle cover is missing or not securely attached.The expiration date printed on the label has passed. In all cases, use new prefilled syringe and call your healthcare provider. C. Gather all materials needed for the injection.Wash your hands thoroughly with soap and water.On clean, well-lit work surface, place the: Prefilled syringeAlcohol wipeCotton ball or gauze padAdhesive bandageSharps disposal container Step 2: Get readyD. Prepare and clean the injection site(s). You can use: ThighStomach area (abdomen), except for 2-inch area right around the navel (belly button)Upper outer area of the buttocks (only if someone else is giving you the injection) Outer area of upper arm (only if someone else is giving you the injection)Clean the injection site with an alcohol wipe. 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 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. E. Hold the prefilled syringe by the needle guard. Carefully pull the needle cover straight off and away from the body. Throw away the needle cover into the sharps disposal container. Do not recap. Do not remove the needle cover from the prefilled syringe until you are ready to inject. Do not twist or bend the needle cover.Do not hold the prefilled syringe by the plunger rod.Do not put the needle cover back onto the prefilled syringe. Important: Throw the needle cover into the sharps disposal container.Step 3: Subcutaneous (under the skin) injectionF. Pinch the injection site to create firm surface. Important: Keep skin pinched while injecting. G. Hold the pinch. Insert the needle into the skin at 45 to 90 degrees. H. Using slow and constant pressure, push the plunger rod down until it reaches the bottom. Step 4: FinishI. When the syringe is empty, keep the plunger rod fully pressed down while you carefully pull the needle straight out from the injection site and off your skin. J. Slowly release the plunger rod and allow the syringe needle guard to automatically cover the exposed needle. Do not recap the needle. Important: When you remove the syringe, if it looks like the medicine is still in the syringe barrel, this means you have not received full dose. Call your healthcare provider right away. K. Examine the injection site. If there is blood, press cotton ball or gauze pad on the injection site. Do not rub the injection site. Apply an adhesive bandage if needed. L. Discard (throw away) the used prefilled syringe. Put the used prefilled syringe in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the syringe in your household trash.If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly 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 FDAs 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.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured byHospira, Inc., Pfizer Company,Lake Forest, IL 60045 USAUS License No. 1974Distributed by Pfizer Labs, division of Pfizer Inc., New York, NY 10017 USA For more information go to www.pfizer.com or call 1-800-438-1985.LAB-1188-2.0Issued: October 2021. Store NYVEPRIA in the refrigerator between 36F to 46F (2C to 8C).. Do not freeze. If NYVEPRIA is accidentally frozen, allow the prefilled syringe to thaw in the refrigerator before injecting.. Do not use NYVEPRIA prefilled syringe that has been frozen more than time. Use new NYVEPRIA prefilled syringe.. 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 NYVEPRIA that has been left at room temperature, 68F to 77F (20C to 25C), for more than 15 days. 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 NYVEPRIA that has been left at room temperature, 68F to 77F (20C to 25C), for more than 15 days.. Keep the NYVEPRIA prefilled syringe out of the reach of children.. 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 NYVEPRIA appears on the carton and prefilled syringe label.. Check the carton and prefilled syringe label to make sure the dose strength is mg/0.6 mL.. You should not inject dose of NYVEPRIA to children weighing less than 45 kg from NYVEPRIA prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the NYVEPRIA prefilled syringe.. Do not use prefilled syringe after the expiration date on the label.. Do not shake the prefilled syringe.Do not remove the needle cover from the prefilled syringe until you are ready to inject. Do not remove the needle cover 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 prefilled syringe if it has been dropped on hard surface. The prefilled syringe may be broken even if you cannot see the break. Use new prefilled syringe.. The prefilled syringe has needle guard that automatically activates to cover the needle after the injection is given. Do not use prefilled syringe if the needle guard has been activated. Use another prefilled syringe that has not been activated and is ready to use.. Do not use the prefilled syringe if the inner carton containing the prefilled syringe is damaged.. Do not try to warm the prefilled syringe by using heat source such as hot water or microwave.. Do not leave the prefilled syringe in direct sunlight. Do not shake the prefilled syringe.. Do not grab the plunger rod.. Do not grab the needle cover.. Do not use the prefilled syringe if:The medicine is cloudy or discolored, or contains flakes or particles.Any part appears cracked or broken.The prefilled syringe has been dropped.The needle cover is missing or not securely attached.The expiration date printed on the label has passed. The medicine is cloudy or discolored, or contains flakes or particles.. Any part appears cracked or broken.. The prefilled syringe has been dropped.. The needle cover is missing or not securely attached.. The expiration date printed on the label has passed.. Prefilled syringe. Alcohol wipe. Cotton ball or gauze pad. Adhesive bandage. Sharps disposal container. Thigh. Stomach area (abdomen), except for 2-inch area right around the navel (belly button). Upper outer area of the buttocks (only if someone else is giving you the injection) Outer area of upper arm (only if someone else is giving you the injection). 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 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.. Do not remove the needle cover from the prefilled syringe until you are ready to inject. Do not twist or bend the needle cover.. Do not hold the prefilled syringe by the plunger rod.. Do not put the needle cover back onto the prefilled syringe.. Put the used prefilled syringe in FDA-cleared sharps disposal container right away after use. Do not throw away (dispose of) the syringe in your household trash.. If you do not have FDA-cleared sharps disposal container, you may use household container that is:made of heavy-duty plastic,can be closed with tight-fitting, puncture-resistant lid, without sharps being able to come out,upright and stable during use,leak-resistant, andproperly labeled to warn of hazardous waste inside the container. made of heavy-duty plastic,. can be closed with 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 FDAs 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.. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure. Figure.

LACTATION SECTION.

8.2 Lactation. Risk SummaryThere 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 mothers clinical need for NYVEPRIA and any potential adverse effects on the breastfed child from NYVEPRIA or from the underlying maternal condition.

MECHANISM OF ACTION SECTION.

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.

MICROBIOLOGY SECTION.

NYVEPRIA (pegfilgrastim-apgf) is biosimilar to NEULASTA (pegfilgrastim).

NONCLINICAL TOXICOLOGY SECTION.

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 to times higher than the recommended human dose (based on body surface area).

OVERDOSAGE SECTION.

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

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL 6 mg/0.6 mL Syringe Label. Nyvepria(TM)(pegfilgrastim-apgf) InjectionRx only6 mg/0.6 mLFor Subcutaneous Use OnlySingle-Dose Prefilled Syringewith Needle GuardNDC 0069-0324-01Mfd by Hospira, Inc., PfizerCompany Lake Forest, IL 60045 USAUS License No. 1974PAA147907. PRINCIPAL DISPLAY PANEL 6 mg/0.6 mL Syringe Label.

PEDIATRIC USE SECTION.

8.4 Pediatric Use. The safety and effectiveness of pegfilgrastim 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 pegfilgrastim in pediatric patients for chemotherapy-induced neutropenia is based on adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients with sarcoma [see Clinical Pharmacology (12.3) and Clinical Studies (14)].

PHARMACODYNAMICS SECTION.

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

PHARMACOKINETICS SECTION.

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 factor. Patients with higher body weights experienced higher systemic exposure to pegfilgrastim after receiving dose normalized for body weight. large variability in the pharmacokinetics of pegfilgrastim was observed. The half-life of pegfilgrastim ranged from 15 to 80 hours after subcutaneous injection. Specific PopulationsNo gender-related differences were observed in the pharmacokinetics of pegfilgrastim, and no differences were observed in the pharmacokinetics of geriatric patients (>=65 years of age) compared with younger patients (<65 years of age) [see Use in Specific Populations (8.5)].. Renal ImpairmentIn 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 ChemotherapyThe pharmacokinetics and safety of pegfilgrastim were studied in 37 pediatric patients with sarcoma in Study [see Clinical Studies (14)]. The mean (+- standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 47.9 (+- 22.5) mcghr/mL in the youngest age group (0 to years, = 11), 22.0 (+- 13.1) mcghr/mL in the to 11 years age group (n 10), and 29.3 (+- 23.2) mcghr/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.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryAlthough available data with NYVEPRIA or pegfilgrastim product use in pregnant women are insufficient to establish whether there is 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 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 background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataPregnant 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 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 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 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).

RECENT MAJOR CHANGES SECTION.

Warnings and Precautions, Thrombocytopenia (5.7)04/2021Warnings and Precautions, Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) (5.10)04/2021.

SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Revised: October 2021 Patient InformationNYVEPRIA(TM) (Nigh-VEP ree-ah) (pegfilgrastim-apgf)injectionSingle-Dose Prefilled SyringeWhat is NYVEPRIANYVEPRIA is man-made form of granulocyte colony-stimulating factor (G-CSF). G-CSF is substance produced by the body. It stimulates the growth of neutrophils, type of white blood cell important in the bodys fight against infection.Do not take NYVEPRIA if you have had serious allergic reaction to pegfilgrastim products or filgrastim products.Before you receive NYVEPRIA, tell your healthcare provider about all of your medical conditions, including if you:have sickle cell disorder.have kidney problems.are pregnant or plan to become pregnant. It is not known if NYVEPRIA will harm your unborn baby.are breastfeeding or plan to breastfeed. It is not known if NYVEPRIA passes into your breast milk.Tell your healthcare provider about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.How will receive NYVEPRIANYVEPRIA is given as an injection under your skin (subcutaneous injection) by healthcare provider. If your healthcare provider decides that the subcutaneous injections can be given at home by you or your caregiver, follow the detailed Instructions for Use that comes with your NYVEPRIA for information on how to prepare and inject dose of NYVEPRIA.You and your caregiver will be shown how to prepare and inject NYVEPRIA before you use it.You should not inject dose of NYVEPRIA to children weighing less than 45 kg from NYVEPRIA prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the NYVEPRIA prefilled syringe.If you are receiving NYVEPRIA because you are also receiving chemotherapy, the last dose of NYVEPRIA should be injected at least 14 days before and 24 hours after your dose of chemotherapy.If you miss dose of NYVEPRIA, talk to your healthcare provider about when you should give your next dose.What are possible side effects of NYVEPRIANYVEPRIA may cause serious side effects, including:Spleen rupture. Your spleen may become enlarged and can rupture. ruptured spleen can cause death. Call your healthcare provider right away if you have pain in the left upper stomach area or your left shoulder.A serious lung problem called Acute Respiratory Distress Syndrome (ARDS). Call your healthcare provider or get emergency help right away if you have shortness of breath with or without fever, trouble breathing, or fast rate of breathing.Serious allergic reactions. NYVEPRIA can cause serious allergic reactions. These reactions can cause rash over your whole body, shortness of breath, wheezing, dizziness, swelling around your mouth or eyes, fast heart rate, and sweating. If you have any of these symptoms, stop using NYVEPRIA and call your healthcare provider or get emergency medical help right away.Sickle cell crises. You may have serious sickle cell crisis, which could lead to death, if you have sickle cell disorder and receive NYVEPRIA. Call your healthcare provider right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing.Kidney injury (glomerulonephritis). NYVEPRIA can cause kidney injury. Call your healthcare provider right away if you develop any of the following symptoms:swelling of your face or ankles blood in your urine or dark colored urineyou urinate less than usual Increased white blood cell count (leukocytosis). Your healthcare provider will check your blood during treatment with NYVEPRIA.Decreased platelet count (thrombocytopenia). Your healthcare provider will check your blood during treatment with NYVEPRIA. Tell your healthcare provider if you have unusual bleeding or bruising during treatment with NYVEPRIA. This could be sign of decreased platelet counts, which may reduce the ability of your blood to clot.Capillary Leak Syndrome. NYVEPRIA can cause fluid to leak from blood vessels into your bodys tissues. This condition is called Capillary Leak Syndrome (CLS). CLS can quickly cause you to have symptoms that may become life-threatening. Get emergency medical help right away if you develop any of the following symptoms:swelling or puffiness and are urinating less than usualtrouble breathingswelling of your stomach area (abdomen) and feeling of fullnessdizziness or feeling fainta general feeling of tiredness Myelodysplastic syndrome and acute myeloid leukemia. If you have breast cancer or lung cancer, when NYVEPRIA is used with chemotherapy and radiation therapy, or with radiation therapy alone, you may have an increased risk of developing precancerous blood condition called myelodysplastic syndrome (MDS) or blood cancer called acute myeloid leukemia (AML). Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding. Call your healthcare provider if you develop these symptoms during treatment with NYVEPRIA.Inflammation of the aorta (aortitis). Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) has been reported in patients who received pegfilgrastim products. Symptoms may include fever, abdominal pain, feeling tired, and back pain. Call your healthcare provider if you experience these symptoms. The most common side effects of NYVEPRIA are pain in the bones, arms, and legs. These are not all the possible side effects of NYVEPRIA. Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store NYVEPRIAStore NYVEPRIA in the refrigerator between 36F to 46F (2C to 8C).Do not freeze. If NYVEPRIA is accidentally frozen, allow the prefilled syringe to thaw in the refrigerator before injecting.Do not use NYVEPRIA prefilled syringe that has been frozen more than time. Use new NYVEPRIA prefilled syringe.Keep the prefilled syringe in the original carton to protect from light or physical damage.Do not shake the prefilled syringe.Take NYVEPRIA out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.Throw away (dispose of) any NYVEPRIA that has been left at room temperature, 68F to 77F (20C to 25C), for more than 15 days.Keep the NYVEPRIA prefilled syringe out of the reach of children.General information about the safe and effective use of NYVEPRIA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use NYVEPRIA for condition for which it was not prescribed. Do not give NYVEPRIA to other people, even if they have the same symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about NYVEPRIA that is written for health professionals.What are the ingredients in NYVEPRIAActive ingredient: pegfilgrastim-apgf.Inactive ingredients: acetate, polysorbate 20, sodium, and sorbitol in water for injection.Manufactured by Hospira, Inc., Pfizer Company, Lake Forest, IL 60045 USAUS License No. 1974Distributed by Pfizer Labs, division of Pfizer Inc., New York, NY 10017 USALAB-1187-3.0For more information go to www.pfizer.com or call 1-800-438-1985.. have sickle cell disorder.. have kidney problems.. are pregnant or plan to become pregnant. It is not known if NYVEPRIA will harm your unborn baby.. are breastfeeding or plan to breastfeed. It is not known if NYVEPRIA passes into your breast milk.. NYVEPRIA is given as an injection under your skin (subcutaneous injection) by healthcare provider. If your healthcare provider decides that the subcutaneous injections can be given at home by you or your caregiver, follow the detailed Instructions for Use that comes with your NYVEPRIA for information on how to prepare and inject dose of NYVEPRIA.. You and your caregiver will be shown how to prepare and inject NYVEPRIA before you use it.. You should not inject dose of NYVEPRIA to children weighing less than 45 kg from NYVEPRIA prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the NYVEPRIA prefilled syringe.. If you are receiving NYVEPRIA because you are also receiving chemotherapy, the last dose of NYVEPRIA should be injected at least 14 days before and 24 hours after your dose of chemotherapy.. If you miss dose of NYVEPRIA, talk to your healthcare provider about when you should give your next dose.. Spleen rupture. Your spleen may become enlarged and can rupture. ruptured spleen can cause death. Call your healthcare provider right away if you have pain in the left upper stomach area or your left shoulder.. serious lung problem called Acute Respiratory Distress Syndrome (ARDS). Call your healthcare provider or get emergency help right away if you have shortness of breath with or without fever, trouble breathing, or fast rate of breathing.. Serious allergic reactions. NYVEPRIA can cause serious allergic reactions. These reactions can cause rash over your whole body, shortness of breath, wheezing, dizziness, swelling around your mouth or eyes, fast heart rate, and sweating. If you have any of these symptoms, stop using NYVEPRIA and call your healthcare provider or get emergency medical help right away.. Sickle cell crises. You may have serious sickle cell crisis, which could lead to death, if you have sickle cell disorder and receive NYVEPRIA. Call your healthcare provider right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing.. Kidney injury (glomerulonephritis). NYVEPRIA can cause kidney injury. Call your healthcare provider right away if you develop any of the following symptoms:swelling of your face or ankles blood in your urine or dark colored urineyou urinate less than usual swelling of your face or ankles blood in your urine or dark colored urine. you urinate less than usual. Increased white blood cell count (leukocytosis). Your healthcare provider will check your blood during treatment with NYVEPRIA.. Decreased platelet count (thrombocytopenia). Your healthcare provider will check your blood during treatment with NYVEPRIA. Tell your healthcare provider if you have unusual bleeding or bruising during treatment with NYVEPRIA. This could be sign of decreased platelet counts, which may reduce the ability of your blood to clot.. Capillary Leak Syndrome. NYVEPRIA can cause fluid to leak from blood vessels into your bodys tissues. This condition is called Capillary Leak Syndrome (CLS). CLS can quickly cause you to have symptoms that may become life-threatening. Get emergency medical help right away if you develop any of the following symptoms:swelling or puffiness and are urinating less than usualtrouble breathingswelling of your stomach area (abdomen) and feeling of fullnessdizziness or feeling fainta general feeling of tiredness swelling or puffiness and are urinating less than usual. trouble breathing. swelling of your stomach area (abdomen) and feeling of fullness. dizziness or feeling faint. general feeling of tiredness. Myelodysplastic syndrome and acute myeloid leukemia. If you have breast cancer or lung cancer, when NYVEPRIA is used with chemotherapy and radiation therapy, or with radiation therapy alone, you may have an increased risk of developing precancerous blood condition called myelodysplastic syndrome (MDS) or blood cancer called acute myeloid leukemia (AML). Symptoms of MDS and AML may include tiredness, fever, and easy bruising or bleeding. Call your healthcare provider if you develop these symptoms during treatment with NYVEPRIA.. Inflammation of the aorta (aortitis). Inflammation of the aorta (the large blood vessel which transports blood from the heart to the body) has been reported in patients who received pegfilgrastim products. Symptoms may include fever, abdominal pain, feeling tired, and back pain. Call your healthcare provider if you experience these symptoms.. Store NYVEPRIA in the refrigerator between 36F to 46F (2C to 8C).. Do not freeze. If NYVEPRIA is accidentally frozen, allow the prefilled syringe to thaw in the refrigerator before injecting.. Do not use NYVEPRIA prefilled syringe that has been frozen more than time. Use new NYVEPRIA prefilled syringe.. Keep the prefilled syringe in the original carton to protect from light or physical damage.. Do not shake the prefilled syringe.. Take NYVEPRIA out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.. Throw away (dispose of) any NYVEPRIA that has been left at room temperature, 68F to 77F (20C to 25C), for more than 15 days.. Logo.

SPL UNCLASSIFIED SECTION.

Limitations of UseNYVEPRIA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

STORAGE AND HANDLING SECTION.

Store refrigerated between 36F to 46F (2C to 8C) in the carton to protect from light. Do not shake. Discard syringes stored at room temperature for more than 15 days. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard syringe if frozen more than once.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryAlthough available data with NYVEPRIA or pegfilgrastim product use in pregnant women are insufficient to establish whether there is 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 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 background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is to 4% and 15 to 20%, respectively.. Data. Animal DataPregnant 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 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 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 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 SummaryThere 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 mothers clinical need for NYVEPRIA and any potential adverse effects on the breastfed child from NYVEPRIA or from the underlying maternal condition.. 8.4 Pediatric Use. The safety and effectiveness of pegfilgrastim 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 pegfilgrastim in pediatric patients for chemotherapy-induced neutropenia is based on adequate and well-controlled studies in adults with additional pharmacokinetic and safety data in pediatric patients with sarcoma [see Clinical Pharmacology (12.3) and Clinical Studies (14)].. 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.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. (5.1)Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue NYVEPRIA in patients with ARDS. (5.2)Serious allergic reactions, including anaphylaxis: Permanently discontinue NYVEPRIA in patients with serious allergic reactions. (5.3)Fatal sickle cell crises: Discontinue NYVEPRIA if sickle cell crisis occurs. (5.4)Glomerulonephritis: Evaluate and consider dose-reduction or interruption of NYVEPRIA if causality is likely. (5.5)Thrombocytopenia: Monitor platelet counts. (5.7)Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using NYVEPRIA in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. (5.10). Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. (5.1). Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue NYVEPRIA in patients with ARDS. (5.2). Serious allergic reactions, including anaphylaxis: Permanently discontinue NYVEPRIA in patients with serious allergic reactions. (5.3). Fatal sickle cell crises: Discontinue NYVEPRIA if sickle cell crisis occurs. (5.4). Glomerulonephritis: Evaluate and consider dose-reduction or interruption of NYVEPRIA if causality is likely. (5.5). Thrombocytopenia: Monitor platelet counts. (5.7). Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using NYVEPRIA in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. (5.10). 5.1Splenic Rupture. Splenic rupture, including fatal cases, can occur following the administration of pegfilgrastim products. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving NYVEPRIA.. 5.2Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving pegfilgrastim products. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving NYVEPRIA, for ARDS. Discontinue NYVEPRIA in patients with ARDS.. 5.3Serious Allergic Reactions. Serious allergic reactions, including anaphylaxis, can occur in patients receiving pegfilgrastim products. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue NYVEPRIA in patients with serious allergic reactions. Do not administer NYVEPRIA to patients with history of serious allergic reactions to pegfilgrastim products or filgrastim products.. 5.4Use in Patients with Sickle Cell Disorders. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving pegfilgrastim products. Discontinue NYVEPRIA if sickle cell crisis occurs.. 5.5Glomerulonephritis. Glomerulonephritis has occurred in patients receiving pegfilgrastim 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 pegfilgrastim products. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of NYVEPRIA.. 5.6Leukocytosis White blood cell (WBC) counts of 100 109/L or greater have been observed in patients receiving pegfilgrastim products. Monitoring of complete blood count (CBC) during NYVEPRIA therapy is recommended.. 5.7Thrombocytopenia Thrombocytopenia has been reported in patients receiving pegfilgrastim products. Monitor platelet counts.. 5.8Capillary Leak Syndrome. Capillary leak syndrome has been reported after G-CSF administration, including pegfilgrastim products, and is characterized by hypotension, hypoalbuminemia, edema and hemoconcentration. Episodes vary in frequency, 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 need for intensive care.. 5.9Potential for Tumor Growth Stimulatory Effects on Malignant Cells. The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim products and filgrastim products act has been found on tumor cell lines. The possibility that pegfilgrastim products act as growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim products are not approved, cannot be excluded.. 5.10Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer. MDS and AML have been associated with the use of pegfilgrastim 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.. 5.11Aortitis. Aortitis has been reported in patients receiving pegfilgrastim 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 NYVEPRIA if aortitis is suspected.. 5.12Nuclear 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.