ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling:oSplenic Rupture [See Warnings and Precautions (5.1)] oAcute Respiratory Distress Syndrome [See Warnings and Precautions (5.2)] oSerious Allergic Reactions [See Warnings and Precautions (5.3)] oUse in Patients with Sickle Cell Disorders [See Warnings and Precautions (5.4)] oGlomerulonephritis [See Warnings and Precautions (5.5)] oLeukocytosis [See Warnings and Precautions (5.6)] oThrombocytopenia [See Warnings and Precautions (5.7)] oCapillary Leak Syndrome [See Warnings and Precautions (5.8)] oPotential for Tumor Growth Stimulatory Effects on Malignant Cells [See Warnings and Precautions (5.9)]oMyelodysplastic syndrome [See Warnings and Precautions (5.10)] oAcute myeloid leukemia [See Warnings and Precautions (5.10)] oAortitis [see Warnings and Precautions (5.11)]. oSplenic Rupture [See Warnings and Precautions (5.1)] oAcute Respiratory Distress Syndrome [See Warnings and Precautions (5.2)] oSerious Allergic Reactions [See Warnings and Precautions (5.3)] oUse in Patients with Sickle Cell Disorders [See Warnings and Precautions (5.4)] oGlomerulonephritis [See Warnings and Precautions (5.5)] oLeukocytosis [See Warnings and Precautions (5.6)] oThrombocytopenia [See Warnings and Precautions (5.7)] oCapillary Leak Syndrome [See Warnings and Precautions (5.8)] oPotential for Tumor Growth Stimulatory Effects on Malignant Cells [See Warnings and Precautions (5.9)]. oMyelodysplastic syndrome [See Warnings and Precautions (5.10)] oAcute myeloid leukemia [See Warnings and Precautions (5.10)] oAortitis [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 Biocon Biologics Inc. at 1-833-986-1468 (1-877-4-INFO-RX) 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 Fulphila 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. 6.1 Clinical 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 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 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%. Leukocytosis. In 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. 6.2 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 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. 6.3 Postmarketing 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. oSplenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions (5.1)] oAcute respiratory distress syndrome (ARDS) [see Warnings and Precautions (5.2)] oAllergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, generalized erythema, and flushing [see Warnings and Precautions (5.3)] oSickle cell crisis [see Warnings and Precautions (5.4)] oGlomerulonephritis [see Warnings and Precautions (5.5)] oLeukocytosis [see Warnings and Precautions (5.6)] oThrombocytopenia [see Warnings and Precautions (5.7)]oCapillary Leak Syndrome [see Warnings and Precautions (5.8)] oInjection site reactions oSweets syndrome, (acute febrile neutrophilic dermatosis), cutaneous vasculitisoMyelodysplastic 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)]oAortitis [see Warnings and Precautions (5.11)]oAlveolar hemorrhage. oSplenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions (5.1)] oAcute respiratory distress syndrome (ARDS) [see Warnings and Precautions (5.2)] oAllergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, generalized erythema, and flushing [see Warnings and Precautions (5.3)] oSickle cell crisis [see Warnings and Precautions (5.4)] oGlomerulonephritis [see Warnings and Precautions (5.5)] oLeukocytosis [see Warnings and Precautions (5.6)] oThrombocytopenia [see Warnings and Precautions (5.7)]. oCapillary Leak Syndrome [see Warnings and Precautions (5.8)] oInjection site reactions oSweets syndrome, (acute febrile neutrophilic dermatosis), cutaneous vasculitis. oMyelodysplastic 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)]. oAortitis [see Warnings and Precautions (5.11)]. oAlveolar hemorrhage.

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).

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING Fulphila single-dose prefilled syringe for manual useFulphila (pegfilgrastim-jmdb) Injection is clear, colorless solution supplied in prefilled single-dose syringe for manual use containing mg pegfilgrastim-jmdb, supplied with 29 gauge, 1/2-inch needle with an UltraSafe Passive Plus(TM) Needle Guard. Fulphila is provided in dispensing pack containing one sterile mg/0.6 mL prefilled syringe.NDC 83257-005-41Fulphila 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 to 8C (36 to 46F) in the carton to protect from light or physical damage. Do not shake. Discard syringes stored at room temperature for more than 72 hours. Avoid freezing; if frozen, thaw in the refrigerator before administration. Discard syringe if frozen more than once.

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 Fulphila 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 Populations. No 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)]. Patients with Renal Impairment. In 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 [see Clinical Studies 14.1]. The mean (+- standard deviation [SD]) systemic exposure (AUC0-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 years, = 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.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES 14.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy 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)]. 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 x109/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 Fulphila 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-jmdb 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 coli transformed with genetically engineered plasmid containing the human G-CSF gene. To produce pegfilgrastim-jmdb 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-jmdb is approximately 39 kD. Fulphila (pegfilgrastim-jmdb) injection is intended for subcutaneous use only and is supplied in single-dose prefilled syringe with 29 gauge needle, with UltraSafe Passive Plus(TM) Needle Guard. 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 contains mg pegfilgrastim-jmdb (based on protein mass only) in sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.7 mg), D-sorbitol (30 mg), polysorbate 20 (0.024 mg) and sodium (0.01 mg) in Water for Injection, USP.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION oPatients with cancer receiving myelosuppressive chemotherapy o6 mg administered subcutaneously once per chemotherapy cycle. (2.1) oDo not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy. (2.1) oUse weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1. (2.2) oPatients with cancer receiving myelosuppressive chemotherapy o6 mg administered subcutaneously once per chemotherapy cycle. (2.1) oDo not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy. (2.1) oUse weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1. (2.2) o6 mg administered subcutaneously once per chemotherapy cycle. (2.1) oDo not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy. (2.1) oUse weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1. (2.2) 2.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy The recommended dosage of Fulphila 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 Fulphila between 14 days before and 24 hours after administration of cytotoxic chemotherapy. 2.2 Administration Fulphila is administered subcutaneously via single-dose prefilled syringe for manual use. Prior to use, remove the carton from the refrigerator and allow the Fulphila prefilled syringe to reach room temperature for 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 Fulphila if discoloration or particulates are observed. Pediatric Patients weighing less than 45 kg. The Fulphila 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 Fulphila 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 Fulphila for pediatric patients weighing less than 45 kg Body WeightFulphila DoseVolume to AdministerLess than 10 kgFor pediatric patients weighing less than 10 kg, administer 0.1 mg/kg (0.01 mL/kg) of Fulphila. See below See below 10 to 20 kg1.5 mg0.15 mL21 to 30 kg2.5 mg0.25 mL31 to 44 kg4 mg0.4 mL.

DOSAGE FORMS & STRENGTHS SECTION.

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

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE Fulphila is leukocyte growth factor indicated to oDecrease 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. (1.1) Limitations of UseFulphila is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. oDecrease 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. (1.1) 1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy Fulphila 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 (14.1)]. Limitations of Use. Fulphila 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 Fulphila: oSplenic rupture and splenomegaly [see Warnings and Precautions (5.1)]oAcute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)]oSerious allergic reactions [see Warnings and Precautions (5.3)]oSickle cell crisis [see Warnings and Precautions (5.4)]oGlomerulonephritis [see Warnings and Precautions (5.5)]oIncreased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with breast and lung cancer who receive pegfilgrastim in conjunction with chemotherapy and/or radiation therapy [see Warnings and Precautions (5.10)]oCapillary Leak Syndrome [see Warnings and Precautions (5.8)]oAortitis [see Warnings and Precautions (5.11)]Instruct patients who self-administer Fulphila using the single-dose prefilled syringe of the: oImportance of following the Instructions for Use. oDangers of reusing syringes. oImportance of following local requirements for proper disposal of used syringes.Manufactured by:Biocon Biologics Inc.245 Main st, 2nd Floor Cambridge, MA 02142 U.S.A.U.S. License No. 2324. oSplenic rupture and splenomegaly [see Warnings and Precautions (5.1)]. oAcute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)]. oSerious allergic reactions [see Warnings and Precautions (5.3)]. oSickle cell crisis [see Warnings and Precautions (5.4)]. oGlomerulonephritis [see Warnings and Precautions (5.5)]. oIncreased risk of Myelodysplastic Syndrome and/or Acute Myeloid Leukemia in patients with breast and lung cancer who receive pegfilgrastim in conjunction with chemotherapy and/or radiation therapy [see Warnings and Precautions (5.10)]. oCapillary Leak Syndrome [see Warnings and Precautions (5.8)]. oAortitis [see Warnings and Precautions (5.11)]. oImportance of following the Instructions for Use. oDangers of reusing syringes. oImportance of following local requirements for proper disposal of used syringes.

LACTATION SECTION.

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 mothers clinical need for Fulphila and any potential adverse effects on the breastfed child from Fulphila 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.

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.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 83257-005-41 Rx onlyFulphila(R) (pegfilgrastim-jmdb)Injection6 mg/0.6 mLSingle-Dose Prefilled SyringePegylated Recombinant Methionyl Human Granulocyte Colony-Stimulating Factor (PEG-r-metHuG-CSF) derived from Coli For Subcutaneous Use OnlySterile Solution No PreservativeOne 0.6 mL Single-DosePrefilled SyringeEach 0.6 mL prefilled syringe contains: mg pegfilgrastim (based on protein mass only) in sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.7 mg), D-sorbitol (30 mg), polysorbate 20 (0.024 mg), and sodium (0.01 mg) in water for injection, USP.No U.S. standard of potencyStore refrigerated at to 8C (36 to 46F) in original carton to Protect from Light. Do Not Freeze or Shake.Keep this and all medication out of the reach of children.Dosage: See prescribing information for dosage and instructions for use.Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142, U.S.A. U.S. License No. 2324 Product of IndiaKR/DRUGS/KTK/28D/07/2006Copyright (C) 2023 Biocon Biologics Inc. All rights reserved.. Fulphila Injection mg/0.6 mL Carton 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 (14.1)].

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 Fulphila 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 Populations. No 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)]. Patients with Renal Impairment. In 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 [see Clinical Studies 14.1]. The mean (+- standard deviation [SD]) systemic exposure (AUC0-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 years, = 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.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary. Although available data with Fulphila 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 2-4% and 15-20%, respectively.. Data. Human Data Retrospective studies indicate that exposure to pegfilgrastim is without significant adverse effect on fetal outcomes and neutropenia. Preterm deliveries have been reported in some patients. 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 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) 03/2021Warnings and Precautions, Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) (5.10) 03/2021.

RISKS.

Risk Summary. Although available data with Fulphila 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 2-4% and 15-20%, respectively.

SPL PATIENT PACKAGE INSERT SECTION.

Patient Information Fulphila(R) (FULL-fil-ah)(pegfilgrastim-jmdb) InjectionSingle-Dose Prefilled SyringeWhat is FulphilaFulphila 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 Fulphila if you have had serious allergic reaction to pegfilgrastim products or filgrastim products. Before you receive Fulphila, tell your healthcare provider about all of your medical conditions, including if you:ohave sickle cell disorder. ohave kidney problems. oare pregnant or plan to become pregnant. It is not known if Fulphila will harm your unborn baby. oare breastfeeding or plan to breastfeed. It is not known if Fulphila 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 Fulphila oFulphila 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 Fulphila for information on how to prepare and inject dose of Fulphila. oYou and your caregiver will be shown how to prepare and inject Fulphila before you use it. oYou should not inject dose of Fulphila to children weighing less than 45 kg from Fulphila prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the Fulphila prefilled syringe. oIf you are receiving Fulphila because you are also receiving chemotherapy, the last dose of Fulphila should be injected at least 14 days before and 24 hours after your dose of chemotherapy. oIf you miss dose of Fulphila, talk to your healthcare provider about when you should give your next dose.What are possible side effects of Fulphila Fulphila may cause serious side effects, including: oSpleen 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. oA serious lung problem called Acute Respiratory Distress Syndrome (ARDS). Call your healthcare provider or get emergency care right away if you have shortness of breath with or without fever, trouble breathing, or fast rate of breathing. oSerious allergic reactions. Fulphila 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 Fulphila and call your healthcare provider or get emergency medical help right away. oSickle cell crises. You may have serious sickle cell crisis if you have sickle cell disorder and receive Fulphila. Serious sickle cell crises have happened in people with sickle cell disorders receiving pegfilgrastim that has sometimes led to death. Call your healthcare provider right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing. oKidney injury (glomerulonephritis). Fulphila can cause kidney injury. Call your healthcare provider right away if you develop any of the following symptoms: oswelling of your face or ankles oblood in your urine or dark colored urine oyou urinate less than usual oIncreased white blood cell count (leukocytosis). Your healthcare provider will check your blood during treatment with Fulphila. oDecreased platelet count (thrombocytopenia). Your healthcare provider will check your blood during treatment with Fulphila. Tell your healthcare provider if you have unusual bleeding or bruising during treatment with Fulphila. This could be sign of decreased platelet counts, which may reduce the ability of your blood to clot.oCapillary Leak Syndrome. Fulphila 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: oswelling or puffiness and are urinating less than usual otrouble breathing oswelling of your stomach-area (abdomen) and feeling of fullness odizziness or feeling faint oa general feeling of tiredness oMyelodysplastic syndrome and acute myeloid leukemia. If you have breast cancer or lung cancer, when Fulphila 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 FulphilaoInflammation 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. 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 Fulphila are pain in the bones, arms, and legs. These are not all the possible side effects of Fulphila. Call your health care provider for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store Fulphila oStore Fulphila in the refrigerator between 36F to 46F (2C to 8C). oTake Fulphila out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.oAvoid freezing. If Fulphila is accidently frozen, allow the prefilled syringe to thaw in the refrigerator before injecting.oDo not use Fulphila prefilled syringe that has been frozen more than time. Use new Fulphila prefilled syringe.oKeep the prefilled syringe in the original carton to protect from light or physical damage. oDo not shake the prefilled syringe.oThrow away (dispose of) any Fulphila that has been left at room temperature, 68F to 77oF (20C to 25oC) for more than 72 hours or frozen more than time. Keep the Fulphila prefilled syringe out of the reach of children. General information about the safe and effective use of Fulphila. Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use Fulphila for condition for which it was not prescribed. Do not give Fulphila 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 Fulphila that is written for health professionals.What are the ingredients in Fulphila Active ingredient: pegfilgrastim-jmdbInactive ingredients: acetate, D-sorbitol, polysorbate 20, and sodium in Water for Injection.Manufactured by: Biocon Biologics Inc.245 Main st, 2nd Floor Cambridge, MA 02142 U.S.A U.S. License No. 2324 Product of India. Code No.: KR/DRUGS/KTK/28D/07/2006 For more information, go to www.fulphila.com or call 1-833-986-1468. This Patient Information has been approved by the U.S. Food and Drug Administration. Revised: 06/2023FULPHILA(R) is registered trademark of Biosimilars New Co Ltd; Biocon Biologics Company.Copyright (C) 2023 Biocon Biologics Inc. All rights reservedManufactured by:Biocon Biologics Inc.245 Main st. 2nd Floor Cambridge, MA 02142 U.S.A.U.S. License No. 2324 Product of India KR/DRUGS/KTK/28D/07/2006Revised: 06/2023BF1639/05 Instructions for UseFULPHILA(R) (FULL-fil-ah)(pegfilgrastim-jmdb)injection, for subcutaneous useSingle-Dose Prefilled SyringeGuide to PartsBefore UseAfter UseImportant: The needle is covered by the gray needle cap before use.Important InformationRead the Patient Information for important information you need to know about Fulphila before using these Instructions for Use. Storing the Fulphila prefilled syringeoStore Fulphila in the refrigerator between 36oF to 46oF (2oC to 8oC).oTake Fulphila out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.oAvoid freezing. If Fulphila is accidentally frozen, allow the prefilled syringe to thaw in the refrigerator before injecting. oDo not use Fulphila prefilled syringe that has been frozen more than time. Use new Fulphila prefilled syringe.oThrow away (dispose of) any Fulphila that has been left at room temperature, 68oF to 77oF (20oC to 25oC) for more than 72 hours or frozen more than time. See Step 4: Disposing of used prefilled syringes. oKeep the prefilled syringe in the original carton to protect from light or physical damage. oFor questions about storage, contact your healthcare provider or pharmacist.oKeep the Fulphila prefilled syringe out of the reach of children.Before you use Fulphila prefilled syringe, read this important information:oIt is important that you do not try to give yourself the injection unless you have received training from your healthcare provider.oThe prefilled syringe has needle safety guard that will be activated to cover the needle after the injection is given. The needle safety guard will help prevent needlestick injuries to anyone who handles the prefilled syringe after the injection has been given.oMake sure that the name Fulphila appears on the carton and prefilled syringe label. Fulphila is given as an injection into the tissue just under the skin (subcutaneous injection).oYou should not inject dose of Fulphila to children weighing less than 45 kg from Fulphila prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the Fulphila prefilled syringe.oDo not use prefilled syringe after the expiration date on the label.oDo not shake the prefilled syringe.oDo not use the prefilled syringe if the carton is open or damaged.oDo not remove the gray needle cap from the prefilled syringe until you are ready to inject.oDo not use the prefilled syringe if it has been dropped on hard surface. The syringe may be broken even if you cannot see the break. Use new prefilled syringe.oDo not attempt to activate the prefilled syringe prior to injection.oDo not attempt to remove the needle safety guard from the prefilled syringe.oDo not attempt to remove the label from the prefilled syringe barrel before injecting your dose of Fulphila.Call your healthcare provider if you have any questions.Step 1: Gather suppliesA Find clean, well-lit and flat work surface, such as table. - Take the prefilled syringe carton out of the refrigerator and place it on your clean work surface. Allow it to reach room temperature for 30 minutes before giving an injection. - Remove the prefilled syringe tray from the carton. - Wash your hands thoroughly with soap and water. - Gather the supplies for the injection: o1 alcohol wipeo1 cotton ball or gauze pad o1 adhesive bandage oan FDA-cleared sharps disposal containerStep 2: Prepare for injectionF Open the tray by peeling away the cover. Grab theneedle safety guard to remove the prefilled syringe from the tray. For safety reasons: oDo not grab the plunger rod.oDo not grasp the gray needle cap.G 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: oThe medicine is cloudy or discolored, or contains flakes or particles. oThe prefilled syringe has been dropped.oAny part appears cracked or broken.oThe gray needle cap is missing or not securely attached.oThe expiration date printed on the label haspassed.In all cases, use new prefilled syringe and call your healthcare provider.H Prepare and clean the injection site. There are injection sites that you can use: othighostomach area (abdomen), except for 2-inch area right around the navel (belly button)oupper outer area of the buttocks (only if someone else is giving you the injection), andothe outer area of the upper arm (only if someone else is giving you the injection).Clean the injection site with an alcohol wipe. Let the skin dry.oDo not touch this area again before injecting.oDo not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.oIf 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.I Hold the prefilled syringe by the needle safety guard.When ready, carefully pull the gray needle cap straight off and away from the body.oDo not twist or bend the gray needle cap. oDo not hold the prefilled syringe by the plunger rod.oDo not put the gray needle cap back onto the prefilled syringe. Dispose of (throw away) the gray needle cap in your household trash.Step 3: Inject the doseJ Pinch the cleaned injection site to create firm surface. Keep skin pinched while injecting.K Hold the pinch. Insert the needle into the skin between 45 to 90 degrees.oDo not touch the cleaned area of the skinL Using slow and constant pressure, push the plunger rod until it reaches the bottom. The plunger must be pushed fully in order to inject the full dose.M Once the entire dose has been injected, the needle safety guard will be triggered. You can do either of the following:oRelease the plunger until the entire needle is covered and then remove the needle from the injection site.oroGently remove the needle from the injection site and release the plunger until the entire needle is covered by the needle safety guard.After releasing the plunger, the needle safety guard will safely cover the injection needle.oOnce the needle has been removed from the injection site, dispose of the syringe and needle in your sharps disposal container right away. See Step 4: Disposing of used prefilled syringes.oIf the needle safety guard is not activated or only partially activated, discard the product (without replacing the needle cap). See Step 4: Disposing of used prefilled syringes.oIf your injection is given by another person, they should also be careful when removing the needle from your skin in order to prevent accidental needlestick injury and possible infections.oWhen you remove the syringe, if it looks like the medicine is still in the syringe barrel, this means you have not received the full dose. Call your healthcare provider right away.N 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.Step 4: Disposing of used prefilled syringesoPut the used prefilled syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away the syringe in the household trash.oIf you do not have an FDA-cleared sharps disposal container, you may use household container that is:omade of heavy-duty plasticocan be closed with tight-fitting, puncture-resistant lid without sharps being able to come outoupright and stable during useoleak-resistantoproperly labeled to warn of hazardous waste inside the containeroWhen 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.Important: Keep the sharps disposal container out of the reach of children.oDo not reuse the prefilled syringe.oDo not recycle prefilled syringes or throw them into household waste.This Instructions for Use has been approved by the U.S. Food and Drug Administration.Manufactured by: Biocon Biologics Inc. 245 Main St, 2nd Floor Cambridge, MA 02142, U.S.A. U.S. License No. 2324 KR/DRUGS/KTK/28D/07/2006Copyright (C) 2023 Biocon Biologics Inc. All rights reserved. Revised: 06/2023 BF1638/05. ohave sickle cell disorder. ohave kidney problems. oare pregnant or plan to become pregnant. It is not known if Fulphila will harm your unborn baby. oare breastfeeding or plan to breastfeed. It is not known if Fulphila passes into your breast milk.. oFulphila 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 Fulphila for information on how to prepare and inject dose of Fulphila. oYou and your caregiver will be shown how to prepare and inject Fulphila before you use it. oYou should not inject dose of Fulphila to children weighing less than 45 kg from Fulphila prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the Fulphila prefilled syringe. oIf you are receiving Fulphila because you are also receiving chemotherapy, the last dose of Fulphila should be injected at least 14 days before and 24 hours after your dose of chemotherapy. oIf you miss dose of Fulphila, talk to your healthcare provider about when you should give your next dose.. oSpleen 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. oA serious lung problem called Acute Respiratory Distress Syndrome (ARDS). Call your healthcare provider or get emergency care right away if you have shortness of breath with or without fever, trouble breathing, or fast rate of breathing. oSerious allergic reactions. Fulphila 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 Fulphila and call your healthcare provider or get emergency medical help right away. oSickle cell crises. You may have serious sickle cell crisis if you have sickle cell disorder and receive Fulphila. Serious sickle cell crises have happened in people with sickle cell disorders receiving pegfilgrastim that has sometimes led to death. Call your healthcare provider right away if you have symptoms of sickle cell crisis such as pain or difficulty breathing. oKidney injury (glomerulonephritis). Fulphila can cause kidney injury. Call your healthcare provider right away if you develop any of the following symptoms: oswelling of your face or ankles oblood in your urine or dark colored urine oyou urinate less than usual oswelling of your face or ankles oblood in your urine or dark colored urine oyou urinate less than usual oIncreased white blood cell count (leukocytosis). Your healthcare provider will check your blood during treatment with Fulphila. oDecreased platelet count (thrombocytopenia). Your healthcare provider will check your blood during treatment with Fulphila. Tell your healthcare provider if you have unusual bleeding or bruising during treatment with Fulphila. This could be sign of decreased platelet counts, which may reduce the ability of your blood to clot.. oCapillary Leak Syndrome. Fulphila 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: oswelling or puffiness and are urinating less than usual otrouble breathing oswelling of your stomach-area (abdomen) and feeling of fullness odizziness or feeling faint oa general feeling of tiredness oswelling or puffiness and are urinating less than usual otrouble breathing oswelling of your stomach-area (abdomen) and feeling of fullness odizziness or feeling faint oa general feeling of tiredness oMyelodysplastic syndrome and acute myeloid leukemia. If you have breast cancer or lung cancer, when Fulphila 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 Fulphila. oInflammation 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. Symptoms may include fever, abdominal pain, feeling tired, and back pain. Call your healthcare provider if you experience these symptoms.. oStore Fulphila in the refrigerator between 36F to 46F (2C to 8C). oTake Fulphila out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.. oAvoid freezing. If Fulphila is accidently frozen, allow the prefilled syringe to thaw in the refrigerator before injecting.. oDo not use Fulphila prefilled syringe that has been frozen more than time. Use new Fulphila prefilled syringe.. oKeep the prefilled syringe in the original carton to protect from light or physical damage. oDo not shake the prefilled syringe.. oThrow away (dispose of) any Fulphila that has been left at room temperature, 68F to 77oF (20C to 25oC) for more than 72 hours or frozen more than time. oStore Fulphila in the refrigerator between 36oF to 46oF (2oC to 8oC).. oTake Fulphila out of the refrigerator 30 minutes before use and allow it to reach room temperature before preparing an injection.. oAvoid freezing. If Fulphila is accidentally frozen, allow the prefilled syringe to thaw in the refrigerator before injecting. oDo not use Fulphila prefilled syringe that has been frozen more than time. Use new Fulphila prefilled syringe.. oThrow away (dispose of) any Fulphila that has been left at room temperature, 68oF to 77oF (20oC to 25oC) for more than 72 hours or frozen more than time. See Step 4: Disposing of used prefilled syringes. oKeep the prefilled syringe in the original carton to protect from light or physical damage. oFor questions about storage, contact your healthcare provider or pharmacist.. oKeep the Fulphila prefilled syringe out of the reach of children.. oIt is important that you do not try to give yourself the injection unless you have received training from your healthcare provider.. oThe prefilled syringe has needle safety guard that will be activated to cover the needle after the injection is given. The needle safety guard will help prevent needlestick injuries to anyone who handles the prefilled syringe after the injection has been given.. oMake sure that the name Fulphila appears on the carton and prefilled syringe label. Fulphila is given as an injection into the tissue just under the skin (subcutaneous injection).. oYou should not inject dose of Fulphila to children weighing less than 45 kg from Fulphila prefilled syringe. dose less than 0.6 mL (6 mg) cannot be accurately measured using the Fulphila prefilled syringe.. oDo not use prefilled syringe after the expiration date on the label.. oDo not shake the prefilled syringe.. oDo not use the prefilled syringe if the carton is open or damaged.. oDo not remove the gray needle cap from the prefilled syringe until you are ready to inject.. oDo not use the prefilled syringe if it has been dropped on hard surface. The syringe may be broken even if you cannot see the break. Use new prefilled syringe.. oDo not attempt to activate the prefilled syringe prior to injection.. oDo not attempt to remove the needle safety guard from the prefilled syringe.. oDo not attempt to remove the label from the prefilled syringe barrel before injecting your dose of Fulphila.. o1 alcohol wipe. o1 cotton ball or gauze pad o1 adhesive bandage oan FDA-cleared sharps disposal container. oDo not grab the plunger rod.. oDo not grasp the gray needle cap.. Make sure the medicine in the prefilled syringe is clear and colorless. oThe medicine is cloudy or discolored, or contains flakes or particles. oThe prefilled syringe has been dropped.. oAny part appears cracked or broken.. oThe gray needle cap is missing or not securely attached.. oThe expiration date printed on the label haspassed.. othigh. ostomach area (abdomen), except for 2-inch area right around the navel (belly button). oupper outer area of the buttocks (only if someone else is giving you the injection), and. othe outer area of the upper arm (only if someone else is giving you the injection).. oDo not touch this area again before injecting.. oDo not inject into areas where the skin is tender, bruised, red, or hard. Avoid injecting into areas with scars or stretch marks.. oIf 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.. oDo not twist or bend the gray needle cap. oDo not hold the prefilled syringe by the plunger rod.. oDo not put the gray needle cap back onto the prefilled syringe. Dispose of (throw away) the gray needle cap in your household trash.. Keep skin pinched. while injecting.. oDo not touch the cleaned area of the skin. The plunger must be pushed fully in. order to inject the full dose.. oRelease the plunger until the entire needle is covered and then remove the needle from the injection site.. oGently remove the needle from the injection site and release the plunger until the entire needle is covered by the needle safety guard.. oOnce the needle has been removed from the injection site, dispose of the syringe and needle in your sharps disposal container right away. See Step 4: Disposing of used prefilled syringes.. oIf the needle safety guard is not activated or only partially activated, discard the product (without replacing the needle cap). See Step 4: Disposing of used prefilled syringes.. oIf your injection is given by another person, they should also be careful when removing the needle from your skin in order to prevent accidental needlestick injury and possible infections.. oWhen you remove the syringe, if it looks like the medicine is still in the syringe barrel, this means you have not received the full dose. Call your healthcare provider right away.. oPut the used prefilled syringe in an FDA-cleared sharps disposal container right away after use. Do not throw away the syringe in the household trash.. oIf you do not have an FDA-cleared sharps disposal container, you may use household container that is:omade of heavy-duty plasticocan be closed with tight-fitting, puncture-resistant lid without sharps being able to come outoupright and stable during useoleak-resistantoproperly labeled to warn of hazardous waste inside the container. omade of heavy-duty plastic. ocan be closed with tight-fitting, puncture-resistant lid without sharps being able to come out. oupright and stable during use. oleak-resistant. oproperly labeled to warn of hazardous waste inside the container. oWhen 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.. oDo not reuse the prefilled syringe.. oDo not recycle prefilled syringes or throw them into household waste.. Instructions for Use Syringe Before Use. Instructions for Use Syringe After Use. Instructions for Use Figure 01. Instructions for Use Figure 02. Instructions for Use Figure 03. Instructions for Use Figure 04. Instructions for Use Figure 05. Instructions for Use Figure 06. Instructions for Use Figure 07. Instructions for Use Figure 08. Instructions for Use Figure 09. Instructions for Use Figure 10.

SPL UNCLASSIFIED SECTION.

1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy Fulphila 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 (14.1)]. Limitations of Use. Fulphila is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary. Although available data with Fulphila 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 2-4% and 15-20%, respectively.. Data. Human Data Retrospective studies indicate that exposure to pegfilgrastim is without significant adverse effect on fetal outcomes and neutropenia. Preterm deliveries have been reported in some patients. 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 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 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 mothers clinical need for Fulphila and any potential adverse effects on the breastfed child from Fulphila 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 (14.1)]. 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 oFatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. (5.1) oAcute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue Fulphila in patients with ARDS. (5.2) oSerious allergic reactions, including anaphylaxis: Permanently discontinue Fulphila in patients with serious allergic reactions. (5.3) oFatal sickle cell crises: Discontinue Fulphila if sickle cell crisis occurs. (5.4) oGlomerulonephritis: Evaluate and consider dose-reduction or interruption of Fulphila if causality is likely. (5.5)oThrombocytopenia: Monitor platelet counts. (5.7)oMyelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using Fulphila in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. (5.10) oFatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture. (5.1) oAcute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue Fulphila in patients with ARDS. (5.2) oSerious allergic reactions, including anaphylaxis: Permanently discontinue Fulphila in patients with serious allergic reactions. (5.3) oFatal sickle cell crises: Discontinue Fulphila if sickle cell crisis occurs. (5.4) oGlomerulonephritis: Evaluate and consider dose-reduction or interruption of Fulphila if causality is likely. (5.5). oThrombocytopenia: Monitor platelet counts. (5.7). oMyelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using Fulphila in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. (5.10) 5.1 Splenic 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 Fulphila. 5.2 Acute 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 Fulphila, for ARDS. Discontinue Fulphila in patients with ARDS. 5.3 Serious 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 Fulphila in patients with serious allergic reactions. Do not administer Fulphila to patients with history of serious allergic reactions to pegfilgrastim products or filgrastim products. 5.4 Use 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 Fulphila if sickle cell crisis occurs. 5.5 Glomerulonephritis Glomerulonephritis has occurred in patients receiving pegfilgrastim. 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. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of Fulphila. 5.6 Leukocytosis 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 Fulphila therapy is recommended. 5.7Thrombocytopenia Thrombocytopenia has been reported in patients receiving pegfilgrastim. Monitor platelet counts.. 5.8 Capillary Leak Syndrome Capillary leak syndrome has been reported after G-CSF administration, including pegfilgrastim, 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. 5.9 Potential 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 in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer. Monitor patients for signs and symptoms of MDS/AML in these settings.. 5.11 Aortitis Aortitis has been reported in patients receiving pegfilgrastim. 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 Fulphila 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.