Pegfilgrastim-Jmdb

1 INDICATIONS AND USAGE Fulphila is a leukocyte growth factor indicated to • Decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. ( 1.1 ) Limitations of Use Fulphila is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. 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 a 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.

2 DOSAGE AND ADMINISTRATION • Patients with cancer receiving myelosuppressive chemotherapy • 6 mg administered subcutaneously once per chemotherapy cycle. ( 2.1 ) • Do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy. ( 2.1 ) • Use weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1. ( 2.2 ) 2.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy The recommended dosage of Fulphila is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle. For dosing in pediatric patients weighing less than 45 kg, refer to Table 1. Do not administer Fulphila between 14 days before and 24 hours after administration of cytotoxic chemotherapy. 2.2 Administration Fulphila is administered subcutaneously via a 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 a minimum of 30 minutes. Discard any prefilled syringe left at room temperature for greater than 72 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer 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 Weight Fulphila Dose Volume to Administer Less than 10 kg For 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 kg 1.5 mg 0.15 mL 21 to 30 kg 2.5 mg 0.25 mL 31 to 44 kg 4 mg 0.4 mL

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [See Warnings and Precautions (5.1) ] • Acute Respiratory Distress Syndrome [See Warnings and Precautions (5.2) ] • Serious Allergic Reactions [See Warnings and Precautions (5.3) ] • Use in Patients with Sickle Cell Disorders [See Warnings and Precautions (5.4) ] • Glomerulonephritis [See Warnings and Precautions (5.5) ] • Leukocytosis [See Warnings and Precautions (5.6) ] • Thrombocytopenia [See Warnings and Precautions (5.7) ] • Capillary Leak Syndrome [See Warnings and Precautions (5.8) ] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [See Warnings and Precautions (5.9) ] • Myelodysplastic syndrome [See Warnings and Precautions (5.10) ] • Acute myeloid leukemia [See Warnings and Precautions (5.10) ] • Aortitis [see Warnings and Precautions (5.11) ] Most common adverse reactions (≥ 5% difference in incidence compared to placebo) are bone pain and pain in extremity. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact 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 a 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 a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pegfilgrastim clinical trials safety data are based upon 932 patients receiving pegfilgrastim in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received pegfilgrastim after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. The following adverse reaction data in Table 2 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m 2 every 21 days (Study 3). A total of 928 patients were randomized to receive either 6 mg pegfilgrastim (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American, or other. The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfilgrastim arm in placebo-controlled clinical trials are bone pain and pain in extremity. Table 2. Adverse Reactions with ≥ 5% Higher Incidence in Pegfilgrastim Patients Compared to Placebo in Study 3 Body System Adverse Reaction Placebo (N = 461) Pegfilgrastim 6 mg SC on Day 2 (N = 467) Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9% Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 10 9 /L) was observed in less than 1% of 932 patients with non-myeloid malignancies receiving pegfilgrastim. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies in the studies described below with the incidence of antibodies in other studies or to other pegfilgrastim products may be misleading. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of pegfilgrastim products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. • Splenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions (5.1) ] • Acute respiratory distress syndrome (ARDS) [see Warnings and Precautions (5.2) ] • Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, and urticaria, generalized erythema, and flushing [see Warnings and Precautions (5.3) ] • Sickle cell crisis [see Warnings and Precautions (5.4) ] • Glomerulonephritis [see Warnings and Precautions (5.5) ] • Leukocytosis [see Warnings and Precautions (5.6) ] • Thrombocytopenia [see Warnings and Precautions (5.7) ] • Capillary Leak Syndrome [see Warnings and Precautions (5.8) ] • Injection site reactions • Sweet’s syndrome, (acute febrile neutrophilic dermatosis), cutaneous vasculitis • Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions (5.10) ] • Aortitis [see Warnings and Precautions (5.11) ] • Alveolar hemorrhage

12.3 Pharmacokinetics The pharmacokinetics of pegfilgrastim was studied in 379 patients with cancer. The pharmacokinetics of pegfilgrastim was nonlinear, and clearance decreased with increases in dose. Neutrophil receptor binding is an important component of the clearance of pegfilgrastim, and serum clearance is directly related to the number of neutrophils. In addition to numbers of neutrophils, body weight appeared to be a factor. Patients with higher body weights experienced higher systemic exposure to pegfilgrastim after receiving a dose normalized for body weight. A large variability in the pharmacokinetics of pegfilgrastim was observed. The half-life of pegfilgrastim ranged from 15 to 80 hours after subcutaneous injection. Specific Populations No gender-related differences were observed in the pharmacokinetics of pegfilgrastim, and no differences were observed in the pharmacokinetics of geriatric patients (≥ 65 years of age) compared with younger patients (< 65 years of age) [see Use in Specific Populations (8.5) ] . Patients with Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. Pediatric Patients with Cancer Receiving Myelosuppressive Chemotherapy The pharmacokinetics and safety of pegfilgrastim were studied in 37 pediatric patients with sarcoma in Study 4 [see Clinical Studies 14.1 ] . The mean (± standard deviation [SD]) systemic exposure (AUC 0-inf ) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11), 22.0 (± 13.1) mcg·hr/mL in the (6 to 11 years age group (n = 10), and 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13). The terminal elimination half-lives of the corresponding age groups were 30.1 (± 38.2) hours, 20.2 (± 11.3) hours, and 21.2 (± 16.0) hours, respectively.