Pegfilgrastim-Cbqv

1 INDICATIONS AND USAGE UDENYCA is a leukocyte growth factor indicated to Decrease the incidence of infection, as manifested by febrile neutropenia, in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. ( 1.1 ) Increase survival in patients acutely exposed to myelosuppressive doses of radiation (Hematopoietic Subsyndrome of Acute Radiation Syndrome). ( 1.2 ) Limitations of Use UDENYCA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. 1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy UDENYCA 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 UDENYCA is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. 1.2 Patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome UDENYCA is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation [see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.2 )] .

2 DOSAGE AND ADMINISTRATION Patients with cancer receiving myelosuppressive chemotherapy 6 mg administered subcutaneously once per chemotherapy cycle. ( 2.1 ) Do not administer between 14 days before and 24 hours after administration of cytotoxic chemotherapy. ( 2.1 ) Use weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1 . ( 2.3 ) Patients acutely exposed to myelosuppressive doses of radiation Two doses, 6 mg each, administered subcutaneously one week apart. Administer the first dose as soon as possible after suspected or confirmed exposure to myelosuppressive doses of radiation, and a second dose one week after. ( 2.2 ) Use weight based dosing for pediatric patients weighing less than 45 kg; refer to Table 1 . ( 2.3 ) 2.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy The recommended dosage of UDENYCA 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 UDENYCA between 14 days before and 24 hours after administration of cytotoxic chemotherapy. 2.2 Patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome The recommended dose of UDENYCA is two doses, 6 mg each, administered subcutaneously one week apart. For dosing in pediatric patients weighing less than 45 kg, refer to Table 1 . Administer the first dose as soon as possible after suspected or confirmed exposure to radiation levels greater than 2 gray (Gy). Administer the second dose one week after the first dose. Obtain a baseline complete blood count (CBC). Do not delay administration of UDENYCA if a CBC is not readily available. Estimate a patient’s absorbed radiation dose (i.e., level of radiation exposure) based on information from public health authorities, biodosimetry if available, or clinical findings such as time to onset of vomiting or lymphocyte depletion kinetics. 2.3 Administration UDENYCA is administered subcutaneously via a single-dose prefilled autoinjector, a single-dose prefilled syringe for manual use or for use with the on-body injector (OBI) for UDENYCA, which is co-packaged with a single dose prefilled syringe for OBI. Use of the OBI for UDENYCA is not recommended for patients with Hematopoietic Subsyndrome of Acute Radiation Syndrome. Use of the OBI has not been studied in pediatric patients. Prior to use‚ remove the carton from the refrigerator and allow UDENYCA to reach room temperature for a minimum of 30 minutes. Discard any UDENYCA left at room temperature for greater than 48 hours. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer UDENYCA if discoloration or particulates are observed. The needle cap on the prefilled syringe and prefilled autoinjector is not made with natural rubber latex. Pediatric Patients Weighing Less than 45 kg The UDENYCA 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 UDENYCA 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 UDENYCA for pediatric patients weighing less than 45 kg Body Weight UDENYCA 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 UDENYCA See below See below 10 - 20 kg 1.5 mg 0.15 mL 21 - 30 kg 2.5 mg 0.25 mL 31 - 44 kg 4 mg 0.4 mL The UDENYCA prefilled autoinjector is not suitable for use in pediatric patients weighing less than 45 kg. The UDENYCA prefilled autoinjector delivers the entire contents (6 mg in 0.6 mL) in a single injection and is not adjustable. 2.4 Advice to Give to Patients or Caregivers Regarding Administration via the Prefilled Autoinjector Only adults can self-administer UDENYCA with the prefilled autoinjector. If subcutaneous injections can be given at home, refer the patient or caregiver to the dose delivery information provided in the Instructions for Use. Provide training to patients or caregivers to ensure they understand how to administer UDENYCA via the prefilled autoinjector. Ensure patients or caregivers understand how to identify that a full dose has been administered by listening for the second 'click' and checking that the 'Orange Indicator' completely blocks the viewing window. Instruct patients or caregivers using the prefilled autoinjector to notify their healthcare provider immediately in order to determine the need for a replacement dose of UDENYCA if they suspect that the full dose may not have been administered. 2.5 Special Healthcare Provider Instructions for the On-body Injector for UDENYCA A healthcare provider must fill the on-body injector (OBI) with UDENYCA using the prefilled syringe and then apply the OBI for UDENYCA to the patient's skin (abdomen or back of arm). The back of the arm may only be used if there is a caregiver available to monitor the status of the OBI for UDENYCA. Approximately 27 hours after the OBI for UDENYCA is applied to the patient's skin, UDENYCA will be delivered over approximately 5 minutes. A healthcare provider may initiate administration with the OBI for UDENYCA on the same day as the administration of cytotoxic chemotherapy, as long as the OBI for UDENYCA delivers UDENYCA no less than 24 hours after administration of cytotoxic chemotherapy. The prefilled syringe co-packaged in UDENYCA ONBODY must only be used with the OBI for UDENYCA. The prefilled syringe contains additional solution to compensate for liquid loss during filling of the OBI and delivery through the OBI for UDENYCA. If the prefilled syringe co-packaged in UDENYCA ONBODY is used for manual subcutaneous injection, the patient will receive an overdose. If the single-dose prefilled syringe for manual use is used with the OBI for UDENYCA, the patient may receive less than the recommended dose. Do not use the OBI for UDENYCA to deliver any other drug product except the UDENYCA prefilled syringe co-packaged with the OBI for UDENYCA. The OBI for UDENYCA should be applied to intact, non-irritated skin on the arm or abdomen. A missed dose could occur due to an OBI for UDENYCA failure or leakage. If the patient misses a dose, a new dose should be administered by single-dose prefilled syringe for manual use, as soon as possible after detection. Refer to the Healthcare Provider Instructions for Use for the OBI for UDENYCA for full administration information. 2.6 Advice to give to Patients Regarding Administration via the On-body Injector for UDENYCA Advise patients to avoid activities such as traveling, driving, or operating heavy machinery during hours 26-29 following application of the on-body injector (OBI) for UDENYCA (this includes the 5-minute delivery period plus an hour post-delivery). Patients should have a caregiver nearby for the first use. Refer the patient to the dose delivery information written on the Patient Instructions for Use. Provide training to patients to ensure they understand when the dose delivery of UDENYCA will begin and how to monitor the OBI for UDENYCA for completed delivery. Ensure patients understand how to identify signs of malfunction of OBI for UDENYCA [see Warnings and Precautions ( 5.12 ) and Patient Counseling Information ( 17 )] . Instruct patients using the OBI to notify their healthcare professional immediately in order to determine the need for a replacement dose of UDENYCA if they suspect that the device may not have performed as intended [see Warnings and Precautions ( 5.12 )] .

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 )] Allergies to Acrylics [see Warnings and Precautions ( 5.4 )] Use in Patients with Sickle Cell Disorders [see Warnings and Precautions ( 5.5 )] Glomerulonephritis [see Warnings and Precautions ( 5.6 )] Leukocytosis [see Warnings and Precautions ( 5.7 )] Thrombocytopenia [see Warnings and Precautions ( 5.8 )] Capillary Leak Syndrome [see Warnings and Precautions ( 5.9 )] Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions ( 5.10 )] Myelodysplastic syndrome [see Warnings and Precautions ( 5.11 )] Acute myeloid leukemia [see Warnings and Precautions ( 5.11 )] Aortitis [see Warnings and Precautions ( 5.13 )] 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 Coherus BioSciences at 1-800-4UDENYCA (1-800-483-3692) or FDA at 1-800-FDA-1088 (1-800-332-1088) or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Pegfilgrastim clinical trials safety data are based upon 932 patients receiving pegfilgrastim in seven randomized clinical trials. The population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and 1% Asian. Patients with breast (n = 823), lung and thoracic tumors (n = 53) and lymphoma (n = 56) received pegfilgrastim after nonmyeloablative cytotoxic chemotherapy. Most patients received a single 100 mcg/kg (n = 259) or a single 6 mg (n = 546) dose per chemotherapy cycle over 4 cycles. The following adverse reaction data in Table 2 are from a randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m 2 every 21 days (Study 3). A total of 928 patients were randomized to receive either 6 mg pegfilgrastim (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and <1% Asian, Native American or other. The most common adverse reactions occurring in ≥ 5% of patients and with a between-group difference of ≥ 5% higher in the pegfilgrastim arm in placebo controlled clinical trials are bone pain and pain in extremity. Table 2. Adverse Reactions with ≥ 5% Higher Incidence in pegfilgrastim Patients Compared to Placebo in Study 3 Body System Adverse Reaction Placebo (N = 461) pegfilgrastim 6 mg SC on Day 2 (N = 467) Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9% Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 10 9 /L was observed in less than 1% of 932 patients with non-myeloid malignancies receiving pegfilgrastim. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity The observed incidence of anti-drug antibodies is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibodies in the studies described below with the incidence of anti-drug antibodies in other studies, including those of pegfilgrastim or of other pegfilgrastim products. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. 6.3 Postmarketing Experience The following adverse reactions have been identified during post approval use of pegfilgrastim products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Splenic rupture and splenomegaly (enlarged spleen) [see Warnings and Precautions ( 5.1 )] Acute respiratory distress syndrome (ARDS) [see Warnings and Precautions ( 5.2 )] Allergic reactions/hypersensitivity, including anaphylaxis, skin rash, urticaria, generalized erythema and flushing [see Warnings and Precautions ( 5.3 )] Sickle cell crisis [see Warnings and Precautions ( 5.5 )] Glomerulonephritis [see Warnings and Precautions ( 5.6 )] Leukocytosis [see Warnings and Precautions ( 5.7 )] Thrombocytopenia [see Warnings and Precautions ( 5.8 )] Capillary leak syndrome [see Warnings and Precautions ( 5.9 )] Injection site reactions Sweet’s syndrome ( acute febrile neutrophilic dermatosis ), cutaneous vasculitis Application site reactions (including events such as application site hemorrhage, application site pain, application site discomfort, application site bruise, and application site erythema) have been reported with the use of the on-body-injector for UDENYCA. Contact dermatitis and local skin reactions such as rash, pruritus, and urticaria have been reported with the use of the on-body-injector for UDENYCA, possibly indicating a hypersensitivity reaction to the adhesive. Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) in patients with breast and lung cancer receiving chemotherapy and/or radiotherapy [see Warnings and Precautions ( 5.11 )] Aortitis [see Warnings and Precautions ( 5.13 )] Alveolar hemorrhage

12.3 Pharmacokinetics The pharmacokinetics of pegfilgrastim were studied in 379 patients with cancer. The pharmacokinetics of pegfilgrastim were 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. In healthy volunteers, the pharmacokinetics of pegfilgrastim were comparable when delivered subcutaneously via a manual prefilled syringe versus via the on-body-injector (OBI) for UDENYCA. 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 )] . Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim. Pediatric Patients with Cancer Receiving Myelosuppressive Chemotherapy The pharmacokinetics and safety of pegfilgrastim were studied in 37 pediatric patients with sarcoma in Study 4 [see Clinical Studies 14.1 ] . The mean (± standard deviation [SD]) systemic exposure (AUC 0-inf ) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11), 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), and 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13). The terminal elimination half-lives of the corresponding age groups were 30.1 (± 38.2) hours, 20.2 (± 11.3) hours, and 21.2 (± 16.0) hours, respectively. Patients Acutely Exposed to Myelosuppressive Doses of Radiation The pharmacokinetics of pegfilgrastim is not available in patients acutely exposed to myelosuppressive doses of radiation. Based on limited pharmacokinetic data in irradiated non-human primates, the area under the concentration-time curve (AUC), reflecting the exposure to pegfilgrastim in non-human primates following a 300 mcg/kg dose of pegfilgrastim, appears to be greater than in humans receiving a 6 mg dose. Results from population modeling and simulation indicate that two 6 mg doses of pegfilgrastim administered one week apart in adults result in clinically relevant effects on duration of grade 3 and 4 neutropenia. In addition, weight-based dosing in pediatric patients weighing less than 45 kg [see Dosage and Administration, Section 2.3 , Table 1 ] provides exposures comparable to those in adults receiving two 6 mg doses one week apart.