PEGFILGRASTIM: 80,974 Adverse Event Reports & Safety Profile

Pegfilgrastim-cbqv is a covalent conjugate of recombinant methionyl human G-CSF and monomethoxypolyethylene glycol. Recombinant methionyl human G-CSF is a water-soluble, 175 amino acid protein with a molecular weight of approximately 19 kilodaltons (kDa). Recombinant methionyl human G-CSF is obtained from the bacterial fermentation of a strain of E coli transformed with a genetically engineered plasmid containing the human G-CSF gene. During the pegfilgrastim-cbqv manufacturing process, fermentation is carried out in nutrient medium containing the antibiotic kanamycin. However, kanamycin is cleared in the manufacturing process and is not detectable in the final product. To produce pegfilgrastim-cbqv, a 20 kDa monomethoxypolyethylene glycol molecule is covalently bound to the N-terminal methionyl residue of recombinant methionyl human G-CSF. The average molecular weight of pegfilgrastim-cbqv is approximately 39 kDa. UDENYCA (pegfilgrastim-cbqv) injection is provided in three presentations: UDENYCA for manual subcutaneous injection is supplied in 0.6 mL prefilled syringes. The prefilled syringe does not bear graduation marks and is designed to deliver the entire contents of the syringe (6 mg/0.6 mL). UDENYCA for subcutaneous injection is supplied in a 0.6 mL prefilled single-dose autoinjector. The prefilled autoinjector delivers the entire contents (6 mg in 0.6mL) in a single injection and is not adjustable. On-body injector (OBI) for UDENYCA is supplied with a prefilled syringe containing 0.67 mL of UDENYCA in solution that delivers 0.6 mL of UDENYCA in solution when used with the OBI for UDENYCA. The syringe does not bear graduation marks and is only to be used with the OBI for UDENYCA. The delivered 0.6 mL dose from either the prefilled syringe for manual subcutaneous injection, the prefilled autoinjector or the OBI for UDENYCA contains 6 mg pegfilgrastim-cbqv (based on protein weight) in a sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.35 mg), polysorbate 20 (0.02 mg), sodium (0.02 mg), and sorbitol (30 mg) in Water for Injection, USP.

AND USAGE ZIEXTENZO 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 ZIEXTENZO is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

1.1 Patients with Cancer Receiving Myelosuppressive Chemotherapy ZIEXTENZO 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 <span class="opacity-50 text-xs">[see Clinical Studies ( 14.1 )]</span>. Limitations of Use ZIEXTENZO 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 ZIEXTENZO is indicated to increase survival in patients acutely exposed to myelosuppressive doses of radiation <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 ) and Clinical Studies ( 14.2 )]</span>.

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 &apos;click&apos; and checking that the &apos;Orange Indicator&apos; 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&apos;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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.12 ) and Patient Counseling Information ( 17 )]</span> . 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.12 )]</span> .

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

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 &lt; 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

AND PRECAUTIONS Fatal splenic rupture: Evaluate patients who report left upper abdominal or shoulder pain for an enlarged spleen or splenic rupture ( 5.1 ) Acute respiratory distress syndrome (ARDS): Evaluate patients who develop fever, lung infiltrates, or respiratory distress. Discontinue UDENYCA in patients with ARDS. ( 5.2 ) Serious allergic reactions, including anaphylaxis: Permanently discontinue UDENYCA in patients with serious allergic reactions. ( 5.3 ) The on-body injector for UDENYCA uses acrylic adhesives. For patients who have reactions to acrylic adhesives, use of this product may result in a significant reaction. ( 5.4 ) Fatal sickle cell crises: Discontinue UDENYCA if sickle cell crisis occurs. ( 5.5 ) Glomerulonephritis: Evaluate and consider dose-reduction or interruption of UDENYCA if causality is likely. ( 5.6 ) Thrombocytopenia: Monitor platelet count ( 5.8 )

Myelodysplastic

Syndrome (MDS) and Acute Myeloid Leukemia (AML): Monitor patients with breast and lung cancer using UDENYCA in conjunction with chemotherapy and/or radiotherapy for signs and symptoms of MDS/AML. ( 5.11 ) Potential device failures: Instruct patients to notify their healthcare provider if they suspect the on-body injector may not have performed as intended. ( 5.12 )

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 UDENYCA.

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 UDENYCA for ARDS. Discontinue UDENYCA 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 UDENYCA in patients with serious allergic reactions. Do not administer UDENYCA to patients with a history of serious allergic reactions to pegfilgrastim products or filgrastim products.

5.4 Allergies to Acrylics The on-body injector (OBI) for UDENYCA uses acrylic adhesive. For patients who have reactions to acrylic adhesives, use of this product may result in a significant reaction.

5.5 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 UDENYCA if sickle cell crisis occurs.

5.6 Glomerulonephritis Glomerulonephritis has occurred in patients receiving pegfilgrastim products. The diagnoses were based upon azotemia, hematuria (microscopic and macroscopic), proteinuria, and renal biopsy. Generally, events of glomerulonephritis resolved after dose reduction or discontinuation of pegfilgrastim products. If glomerulonephritis is suspected, evaluate for cause. If causality is likely, consider dose-reduction or interruption of UDENYCA.

5.7 Leukocytosis White blood cell (WBC) counts of 100 x 10 9 /L or greater have been observed in patients receiving pegfilgrastim products. Monitoring of complete blood count (CBC) during UDENYCA therapy is recommended.

5.8 Thrombocytopenia Thrombocytopenia has been reported in patients receiving pegfilgrastim products. Monitor platelet counts.

5.9 Capillary Leak Syndrome Capillary leak syndrome has been reported after G-CSF administration, including pegfilgrastim products, and is characterized by hypotension, hypoalbuminemia, edema, and hemoconcentration. Episodes vary in frequency, severity and may be life-threatening if treatment is delayed. Patients who develop symptoms of capillary leak syndrome should be closely monitored and receive standard symptomatic treatment, which may include a need for intensive care.

5.10 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 a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim products are not approved, cannot be excluded.

5.11 Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) in Patients with Breast and Lung Cancer MDS and AML have been associated with the use of pegfilgrastim products in conjunction with chemotherapy and/or radiotherapy in patients with breast and lung cancer. Monitor patients for signs and symptoms of MDS/AML in these settings.

5.12 Potential Device failures Missed or partial doses have been reported in patients receiving UDENYCA via the on-body injector (OBI) due to the device not performing as intended. In the event of a missed or partial dose, patients may be at increased risk of events such as neutropenia, febrile neutropenia and/or infection than if the dose had been correctly delivered. 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.

5.13 Aortitis Aortitis has been reported in patients receiving pegfilgrastim products. It may occur as early as the first week after start of therapy. Manifestations may include generalized signs and symptoms such as fever, abdominal pain, malaise, back pain, and increased inflammatory markers (e.g., c-reactive protein and white blood cell count). Consider aortitis in patients who develop these signs and symptoms without known etiology. Discontinue UDENYCA if aortitis is suspected.

5.14 Nuclear 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.