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Basis for Neulasta ® (Pegfilgrastim) Approval. Amgen Neulasta ® Approved 01/31/02 Jeff Summers DBOP OODP CDER. Mechanism of Action. Both Neulasta ® and Neupogen ™ function as granulocyte colony stimulating factors Neulasta ® (pegfilgrastim) is a pegylated version of Neupogen ™

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basis for neulasta pegfilgrastim approval

Basis for Neulasta® (Pegfilgrastim) Approval



Approved 01/31/02

Jeff Summers


mechanism of action
Mechanism of Action
  • Both Neulasta® and Neupogen™ function as granulocyte colony stimulating factors
    • Neulasta® (pegfilgrastim) is a pegylated version of Neupogen™
    • Neupogen™ (Filgrastim) is a nonglycosylated N-terminal methionine modified recombinant human granulocyte colony stimulating factor (G-CSF) protein
granulocyte colony stimulating factors
Granulocyte Colony Stimulating Factors
  • G-CSF
    • Controls proliferation of committed progenitor cells and influences their maturation into mature neutrophils.
    • Stimulates the release of neutrophils from bone marrow storage pools and reduces their maturation time.
    • Acts to increase the phagocytic activity of mature neutrophils.
    • In patients receiving cytotoxic chemotherapy, G-CSF can accelerate neutrophil recovery, leading to a reduction in duration of the neutropenic phase .
studies submitted for neulasta approval
Studies submitted for Neulasta® Approval
  • Two randomized, double-blind, non-inferiority studies
    • Dosing
      • Study 1 used 100 ug/kg dose
      • Study 2 used a fixed 6 mg dose
    • Population
      • High-risk Stage II or Stage III/IV Breast Cancer patients
      • Age ≥ 18 years
      • Receiving Docetaxel and Doxorubicin
    • Endpoint
      • Duration of severe neutropenia comparing Neulasta® to Neupogen™


Mean days of severe neutropenia

Difference in means (95% CI)

Table 1. Mean Days of Severe Neutropenia (in Cycle 1)



Study 1

n = 157





Study 2

N = 310





Study 1 dose = 6 mg x1; study 2 dose = 100 mcg/kg


Primary Endpoint

study results
Study Results

Secondary Endpoints

 In both studies the results for the following were similar for both Neulasta and Neupogen:

●DSN in cycles 2 through 4

●Depth of ANC nadir in cycles 1 through 4

●Rates of FN by cycle and across all cycles

●Time to ANC recovery by cycle and across all cycles

label indication and usage
Label Indication and Usage

Neulasta® 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.

pediatric aspects of the neulasta label
Pediatric Aspects of the Neulasta® Label


Pediatric Use

The safety and effectiveness of Neulasta™ in pediatric patients have not been established. The 6 mg fixed dose single-use syringe formulation should not be used in infants, children, and smaller adolescents weighing less than 45 kg.


Pediatric Aspects of the Neupogen Label

  • Neupogen is approved for use in children with severe chronic neutropenia
  • Studied in patients with Neuroblastoma
  • Formulation allows for dosing based on mcg/kg
pediatric research equity act
Pediatric Research Equity Act
  • If the course of the disease and the effects of the drug are sufficiently similar in adults and pediatric patients, the Secretary may conclude that pediatric effectiveness can be extrapolated from adequate and well-controlled studies in adults, usually supplemented with other information obtained in pediatric patients, such as pharmacokinetic studies.
neulasta pharmacokinetics
Neulasta® Pharmacokinetics
  • Renal impairment had no influence on PK
  • Maximum Neulasta®concentration was achieved approximately 30 hours after SC administration
  • Volume of distribution at steady state approximated plasma volume/central compartment
  • Elimination is primarily via a neutrophil-mediated clearance mechanism
  • Half-life variable: chemotherapy setting 33 hrs compared to 3.37 hours for filgrastim

The Controlled Clinical Trial Safety Data Base of Neulasta® contains 932 patients

  • Bone pain

Post-marketing experience revealed the following SAEs:

  • Rare incidence of splenic rupture, allergic reactions, and sickle cell crises
issues for a pediatric neulasta pmc trial
Issues for a Pediatric Neulasta® PMC Trial
  • Is there any reason to expect the mechanism of action or efficacy to be different in a pediatric population?
  • Will establishing PK in pediatric age groups likely to be treated with pegfilgrastim ensure the safe use in pediatric patients?
  • Is the approved dosage form likely to be useful in the younger pediatric age groups
post marketing commitment pediatric study
Post Marketing Commitment Pediatric Study
  • To submit results from an ongoing study evaluating the pharmacokinetics (PK), safety and efficacy of Pegfilgrastim in pediatric sarcoma patients receiving a single dose per cycle of Filgrastim-SD/01 as an adjunct to VadriaC/IE chemotherapy.
  • Expanded access study.
  • To develop a pediatric dosage form