neulasta(pegfilgrastim) injection, solution 
[Amgen Manufacturing, Limited]
DESCRIPTION
Neulasta® (pegfilgrastim) is a covalent conjugate of recombinant methionyl human G‑CSF (Filgrastim) and monomethoxypolyethylene glycol. Filgrastim is a water‑soluble 175 amino acid protein with a molecular weight of approximately 19 kilodaltons (kD). Filgrastim is obtained from the bacterial fermentation of a strain of Escherichia coli transformed with a genetically engineered plasmid containing the human G‑CSF gene. To produce pegfilgrastim, a 20 kD monomethoxypolyethylene glycol molecule is covalently bound to the N‑terminal methionyl residue of Filgrastim. The average molecular weight of pegfilgrastim is approximately 39 kD.
Neulasta® is supplied in 0.6 mL prefilled syringes for subcutaneous injection. Each syringe contains 6 mg pegfilgrastim (based on protein weight), in a sterile, clear, colorless, preservative-free solution (pH 4.0) containing acetate (0.35 mg), sorbitol (30.0 mg), polysorbate 20 (0.02 mg), and sodium (0.02 mg) in water for injection, USP.
CLINICAL PHARMACOLOGY
Both Filgrastim and pegfilgrastim 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.1,2 Studies on cellular proliferation, receptor binding, and neutrophil function demonstrate that Filgrastim and pegfilgrastim have the same mechanism of action. Pegfilgrastim has reduced renal clearance and prolonged persistence in vivo as compared to Filgrastim.
Pharmacokinetics
The pharmacokinetics and pharmacodynamics of Neulasta® were studied in 379 patients with cancer. The pharmacokinetics of Neulasta® were nonlinear in cancer patients and clearance decreased with increases in dose. Neutrophil receptor binding is an important component of the clearance of Neulasta®, and serum clearance is directly related to the number of neutrophils. For example, the concentration of Neulasta® declined rapidly at the onset of neutrophil recovery that followed myelosuppressive chemotherapy. In addition to numbers of neutrophils, body weight appeared to be a factor. Patients with higher body weights experienced higher systemic exposure to Neulasta® after receiving a dose normalized for body weight. A large variability in the pharmacokinetics of Neulasta® was observed in cancer patients. The half‑life of Neulasta® ranged from 15 to 80 hours after subcutaneous injection.
Special Populations
No gender‑related differences were observed in the pharmacokinetics of Neulasta®, and no differences were observed in the pharmacokinetics of geriatric patients (≥ 65 years of age) compared to younger patients (< 65 years of age) (see PRECAUTIONS, Geriatric Use). In a study of 30 patients with varying degrees of renal dysfunction including end-stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim; thus, dose adjustment in patients with renal dysfunction is not necessary. The pharmacokinetic profile in pediatric populations or in patients with hepatic insufficiency has not been assessed.
CLINICAL STUDIES
Neulasta® was eva luated in three randomized, double‑blind, controlled studies. Studies 1 and 2 were active-controlled studies that employ