March 6, 2015
On March 6, 2015, the U. S. Food and Drug Administration approved filgrastim-sndz (ZARXIO™ Injection, Sandoz Inc.),as a biosimilar to US-licensed Neupogen® for the five indications for which US-licensed Neupogen® is approved.The formulation of ZARXIO™ differs from that of US-licensed Neupogen® in one inactive component.
The approval of ZARXIO™ was based on review of evidence that included comparative structural and functional characterization, animal studies, human pharmacokinetic (PK) and pharmacodynamics (PD), and clinical immunogenicity data, and other clinical safety and effectiveness data which demonstrate ZARXIO™ is highly similar to US-licensed Neupogen® notwithstanding minor differences in clinically inactive components and that there are no clinically meaningful differences between ZARXIO™ and US-licensed Neupogen®.
The structural and functional studies demonstrated that ZARXIO™ has the same amino acid sequence as US-licensed Neupogen®. These studies also demonstrated that functional properties such as biological activity and receptor binding as well as physicochemical properties such as higher order structure, and product-related substances and impurities of ZARXIO™ are highly similar to US-licensed Neupogen®. In addition, ZARXIO™ was found to have a similar stability profile as US-licensed Neupogen®. In these comparative studies, a total of 20 lots of ZARXIO™ drug product, 6 lots of EP2006 drug substance (DS), and 10-15 lots of US-licensed Neupogen® were evaluated.
The results from these studies demonstrated that ZARXIO™ is highly similar to US-licensed Neupogen®, notwithstanding minor differences in clinically inactive components. The analytical similarity studies did not raise residual uncertainties about the demonstration of highly similar between ZARXIO™ and US-licensed Neupogen®.
There were four pharmacokinetic (PK) and pharmacodynamic (PD) studies that evaluated subcutaneous (SC) doses of 1-10 mcg/kg in healthy subjects to evaluate the PK and PD similarity of ZARXIO™ with US-licensed Neupogen® or EU-approved Neupogen®. In addition to PK, these studies evaluated absolute neutrophil counts (ANC) and CD34+ cell counts as relevant and sensitive PD markers for neutropenia and mobilization of hematopoietic stem cells for the similarity assessment. Among these, three studies utilized EU-approved Neupogen® as active comparator. The analytical pair-wise comparisons of ZARXIO™, US-licensed Neupogen®, and EU-approved Neupogen® met the pre-specified criteria for analytical similarity and established a scientific bridge to justify the relevance of the PK/PD data generated using EU-approved Neupogen®.
The PK and PD studies support a demonstration of PK and PD similarity between ZARXIO™ and US-licensed Neupogen®. The 90% CI for AUC and Cmax after a single dose were within the pre-defined limits of 80-125%. Similarly, the 95% CI for AUEC and ANCmax for ANC after a single dose were within the pre-defined limits of 80-125%. The 95% CI for AUEC and CD34max for CD34+ cell counts after multiple doses were within the limits of 80-125%.
Safety data were evaluated in 204 healthy subjects and in 214 patients with breast cancer. The safety profile of ZARXIO™ was similar to that of US-licensed or EU-approved Neupogen®.
The recommended dose and schedule for ZARXIO™ is the same as for US-licensed Neupogen®.
Full prescribing information, including dosing, safety, warnings and contraindications, is available at: www.accessdata.fda.gov/drugsatfda_docs/label/2015/125553lbl.pdf
Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System by completing a form online at http://www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178) or mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).