Introduction: Marketed therapeutic products are subject to periodic benefit-risk evaluation reports (PBRERs), which provide comprehensive worldwide safety assessments and benefit-risk analyses. The short-acting recombinant human granulocyte colony-stimulating factor (rG-CSF) is known as filgrastim (Tevagrastim®, Ratiograstim®, Biograstim®) in Europe (approved in 2008) and tbo-filgrastim (Granix®) in the United States (approved in 2012). In the United States, Granix is indicated for reducing the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Here, we present the accumulated safety data from the PBRER for the rG-CSFs collected in a 3-year period from the 52 countries in which the product was registered.Methods: Cumulative data were collected since initial approval in 2008. This PBRER period includes data captured from September 16, 2012, to September 15, 2015. Data were collected from spontaneous reports submitted by healthcare professionals and consumers, the scientific literature, competent authorities, and solicited case reports. Adverse reactions were categorized by system organ class (SOC), source, and seriousness. Pharmacovigilance in Europe requires screening of all adverse reaction reports and antibody assessment for cases of suspected immunogenicity. Safety concerns identified by the originator during the use of filgrastim were described in the risk management plan (RMP; version 8; dated 14 May 2012).Results: During this PBRER period, the estimated exposure to the rG-CSFs was ~4,314,994 patient-days. As of September 15, 2015, the estimated cumulative exposure to the rG-CSFs was ~8,741,835 patient-days over 7 years. Estimated cumulative exposure to the rG-CSFs in clinical trials were 190 patient-days in healthy subjects and 22,099 patient-days in patients with cancer. The global safety database processed 561 rG-CSFs case reports from initial product approval through September 15, 2015 (~9 years), including 339 (60%) from this PBRER period (~3 years). Postmarketing data sources cumulatively reported 1133 adverse reactions, 702 (62%) from this PBRER period. The most common adverse events (AEs) reported during this PBRER period per SOC are summarized in the figure. The most frequently reported serious AEs associate with general disorders and administration site conditions during this period were pyrexia (11 reports) and ineffective drug (8). Reports of serious bone pain (3 reports), back pain (2), muscular weakness (2), musculoskeletal pain (2), and myalgia (2) were also received during this period. The most common AEs associated with serious skin conditions were pruritus and urticarial (5 reports each). Two additional safety concerns (capillary leak syndrome [CLS] and cytokine release syndrome [CRS]) were identified by the originator during the use of filgrastim and were subsequently added to the RMP based on recommendations from the Pharmacovigilance Risk Assessment Committee. As of September 15, 2015, one report of CLS and no reports of CRS have been received. Overall, reported cases of immunogenicity showed no impact on efficacy or pharmacokinetics/ pharmacodynamics of the rG-CSFs. Updated data will be presented at the conference as available.Conclusions: No significant changes in the safety or risk-benefit profiles were identified for the rG-CSFs relative to other filgrastim products during this reporting period, and reported cases of immunogenicity showed no clinically relevant impact. [Display omitted] DisclosuresAbboud:Teva: Speakers Bureau; Alexion, Baxalta, Pharmacyclics, Takeda, Cardinal Health: Honoraria; Merck, Teva, Novartis, Pfizer, Seattle Genetics: Research Funding; Gerson and Lehman Group (GLG): Consultancy. Lang:Teva ratiopharm: Employment. Lammerich:Teva ratiopharm/Teva Pharmaceuticals, Inc.: Employment. Buchner:Merckle GmbH member of TEVA Group: Employment; Teva Pharmaceuticals, Inc.: Equity Ownership. Liu:Teva Pharmaceuticals, Inc.: Employment. Mueller:Teva Pharmaceuticals, Inc.: Employment, Equity Ownership. Pathak:Teva Pharmaceuticals: Employment, Equity Ownership.
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Open Access
Dec 25, 2023
Shinya Takada + 10
