Long-Term Safety of a Four-Factor Prothrombin Complex Concentrate (Kcentra®/Beriplex® P/N): An Updated Pharmacovigilance Review.

Introduction:  Four-factor prothrombin complex concentrate (4F-PCC) is recommended for vitamin K antagonist reversal in patients with major bleeding or in need of surgery. The most important risk associated with the use of 4F-PCC is the occurrence of thromboembolic events (TEEs). In this review, we aim to evaluate the safety profile of a 4F-PCC (Kcentra®/Beriplex® P/N; CSL Behring, Marburg, Germany) by reviewing pharmacovigilance data.
Methods:  A retrospective analysis of postmarketing pharmacovigilance data of Kcentra®/Beriplex® P/N from February 1996 to April 2022 was performed and complemented by a review of clinical studies published between January 2012 and April 2022.
Results:  A total of 2,321,443 standard infusions of Kcentra®/Beriplex® P/N were administered during the evaluation period. Adverse drug reactions (ADRs) were reported in 614 cases (∼1 per 3,781 standard infusions) and 233 of these cases (37.9%) experienced suspected TEEs related to 4F-PCC (∼1 per 9,963 standard infusions); most of these cases had pre-existing or concomitant conditions likely to be significant risk factors for thrombosis. TEE rates were similar when 4F-PCC was used on-label or off-label for direct oral anticoagulant-associated bleeding. Thirty-six cases (5.9%) reported hypersensitivity type reactions (∼1 per 64,485 standard infusions). No confirmed case of viral transmission related to 4F-PCC use was reported. The published literature also revealed a favorable safety profile of 4F-PCC.
Conclusion:  Analysis of postmarketing pharmacovigilance safety reports demonstrated that treatment with 4F-PCC was associated with few ADRs and a low rate of TEEs across multiple indications and settings, thus confirming a positive safety profile of 4F-PCC.
Competing Interests: T.J.M. is a consultant for CSL Behring, Octapharma, Alexion-Astra Zeneca, and Cellphire. E.L.-L. has received lecture honoraria and advisory fees from Astra Zeneca, Bayer AG, Boehringer Ingelheim, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Portola, Norgine, Roche, CSL Behring, Viatris, and Aspen and institutional research support from Bayer AG, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, and CSL Behring. A.V. and D.S.S. are employees of CSL Behring.
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