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ORIGINAL ARTICLES
Bupivacaine Extended-Release Liposome Injection Exhibits a Favorable Cardiac Safety Profile
  1. Sergio D. Bergese, MD*,
  2. Erol Onel, MD†,
  3. Michael Morren, RPh, MBA‡ and
  4. Joel Morganroth, MD§
  1. From the *Departments of Anesthesiology and Neurological Surgery, Ohio State University, Columbus, OH;
  2. †Pacira Pharmaceuticals, Inc, and
  3. ‡Peloton Advantage, LLC, Parsippany, NJ; and
  4. §eResearch Technology, Inc, Philadelphia, PA.
  1. Address correspondence to: Sergio D. Bergese, MD, Ohio State University Medical Center, Department of Anesthesiology, 410 W 10th Ave, Doan Hall N411, Columbus, OH 43210 (e-mail: sergio.bergese{at}osumc.edu).

Abstract

Background and Objectives Bupivacaine extended-release liposome injection is an investigational local analgesic intended for use in postsurgical pain management. In recognition of the incompletely characterized association of bupivacaine use and cardiac effects, this article reviews the cardiac safety profile of this novel formulation of bupivacaine.

Methods Findings from paired electrocardiograms (ECGs), corresponding pharmacokinetic assessments, and cardiovascular adverse events (AEs) in a phase 2, randomized, double-blind, dose-ranging study of bupivacaine extended-release (150, 300, 450, or 600 mg) or bupivacaine HCl 150 mg with epinephrine administered intraoperatively via wound infiltration in patients undergoing total knee arthroplasty (n = 138), were assessed for potential causality. Results from 4 phase 1 bupivacaine extended-release studies that also obtained ECG and/or Holter monitor findings (n = 169) were assessed. In addition, incidences of cardiovascular AEs reported across 10 bupivacaine extended-release wound infiltration studies (n = 1459) were pooled and assessed.

Results In the phase 2 study, mean change from baseline in QRS duration and QTcF duration across dose levels of bupivacaine extended-release was similar (range, −1 to +4 milliseconds and −7 to −10 milliseconds) compared with bupivacaine HCl (−1 millisecond and −6 milliseconds). Mean change from baseline in heart rate, PR interval, and QRS interval was similar between treatment groups as well. No clinically relevant ECG changes or cardiac AEs with bupivacaine extended-release were observed in the other clinical studies.

Conclusions A focused assessment of ECG data from a phase 2 study and cardiac findings/AEs data from other studies in the bupivacaine extended-release development program did not reveal any cardiac safety issues.

https://doi.org/10.1097/AAP.0b013e31823d0a80

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    Footnotes

    • Dr Bergese has received research support from Pacira Pharmaceuticals, Inc. Dr Onel is an employee of Pacira Pharmaceuticals, Inc. Dr Morren provided editorial and writing assistance supported by Pacira Pharmaceuticals, Inc. Dr Morganroth is an employee of eRT (eResearchTechnology, Inc), which provides services to the pharmaceutical industry in determining electrocardiogram analysis and cardiac safety and is a consultant to Pacira Pharmaceuticals, Inc, for cardiac analysis and in generation of the reports included in this article.

    • Dr Bergese was involved with the phase 2 and 3 study design, data analysis, manuscript preparation, review, and final approval. Dr Onel was involved in all study design, statistical analysis, manuscript preparation, and final approval. Mr Morren was involved in literature searching, writing, and editorial revisions based on coauthor feedback throughout the manuscript preparation process and final approval. Dr Morganroth analyzed all electrocardiogram data from both the phase 2 and 3 studies and was involved in manuscript review and final approval.