Clinical Drug Investigation

, Volume 33, Issue 2, pp 109–115 | Cite as

Pharmacokinetic Profile of Liposome Bupivacaine Injection Following a Single Administration at the Surgical Site

  • DeeDee Hu
  • Erol Onel
  • Neil Singla
  • William G. Kramer
  • Admir Hadzic
Review Article


Local anaesthetics are often used as part of multimodal pain management techniques to manage postsurgical pain and lessen the need for opioid analgesics; however, the duration of action of traditional formulations of local anaesthetics is short. Liposome bupivacaine is a novel, multivesicular formulation designed for rapid absorption, prolonged release of bupivacaine, and analgesia following a single intra-operative administration into the surgical wound. This article provides a summary of the pharmacokinetic profile of liposome bupivacaine compared with bupivacaine HCl based on data compiled from four randomized, active- and placebo-controlled trials that included pharmacokinetic assessments following single administrations of study drug. Each study evaluated the safety, efficacy and pharmacokinetic profile of liposome bupivacaine in separate surgical populations (patients undergoing inguinal hernia repair, total knee arthroplasty, haemorrhoidectomy or bunionectomy). Pharmacokinetic parameters included maximum plasma drug concentration (Cmax), area under the curve (AUC) for plasma bupivacaine concentration over time extrapolated to infinity (AUC), time to observed Cmax (tmax) and terminal elimination half-life of bupivacaine (t½). The studies assessed single administrations of liposome bupivacaine at dose levels ranging from 106 to 532 mg or bupivacaine HCl 100 to 150 mg or placebo (0.9 % sodium chloride) given locally via wound infiltration at the end of surgery prior to wound closure. Male and non-pregnant female patients (n = 253) aged ≥18 years, scheduled to undergo surgery as per the specific protocol for each study, were enrolled. Patient characteristics were stratified by liposome bupivacaine doses ≤266 mg and >266 mg, and bupivacaine HCl treatment arms. Pharmacokinetic parameters for liposome bupivacaine doses of 106, 266, 399 and 532 mg were compared. Plasma concentration versus time profiles were quantitatively similar across these four dose levels of liposome bupivacaine, with an initial peak occurring within 1 h after administration followed by a second peak about 12–36 h later. The overall incidence of adverse events was lower in the liposome bupivacaine ≤266-mg group than the liposome bupivacaine >266-mg and bupivacaine HCl groups (100- or 150-mg doses). In summary, liposome bupivacaine was well tolerated across the four studies and varied surgical models, and exhibited bimodal kinetics with rapid uptake observed during the first few hours and prolonged release through 96 h after administration.

Supplementary material

40261_2012_43_MOESM1_ESM.pdf (14 kb)
Supplementary material 1 (PDF 13 kb)


  1. 1.
    Apfelbaum JL. Practice guidelines for acute pain management in the perioperative setting: an updated report by the American Society of Anesthesiologists Task Force on Acute Pain Management. Anesthesiology. 2012;116(2):248–73.CrossRefGoogle Scholar
  2. 2.
    Buvanendran A, Kroin JS. Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol. 2009;22(5):588–93.PubMedCrossRefGoogle Scholar
  3. 3.
    Jirasiritham S, Tantivitayatan K, Jirasiritham S. Perianal blockage with 0.5% bupivacaine for postoperative pain relief in hemorrhoidectomy. J Med Assoc Thai. 2004;87(6):660–4.PubMedGoogle Scholar
  4. 4.
    Mahabir RC, Peterson BD, Williamson JS, et al. Locally administered ketorolac and bupivacaine for control of postoperative pain in breast augmentation patients. Plast Reconstr Surg. 2004;114(7):1910–6.PubMedCrossRefGoogle Scholar
  5. 5.
    Moiniche S, Mikkelsen S, Wetterslev J, et al. A qualitative systematic review of incisional local anaesthesia for postoperative pain relief after abdominal operations. Br J Anaesth. 1998;81(3):377–83.PubMedCrossRefGoogle Scholar
  6. 6.
    Kastrissios H, Triggs EJ, Sinclair F, et al. Plasma concentrations of bupivacaine after wound infiltration of an 0.5% solution after inguinal herniorrhaphy: a preliminary study. Eur J Clin Pharmacol. 1993;44(6):555–7.PubMedCrossRefGoogle Scholar
  7. 7.
    Joshi GP, Neugebauer EA, on behalf of the PROSPECT Collaboration. Evidence-based management of pain after haemorrhoidectomy surgery. Br J Surg. 2010;97(8):1155–68.PubMedCrossRefGoogle Scholar
  8. 8.
    Chester JF, Stanford BJ, Gazet JC. Analgesic benefit of locally injected bupivacaine after hemorrhoidectomy. Dis Colon Rectum. 1990;33(6):487–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Moiniche S, Kehlet H, Dahl JB. A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: the role of timing of analgesia. Anesthesiology. 2002;96(3):725–41.PubMedCrossRefGoogle Scholar
  10. 10.
    Bupivacaine hydrochloride [package insert]. Lake Forest, IL: Hospira, Inc.; 2010.Google Scholar
  11. 11.
    Haas E, Onel E, Miller H, et al. A double-blind, randomized, active-controlled study for post-hemorrhoidectomy pain management with liposome bupivacaine, a novel local analgesic formulation. Am Surg. 2012;78(5):574–81.PubMedGoogle Scholar
  12. 12.
    Bramlett K, Onel E, Viscusi ER, et al. A randomized, double-blind, dose-ranging study comparing wound infiltration of DepoFoam bupivacaine, an extended-release liposomal bupivacaine, to bupivacaine HCl for postsurgical analgesia in total knee arthroplasty. Knee. 2012;19(5):530–6.PubMedCrossRefGoogle Scholar
  13. 13.
    Gorfine SR, Onel E, Patou G, et al. Bupivacaine extended-release liposome injection for prolonged postsurgical analgesia in patients undergoing hemorrhoidectomy: a multicenter, randomized, double-blind, placebo-controlled trial. Dis Colon Rectum. 2011;54(12):1552–9.PubMedCrossRefGoogle Scholar
  14. 14.
    Smoot JD, Bergese SD, Onel E, et al. The efficacy and safety of DepoFoam® bupivacaine in patients undergoing bilateral, cosmetic, submuscular augmentation mammoplasty: a randomized, double-blind, active-control study. Aesthet Surg J. 2012;32(1):69–76.PubMedCrossRefGoogle Scholar
  15. 15.
    Langford RM, Chappell GM, Karrasch JA. A single administration of DepoBupivacaine intraoperatively results in prolonged detectable plasma bupivacaine and analgesia in patients undergoing inguinal hernia repair [abstract P-9088]. Presented at: Annual Postgraduate Assembly in Anesthesiology of the New York State Society of Anesthesiologists; 2008 Dec 12–16; New York (NY).Google Scholar
  16. 16.
    Golf M, Daniels SE, Onel E. A phase 3, randomized, placebo-controlled trial of DepoFoam(R) bupivacaine (extended-release bupivacaine local analgesic) in bunionectomy. Adv Ther. 2011;28(9):776–88.PubMedCrossRefGoogle Scholar
  17. 17.
    International Conference on Harmonisation Working Group. ICH Harmonised Tripartite Guideline: Guideline for Good Clinical Practice E6 (R1). International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use; June 10, 1996; Washington, DC [online]. Available from URL: Accessed April 19, 2012.
  18. 18.
    World Medical Association. Declaration of Helsinki: ethical principles for medical research involving human subjects [online]. Available from URL: Accessed April 19, 2012.
  19. 19.
    US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research, Center for Veterinary Medicine. Guidance for Industry: Bioanalytical Method Validation. 2001 May 1.Google Scholar
  20. 20.
    Exparel [package insert]. San Diego, CA: Pacira Pharmaceuticals, Inc.; 2011.Google Scholar
  21. 21.
    Bergese SD, Ramamoorthy S, Patou G, et al. Efficacy profile of liposome bupivacaine, a novel formulation of bupivacaine for postsurgical analgesia. J Pain Res. 2012;5:107–16.PubMedCrossRefGoogle Scholar
  22. 22.
    Jorfeldt L, Lofstrom B, Pernow B, et al. The effect of local anaesthetics on the central circulation and respiration in man and dog. Acta Anaesthesiol Scand. 1968;12(4):153–69.PubMedCrossRefGoogle Scholar
  23. 23.
    Bardsley H, Gristwood R, Baker H, et al. A comparison of the cardiovascular effects of levobupivacaine and rac-bupivacaine following intravenous administration to healthy volunteers. Br J Clin Pharmacol. 1998;46(3):245–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Naseem A, Harada T, Wang D, et al. Bupivacaine extended release liposome injection does not prolong QTc interval in a thorough QT/QTc study in healthy volunteers. J Clin Pharmacol. 2012;52(9):1441–7.PubMedCrossRefGoogle Scholar
  25. 25.
    Bergese SD, Onel E, Morren M, et al. Bupivacaine extended-release liposome injection exhibits a favorable cardiac safety profile. Reg Anesth Pain Med. 2012;37(2):145–51.PubMedCrossRefGoogle Scholar
  26. 26.
    Onel E, Warnott K, Markvicka T, et al. Pharmacokinetics of depobupivacaine (EXPAREL), a novel bupivacaine extended-release liposomal injection, in volunteers with moderate hepatic impairment [abstract]. Clin Pharmacol Ther. 2011;89(Suppl 1):S28–9.Google Scholar

Copyright information

© Springer International Publishing Switzerland 2012

Authors and Affiliations

  • DeeDee Hu
    • 1
  • Erol Onel
    • 2
  • Neil Singla
    • 3
  • William G. Kramer
    • 4
  • Admir Hadzic
    • 5
  1. 1.Clinical Specialist, Critical Care and CardiologyMemorial Hermann Memorial City Medical CenterHoustonUSA
  2. 2.Pacira Pharmaceuticals, Inc.ParsippanyUSA
  3. 3.Lotus Clinical Research, LLCPasadenaUSA
  4. 4.Kramer Consulting LLCNorth PotomacUSA
  5. 5.St. Luke’s HospitalNew YorkUSA

Personalised recommendations