Safety Evaluation of EXPAREL (DepoFoam Bupivacaine) Administered by Repeated Subcutaneous Injection in Rabbits and Dogs: Species Comparison

Abstract

EXPAREL (bupivacaine extended-release liposome injection), DepoFoam bupivacaine, is in development for prolonged postsurgical analgesia. Repeat-dose toxicity studies were conducted in rabbits and dogs to compare the potential local and systemic toxicities of EXPAREL and bupivacaine HCl (Bsol), and the reversibility of any effects. Dogs tolerated much larger doses than rabbits. EXPAREL-related minimal-to-moderate granulomatous inflammation was noted at the injection sites. In recovery animals, the granulomatous inflammation was observed less frequently and was characterized by an increased number of multinucleated giant cells. These effects were considered a normal response to liposomes and nonadverse. Rabbits are more sensitive than dogs. In rabbits, convulsions were noted with EXPAREL and more frequently with Bsol; a NOAEL was not identified. In dogs, EXPAREL was well tolerated (NOAEL > 30 mg/kg/dose). The cumulative exposure of EXPAREL in these studies is well in excess of the proposed maximum single-dose exposure that is intended in humans.

The Efficacy of Liposomal Bupivacaine in Lumbar Spine Surgery

“…This finding would suggest that the second hospital day is an important time for added pain control postoperatively. As standard bupivacaine produces an anesthetic effect that lasts only 9 hours, LB may be more beneficial as it will still be effective during this critical time period [8,9].…”

“…Due to its relative short duration, there has been an emergence of formulations that can prolong the local anesthetic effect, such as Liposomal Bupivacaine (LB; Exparel, Pacira Pharmaceuticals Inc., Parsippany, NJ, USA). LB consists of 3% free bupivacaine for immediate effects and 97% liposomal-bound bupivacaine, which allows for a slow release and prolonged anesthetic effect lasting up to 72 hours after administration [8,9]. The use of LB in Total Knee Arthroplasty (TKA) has been heavily investigated with studies demonstrating varying results.…”

Best evidence in multimodal pain management in spine surgery and means of assessing postoperative pain and functional outcomes

“…To combat this, multivesicular liposomes containing bupivacaine have recently been developed that allow for sustained drug release over several days [52,53]. It is indicated for single-dose administration into the surgical site to produce postsurgical analgesia.…”

Local Toxicity from Local Anesthetic Polymeric Microparticles

“…A very broad range of controlled release formulations have been developed to provide prolonged duration local anesthesia, including polymeric microspheres, [1][2][3][4][5][6][7] surgically implantable pellets, 8 microcrystals, 9 liposomes, [10][11][12][13][14][15] (including a formulation undergoing human clinical trials 16,17 ) lipospheres, 18 cross-linkable hyaluronic acid matrices, 19 lipidprotein-sugar particles, 20,21 cyclodextrin complexes, 22,23 liposomes loaded with cyclodextrin complexes 24 and implantable membrane matrices. 25,26 Such systems have extended the duration of nerve block to varying degrees ranging from hours to weeks, but have not been widely adopted clinically.…”

“…32,[38][39][40] Reporting of local tissue injury from local anesthetic controlled release formulations has been variable, in both animal and human studies. Most do not describe myotoxicity [2][3][4][5][7][8][9][11][12][13][14][15]18,[22][23][24] (including the liposomal formulation undergoing human trials 16,17 ), while some others document mild muscle injury comparable to single injections of unencapsulated drug. 10,25,26 In our own work, we have found muscle injury to be a ubiquitous finding in a wide range of extended-release bupivacaine formulations independent of the delivery vehicle 6,19,21,41 or co-encapsulated agent, 32,37,42,43 and it is sometimes severe.…”