EXPAREL Briefing Document: 14-15 February 2018 FDA Advisory Committee Meeting FDA ADVISORY COMMITTEE MEETING BRIEFING DOCUMENT ® EXPAREL (bupivacaine liposome injectable suspension) MEETING OF THE ANESTHETIC AND ANALGESIC DRUG PRODUCTS ADVISORY COMMITTEE MEETING DATE: 14-15 February 2018 AVAILABLE FOR PUBLIC RELEASE EXPAREL Briefing Document: 14-15 February 2018 FDA Advisory Committee Meeting TABLE OF CONTENTS Table of Contents ............................................................................................................................ 2 List of Tables .................................................................................................................................. 5 List of Figures ................................................................................................................................. 6 1 Executive Summary ................................................................................................................ 9 1.1 Rationale for the Use of EXPAREL as a Nerve Block .................................................. 10 1.2 Regulatory History ......................................................................................................... 12 1.3 Clinical Pharmacology ................................................................................................... 13 1.4 Efficacy Findings ........................................................................................................... 14 1.5 Safety Findings ............................................................................................................... 21 1.6 Conclusions .................................................................................................................... 23 2 Rationale for the Use of EXPAREL as Nerve Block ........................................................... 24 2.1 Current Treatment Landscape for Postsurgical Pain Management ................................ 24 2.2 Limitations of Current Postsurgical Analgesic Treatment Options ............................... 25 2.2.1 Continuous Peripheral Nerve Blocks ...................................................................... 26 2.2.2 Opioid Analgesics ................................................................................................... 26 2.3 Potential Clinical Advantages of EXPAREL as a Nerve Block .................................... 27 3 EXPAREL Product Description and Clinical Development ................................................ 28 3.1 Proposed Indication ........................................................................................................ 28 3.2 Treatment Administration and Dosing Regimen ........................................................... 28 3.3 Mechanism of Action ..................................................................................................... 29 3.4 Regulatory History ......................................................................................................... 29 3.5 Clinical Studies .............................................................................................................. 30 4 Clinical Pharmacology .......................................................................................................... 33 4.1 Overview of Clinical Pharmacology Program ............................................................... 33 4.2 Pharmacokinetic Characteristics .................................................................................... 34 4.2.1 EXPAREL Versus Bupivacaine HCl in Regional Analgesia ................................. 35 4.2.2 Pharmacokinetics of Phase 3 Dosing Regimens ..................................................... 35 4.2.3 Population PK Modeling......................................................................................... 36 5 Clinical Efficacy ................................................................................................................... 38 5.1 Phase 3 Clinical Study Design ....................................................................................... 39 5.1.1 Overview of Pivotal Studies for Regional Analgesia ............................................. 39 Page 2 of 94 EXPAREL Briefing Document: 14-15 February 2018 FDA Advisory Committee Meeting 5.1.2 Study Designs ......................................................................................................... 39 5.1.3 Enrollment Criteria ................................................................................................. 41 5.1.4 Perioperative Medications ...................................................................................... 42 5.1.5 Rescue Pain Medications ........................................................................................ 42 5.1.6 Efficacy Endpoints .................................................................................................. 43 5.2 Patient Disposition ......................................................................................................... 44 5.3 Patient Demographic and Baseline Characteristics ........................................................ 46 5.4 Study 327 Results ........................................................................................................... 48 5.4.1 Primary Endpoint .................................................................................................... 48 5.4.2 Secondary Endpoints .............................................................................................. 48 5.5 Study 322 Results ........................................................................................................... 50 5.6 Study 323 – Part 1 Results ............................................................................................. 51 5.7 Study 323 – Part 2 Results ............................................................................................. 52 5.7.1 Primary Endpoint .................................................................................................... 52 5.7.2 Secondary Endpoints .............................................................................................. 53 5.8 Study 326 Results ........................................................................................................... 54 5.9 Subgroup Analyses ......................................................................................................... 56 5.10 Efficacy in Supportive Studies ....................................................................................... 56 5.10.1 Study 1601 .............................................................................................................. 57 5.10.2 Study 1602 .............................................................................................................. 59 5.11 Efficacy Conclusions...................................................................................................... 60 6 Clinical Safety ....................................................................................................................... 62 6.1 Treatment Exposure ....................................................................................................... 62 6.2 Adverse Events ............................................................................................................... 63 6.2.1 Serious Adverse Events .......................................................................................... 64 6.2.2 Deaths ..................................................................................................................... 65 6.2.3 AEs Leading to Study Discontinuation................................................................... 66 6.3 Adverse Events of Special Interest................................................................................. 66 6.3.1 Local Anesthetic Systemic Toxicity ....................................................................... 66 6.3.2 Falls ......................................................................................................................... 69 6.3.3 Sensory and Motor Function ................................................................................... 69 6.4 Cardiovascular Safety .................................................................................................... 73 Page 3 of 94 EXPAREL Briefing Document: 14-15 February 2018 FDA Advisory Committee Meeting 6.4.1 Tachycardia and Bradycardia ................................................................................. 73 6.4.2 FDA-Specified Arrhythmias of Interest.................................................................. 74 6.5 Safety by Subgroups....................................................................................................... 77 6.6 Postmarketing Data ........................................................................................................ 77 6.7 Safety Conclusions ......................................................................................................... 78 7 Clinical Summary ................................................................................................................. 79 8 References ............................................................................................................................. 81 Appendix 1 – Schedule of Study Procedures and Assessments ................................................... 85 Appendix 2 – Death Narratives ....................................................................................................