Advisory Committee Briefing Materials: Available for Public Release Joint Meeting of the Anesthetic and Analgesic Drug Products and the Drug Safety and Risk Management Advisory Committees October 5, 2016 kaleo, Inc. Briefing Dossier Advisory Committee Briefing Materials: Available for Public Release TABLE OF CONTENTS LIST OF FIGURES .........................................................................................................................3 LIST OF TABLES ...........................................................................................................................4 LIST OF ABBREVIATIONS ..........................................................................................................5 LIST OF APPENDICIES ................................................................................................................6 1. EXECUTIVE SUMMARY ......................................................................................................7 2. BACKGROUND ....................................................................................................................11 2.1. Opioid Overdose Epidemic ...........................................................................................11 2.2. Naloxone Products Used in Medical Settings ...............................................................12 2.3. Naloxone HCl Products Used in the Community Setting .............................................14 3. SCIENTIFIC BACKGROUND..............................................................................................19 3.1. Naloxone HCl and EVZIO Safety ................................................................................19 3.1.1. Literature Review of Naloxone HCl Safety ......................................................19 3.1.2. EVZIO Post-Marketing Safety Surveillance .....................................................20 3.2. Preclinical Pharmacokinetics ........................................................................................21 3.2.1. Absorption .........................................................................................................21 3.2.2. Distribution .......................................................................................................23 3.2.3. Metabolism (Interspecies Comparison) ............................................................24 3.2.4. Excretion ...........................................................................................................24 3.3. Clinical Pharmacokinetics and Pharmacodynamics......................................................25 3.3.1. Pharmacokinetics of Intravenous Administration of Naloxone HCl ................25 3.3.2. Pharmacokinetics of Naloxone HCl Administered Intramuscular/Subcutaneous .............................................................................27 3.3.3. Pharmacokinetics of Naloxone HCl Administered Via the Intranasal Route .................................................................................................................29 3.3.4. Pharmacodynamics - Published Literature........................................................36 3.4. Data to Support the Device Constituent Component of Naloxone Delivery Products Intended for Use in the Community Setting ...........................................38 3.4.1. EVZIO Product Characteristics.........................................................................39 3.4.2. EVZIO Sharps Injury Prevention Feature .........................................................41 3.4.3. EVZIO Features that Aid the User after Administering a Dose .......................41 3.4.4. In vitro Performance Testing of EVZIO for “Real Word” Use ........................41 3.4.5. Human Factors Studies for EVZIO ...................................................................42 4. DISCUSSION AND CONCLUSIONS ..................................................................................44 5. REFERENCES .......................................................................................................................47 2 1 September 2016 Advisory Committee Briefing Materials: Available for Public Release LIST OF FIGURES Figure 1. Serum and Brain Concentrations of Naloxone in the Rat after Intravenous Administration ............................................................................................................22 Figure 2. Pharmacokinetic Profile of Morphine and Naloxone in the Rat .................................23 Figure 3. Naloxone Plasma Concentration-Time Profiles Following Intravenous Administration of 2 mg Naloxone HCl ......................................................................26 Figure 4. Naloxone Plasma Concentration-Time Profiles Following Intravenous Administration of 0.035 mg/kg Naloxone HCl ..........................................................27 Figure 5. Mean (±SD) Naloxone Plasma Concentration-Time Profiles Following Intramuscular/Subcutaneous Administration of 0.4 mg Naloxone HCl .....................28 Figure 6. Naloxone Plasma Concentration-Time Profiles Following IN Administration of 20 mg Naloxone HCl Powder ................................................................................30 Figure 7. Mean Naloxone Plasma Concentration-Time Profiles Following Intranasal Administration of Naloxone HCl (NARCAN Nasal Spray) .......................................31 Figure 8. Mean (±SD) Naloxone Plasma Concentration-Time Profiles of 2.0 mg Naloxone HCl Administered Using an Intranasal Naloxone Kit and Intramuscular Using a Standard Syringe ....................................................................33 Figure 9. Mean (±SD) Naloxone Plasma Concentration-Time Profiles following Intranasal Administration of 2.0 mg Naloxone with and without Vasoconstrictor Pre-treatment, (A) 0-6 hour and (B) 0-1 hour ..................................35 Figure 10. The Effects of (A) Placebo, (B) 0.2 mg Naloxone HCl, and (C) 0.4 mg Naloxone HCl, 30 Minutes after Administration of Morphine ..................................36 Figure 11. The Effects of (A) Placebo, (B) 0.025 mg Naloxone HCl, (C) 0.1 mg Naloxone HCl, and (D) 0.4 mg Naloxone HCl, 55 Minutes after Administration of Morphine-6-Glucuronide ..............................................................37 Figure 12. The Effects of Placebo, 1 mg Naloxone HCl, 5 mg Naloxone HCl, and 10 mg Naloxone HCl after Intravenous Administration of Buprenorphine ....................38 Figure 13. Illustration of EVZIO, EVZIO Outer Case, and a Used EVZIO ................................40 Figure 14. Illustration of a Trainer for EVZIO ............................................................................41 3 1 September 2016 Advisory Committee Briefing Materials: Available for Public Release LIST OF TABLES Table 1. Naloxone HCl Products Currently Used in the Out of Hospital Setting ....................15 Table 2. United States Distribution Information for EVZIO ....................................................21 Table 3. Spontaneous Adverse Event Reports for EVZIO .......................................................21 Table 4. Summary of Naloxone Plasma Pharmacokinetic Parameters and Comparative Bioavailability Results (Study IJ-900DV-03O) ....................................29 Table 5. Comparison of Intranasal 2.0 mg Naloxone HCl Pharmacokinetics in Subjects with Chronic Rhinitis with and without Concomitant Nasal Vasoconstrictor Use ....................................................................................................35 Table 6. Summary of Successful Critical Task Completion in Two Controlled Usability Studies .........................................................................................................43 4 1 September 2016 Advisory Committee Briefing Materials: Available for Public Release LIST OF ABBREVIATIONS Abbreviation Term ASTM American Society for Testing and Materials AUC0-t area under the concentration-time curve from baseline to the last measurable concentration AUC0-inf area under the concentration-time curve from baseline extrapolated to infinity AUC0-Tmax area under the curve from time zero to the Tmax for each subject in the 2.0 mg IN study arm Cmax maximum plasma concentration CI Confidence Interval CNS central nervous system FDA Food and Drug Administration g%CV geometric percent coefficient of variation HCl hydrochloride salt hr hours IFU instructions for use IEC International Electrotechnical Commission IN intranasal(ly) IM Intramuscular(ly) ISO International Organization for Standardization ISTA International Safe Transit Association IV intravenous(ly) M6G morphine-6-glucuronide MedDRA Medical Dictionary for Regulatory Activities min minutes NDA new drug application PK pharmacokinetics PIL patient information leaflet SC subcutaneous(ly) SD standard deviation T1/2 terminal-phase elimination half-life Tmax time at maximum plasma concentration UL Underwriter Laboratories USP United States Pharmacopeia 5 1 September 2016 Advisory Committee Briefing Materials: Available for Public Release LIST OF APPENDICIES Appendix 1: EVZIO (naloxone HCl injection) Auto-Injector: Prescribing Information April 2014 Appendix 2: EVZIO (naloxone HCl injection) Auto-Injector: Patient Information / Instructions for Use April 2014 Appendix 3: Trainer for EVZIO: Trainer Instructions for Use April 2014 Appendix 4: Opioid Emergencies and Life-Threatening Respiratory Depression: Kaleo, Inc. 2016 6 1 September 2016 Advisory Committee Briefing Materials: Available for Public Release 1. EXECUTIVE SUMMARY The