CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 204200Orig1s000 204200Orig2s000 MEDICAL REVIEW(S) CLINICAL REVIEW Application Type NDA Application Number(s) 204-200 and 204-640 Priority or Standard Standard Submit Date(s) March 7, 2012 Received Date(s) March 7, 2012 PDUFA Goal Date January 7, 2013 Division / Office DPARP/OND Reviewer Name(s) Peter Starke, MD Review Completion Date October 29, 2012 Established Name Epinephrine injection, USP, 1mg/mL (Proposed) Trade Name Adrenalin® Therapeutic Class Catecholamine Applicant JHP Pharmaceuticals, LLC Formulation(s) Solution for injection Proposed Dosing Hypersensitivity reactions: IM or SC Regimen injection(b) (4) [Ophthalmic use: Topical irrigation or intraocular bolus injection] Proposed Indication(s) Hypersensitivity reactions: severe acute anaphylactic reactions, (b) (4) [Ophthalmic use: induction and maintenance of mydriasis during cataract surgery] Intended Population(s) Hypersensitivity reactions: No age restrictions [Ophthalmic use: No age restrictions] Reference ID: 3209828 Clinical Review ● Peter Starke, MD NDA 204-200 ● Adrenalin® (epinephrine) MEDICAL OFFICER REVIEW Division of Pulmonary, Allergy and Rheumatology Products (DPARP) SUBMISSIONS REVIEWED IN THIS DOCUMENT Document Date CDER Stamp Date Submission Comments March 7, 2012 March 7, 2012 SD-1, eCTD-0000 New NDA submission April 9, 2012 April 9, 2012 SD-2, eCTD-0001 PREA waiver request – Anaphylaxis April 9, 2012 April 9, 2012 SD-3, eCTD-0002 PREA waiver request – Mydriasis April 18, 2012 April 18, 2012 SD-4, eCTD-0003 Request for proprietary name review Sept 5, 2012 Sept 6, 2012 SD-22, eCTD-0021 Draft Ophthalmic Labeling Oct 22, 2012 Oct 22, 2012 SD-27, eCDT-0026 Certification that EpiPen is the reference for the 505(b)(2) application RECOMMENDED REGULATORY ACTION NDA/SUPPLEMENTS: X APPROVAL COMPLETE RESPONSE OTHER ACTION: 2 Reference ID: 3209828 Clinical Review ● Peter Starke, MD NDA 204-200 ● Adrenalin® (epinephrine) Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 7 1.1 Recommendation on Regulatory Action ............................................................. 7 1.2 Risk Benefit Assessment.................................................................................... 7 1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 8 1.4 Recommendations for Postmarket Requirements and Commitments ................ 9 1.5 Pediatric Issues .................................................................................................. 9 2 INTRODUCTION AND REGULATORY BACKGROUND ........................................ 9 2.1 Introduction......................................................................................................... 9 2.2 Regulatory Background.................................................................................... 11 2.3 Product Information .......................................................................................... 13 2.4 Tables of Currently Available Treatments for Proposed Indications ................. 16 2.5 Availability of Proposed Active Ingredient in the United States ........................ 17 2.5.1 Single-ingredient epinephrine products for injection .................................. 17 2.5.2 Other epinephrine-containing products ...................................................... 19 2.6 Important Safety Issues With Consideration to Related Drugs......................... 20 2.7 Summary of Presubmission Regulatory Activity Related to Submission .......... 21 2.8 Other Relevant Background Information .......................................................... 22 3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 25 3.1 Submission Quality and Integrity ...................................................................... 25 3.2 Compliance with Good Clinical Practices ......................................................... 25 3.3 Financial Disclosures........................................................................................ 26 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 26 4.1 Chemistry Manufacturing and Controls ............................................................ 26 4.2 Clinical Microbiology......................................................................................... 27 4.3 Preclinical Pharmacology/Toxicology ............................................................... 28 4.4 Clinical Pharmacology...................................................................................... 28 4.4.1 Requirement for in vivo bioequivalence ..................................................... 28 4.4.2 Pharmacology of Epinephrine .................................................................... 28 3 Reference ID: 3209828 Clinical Review ● Peter Starke, MD NDA 204-200 ● Adrenalin® (epinephrine) 5 SOURCES OF CLINICAL DATA............................................................................ 31 5.1 Tables of Studies/Clinical Trials ....................................................................... 32 5.2 Review Strategy ............................................................................................... 32 5.3 Discussion of Individual Studies/Clinical Trials................................................. 32 6 REVIEW OF EFFICACY......................................................................................... 32 Efficacy Summary...................................................................................................... 32 6.1 Indication(s)...................................................................................................... 33 6.1.1 Treatment of Anaphylaxis .......................................................................... 33 6.1.2 Other Indications........................................................................................ 43 7 REVIEW OF SAFETY............................................................................................. 45 Safety Summary ........................................................................................................ 45 7.1 Methods............................................................................................................ 46 7.2 Adequacy of Safety Assessments .................................................................... 46 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations..................................................................................... 47 7.2.2 Explorations for Dose Response................................................................ 47 7.2.3 Data from Animals...................................................................................... 48 7.2.4 Routine Clinical Testing ............................................................................. 49 7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 49 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 49 7.3 Major Safety Results ........................................................................................ 49 7.3.1 Deaths........................................................................................................ 49 7.3.2 Nonfatal Serious Adverse Events .............................................................. 49 7.3.3 Dropouts and/or Discontinuations .............................................................. 50 7.3.4 Significant Adverse Events ........................................................................ 50 7.3.5 Submission Specific Primary Safety Concerns .......................................... 50 7.4 Supportive Safety Results ................................................................................ 50 7.4.1 Common Adverse Events .......................................................................... 50 7.4.2 Laboratory Findings ................................................................................... 50 7.4.3 Vital Signs .................................................................................................. 51 7.4.4 Electrocardiograms (ECGs) ....................................................................... 51 4 Reference ID: 3209828 Clinical Review ● Peter Starke, MD NDA 204-200 ● Adrenalin® (epinephrine) 7.4.5 Special Safety Studies/Clinical Trials......................................................... 51 7.4.6 Immunogenicity.......................................................................................... 51 7.5 Other Safety Explorations................................................................................. 51 7.5.1 Dose Dependency for Adverse Events ...................................................... 51 7.5.2 Time Dependency for Adverse Events....................................................... 51 7.5.3 Drug-Demographic Interactions ................................................................. 51 7.5.4 Drug-Disease Interactions.......................................................................... 51 7.5.5 Drug-Drug Interactions............................................................................... 52 7.6 Additional Safety Evaluations ........................................................................... 53 7.6.1 Human Carcinogenicity.............................................................................