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N22-029S012 Methyl Salicylate Clinical 2 PREA

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N22-029S012 Methyl Salicylate Clinical 2 PREA Clinical Review Ryan Raffaelli, M.D. NDA 22-029/ S-012 SALONPAS® Pain Relief Patch (Arthritis Pain Patch) (10% methyl salicylate and 3% L- menthol) – Efficacy Supplement for PREA PMR CLINICAL REVIEW Application Type NDA 505(b)2 Application Number(s) 22029/S-012 Priority or Standard Standard Submit Date(s) May 30, 2012 Received Date(s) May 31, 2012 PDUFA Goal Date March 31, 2013 Division / Office DNCE/ ODE IV Reviewer Name(s) Ryan Raffaelli, M.D. Review Completion Date February 20, 2013 Established Name Methyl salicylate and L- menthol (Proposed) Trade Name SALONPAS® Pain Relief Patch and SALONPAS® Arthritis Pain Patch Therapeutic Class Counterirritants Applicant Hisamitsu Pharmaceutical Co., Inc. Formulation(s) Patch Dosing Regimen One patch applied for 8-12 hours; not more than two 1 Reference ID: 3264037 Clinical Review Ryan Raffaelli, M.D. NDA 22-029/ S-012 SALONPAS® Pain Relief Patch (Arthritis Pain Patch) (10% methyl salicylate and 3% L- menthol) – Efficacy Supplement for PREA PMR patches per day or for more than three days Indication(s) Temporary relief of mild to moderate aches and pains Intended Population(s) 18 years of age and older 2 Reference ID: 3264037 Clinical Review Ryan Raffaelli, M.D. NDA 22-029/ S-012 SALONPAS® Pain Relief Patch (Arthritis Pain Patch) (10% methyl salicylate and 3% L- menthol) – Efficacy Supplement for PREA PMR Table of Contents 1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 7 1.1 Recommendation on Regulatory Action ............................................................. 7 1.2 Risk Benefit Assessment .................................................................................... 8 1.4 Recommendations for Postmarket Requirements and Commitments ................ 9 2 INTRODUCTION AND REGULATORY BACKGROUND ...................................... 10 2.1 Product Information .......................................................................................... 10 2.2 Currently Available Treatments for Proposed Indications ................................. 11 2.3 Availability of Proposed Active Ingredients in the United States....................... 12 2.4 Important Safety Issues With Consideration to Related Drugs ......................... 14 2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 15 2.6 Other Relevant Background Information .......................................................... 15 3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 15 3.1 Submission Quality and Integrity ...................................................................... 15 3.2 Compliance with Good Clinical Practices ......................................................... 16 3.3 Financial Disclosures........................................................................................ 17 4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW DISCIPLINES ......................................................................................................... 17 4.1 Chemistry Manufacturing and Controls ............................................................ 17 4.2 Clinical Microbiology ......................................................................................... 18 4.3 Preclinical Pharmacology/Toxicology ............................................................... 18 4.4 Clinical Pharmacology ...................................................................................... 18 4.4.1 Mechanism of Action.................................................................................. 18 4.4.2 Pharmacodynamics.................................................................................... 19 4.4.3 Pharmacokinetics ....................................................................................... 19 5 SOURCES OF CLINICAL DATA............................................................................ 22 5.1 Tables of Studies/Clinical Trials ....................................................................... 22 5.2 Review Strategy ............................................................................................... 23 6 REVIEW OF EFFICACY ......................................................................................... 24 Efficacy Summary...................................................................................................... 24 7 REVIEW OF SAFETY............................................................................................. 24 Safety Summary ........................................................................................................ 24 7.1 Methods............................................................................................................ 25 7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 25 7.1.2 Categorization of Adverse Events .............................................................. 26 3 Reference ID: 3264037 Clinical Review Ryan Raffaelli, M.D. NDA 22-029/ S-012 SALONPAS® Pain Relief Patch (Arthritis Pain Patch) (10% methyl salicylate and 3% L- menthol) – Efficacy Supplement for PREA PMR 7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence.................................................................................................... 26 7.2 Adequacy of Safety Assessments .................................................................... 26 7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target Populations ..................................................................................... 26 7.2.2 Explorations for Dose Response................................................................ 28 7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 28 7.3 Major Safety Results ........................................................................................ 28 7.3.1 Deaths........................................................................................................ 28 7.3.2 Nonfatal Serious Adverse Events .............................................................. 28 7.3.3 Dropouts and/or Discontinuations .............................................................. 28 7.3.4 Significant Adverse Events ........................................................................ 29 7.3.5 Submission Specific Primary Safety Concerns .......................................... 29 7.4 Supportive Safety Results ................................................................................ 30 7.4.1 Common Adverse Events .......................................................................... 30 7.4.2 Laboratory Findings ................................................................................... 31 7.4.3 Vital Signs .................................................................................................. 31 7.4.5 Special Safety Studies/Clinical Trials ......................................................... 32 7.5 Other Safety Explorations................................................................................. 32 7.5.1 Dose Dependency for Adverse Events ...................................................... 32 7.5.2 Time Dependency for Adverse Events ....................................................... 33 7.5.3 Drug-Demographic Interactions ................................................................. 34 7.5.4 Drug-Disease Interactions.......................................................................... 34 7.5.5 Drug-Drug Interactions ............................................................................... 34 7.6 Additional Safety Evaluations ........................................................................... 34 7.6.1 Human Carcinogenicity .............................................................................. 34 7.6.2 Human Reproduction and Pregnancy Data................................................ 34 7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 35 7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 35 8 POSTMARKET EXPERIENCE............................................................................... 35 9 APPENDICES ........................................................................................................ 39 9.1 Literature Review/References .......................................................................... 39 9.2 Labeling Recommendations ............................................................................. 39 4 Reference ID: 3264037 Clinical Review Ryan Raffaelli, M.D. NDA 22-029/ S-012 SALONPAS® Pain Relief Patch (Arthritis Pain Patch) (10% methyl salicylate and 3% L- menthol) – Efficacy Supplement for PREA PMR List of Tables Table 1: Counterirritant Active Ingredients for External Analgesia (Tentative Final Monograph) Table 2: U.S. Marketed SALONPAS® Products Containing Methyl Salicylate and Menthol Table 3: Summary of Multiple Dose PK Trials - Mean (SD) Peak Methyl Salicylate Levels Table 4: Summary of Multiple Dose PK Trials - Mean (SD) Peak Menthol Levels Table 5: List of Clinical Studies Submitted to the NDA Table 6: Overall Exposure in Clinical Trials Performed by Applicant – Single and Multiple Use Table 7: Adverse Events Reported ≥ 2 Times in PK Trials Table 8: Adverse Events Reported ≥ 2 Times in the Efficacy Trial (FS-67-HP01-E02) Table 9: Salicylate Levels from Single Dose PK Trial (FS-67-HP01-PK1) by Age and Gender at Tmax - 4 Hours
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