CENTER FOR DRUG EVALUATION AND RESEARCH APPLI CA I 0N NUMBER: 2056410rig15000 OTHER Clinical Investigator Financial Disclosure Review Template Application Number: 205-641 Submission Date(s): June 27, 2013 Applicant: Merck Product: mometasone furoate MDI Reviewer: K. Witzmann, MD Date of Review: March 21, 2014 Covered Clinical Study (Name and/or Number): P04334 and P04431 Was a list of clinical investigators provided: Yes No (Request list from applicant) Total number of investigators identified: 2 Number of investigators who are sponsor employees (including both full-time and part-time employees): none Number of investigators with disclosable financial interests/arrangements (Form FDA 3455): 2 If there are investigators with disclosable financial interests/arrangements, identify the number of investigators with interests/arrangements in each category (as defined in 21 CFR 54.2(a), (b), (c) and (f)): Compensation to the investigator for conducting the study where the value could be influenced by the outcome of the study: none Significant payments of other sorts: 2 Proprietary interest in the product tested held by investigator: none Significant equity interest held by investigator in sponsor of covered study: none Is an attachment provided with details of the disclosable financial interests/arrangements: Yes X No (Request details from applicant) Is a description of the steps taken to minimize potential bias provided: Yes X No (Request information from applicant) Number of investigators with certification of due diligence (Form FDA 3454, box 3) None Is an attachment provided with the reason: Not Applicable Reference ID: 3493618 Yes No (Request explanation from applicant) The ?nancial disclosure information for the two pivotal trials was already submitted in 2009 as part of the review for the Dulera product, under NDA 22-518, and which revealed two investigators with disclosable ?nancial interests or agreements over $25,000 (honoraria of $30,000 and $50,000) with the Applicant: We) $30,000 honoraria We) $50,000 honoraria and consulting fees (m6) These signi?cant payments of other sorts (SPOOS) were determined to not have signi?cant impact upon the conduct of these clinical trials, given that the study designs were that of randomized, double-blinded, controlled trials, with objective spirometric endpoints, and since each investigator was only responsible for enrolling a small number of patients to each large, multi-center trial. Reference ID: 3493618 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------KIMBERLY A WITZMANN 04/22/2014 ANTHONY G DURMOWICZ 04/22/2014 Reference ID: 3493618 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA/BLA # Product Name: NDA# 205-641 Asmanex HFA A 6-month safety study, with a 6-month extension of two doses of mometasone furoate / formoterol fumarate combination MDI compared to fluticasone / salmeterol combination DPI children 5-11 years of age with persistent asthma. [PMR# 1658-6 under NDA# 22-518] PMR/PMC Schedule Milestones: Final Protocol Submission: Study/Trial Completion: Final Report Submission: Other: 10/31/2015 09/30/2018 02/28/2019 N/A 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other Asthma is a chronic inflammatory disorder of the airways and a leading chronic disease in children with an estimated prevalence of asthma in children 0-17 years of age of 9.6 %. The safety and efficacy of mometasone HFA pMDI has been established in adults, and those studies support further evaluation of the safety and efficacy in children; this can be done postapproval. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” PMR/PMC Development Template Reference ID: 3493525 Last Updated 4/22/2014 Page 1 of 4 The objective is to evaluate the long-term safety of mometasone/ formoterol HFA pMDI in pediatric patients age 5 to 11 years of age. 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. A 6 month safety study with a 6 month extension evaluating the same dose(s) of mometasone furoate/formoterol fumarate HFA pMDI from Study 1 to determine the longterm safety of mometasone HFA pMDI in pediatric patients ages 5 to 11 years who are symptomatic on ICS. PMR/PMC Development Template Reference ID: 3493525 Last Updated 4/22/2014 Page 2 of 4 Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Template Reference ID: 3493525 Last Updated 4/22/2014 Page 3 of 4 PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) PMR/PMC Development Template Reference ID: 3493525 Last Updated 4/22/2014 Page 4 of 4 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------SALLY M SEYMOUR 04/22/2014 Reference ID: 3493525 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA/BLA # Product Name: NDA# 205-641 Asmanex HFA A 12-week, double-blind, active-controlled, efficacy and safety study of two doses of mometasone furoate / formoterol fumarate combination MDI compared with the corresponding doses of mometasone furoate monotherapy MDI in the treatment of children ages 5-11 with persistent asthma. [PMR# 1658-5 under NDA# 22-518] PMR/PMC Schedule Milestones: Final Protocol Submission: Study/Trial Completion: Final Report Submission: Other: 10/31/2015 09/30/2018 02/28/2019 N/A 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other Asthma is a chronic inflammatory disorder of the airways and a leading chronic disease in children with an estimated prevalence of asthma in children 0-17 years of age of 9.6 %. The safety and efficacy of mometasone HFA pMDI has been established in adults, and those studies support further evaluation of the safety and efficacy in children; this can be done postapproval. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” PMR/PMC Development Template Reference ID: 3493521 Last Updated 4/22/2014 Page 1 of 4 The objective is to demonstrate the efficacy and safety of mometasone/formoterol HFA pMDI as a fixed-dose combination containing mometasone furoate and formoterol fumarate compared with the corresponding dose(s) of mometasone furoate HFA pMDI monotherapy, each administered as 2 inhalations twice daily, in children ages 5 to 11 years not adequately controlled on ICS. The dose(s) of mometasone furoate to be used in this Study will be determined by the results of Study 1. 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. A randomized, double-blind, parallel-group, 12-week study of two doses of mometasone furoate/formoterol fumarate HFA pMDI compared with the corresponding dose(s) of mometasone furoate monotherapy in an HFA pMDI formulation to determine the efficacy and safety of mometasone furoate/formoterol fumarate HFA pMDI in pediatric patients ages 5 to 11 years who are symptomatic on ICS. The dose(s) of mometasone furoate chosen for evaluation must be dose(s) that could be safe and efficacious as a single ingredient HFA pMDI formulation. PMR/PMC Development Template Reference ID: 3493521 Last Updated 4/22/2014 Page 2 of 4 Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology) Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation of Question 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint (e.g., manufacturing, stability) Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease, background rates of adverse events) Clinical trials primarily designed to further define efficacy (e.g., in another condition, different disease severity, or subgroup) that are NOT required under Subpart H/E Dose-response study or clinical trial performed for effectiveness Nonclinical study, not safety-related (specify) Other 5. Is the PMR/PMC clear, feasible, and appropriate? Does the study/clinical trial meet criteria for PMRs or PMCs? Are the objectives clear from the description of the PMR/PMC? Has the applicant adequately justified the choice of schedule milestone dates? Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine feasibility, and contribute to the development process? Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Template Reference ID: 3493521 Last Updated 4/22/2014 Page 3 of 4 PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) PMR/PMC Development Template Reference ID: 3493521 Last Updated 4/22/2014 Page 4 of 4 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------SALLY M SEYMOUR 04/22/2014 Reference ID: 3493521 PMR/PMC Development Template This template should be completed by the PMR/PMC Development Coordinator and included for each PMR/PMC in the Action Package. NDA/BLA # Product Name: NDA# 205-641 Asmanex HFA PMR/PMC Description: A 12-week, randomized, placebo-controlled, dose-ranging efficacy and safety study of mometasone furoate metered dose inhaler (MDI) in the treatment of children ages 5-11 years with persistent asthma. [PMR Study #1658-4 under NDA 22-518] PMR/PMC Schedule Milestones: Final Protocol Submission: Study/Trial Completion: Final Report Submission: Other: completed 04/30/2015 09/30/2015 N/A 1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a pre-approval requirement. Check type below and describe. Unmet need Life-threatening condition Long-term data needed Only feasible to conduct post-approval Prior clinical experience indicates safety Small subpopulation affected Theoretical concern Other Asthma is a chronic inflammatory disorder of the airways and a leading chronic disease in children with an estimated prevalence of asthma in children 0-17 years of age of 9.6 %. The safety and efficacy of mometasone HFA pMDI has been established in adults, and those studies support further evaluation of the safety and efficacy in children; this can be done postapproval. 2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new safety information.” PMR/PMC Development Template Reference ID: 3493518 Last Updated 4/22/2014 Page 1 of 4 The objective is to determine the appropriate dose(s) of mometasone HFA pMDI for pediatric patients 5 to 11 years of age, in order to provide appropriate efficacy and safety information for this pediatric age group with asthma 3. If the study/clinical trial is a PMR, check the applicable regulation. If not a PMR, skip to 4. - Which regulation? Accelerated Approval (subpart H/E) Animal Efficacy Rule Pediatric Research Equity Act FDAAA required safety study/clinical trial - If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply) Assess a known serious risk related to the use of the drug? Assess signals of serious risk related to the use of the drug? Identify an unexpected serious risk when available data indicate the potential for a serious risk? - If the PMR is a FDAAA safety study/clinical trial, will it be conducted as: Analysis of spontaneous postmarketing adverse events? Do not select the above study/clinical trial type if: such an analysis will not be sufficient to assess or identify a serious risk Analysis using pharmacovigilance system? Do not select the above study/clinical trial type if: the new pharmacovigilance system that the FDA is required to establish under section 505(k)(3) has not yet been established and is thus not sufficient to assess this known serious risk, or has been established but is nevertheless not sufficient to assess or identify a serious risk Study: all other investigations, such as investigations in humans that are not clinical trials as defined below (e.g., observational epidemiologic studies), animal studies, and laboratory experiments? Do not select the above study type if: a study will not be sufficient to identify or assess a serious risk Clinical trial: any prospective investigation in which the sponsor or investigator determines the method of assigning investigational product or other interventions to one or more human subjects? 4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the study or trial will be performed in a subpopulation, list here. PMR/PMC Development Template Reference ID: 3493518 Last Updated 4/22/2014 Page 2 of 4 The study will be a double-blind. randomized. parallel-group. placebo-controlled. ef?cacy and safety study in children 5 to 11 years with asthma comparing mometasone furoate delivered in an HFA formulation with placebo. The duration must be at least 6 weeks. and the doses of mometasone furoate chosen for evaluation must include at least two doses that could provide a safe and ef?cacious dose of mometasone ?rroate as a single-ingredient HFA fonnulation. The study protocol must include appropriate safety monitoring (mu) Required Observational pharmacoepidemiologic study Registry studies Primary safety study or clinical trial Pharrnacogenetic or pharmacogenomic study or clinical trial if required to ftu'ther assess safety Thorough Q-T clinical trial Nonclinical (animal) safety study carcinogenicity. reproductive toxicology) Nonclinical study (laboratory resistance. receptor af?nity. quality study related to safety) Pharmacokinetic studies or clinical trials Drug interaction or bioavailability studies or clinical trials Dosing trials Continuation esrion 4 Additional data or analysis required for a previously submitted or expected study/clinical trial (provide explanation) Meta-analysis or pooled analysis of previous studies/clinical trials Immunogenicity as a marker of safety Other (provide explanation) Agreed upon: Quality study without a safety endpoint manufacturing. stability) Phannacoepidemiologic study not related to safe drug use natural history of disease. background rates of adverse events) Clinical trials primarily designed to further de?ne efficacy in another condition. different disease severity. or subgroup) that are NOT required under Subpart Dose-response study or clinical trial performed for effectiveness Nonclinical study. not safety-related (specify) Other 5. Is the clear. feasible. and appropriate? Does the study/clinical trial meet criteria for PMRs or Are the objectives clear from the description of the Has the applicant adequately justi?ed the choice of schedule milestone dates? Has the applicant had suf?cient time to review the ask questions. determine feasibility. and contribute to the development process? Development Template Last Updated 4/22/2014 Page 3 of 4 Reference ID: 3493518 Check if this form describes a FDAAA PMR that is a randomized controlled clinical trial If so, does the clinical trial meet the following criteria? There is a significant question about the public health risks of an approved drug There is not enough existing information to assess these risks Information cannot be gained through a different kind of investigation The trial will be appropriately designed to answer question about a drug’s efficacy and safety, and The trial will emphasize risk minimization for participants as the protocol is developed PMR/PMC Development Coordinator: This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug quality. _______________________________________ (signature line for BLAs) PMR/PMC Development Template Reference ID: 3493518 Last Updated 4/22/2014 Page 4 of 4 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------SALLY M SEYMOUR 04/22/2014 Reference ID: 3493518 SEALD Director Sign-Off Review of the End-of-Cycle Prescribing Information: Outstanding Format Deficiencies Product Title1 Applicant Application/Supplement Number Type of Application Indication(s) ASMANEX® HFA 100 mcg (mometasone furoate) Inhalation Aerosol ASMANEX® HFA 200 mcg (mometasone furoate) Inhalation Aerosol FOR ORAL INHALATION Merck Sharp & Dohme Corp. NDA 205641 Original Maintenance treatment of asthma as prophylactic therapy in patients 12 years of age and older. Office/Division Division Project Manager Date FDA Received Application Goal Date ODE II/DPARP Jessica Lee June 27, 2013 April 27, 2014 Date PI Received by SEALD SEALD Review Date SEALD Labeling Reviewer Acting SEALD Division Director April 11, 2014 April 14, 2014 Elizabeth Donohoe Sandra Kweder 1 Product Title that appears in draft agreed-upon prescribing information (PI) This Study Endpoints and Labeling Development (SEALD) Director sign-off review of the end-of-cycle, prescribing information (PI) for important format items reveals outstanding format deficiencies that should be corrected before taking an approval action. After these outstanding format deficiencies are corrected, the SEALD Director will have no objection to the approval of this PI. The Selected Requirements of Prescribing Information (SRPI) is a checklist of 42 important format PI items based on labeling regulations [21 CFR 201.56(d) and 201.57] and guidances. The word “must” denotes that the item is a regulatory requirement, while the word “should” denotes that the item is based on guidance. Each SRPI item is assigned with one of the following three responses: • NO: The PI does not meet the requirement for this item (deficiency). • YES: The PI meets the requirement for this item (not a deficiency). • N/A: This item does not apply to the specific PI under review (not applicable). Reference ID: 3489140 Selected Requirements of Prescribing Information Highlights See Appendix A for a sample tool illustrating the format for the Highlights. HIGHLIGHTS GENERAL FORMAT and HORIZONTAL LINES IN THE PI NO YES 1. Highlights (HL) must be in a minimum of 8-point font and should be in two-column format, with ½ inch margins on all sides and between columns. Comment: The top margin is > 1/2 inch. 2. The length of HL must be one-half page or less (the HL Boxed Warning does not count against the one-half page requirement) unless a waiver has been granted in a previous submission (e.g., the application being reviewed is an efficacy supplement). Instructions to complete this item: If the length of the HL is one-half page or less, then select “YES” in the drop-down menu because this item meets the requirement. However, if HL is longer than one-half page:  For the Filing Period: • For efficacy supplements: If a waiver was previously granted, select “YES” in the dropdown menu because this item meets the requirement. • For NDAs/BLAs and PLR conversions: Select “NO” because this item does not meet the requirement (deficiency). The RPM notifies the Cross-Discipline Team Leader (CDTL) of the excessive HL length and the CDTL determines if this deficiency is included in the 74day or advice letter to the applicant.  For the End-of-Cycle Period: • Select “YES” in the drop down menu if a waiver has been previously (or will be) granted by the review division in the approval letter and document that waiver was (or will be) granted. Comment: The sponsor has requested a waiver;it is assumed the review division will grant the waiver. YES 3. A horizontal line must separate HL from the Table of Contents (TOC). A horizontal line must separate the TOC from the FPI. Comment: There is excess white space between TOC and the horizontal line above FPI. For improved readability, consider deleting this excess white space. YES 4. All headings in HL must be bolded and presented in the center of a horizontal line (each horizontal line should extend over the entire width of the column as shown in Appendix A). The headings should be in UPPER CASE letters. Comment: YES 5. White space should be present before each major heading in HL. There must be no white space between the HL Heading and HL Limitation Statement. There must be no white space between the product title and Initial U.S. Approval. See Appendix A for a sample tool illustrating white space in HL. Comment: YES 6. Each summarized statement or topic in HL must reference the section(s) or subsection(s) of the Full Prescribing Information (FPI) that contain more detailed information. The preferred format SRPI version 3: October 2013 Reference ID: 3489140 Page 2 of 10 Selected Requirements of Prescribing Information YES is the numerical identifier in parenthesis [e.g., (1.1)] at the end of each summarized statement or topic. Comment: The Labeling Review Tool (LRT) recommends use of bullets "•" when there is more than one item (e.g., piece of information) under each heading in HL; for improved readability, recommend adding bullets under D&A.. 7. Section headings must be presented in the following order in HL: Section Required/Optional Required • Highlights Heading Required • Highlights Limitation Statement Required • Product Title Required • Initial U.S. Approval Required if a BOXED WARNING is in the FPI • Boxed Warning Required for only certain changes to PI* • Recent Major Changes Required • Indications and Usage Required • Dosage and Administration Required • Dosage Forms and Strengths Required (if no contraindications must state “None.”) • Contraindications Not required by regulation, but should be present • Warnings and Precautions Required • Adverse Reactions Optional • Drug Interactions Optional • Use in Specific Populations • Patient Counseling Information Statement Required Required • Revision Date * RMC only applies to the BOXED WARNING, INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS sections. Comment: HIGHLIGHTS DETAILS Highlights Heading YES YES 8. At the beginning of HL, the following heading must be bolded and should appear in all UPPER CASE letters: “HIGHLIGHTS OF PRESCRIBING INFORMATION”. Comment: Highlights Limitation Statement 9. The bolded HL Limitation Statement must include the following verbatim statement: “These highlights do not include all the information needed to use (insert name of drug product) safely and effectively. See full prescribing information for (insert name of drug product).” The name of drug product should appear in UPPER CASE letters. Comment: Product Title in Highlights YES 10. Product title must be bolded. Comment: NO Initial U.S. Approval in Highlights 11. Initial U.S. Approval in HL must be bolded, and include the verbatim statement “Initial U.S. SRPI version 3: October 2013 Reference ID: 3489140 Page 3 of 10 Selected Requirements of Prescribing Information Approval:” followed by the 4-digit year. Comment: The 4-digit year is missing and should state: "2014" N/A N/A N/A N/A N/A N/A N/A YES Boxed Warning (BW) in Highlights 12. All text in the BW must be bolded. Comment: 13. The BW must have a heading in UPPER CASE, containing the word “WARNING” (even if more than one warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the warning (e.g., “WARNING: SERIOUS INFECTIONS and ACUTE HEPATIC FAILURE”). The BW heading should be centered. Comment: 14. The BW must always have the verbatim statement “See full prescribing information for complete boxed warning.” This statement should be centered immediately beneath the heading and appear in italics. Comment: 15. The BW must be limited in length to 20 lines (this includes white space but does not include the BW heading and the statement “See full prescribing information for complete boxed warning.”). Comment: Recent Major Changes (RMC) in Highlights 16. RMC pertains to only the following five sections of the FPI: BOXED WARNING, INDICATIONS AND USAGE, DOSAGE AND ADMINISTRATION, CONTRAINDICATIONS, and WARNINGS AND PRECAUTIONS. RMC must be listed in the same order in HL as the modified text appears in FPI. Comment: 17. The RMC must include the section heading(s) and, if appropriate, subsection heading(s) affected by the recent major change, together with each section’s identifying number and date (month/year format) on which the change was incorporated in the PI (supplement approval date). For example, “Warnings and Precautions, Acute Liver Failure (5.1) --- 9/2013”. Comment: 18. The RMC must list changes for at least one year after the supplement is approved and must be removed at the first printing subsequent to one year (e.g., no listing should be one year older than revision date). Comment: Indications and Usage in Highlights 19. If a product belongs to an established pharmacologic class, the following statement is required under the Indications and Usage heading in HL: “(Product) is a (name of established pharmacologic class) indicated for (indication)”. Comment: Dosage Forms and Strengths in Highlights SRPI version 3: October 2013 Reference ID: 3489140 Page 4 of 10 Selected Requirements of Prescribing Information N/A YES YES 20. For a product that has several dosage forms (e.g., capsules, tablets, and injection), bulleted subheadings or tabular presentations of information should be used under the Dosage Forms and Strengths heading. Comment: Contraindications in Highlights 21. All contraindications listed in the FPI must also be listed in HL or must include the statement “None” if no contraindications are known. Each contraindication should be bulleted when there is more than one contraindication. Comment: Adverse Reactions in Highlights 22. For drug products other than vaccines, the verbatim bolded statement must be present: “To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer’s U.S. phone number) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch”. Comment: Patient Counseling Information Statement in Highlights YES 23. The Patient Counseling Information statement must include one of the following three bolded verbatim statements that is most applicable: If a product does not have FDA-approved patient labeling: • “See 17 for PATIENT COUNSELING INFORMATION” If a product has FDA-approved patient labeling: • “See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling” • “See 17 for PATIENT COUNSELING INFORMATION and Medication Guide” Comment: NO Revision Date in Highlights 24. The revision date must be at the end of HL, and should be bolded and right justified (e.g., “Revised: 9/2013”). Comment: The date is missing and should state: "4/2014". SRPI version 3: October 2013 Reference ID: 3489140 Page 5 of 10 Selected Requirements of Prescribing Information Contents: Table of Contents (TOC) See Appendix A for a sample tool illustrating the format for the Table of Contents. 25. The TOC should be in a two-column format. Comment: YES 26. The following heading must appear at the beginning of the TOC: “FULL PRESCRIBING INFORMATION: CONTENTS”. This heading should be in all UPPER CASE letters and bolded. Comment: N/A 27. The same heading for the BW that appears in HL and the FPI must also appear at the beginning of the TOC in UPPER CASE letters and bolded. Comment: YES 28. In the TOC, all section headings must be bolded and should be in UPPER CASE. Comment: YES 29. In the TOC, all subsection headings must be indented and not bolded. The headings should be in title case [first letter of all words are capitalized except first letter of prepositions (through), articles (a, an, and the), or conjunctions (for, and)]. Comment: YES 30. The section and subsection headings in the TOC must match the section and subsection headings in the FPI. Comment: YES 31. In the TOC, when a section or subsection is omitted, the numbering must not change. If a section or subsection from 201.56(d)(1) is omitted from the FPI and TOC, the heading “FULL PRESCRIBING INFORMATION: CONTENTS” must be followed by an asterisk and the following statement must appear at the end of TOC: “*Sections or subsections omitted from the full prescribing information are not listed.” Comment: YES SRPI version 3: October 2013 Reference ID: 3489140 Page 6 of 10 Selected Requirements of Prescribing Information Full Prescribing Information (FPI) FULL PRESCRIBING INFORMATION: GENERAL FORMAT YES 32. The bolded section and subsection headings in the FPI must be named and numbered in accordance with 21 CFR 201.56(d)(1) as noted below (section and subsection headings should be in UPPER CASE and title case, respectively). If a section/subsection required by regulation is omitted, the numbering must not change. Additional subsection headings (i.e., those not named by regulation) must also be bolded and numbered. BOXED WARNING 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology (by guidance) 12.5 Pharmacogenomics (by guidance) 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION YES Comment: 33. The preferred presentation for cross-references in the FPI is the section (not subsection) heading followed by the numerical identifier. The entire cross-reference should be in italics and enclosed within brackets. For example, “[see Warnings and Precautions (5.2)]” or “[see Warnings and Precautions (5.2)]”. Comment: SRPI version 3: October 2013 Reference ID: 3489140 Page 7 of 10 Selected Requirements of Prescribing Information N/A 34. If RMCs are listed in HL, the corresponding new or modified text in the FPI sections or subsections must be marked with a vertical line on the left edge. Comment: FULL PRESCRIBING INFORMATION DETAILS FPI Heading YES N/A N/A N/A YES 35. The following heading must be bolded and appear at the beginning of the FPI: “FULL PRESCRIBING INFORMATION”. This heading should be in UPPER CASE. Comment: BOXED WARNING Section in the FPI 36. In the BW, all text should be bolded. Comment: 37. The BW must have a heading in UPPER CASE, containing the word “WARNING” (even if more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS INFECTIONS and ACUTE HEPATIC FAILURE”). Comment: CONTRAINDICATIONS Section in the FPI 38. If no Contraindications are known, this section must state “None.” Comment: ADVERSE REACTIONS Section in the FPI 39. When clinical trials adverse reactions data are included (typically in the “Clinical Trials Experience” subsection of ADVERSE REACTIONS), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.” Comment: YES 40. When postmarketing adverse reaction data are included (typically in the “Postmarketing Experience” subsection of ADVERSE REACTIONS), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “The following adverse reactions have been identified during post-approval use of (insert drug name). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.” Comment: YES PATIENT COUNSELING INFORMATION Section in the FPI 41. Must reference any FDA-approved patient labeling in Section 17 (PATIENT COUNSELING INFORMATION section). The reference should appear at the beginning of Section 17 and SRPI version 3: October 2013 Reference ID: 3489140 Page 8 of 10 Selected Requirements of Prescribing Information YES include the type(s) of FDA-approved patient labeling (e.g., Patient Information, Medication Guide, Instructions for Use). Comment: 42. FDA-approved patient labeling (e.g., Medication Guide, Patient Information, or Instructions for Use) must not be included as a subsection under section 17 (PATIENT COUNSELING INFORMATION). All FDA-approved patient labeling must appear at the end of the PI upon approval. Comment: SRPI version 3: October 2013 Reference ID: 3489140 Page 9 of 10 Selected Requirements of Prescribing Information Appendix A: Format of the Highlights and Table of Contents SRPI version 3: October 2013 Reference ID: 3489140 Page 10 of 10 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------ELIZABETH A DONOHOE 04/14/2014 ERIC R BRODSKY 04/14/2014 I agree. Eric Brodsky, SEALD labeling team leader, signing for Sandra Kweder, Acting SEALD Director. Reference ID: 3489140 Department of Health and Human Services Public Health Service Food and Drug Administration Center for Drug Evaluation and Research Office of Medical Policy Initiatives Division of Medical Policy Programs PATIENT LABELING REVIEW Date: March 24, 2014 To: Badrul Chowdhury, M.D., Director Division of Pulmonary, Allergy and Rheumatology (DPARP) Through: LaShawn Griffiths, MSHS-PH, BSN, RN Associate Director for Patient Labeling Division of Medical Policy Programs (DMPP) Robin Duer, MBA, BSN, RN Senior Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) From: Twanda Scales, RN, BSN, MSN/Ed. Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Matthew J. Falter, Pharm.D. Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Subject: Review of Patient Labeling: Patient Package Insert (PPI) and Instructions for Use (IFU) Drug Name (established ASMANEX HFA (mometasone furoate) name): Dosage Form and Route: 100mcg and 200mcg Inhalation Aerosol Application Type/Number: NDA 205641 Applicant: Merck 1 Reference ID: 3476004 1 INTRODUCTION On June 27, 2013, Merck submitted, for the Agency’s review, an Original New Drug Application for NDA 205641, ASMANEX HFA (mometasone furoate) Metered Dose Inhaler. ASMANEX HFA (mometasone furoate) Metered Dose Inhaler is indicated for maintenance treatment of asthma as prophylactic therapy in patients 12 years of age and older and has limitation of use that this product is not indicated for the relief of acute bronchospasm. This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to request by the Division of Pulmonary, Allergy and Rheumatology Products (DPARP) on August 5, 2013, and August 2, 2013, respectively for DMPP and OPDP to review the Applicant’s proposed Patient Package Insert (PPI) and Instructions for Use (IFU) for ASMANEX HFA (mometasone furoate) Metered Dose Inhaler. 2 3 MATERIAL REVIEWED • Draft ASMANEX HFA (mometasone furoate) Metered Dose Inhaler PPI and IFU received on June 27, 2013 and received by DMPP on March 11, 2014. • Draft ASMANEX HFA (mometasone furoate) Metered Dose Inhaler PPI and IFU received on June 27, 2013 and received by OPDP on March 11, 2014. • Draft ASMANEX HFA (mometasone furoate) Metered Dose Inhaler Prescribing Information (PI) received on June 27, 2013, revised by the Review Division throughout the review cycle, and received by DMPP on March 11, 2014. • Draft ASMANEX HFA (mometasone furoate) Metered Dose Inhaler Prescribing Information (PI) received on June 27, 2013, revised by the Review Division throughout the review cycle, and received by OPDP on March 11, 2014. • Approved DULERA (mometasone furoate/formoterol dihydrate) Inhalation Aerosol comparator labeling dated August 21, 2013. • Approved ALVESCO (ciclesonide) Inhlalation Aerosol comparator labeling dated December 17, 2012. • Approved FLOVENT HFA (fluticasone propionate) Inhalation Aerosol comparator labeling dated July 18, 2013. • FLOVENT DISKUS (fluticasone propionate) Inhalation Powder comparator labeling dated February 19, 2014. REVIEW METHODS To enhance patient comprehension, materials should be written at a 6th to 8th grade reading level, and have a reading ease score of at least 60%. A reading ease score of 60% corresponds to an 8th grade reading level. In our review of the PPI and IFU the target reading level is at or below an 8th grade level. 2 Reference ID: 3476004 Additionally, in 2008 the American Society of Consultant Pharmacists Foundation (ASCP) in collaboration with the American Foundation for the Blind (AFB) published Guidelines for Prescription Labeling and Consumer Medication Information for People with Vision Loss. The ASCP and AFB recommended using fonts such as Verdana, Arial or APHont to make medical information more accessible for patients with vision loss. We have reformatted the PPI and IFU documents using the Verdana font, size 11. In our review of the PPI and IFU we have: 4 • simplified wording and clarified concepts where possible • ensured that the PPI and IFU are consistent with the Prescribing Information (PI) • removed unnecessary or redundant information • ensured that the PPI and IFU are free of promotional language or suggested revisions to ensure that it is free of promotional language • ensured that the PPI and IFU are consistent with the approved comparator labeling where applicable. • ensured that the PPI and IFU meet the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006) CONCLUSIONS The PPI and IFU are acceptable with our recommended changes. 5 RECOMMENDATIONS • Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence. • Our review of the PPI and IFU is appended to this memorandum. Consult DMPP and OPDP regarding any additional revisions made to the PI to determine if corresponding revisions need to be made to the PPI and IFU. Please let us know if you have any questions. 23 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page 3 Reference ID: 3476004 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------TWANDA D SCALES 03/24/2014 MATTHEW J FALTER 03/24/2014 ROBIN E DUER 03/24/2014 LASHAWN M GRIFFITHS 03/24/2014 Reference ID: 3476004 FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion ****Pre-decisional Agency Information**** Memorandum Date: March 21, 2014 To: Jessica Lee, Pharm.D. Regulatory Project Manager Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) From: Matthew Falter, Pharm.D. Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) CC: Kathleen Klemm, Pharm.D. Group Leader, OPDP Subject: NDA 205641 OPDP Labeling Comments for ASMANEX® HFA (mometasone furoate) Inhalation Aerosol 100 mcg and 200 mcg FOR ORAL INHALATION (Asmanex HFA) Reference is made to DPARP’s August 2, 2013, consult request for OPDP’s comments regarding the proposed Package Insert (PI), Patient Package Insert (PPI) and Carton and Container labeling for Asmanex HFA. OPDP has revised the proposed PI. Our comments on the proposed PI are based on the proposed draft marked-up labeling titled “NDA 205641_ASMANEX HFA PI- clean copy for consultants (from v.4) .doc” that was sent via email from DPARP to OPDP on March 11, 2014. OPDP’s comments on the proposed PI are provided directly in the marked-up document attached (see below). OPDP’s has reviewed the proposed Carton and Container Labeling submitted by the applicant and available in the EDR at:   \\cdsesub1\evsprod\nda205641\0000\m1\us\mk0887-100mcg-samplelabel-120-6180000.pdf \\cdsesub1\evsprod\nda205641\0000\m1\us\mk0887-100mcg-samplecarton-120-6179800.pdf 1 Reference ID: 3475061        \\cdsesub1\evsprod\nda205641\0000\m1\us\mk0887-100mcg-tradecarton-120-6178000.pdf \\cdsesub1\evsprod\nda205641\0000\m1\us\mk0887-100mcg-trade-label120-6178100.pdf \\cdsesub1\evsprod\nda205641\0000\m1\us\mk0887-200mcg-samplecarton-120-6179900.pdf \\cdsesub1\evsprod\nda205641\0000\m1\us\mk0887-200mcg-samplelabel-120-6180100.pdf \\cdsesub1\evsprod\nda205641\0000\m1\us\mk0887-200mcg-tradecarton-120-6178200.pdf \\cdsesub1\evsprod\nda205641\0000\m1\us\mk0887-200mcg-trade-label120-6178300.pdf \\cdsesub1\evsprod\nda205641\0000\m1\us\mk0887-all-trade-sampleactuatorlabel-120-6177900.pdf OPDP does not have any comments on the proposed Carton and Container labels at this time. OPDP’s review and comments on the proposed PPI and proposed Instructions for Use (IFU)1 was conducted in collaboration with the Division of Medical Policy Programs (DMPP). This review will be provided under separate cover and submitted into DARRTS at a later date. Thank you for the opportunity to comment on the proposed labeling. If you have any questions regarding this review, please contact Matthew Falter at (301) 796-2287 or matthew.falter@fda.hhs.gov. 18 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page 1 While the Consult Request did not specifically request OPDP’s review of the proposed IFU, changes to the IFU were made as part of DMPP’s review. As such, OPDP also reviewed the PPI and IFU in collaboration with DMPP. 2 Reference ID: 3475061 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------MATTHEW J FALTER 03/21/2014 Reference ID: 3475061 LABEL AND LABELING REVIEW Division of Medication Error Prevention and Analysis (DMEPA) Office of Medication Error Prevention and Risk Management (OMEPRM) Office of Surveillance and Epidemiology (OSE) Center for Drug Evaluation and Research (CDER) *** This document contains proprietary information that cannot be released to the public*** Date of This Review: February 25, 2014 Requesting Office or Division: Division of Division of Pulmonary, Allergy, and Rheumatology Products (DPARP) Application Type and Number: NDA 205641 Product Name and Strength: Asmanex HFA (Mometasone Furoate) Inhalation Aerosol 100 mcg and 200 mcg Product Type: Single Ingredient Product Rx or OTC: Rx Applicant/Sponsor Name: Merck & Co. Inc. Submission Date: June 27, 2013 OSE RCM #: 2013-1600 DMEPA Primary Reviewer: Lissa C. Owens, PharmD DMEPA Team Leader: Lubna Merchant, M.S., PharmD 1 Reference ID: 3460221 1 REASON FOR REVIEW This review responds to a request from DPARP to evaluate the proposed prescribing information, patient instructions for use, carton labeling and container labels for areas of vulnerability that could lead to medication errors. DPARP requested this review as part of their evaluation for NDA 205641. 2 MATERIALS REVIEWED We considered the materials listed in Table 1 for this review. The Appendices provide the methods and results for each material reviewed. Table 1. Materials Considered for this Label and Labeling Review Material Reviewed Appendix Section (for Methods and Results) Product Information/Prescribing Information A FDA Adverse Event Reporting System (FAERS) Labels and Labeling 3 OVERALL ASSESSMENT OF THE MATERIALS REVEIWED The Applicant is proposing to use the currently marketed product, Asmanex, in a hydrofluroalkane (HFA) formulation. Asmanex is currently available as a Twisthaler. In our FAERS search we did not identify any cases of confusion with the root name ?Asmanex.? The remaining cases involve product quality issues with the Twisthaler, which are being evaluated in a postmarketing signal and do not foresee the same issues with the HFA inhaler as they are two different inhalers. We performed a risk assessment of the proposed Full Prescribing Information, Patient Instructions for Use, Labels and Labeling to identify deficiencies that may lead to medication errors. We note that there are areas of the label and labeling and patient instructions for use that may be improved to increase readability to ensure safe use of the product. 4 CONCLUSION RECOMMENDATIONS We conclude that the proposed labels and labeling can be improved to increase readability on the label to promote the safe use of the product. We defer to the Division of Medical Policy Programs (DMPP) for further comments and/or recommendations. Reference ID: 3460221 4.1 RECOMMENDATIONS FOR THE APPLICANT/SPONSOR DMEPA recommends the following be implemented prior to approval. A. All Carton Labeling and Container Labels 1. Remove the line above the trade name and under the NDC number to reduce clutter and increase readability. 2. Decrease the font size of the statement ‘Shake well before using’ as it competes for prominence with the proprietary name. 3. Unbold the ‘Rx only’ statement. B. Patient Instructions For Use 1. Under the heading ‘Before you use Asmanex HFA for the first time, you must prime the inhaler,’ revise step one to read: ‘ To prime the inhaler, hold it in the upright position away from your face, and press down firmly and fully on the top of the canister until it stops moving in the actuator. Do this 4 times to release a total of 4 actuations (puffs) into the air.’ 3 Reference ID: 3460221 APPENDICES: METHODS 81 RESULTS FOR EACH MATERIALS REVIEWED APPENDIX A. PRODUCT INFORMATION Table 2 presents relevant product information for Asmanex HFA that Merck Co. Inc. submitted on June 27, 2013. Table 2. Relevant Product Information for Asmanex HFA Active Ingredient Mometasone Furoate Indication Maintenance treatment of Asthma as prophylactic therapy in patients 12 and older Route of Administration Oral Inhalation Dosage Form Inhalation Aerosol Strength 100 and 200 Dose and Frequency 2 inhalations twice daily How Supplied Pressurized aluminum canister with a blue plastic actuator integrated with a dose counter Storage to to excursions permitted from to to APPENDIX B. FDA ADVERSE EVENT REPORTING SYSTEM (FAERS) B.1 Methods We searched the FDA Adverse Event Reporting System (FAERS) on February 21, 2014 using the criteria in Table 3, and then individually reviewed each case. We limited our search to the date of our last review (OSE RCM 2007-1355 and 2008-29 dated January 15, 2008). Table 3: FAERS Search Strategy Date Range January 15, 2008 to February 20, 2014 Drug Names Asmanex Search Strategy Medication Errors Product Packaging Issues Product Label Issues Product Quality Issues 3.2 Results Our search identified 851 cases. There were no cases of name confusion between the root name ?Asmanex? and other products. The remaining cases are currently being evaluated in a post-marketing signal. Reference ID: 3460221 B.4 Description of FAERS The FDA Adverse Event Reporting System (FAERS) is a database that contains information on adverse event and medication error reports submitted to FDA. The database is designed to support the FDA's postmarket safety surveillance program for drug and therapeutic biologic products. The informatic structure of the FAERS database adheres to the international safety reporting guidance issued by the International Conference on Harmonisation. Adverse events and medication errors are coded to terms in the Medical Dictionary for Regulatory Activities (MedDRA) terminology. Product names are coded using the FAERS Product Dictionary. More information about FAERS can be found at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Surveillance/AdverseD rugEffects/default.htm. 5 Reference ID: 3460221 APPENDIX C. LABELS AND LABELING C.1 List of Labels and Labeling Reviewed Using the principles of human factors and Failure Mode and Effects Analysis,1 along with postmarket medication error data, we reviewed the following Dulera labels and labeling submitted by Merck & Co. Inc. on June 27, 2013.      Container label Carton labeling Professional Sample label Professional Sample Carton Labeling Instructions for Use (b) (4) 4 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page 1 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004. 6 Reference ID: 3460221 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------LISSA C OWENS 02/25/2014 LUBNA A MERCHANT 02/25/2014 Reference ID: 3460221 REGULATORY PROJECT MANAGER PHYSICIAN’S LABELING RULE (PLR) FORMAT REVIEW OF THE PRESCRIBING INFORMATION To be completed for all new NDAs, BLAs, Efficacy Supplements, and PLR Conversion Supplements Application: NDA 205641 Application Type: NDA Name of Drug: Asmanex HFA (mometasone furoate) 100 mcg and 200 mcg Inhalation Aerosol Applicant: Merck Sharp & Dohme Corp. Submission Date: 6/27/13 Receipt Date: 6/27/13 1.0 Regulatory History and Applicant’s Main Proposals New Drug Application (NDA) for Asmanex HFA (mometasone furoate) Inhalation Aerosol, NDA 205641, is proposed for mometasone furoate monotherapy for the treatment of asthma in patients 12 years of age and older. The Sponsor, Merck, proposes mometasone furoate (Asmanex HFA) as a stepdown inhaled corticosteroid (ICS) for patients who no longer need continuous long-acting beta-agonist (LABA) treatment. Mometasone furoate is the active ingredient in the Sponsor’s approved products, Asmanex Twisthaler (NDA 21067) and Dulera (NDA 22518). 2.0 Review of the Prescribing Information (PI) This review is based on the applicant’s submitted Microsoft Word format of the PI. The applicant’s proposed PI was reviewed in accordance with the labeling format requirements listed in the “Selected Requirements for Prescribing Information (SRPI)” checklist (see the Appendix). 3.0 Conclusions/Recommendations SRPI format deficiencies were identified in the review of this PI. For a list of these deficiencies see the Appendix. RPM PLR Format Review of the PI: Last Updated May 2012 Reference ID: 3366786 Page 1 of 8 4.0 Appendix Selected Requirements of Prescribing Information (SRPI) The Selected Requirement of Prescribing Information (SRPI) version 2 is a 48-item, drop-down checklist of critical format elements of the prescribing information (PI) based on labeling regulations (21 CFR 201.56 and 201.57) and labeling guidances. Highlights (HL) YES NO YES YES YES GENERAL FORMAT 1. Highlights (HL) must be in two-column format, with ½ inch margins on all sides and in a minimum of 8-point font. Comment: 2. The length of HL must be less than or equal to one-half page (the HL Boxed Warning does not count against the one-half page requirement) unless a waiver has been is granted in a previous submission (i.e., the application being reviewed is an efficacy supplement). Instructions to complete this item: If the length of the HL is less than or equal to one-half page then select “YES” in the drop-down menu because this item meets the requirement. However, if HL is longer than one-half page:  For the Filing Period (for RPMs)  For efficacy supplements: If a waiver was previously granted, select “YES” in the dropdown menu because this item meets the requirement.  For NDAs/BLAs and PLR conversions: Select “NO” in the drop-down menu because this item does not meet the requirement (deficiency). The RPM notifies the CrossDiscipline Team Leader (CDTL) of the excessive HL length and the CDTL determines if this deficiency is included in the 74-day or advice letter to the applicant.  For the End-of Cycle Period (for SEALD reviewers)  The SEALD reviewer documents (based on information received from the RPM) that a waiver has been previously granted or will be granted by the review division in the approval letter. Comment: The sponsor requests 1/2 page waiver, which will be considered during labeling discussions. 3. All headings in HL must be presented in the center of a horizontal line, in UPPER-CASE letters and bolded. Comment: 4. White space must be present before each major heading in HL. Comment: 5. Each summarized statement in HL must reference the section(s) or subsection(s) of the Full Prescribing Information (FPI) that contains more detailed information. The preferred format is the numerical identifier in parenthesis [e.g., (1.1)] at the end of each information summary (e.g. end of each bullet). SRPI version 2: Last Updated May 2012 Reference ID: 3366786 Page 2 of 8 Selected Requirements of Prescribing Information (SRPI) YES Comment: 6. Section headings are presented in the following order in HL: Section Required/Optional Required  Highlights Heading Required  Highlights Limitation Statement Required  Product Title Required  Initial U.S. Approval Required if a Boxed Warning is in the FPI  Boxed Warning Required for only certain changes to PI*  Recent Major Changes Required  Indications and Usage Required  Dosage and Administration Required  Dosage Forms and Strengths Required (if no contraindications must state “None.”)  Contraindications Not required by regulation, but should be present  Warnings and Precautions Required  Adverse Reactions Optional  Drug Interactions Optional  Use in Specific Populations  Patient Counseling Information Statement Required Required  Revision Date * RMC only applies to the Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications, and Warnings and Precautions sections. YES Comment: 7. A horizontal line must separate HL and Table of Contents (TOC). Comment: HIGHLIGHTS DETAILS YES YES Highlights Heading 8. At the beginning of HL, the following heading must be bolded and appear in all UPPER CASE letters: “HIGHLIGHTS OF PRESCRIBING INFORMATION”. Comment: Highlights Limitation Statement 9. The bolded HL Limitation Statement must be on the line immediately beneath the HL heading and must state: “These highlights do not include all the information needed to use (insert name of drug product in UPPER CASE) safely and effectively. See full prescribing information for (insert name of drug product in UPPER CASE).” Comment: YES Product Title 10. Product title in HL must be bolded. Comment: YES Initial U.S. Approval 11. Initial U.S. Approval in HL must be placed immediately beneath the product title, bolded, and include the verbatim statement “Initial U.S. Approval:” followed by the 4-digit year. Comment: SRPI version 2: Last Updated May 2012 Reference ID: 3366786 Page 3 of 8 Selected Requirements of Prescribing Information (SRPI) N/A N/A N/A N/A N/A N/A N/A N/A N/A YES Boxed Warning 12. All text must be bolded. Comment: 13. Must have a centered heading in UPPER-CASE, containing the word “WARNING” (even if more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS INFECTIONS”). Comment: 14. Must always have the verbatim statement “See full prescribing information for complete boxed warning.” centered immediately beneath the heading. Comment: 15. Must be limited in length to 20 lines (this does not include the heading and statement “See full prescribing information for complete boxed warning.”) Comment: 16. Use sentence case for summary (combination of uppercase and lowercase letters typical of that used in a sentence). Comment: Recent Major Changes (RMC) 17. Pertains to only the following five sections of the FPI: Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications, and Warnings and Precautions. Comment: 18. Must be listed in the same order in HL as they appear in FPI. Comment: 19. Includes heading(s) and, if appropriate, subheading(s) of labeling section(s) affected by the recent major change, together with each section’s identifying number and date (month/year format) on which the change was incorporated in the PI (supplement approval date). For example, “Dosage and Administration, Coronary Stenting (2.2) --- 3/2012”. Comment: 20. Must list changes for at least one year after the supplement is approved and must be removed at the first printing subsequent to one year (e.g., no listing should be one year older than revision date). Comment: Indications and Usage 21. If a product belongs to an established pharmacologic class, the following statement is required in the Indications and Usage section of HL: [(Product) is a (name of class) indicated for (indication)].” Comment: Dosage Forms and Strengths SRPI version 2: Last Updated May 2012 Reference ID: 3366786 Page 4 of 8 Selected Requirements of Prescribing Information (SRPI) YES YES YES YES YES 22. For a product that has several dosage forms, bulleted subheadings (e.g., capsules, tablets, injection, suspension) or tabular presentations of information is used. Comment: Contraindications 23. All contraindications listed in the FPI must also be listed in HL or must include the statement “None” if no contraindications are known. Comment: 24. Each contraindication is bulleted when there is more than one contraindication. Comment: Adverse Reactions 25. For drug products other than vaccines, the verbatim bolded statement must be present: “To report SUSPECTED ADVERSE REACTIONS, contact (insert name of manufacturer) at (insert manufacturer’s U.S. phone number) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch”. Comment: Patient Counseling Information Statement 26. Must include one of the following three bolded verbatim statements (without quotation marks): If a product does not have FDA-approved patient labeling:  “See 17 for PATIENT COUNSELING INFORMATION” If a product has FDA-approved patient labeling:  “See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.”  “See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.” Comment: YES Revision Date 27. Bolded revision date (i.e., “Revised: MM/YYYY or Month Year”) must be at the end of HL. Comment: Contents: Table of Contents (TOC) YES YES GENERAL FORMAT 28. A horizontal line must separate TOC from the FPI. Comment: 29. The following bolded heading in all UPPER CASE letters must appear at the beginning of TOC: “FULL PRESCRIBING INFORMATION: CONTENTS”. Comment: YES SRPI version 2: Last Updated May 2012 Reference ID: 3366786 Page 5 of 8 Selected Requirements of Prescribing Information (SRPI) 30. The section headings and subheadings (including title of the Boxed Warning) in the TOC must N/A 31. YES 32. YES 33. YES 34. YES 35. match the headings and subheadings in the FPI. Comment: The same title for the Boxed Warning that appears in the HL and FPI must also appear at the beginning of the TOC in UPPER-CASE letters and bolded. Comment: All section headings must be bolded and in UPPER CASE. Comment: All subsection headings must be indented, not bolded, and in title case. Comment: When a section or subsection is omitted, the numbering does not change. Comment: If a section or subsection from 201.56(d)(1) is omitted from the FPI and TOC, the heading “FULL PRESCRIBING INFORMATION: CONTENTS” must be followed by an asterisk and the following statement must appear at the end of TOC: “*Sections or subsections omitted from the Full Prescribing Information are not listed.” Comment: Full Prescribing Information (FPI) YES YES YES GENERAL FORMAT 36. The following heading must appear at the beginning of the FPI in UPPER CASE and bolded: “FULL PRESCRIBING INFORMATION”. Comment: 37. All section and subsection headings and numbers must be bolded. Comment: 38. The bolded section and subsection headings must be named and numbered in accordance with 21 CFR 201.56(d)(1) as noted below. If a section/subsection is omitted, the numbering does not change. Boxed Warning 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 6 ADVERSE REACTIONS 7 DRUG INTERACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.2 Labor and Delivery 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use SRPI version 2: Last Updated May 2012 Reference ID: 3366786 Page 6 of 8 Selected Requirements of Prescribing Information (SRPI) 9 DRUG ABUSE AND DEPENDENCE 9.1 Controlled Substance 9.2 Abuse 9.3 Dependence 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 12.4 Microbiology (by guidance) 12.5 Pharmacogenomics (by guidance) 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 15 REFERENCES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION Comment: YES YES N/A N/A N/A N/A NO 39. FDA-approved patient labeling (e.g., Medication Guide, Patient Information, or Instructions for Use) must not be included as a subsection under Section 17 (Patient Counseling Information). All patient labeling must appear at the end of the PI upon approval. Comment: 40. The preferred presentation for cross-references in the FPI is the section heading (not subsection heading) followed by the numerical identifier in italics. For example, [see Warnings and Precautions (5.2)]. Comment: 41. If RMCs are listed in HL, the corresponding new or modified text in the FPI sections or subsections must be marked with a vertical line on the left edge. Comment: FULL PRESCRIBING INFORMATION DETAILS Boxed Warning 42. All text is bolded. Comment: 43. Must have a heading in UPPER-CASE, containing the word “WARNING” (even if more than one Warning, the term, “WARNING” and not “WARNINGS” should be used) and other words to identify the subject of the Warning (e.g., “WARNING: SERIOUS INFECTIONS”). Comment: 44. Use sentence case (combination of uppercase and lowercase letters typical of that used in a sentence) for the information in the Boxed Warning. Comment: Contraindications 45. If no Contraindications are known, this section must state “None”. SRPI version 2: Last Updated May 2012 Reference ID: 3366786 Page 7 of 8 Selected Requirements of Prescribing Information (SRPI) YES Comment: Contraindications are listed. Adverse Reactions 46. When clinical trials adverse reactions data is included (typically in the “Clinical Trials Experience” subsection of Adverse Reactions), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.” Comment: YES 47. When postmarketing adverse reaction data is included (typically in the “Postmarketing Experience” subsection of Adverse Reactions), the following verbatim statement or appropriate modification should precede the presentation of adverse reactions: “The following adverse reactions have been identified during post-approval use of (insert drug name). Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.” Comment: YES Patient Counseling Information 48. Must reference any FDA-approved patient labeling, include the type of patient labeling, and use one of the following statements at the beginning of Section 17:  “See FDA-approved patient labeling (Medication Guide)”  “See FDA-approved patient labeling (Medication Guide and Instructions for Use)”  “See FDA-approved patient labeling (Patient Information)"  “See FDA-approved patient labeling (Instructions for Use)"  “See FDA-approved patient labeling (Patient Information and Instructions for Use)” Comment: SRPI version 2: Last Updated May 2012 Reference ID: 3366786 Page 8 of 8 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JESSICA K LEE 09/03/2013 LADAN JAFARI 09/03/2013 Reference ID: 3366786 RPM FILING REVIEW (Including Memo of Filing Meeting) To be completed for all new NDAs, BLAs, and Ef?cacy Supplements [except SE8 (labeling change with clinical data) and SE9 (manufacturing change with clinical data] Application Information NDA 205641 NDA Supplement Ef?cacy Supplement Type SE- BLA Supplement Proprietary Name: Asmanex HFA Established/Proper Name: mometasone furoate metered dose inhaler Dosage Form: Metered Dose Inhaler 100 and 200 Applicant: Merck Sharp Dolnne C01p. Agent for Applicant (if applicable): Date of Application: 6/26/13 Date of Receipt: 6/27/13 Date clock started after UN: PDUFA Goal Date: 4/27/14 Action Goal Date (if different): Filing Date: 8/26/13 Date of Filing Meeting: 8/7/13 Chemical Classi?cation: (1.2.3 etc.) (original NDAs only) Proposed change(s): Asthma Type of Original NDA: 505(b)(1) AND (if applicable) J: 505(b)(2) Type of NDA Supplement: 505(b)(1) El 505(b)(2) If 505(b)(2): Dra? the ?505(b)(2) Assessment? review found at: . . .- and refer to Appendix A for further information. Review Classi?cation: Standard Priority If the application includes a complete response to pediatric WR, review classi?cation is PriorityTropical Disease Priority If a tropical disease priority review voucher was submitted, review Review Voucher submitted classi?cation is Priority. Resubmission after withdrawal? I Resubmission after refuse to ?le? Part 3 Combination Product? El Convenience kit/Co-package Pre-?lled drug delivery device/system (syringe. patch. etc.) Of?ce of El Pre-?lled biologic delivery device/system (syringe, patch. etc.) Combina?io? Device coated/impregnated/combined with o" a? ?cent? El Device coated/impregnated/c0111bined with biologic Separate products requiring cross-labeling El Drug/Biologic El Possible combination based on cross-labeling of separate products Other (drug/device/biological product) Version: 5/ 10/13 1 Reference ID: 3366779 Fast Track Designation PMC response Breakthrough Therapy Designation El PMR response: Rolling Review [505(0)] El Orphan Designation El PREA deferred pediatric studies [21 CF CFR El switch. Full Accelerated approval con?rmato1y studies (21 CFR switch. Partial 314.510/21 CFR 601.41) Direct-to-OTC Animal rule postmarketing studies to verify clinical bene?t and safety (21 CFR 314.610/21 CFR 601.42) Other: Collaborative Review Division (if OTC product): List referenced IND Number(s): 112669 Goal Dates/Product Names/Classi?cation Properties YES NO NA Comment PDUFA and Action Goal dates con'ect in tracking system? If no, ask the document room staff to correct them immediately. These are the dates used for calculating inspection dates. Are the proprietary. established/proper. and applicant names correct in tracking system? If no, ask the document room staff to make the corrections. Also, ask the document room staff to add the established/proper name to the supporting if not already entered into tracking system. Is the review priority (S or P) and all appropriate classi?cations/properties entered into tracking system chemical classi?cation. combination product classi?cation. 505 orphan d?lg)? For supplements, check the New Application and New Supplement Notification Checklists for a list of all classifications/properties at: hmM/in side. tda. DER/Ot?ceo?nsines sProcessSuggort/ucm] 63 969. In a If no, ask the document room staff to make the appropriate entries. Application Integrity Policy YES NO NA Comment Is the application affected by the Application Integrity Policy Check the AIP list at: . lh rm If yes. explain in comment column. If affected by AIP. has been noti?ed of the submission? If yes, date noti?ed: User Fees YES NO NA Comment Is Form 3397 (User Fee Cover Sheet) included with authorized signature? Version: 5/ 10/13 2 Reference ID: 3366779 User Fee Status Payment for this application: If a user fee is required and it has not been paid (and it Paid is not exempted or waived), the application is El Exempt (orphan. government) unacceptable for filing following a 5-day grace period. El Waived small business_ public health) Review stops. Send Unacceptable for Filing (UN) letter Not required and contact user fee staff Payment of other user fees: If the firm is in arrears for other fees (regardless of Not ill arrears whether a user fee has been paid for this application), In arrears the application is unacceptable for ?ling (5-day grace period does not apply). Review stops. Send UN letter and contact the user fee staff 505(b)(2) YES NO NA Comment Ef?cacy Supplements only) Is the application for a duplicate of a listed drug and eligible for approval under section 5050) as an Is the application for a duplicate of a listed drug whose only difference is that the extent to which the active ingredient(s) is absorbed or otherwise made available to the site of action is less than that of the reference listed drug [see 21 CFR Is the application for a duplicate of a listed drug whose only difference is that the rate at which the proposed product?s active ingredient(s) is absorbed or made available to the site of action is unintentionally less than that of the listed drug [see 21 CFR If you answered yes to any of the above questions, the application may be refused for filing under 21 FR Contact the 505(b)(2) review staff in the Immediate Of?ce of New Drugs Is there miexpired exclusivity on any drug product containing the active moiety 5-year. 3-year. orphan. or pediatric exclusivity)? Check the Electronic Orange Book at: accessdata. tda. gov/5criets/cder/ob/detault. If yes. please list below: Application No. Drug Name Exclusivity Code Exclusivity Expiration If there is unexpired, 5?_vear exclusivity remaining on the active moiety for the proposed drug product, a 505 application cannot be submitted until the period of exclusivity expires (unless the applicant provides paragraph I patent certi?cation; then an application can be submitted fom'years after the date of approval. Pediatric exclusivity will extend both of the time??ames in this provision by 6 months. 21 CFR Unexpired, 3- vear exclusivity mav block the approval but not the submission of a 5 05 application. Exclusivity YES NO NA Comment Does another product (same active moiety) have orphan exclusivity for the same indication? Check the Orphan Drug Version: 5/ 10/13 3 Reference ID: 3366779 Designations and Approvals list at: If another product has orphan exclusivity. is the product considered to be the same product according to the orphan drug de?nition of sameness [see 21 CFR If yes, consult the Director, Division of Regu latory Po 1 i Q, 11, 01770? 0f Regulatory Policy Has the applicant requested 5-year or 3-year Waxman-Hatch exclusivity? efficacy supplements only) If yes. years requested: Note: An applicant can receive exclusivity without requesting it; therefore, requesting exclusivity is not required. Is the proposed product a single enantiomer of a racemic drug previously approved for a different therapeutic use (NDAs only If yes. did the applicant: elect to have the single enantiomer (contained as an active ingredient) not be considered the same active ingredient as that contained in an already approved racemic drug. and/or request exclusivity pursuant to section 505(11) of the Act (per Section 1113)? If yes, contact Mary Ann Holovac, Director of Drug Information, Format and Content All paper (except for COL) All electronic Do not check mixed submission if the only electronic component Mixed (paper/electronic) is the content of labeling (COL). CTD Mixed If mixed (paper/electronic) submission, which parts of the application are submitted in electronic format? Overall Format/Content YES NO NA Comment If electronic submission, does it follow the guidance?1 If not, explain waiver granted). Index: Does the submission contain an accurate comprehensive index? Is the submission complete as required under 21 CFR 314.50 e?icaev supplements) or under 21 FR 601.2 efficacv supplements) including: http://wuw Version: 5/ 10/13 4 Reference ID: 3366779 legible English (or translated into English) pagination El navigable hyperlinks (electronic submissions only) If no. explain. BLAs only: Companion application received if a shared or divided manufactiuing airangement? If yes. BLA Forms and Certi?cations Electronic fonns and certi?cations with electronic signatures (scanned, digital, or electronic similar to DARR S, e. are acceptable. Otherwise, paper forms and certi?cations with hand?written signatures must be included. arms include: user fee cover sheet (3397), application form (35 6h), patent infonnation (3542a), ?nancial disclosure (3454/3455), and clinical trials (36 74); Certi?cations include: debarment certi?cation, patent certi?cation?), ?eld (OPT certi?cation, and pediatric certi?cation. Application Form YES NO NA Comment Is form FDA 35611 included with authorized signature per 21 CFR If foreign applicant, a US. agent must sign the form [see 21 FR Are all establislnnents and their registration numbers listed 011 the form/attached to the form? Patent Information YES NO NA Comment ef?cacy supplements only) Is patent information submitted on form FDA 3542a per 21 CFR Financial Disclosure YES NO NA Comment Are fmancial disclosm?e forms FDA 3454 and/or 3455 Cross-referenced to included with authorized signature per 21 CFR and NDA 22-518~ in Module 1.3.4 Forms must be signed by the APPLICANT, not an Agent [see 21 CFR Note: Financial disclosure is required for bioequivalence studies that are the basis for approval. Clinical Trials Database YES NO NA Comment Is fonn FDA 3674 included with authorized signature? If yes, ensure that the application is also coded with the supporting document category, arm 36 74. Version: 5/ 10/13 5 Reference ID: 3366779 If no, ensure that language requesting submission of the form is included in the acknowledgement letter sent to the applicant Debarment Certi?cation YES NO NA Comment Is a correctly worded Debarment Certi?cation included with authorized signature? Certification is not required for supplements if submitted in the original application; If foreign applicant, the applicant and the US. Agent must sign the certi?cation [per Guidance for Industry: Submitting Debarment erti?cations]. Note: Debannent Certi?cation should use wording in Act Section 306(k)(1) ?[Name of applicant] hereby certi?es that it did not and will not use in any capacity the services of any person debarred under section 306 of the Federal Food, Drug, and Cosmetic Act in connection with this application. Applicant may not use wording such as, ?To the best of mv knowledge". Field Copy Certi?cation YES NO NA Comment ef?cacy supplements only) For paper submissions only: 15 a Field Copy Certi?cation (that it is a true copy of the CMC technical section) included? Field opy Certification is not needed if there is no CMC technical section or if this is an electronic submission (the Field Of?ce has access to the EDR) If maroon ?eld copy jackets from foreign applicants are received, return them to CDR for delivery to the appropriate ?eld o?ice. Controlled Substance/Product with Abuse Potential YES NO NA Comment For NMEs: Is an Abuse Liability Assessment. including a proposal for scheduling. submitted per 21 FR If yes, date consult sent to the Controlled Substance Sta?: For non-NMEs: Date of consult sent to Controlled Substance Sta? Pediatrics YES NO NA Comment PREA Does the application trigger If yes, notify RPM meeting is required)2 Note: NDAs/BLAs/e?icacy supplements for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration trigger PREA. All waiver deferral requests, pediatric plans, and pediatric assessment studies must be 2 http://inside Version: 5/ 10/13 Reference ID: 3366779 reviewed by prior to approval of the If the application triggers PREA. are the required pediatric assessment studies or a full waiver of pediatric studies included? If studies or full waiver not included, is a request for full waiver of pediatric studies OR a request for partial waiver and/or deferral with a pediatric plan included? If no, request in 74-day letter If a request for full waiver/partial waiver/deferral is included. does the application contain the certi?cation(s) required by FDCA Section 5053(a)(3) and If no, request in 74-day letter BPCA (N efficacy supplements only): Is this submission a complete response to a pediatric Written Request? If yes, notify Pediatric Exclusivitv Board RPM (pediatric exclusivity determination is required)3 Proprietary Name YES NO NA Comment Is a proposed proprietary name submitted? The 74-day letter will include a If yes, ensure that the application is also coded with the that the sponsor. supporting document category, ?Proprietary Name/Request for a. proprietary Review. name revrew request. REMS YES NO NA Comment Is a REMS submitted? If yes, send consult to and notify via the CDER 0S1 RMP mailbox Prescription Labeling El Not applicable Check all types of labeling submitted. Package Insert (PI) Patient Package Insert (PPI) Instructions for Use (IFU) Medication Guide (MedGuide) Carton labels El Immediate container labels Diluent El Other (specify) YES NO NA Comment Is Electronic Content of Labeling (COL) submitted in SPL 3 http://inside Version: 5/10/13 7 Reference ID: 3366779 format? If no, request applicant to submit SPL before the ?ling date. Is the PI submitted in PLR format?4 If PI not submitted in PLR format. was a waiver or deferral requested before the application was received or in the submission? If requested before application was submitted. what is the status of the request? If no waiver or deferral, request applicant to submit labeling in PLR format before the ?ling date. All labeling (PI. PPI. MedGuide. IFU. carton and container labels) consulted to MedGuide. PPI. IFU (plus PI) consulted to (send WORD version If available) Carton and container labels. PI. PPI sent to and appropriate CMC review of?ce (OBP or OTC Labeling Not Applicable Check all types of labeling submitted. Outer carton label container label El Blister card Blister backing label Consumer Information Lea?et Physician sample Consumer sample Other (specify) YES NO NA Comment Is electronic content of labeling (COL) submitted? If no, request in 74-day letter. Are aimotated speci?cations submitted for all stock keeping units If no, request in 74-day letter. If representative labeling is submitted. are all represented SKUs defmed? If no, request in 74-day letter. All labeling/packaging. and cmrent approved Rx PI (if switch) sent to Other Consults YES NO NA Comment Are additional consults needed? IFU to DRH: QT study report to QT Interdisciplinary Review Team) 4 http:// inside 2 5 5 7 6 .htm Version: 5/10/13 8 Reference ID: 3366779 If yes, speeijj' eonsult(s) and date(s) sent: Meeting Minutes/SPAS YES NO NA Comment End-of Phase 2 meeting(s)? Date(s): If yes, distribute minutes before filing meeting Pre-NDA/Pre-BLA/Pre-Supplement meeting(s)? Meeting cancelled on Date(s): 9/9/11; 9/14/13 9/ 13/ 1 1- Enclosed Preliminary If yes, distribute minutes before ?ling meeting Comments and clari?cations. Any Special Protocol Assessments Date(s): If yes, distribute letter amt/or relevant minutes before ?ling meeting Version: 5/ 10/13 9 Reference ID: 3366779 ATTACHMENT MEMO OF FILING MEETING DATE: 8/7/13 NDA 205641 PROPRIETARY NAME: Asmanex HFA NAME: mometasone fiu'oate DOSAGE 100 incg and 200 APPLICANT: Merck Sharp Dohme Corp PROPOSED CHAN Asthma BACKGROUND: New Drug Application (NDA) for Asmanex HFA (mometasone furoate) Inhalation Aerosol, NDA 205641, is proposed for mometasone ?u'oate monotherapy for the treatment of asthma in patients 12 years of age and older. The Sponsor, Merck, proposes mometasone furoate (Asmanex EPA) as a step-down inhaled corticosteroid (IC S) for patients who no longer need continuous long-acting beta-agonist (LABA) treatment. Mometasone flu?oate is the active ingredient in the Sponsor?s approved products, Asmanex Twisthaler (NDA 21067) and Dulera (NDA 22518). REVIEW TEAM: Discipline/Organization Names Present at ?ling meeting? (Y or N) Regulatory Project Management RPM: Jessica Lee Ladan Jafari Cross-Discipline Team Leader (CDTL) Anthony Dmmowicz Clinical Reviewer: Kim Witzmann TL: Anthony Diumowicz Social Scientist Review (for OTC Reviewer: products) TL: OTC Labeling Review (for OTC Reviewer: products) TL: Version: 5/10/13 10 Reference ID: 3366779 Clinical Microbiology (for antimicrobial products) Reviewer: N/A TL: Version: 5/10/13 Reference ID: 3366779 11 Clinical Pharmacology Biostatistics Nonclinical (Pharmacology/Toxicology) Reviewer: Dinko Rekic Y TL: Satjit Brar Y Reviewer: David Hoberman Y TL: Joan Buenconsejo Y Reviewer: Tim Robison Y TL: Statistics (carcinogenicity) Reviewer: N/A TL: Immunogenicity (assay/assay validation) (for BLAs/BLA efficacy supplements) TL: Product Quality (CMC) Reviewer: Xiaobin Shen Y TL: Craig Bertha Y Reviewer: Bryan Riley N TL: Stephen Langille N Quality Microbiology (for sterile products) CMC Labeling Review Reviewer: N/A Reviewer: TL: Facility Review/Inspection Reviewer: N/A TL: OSE/DMEPA (proprietary name) Reviewer: TL: OSE/DRISK (REMS) Reviewer: TL: OC/OSI/DSC/PMSB (REMS) Reviewer: TL: Version: 5/10/13 Reference ID: 3366779 12 Bioresearch Monitoring (OSI) Reviewer: TL: Controlled Substance Staff (CSS) Reviewer: TL: Other reviewers Other attendees FILING MEETING DISCUSSION: GENERAL 0 505(b)(2) ?ling issues: 0 Is the application for a duplicate of a listed drug and eligible for approval Imder section 5050) as an 0 Did the applicant provide a scienti?c ?bridge? demonstrating the relationship between the proposed product and the referenced literature? Describe the scienti?c bridge studies): Not Applicable DYEsleo DYESEINO 0 Per reviewers. are all parts in English or English translation? If no. explain: 0 Electronic Submission List comments: Not Applicable CLINICAL Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter 0 Clinical study site(s) inspections(s) needed? YES NO If no, explain: 0 Advisory Committee Meeting needed? YES Version: 5/10/13 Reference ID: 3366779 13 Comments: If no, for an NME NDA or original BLA , include the reason. For example: o this drug/biologic is not the first in its class o the clinical study design was acceptable o the application did not raise significant safety or efficacy issues o the application did not raise significant public health questions on the role of the drug/biologic in the diagnosis, cure, mitigation, treatment or prevention of a disease  Abuse Liability/Potential Date if known: NO To be determined Reason: Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter  Not Applicable YES NO If the application is affected by the AIP, has the division made a recommendation regarding whether or not an exception to the AIP should be granted to permit review based on medical necessity or public health significance? Comments: CLINICAL MICROBIOLOGY Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter CLINICAL PHARMACOLOGY Not Applicable FILE REFUSE TO FILE Comments:  Clinical pharmacology study site(s) inspections(s) needed? Review issues for 74-day letter YES NO BIOSTATISTICS Not Applicable FILE REFUSE TO FILE Comments: NONCLINICAL Version: 5/10/13 Reference ID: 3366779 Review issues for 74-day letter Not Applicable 14 (PHARMACOLOGY/TOXICOLOGY) FILE REFUSE TO FILE Review issues for 74-day letter Comments: IMMUNOGENICITY (BLAs/BLA efficacy supplements only) Not Applicable FILE REFUSE TO FILE Review issues for 74-day letter Comments: PRODUCT QUALITY (CMC) Not Applicable FILE REFUSE TO FILE Comments: Review issues for 74-day letter Environmental Assessment  Categorical exclusion for environmental assessment (EA) requested? YES NO If no, was a complete EA submitted? YES NO If EA submitted, consulted to EA officer (OPS)? YES NO Comments: Quality Microbiology (for sterile products) Not Applicable  YES NO Was the Microbiology Team consulted for validation of sterilization? (NDAs/NDA supplements only) Comments: Facility Inspection Not Applicable  Establishment(s) ready for inspection? YES NO  Establishment Evaluation Request (EER/TBP-EER) submitted to OMPQ? YES NO Comments: Version: 5/10/13 Reference ID: 3366779 15 Facilig?llvlicrobiology Review (BLAs only) Comments: Not Applicable FILE El REFUSE TO FILE Review issues for 74-day letter CMC Labeling Review Comments: Review issues for 74-day letter APPLICATIONS IN THE PROGRAM (PDUFA V) (N ME NDAs/Original BLAs) Were there agreements made at the application?s pre-submission meeting (and docmnented in the minutes) regarding certain late submission components that could be submitted within 30 days after receipt of the original application? If so. were the late submission components all submitted within 30 days? EYES What late submission components. if any, arrived after 30 days? Was the application otherwise complete upon submission, including those applications where there were no agreements regarding late submission components? Is a comprehensive and readily located list of all clinical sites included or referenced in the application? Is a comprehensive and readily located list of all manufacturing facilities included or referenced in the application? EYES EINO REGULATORY PROJECT MANAGEMENT ?gnatorv Authority: Lydia Gilbert McClain Version: 5/ 10/13 Reference ID: 3366779 16 Date of Mid-Cycle Meeting (for NME in ?the Program? PDUFA V): 21? Century Review Milestones (see attached) (listing review milestones in this docmnent is optional): Comments: REGULATORY CI The application is 1msuitable for ?ling. Explain why: The application. on its face. appears to be suitable for ?ling. Review Issues: No review issues have been identi?ed for the 74-day letter. Review issues have been identi?ed for the 74-day letter. List (optional): Review Classi?cation: Standard Review Priority Review ACTIONS ITEMS Ensure that any updates to the review priority (S or P) and classi?cations/properties are entered into tracking system chemical classi?cation. combination product classi?cation. 505(b)(2). orphan drug). If RTF. notify everybody who already received a consult request. OSE PM. and Product Quality PM (to cancel If ?led. and the application is wider AIP. prepare a letter either granting (for signatlu?e by Center Director) or denying (for signature by ODE Director) an exception for review. supplements: If ?led. send 60-day ?ling letter If priority review: 0 notify sponsor in writing by day 60 (For supplements: include in 60-day ?ling letter: For supplements: see CST for choices) 0 notify OMPQ (so facility inspections can be scheduled earlier) Send review issues/no review issues by day 74 Conduct a PLR format labeling review and include labeling issues in the 74-day letter Update the PDUFA DARRTS page (for NMZE NDAs in the Program) dual: supplements: Send the Product Information Sheet to the product reviewer and Version: 5/10/13 17 Reference ID: 3366779 the Facility Information Sheet to the facility reviewer for completion. Ensure that the completed forms are forwarded to the CDER RMS-BLA Superuser for data entry into RMS-BLA one month prior to taking an action [These sheets may be found in the CST eRoom at: http://eroom.fda.gov/eRoom/CDER2/CDERStandardLettersCommittee/0 1685f ] Other Version: 5/10/13 Reference ID: 3366779 18 Appendix A (NDA and NDA Supplements only) NOTE: The term "original application" or "original NDA" as used in this appendix denotes the NDA submitted. It does not refer to the reference drug product or "reference listed drug." An original application is likely to be a 505(b)(2) application if: (1) it relies on published literature to meet any of the approval requirements, and the applicant does not have a written right of reference to the underlying data. If published literature is cited in the NDA but is not necessary for approval, the inclusion of such literature will not, in itself, make the application a 505(b)(2) application, (2) it relies for approval on the Agency's previous findings of safety and efficacy for a listed drug product and the applicant does not own or have right to reference the data supporting that approval, or (3) it relies on what is "generally known" or "scientifically accepted" about a class of products to support the safety or effectiveness of the particular drug for which the applicant is seeking approval. (Note, however, that this does not mean any reference to general information or knowledge (e.g., about disease etiology, support for particular endpoints, methods of analysis) causes the application to be a 505(b)(2) application.) Types of products for which 505(b)(2) applications are likely to be submitted include: fixed-dose combination drug products (e.g., heart drug and diuretic (hydrochlorothiazide) combinations); OTC monograph deviations (see 21 CFR 330.11); new dosage forms; new indications; and, new salts. An efficacy supplement can be either a (b)(1) or a (b)(2) regardless of whether the original NDA was a (b)(1) or a (b)(2). An efficacy supplement is a 505(b)(1) supplement if the supplement contains all of the information needed to support the approval of the change proposed in the supplement. For example, if the supplemental application is for a new indication, the supplement is a 505(b)(1) if: (1) The applicant has conducted its own studies to support the new indication (or otherwise owns or has right of reference to the data/studies), (2) No additional information beyond what is included in the supplement or was embodied in the finding of safety and effectiveness for the original application or previously approved supplements is needed to support the change. For example, this would likely be the case with respect to safety considerations if the dose(s) was/were the same as (or lower than) the original application, and. (3) All other “criteria” are met (e.g., the applicant owns or has right of reference to the data relied upon for approval of the supplement, the application does not rely Version: 5/10/13 Reference ID: 3366779 19 for approval on published literature based on data to which the applicant does not have a right of reference). An efficacy supplement is a 505(b)(2) supplement if: (1) Approval of the change proposed in the supplemental application would require data beyond that needed to support our previous finding of safety and efficacy in the approval of the original application (or earlier supplement), and the applicant has not conducted all of its own studies for approval of the change, or obtained a right to reference studies it does not own. For example, if the change were for a new indication AND a higher dose, we would likely require clinical efficacy data and preclinical safety data to approve the higher dose. If the applicant provided the effectiveness data, but had to rely on a different listed drug, or a new aspect of a previously cited listed drug, to support the safety of the new dose, the supplement would be a 505(b)(2), (2) The applicant relies for approval of the supplement on published literature that is based on data that the applicant does not own or have a right to reference. If published literature is cited in the supplement but is not necessary for approval, the inclusion of such literature will not, in itself, make the supplement a 505(b)(2) supplement, or (3) The applicant is relying upon any data they do not own or to which they do not have right of reference. If you have questions about whether an application is a 505(b)(1) or 505(b)(2) application, consult with your OND ADRA or OND IO. Version: 5/10/13 Reference ID: 3366779 20 --------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature. --------------------------------------------------------------------------------------------------------/s/ ---------------------------------------------------JESSICA K LEE 09/03/2013 LADAN JAFARI 09/03/2013 Reference ID: 3366779