204569orig1s000 - food and drug administration · 1. css has recommended that suvorexant be placed...

CENTER FOR DRUG EVALUATION AND RESEARCH

APPLICATION NUMBER:

204569Orig1s000

OTHER REVIEW(S)

suvorexant.NDA204569.20140730.doc 1 of 2

M E M O R A N D U MDepartment of Health and Human Services

Food and Drug AdministrationCenter for Drug Evaluation and Research

Date: July 30, 2014

To: Billy Dunn, M.D., Acting DirectorDivision of Neurology Products

Through: Michael Klein, Ph.D., DirectorSilvia Calderon, Ph.D., Team LeaderControlled Substance Staff

From: Chad J. Reissig, Ph.D., PharmacologistControlled Substance Staff

Subject: Belsomra (suvorexant) NDA 204,569Indication: Insomnia characterized by difficulties withsleep onset and/or sleep maintenanceDosages: 5, 10, 15, and 20 mgSponsor: Merck

Materials reviewed: Sponsor’s Label information

Table of Contents

1 BACKGROUND: ...............................................................................................................................................1

2 CONCLUSIONS: ...............................................................................................................................................2

3 RECOMMENDATIONS:..................................................................................................................................2

1 Background

The Division of Neurology Products consulted CSS to review the resubmission of suvorexant (Belsomra). According to the Sponsor, suvorexant is an orally active, dual orexin receptor antagonist indicated for the treatment of insomnia. Orexin is a preprohormone that is cleaved in vivo into two peptide neurotransmitters, orexin A and orexin B. These orexins bind with a high degree of selectivity to two different G-protein coupled receptors (GPCRs): orexin receptor 1(OX1R) and orexin receptor 2 (OX2R). The orexin receptors are broadly expressed in cortical, thalamic, and hypothalamic neuronal circuits and implicated in numerous physiological functions including feeding behavior and the regulation of sleep/arousal transitions. The Sponsor claims that by blocking the wakefulness promoting effects of orexin A and B, suvorexant facilitates sleep. The Sponsor believes that the mechanism of action of suvorexant will improve sleep induction, sleep maintenance, consolidate fragmented sleep architecture, and

Reference ID: 3601536

suvorexant.NDA204569.20140730.doc 2 of 2

improve the duration of REM sleep. The Sponsor claims that tolerance to suvorexant is limited and that post-dose, morning after effects are minimal.

In the initial review of suvorexant (DARRTS entry on April 29, 2013 by Chad J. Reissig, Ph.D.),CSS noted its reinforcing effects. Based upon the CSS assessment, FDA and HHS recommended that suvorexant be placed in Schedule IV of the Controlled Substances Act (CSA).

No new abuse potential related information has been submitted since CSS’ 2013 review.

2 Conclusions:

1. CSS has recommended that suvorexant be placed in Schedule IV of the Controlled Substances Act (CSA).

2. On Thursday, February 13, 2014, the Drug Enforcement Administration (DEA) published a notice of proposed rulemaking in the Federal Register, proposing that suvorexant be placed into Schedule IV of the CSA (FR Doc No: 2014-03124).

3. On June 4, 2014 CSS informed DEA of the upcoming PDUFA date for suvorexant.

3 Recommendations (to be conveyed to the Sponsor):

1. We remind the Sponsor of their agreement not to market suvorexant (Belsomra) until DEA finalizes scheduling under the Controlled Substances Act.


---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

CHAD REISSIG07/30/2014

SILVIA N CALDERON07/30/2014

MICHAEL KLEIN07/30/2014


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FINAL 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: July 14, 2014

Requesting Office or Division: Division of Neurology Products (DNP)

Application Type and Number: NDA 204569

Product Name and Strength: Belsomra (Suvorexant) Tablets

5 mg, 10 mg, 15 mg, 20 mg

Product Type: Single Strength Product

Rx or OTC: Rx

Applicant/Sponsor Name: Merck Sharp and Dohme Corp.

Submission Date: February 14, 2014, May 21, 2014, and July 10, 2014

OSE RCM #: 2014-452

DMEPA Primary Reviewer: Jacqueline Sheppard, PharmD

DMEPA Acting Team Leader: Tingting Gao, PharmD


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If you have further questions or need clarifications, please contact Ermias Zerislassie, OSE

project manager, at 301-796-0097.


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APPENDIX C. PREVIOUS DMEPA REVIEWSC.1 Methods

We searched the L: Drive on July 11, 2014 using the terms, Suvorexant to identify labeling reviews previously performed by DMEPA.

C.2 Results

The search yielded the following labeling reviews:

1. Neshiewat, J. Label, labeling, and packaging review of Suvorexant Tablets (NDA 204569). FDA/CDER/OSE/DMEPA. 2013 May 6. RCM 2012-2028.

A labeling review was conducted on May 6, 2013 prior to the complete response of NDA 204569. In OSE RCM 2012-2018 (NDA 204569), DMEPA concluded that the proposed labels and labeling could be improved to clarify important information and to help promote the safe use of the product. Most of our previous recommendations for the Prescribing Information, and container labels and carton labeling were implemented in the revised label and labeling.However, two recommendations were not implemented and are listed in Section 4.2.

2. Sheppard, J. Label, labeling, and packaging review of Suvorexant Tablets (NDA 204569). FDA/CDER/OSE/DMEPA. 2014 June 6. RCM 2014-452.

A labeling review was conducted on June 6, 2014. In OSE RCM 2014-452, DMEPA concluded that the proposed labels and labeling could be improved to clarify important information and to help promote the safe use of the product. Recommendations were made to increase prominence of strength statement and to change the presentation of dosing instruction on the professional samples to decrease potential overdose.


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APPENDIX G. LABELS AND LABELING G.1 List of Labels and Labeling ReviewedUsing the principles of human factors and Failure Mode and Effects Analysis,2 along with postmarket medication error data, we reviewed the following Belsomra labels and labeling submitted by Merck on February 14, 2014 and July 10, 2014.

Professional Sample Wallet Labels

Blister Card Label

Blister Card Plastic Case Labeling

Carton Labeling

2 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.


8 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page


JACQUELINE E SHEPPARD07/14/2014

TINGTING N GAO07/14/2014


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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: June 18, 2014

To: Billy Dunn, M.D., Acting-Director Division of Neurology Products (DNP)

Through: LaShawn Griffiths, RN, MSHS-PH, BSN Associate Director, Patient Labeling Team Division of Medical Policy Programs (DMPP) Melissa Hulett, RN, BSN, MSBA Team Leader, Patient Labeling Team Division of Medical Policy Programs (DMPP)

From: Twanda Scales, RN, MSN/Ed. Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Melinda McLawhorn, PharmD, BCPS Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

Subject: Review of Patient Labeling: Medication Guide (MG)

Drug Name: BELSOMRA (suvorexant)

Dosage Form and Route: Tablets

Application Type/Number:

NDA 204569

Applicant: Merck, Sharp & Dohme Corp.


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1 INTRODUCTION

On February 14, 2014, Merck, Sharp & Dohme Corp., a subsidiary of Merck and Co., Inc. (Merck) submitted for the Agency’s review a New Drug Application (NDA) Resubmission for NDA 204569 for BELSOMRA (suvorexant (MK-4305)) tablets. Merck considers this resubmission a complete response to the deficiencies outlined in the FDA Complete Response (CR) letter received on June 28, 2013, following the Agency’s review of the initial NDA submission of August 30, 2012.

BELSOMRA (suvorexant) is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Proprietary Name Review Request for BELSOMRA was submitted by the Merck on July 2, 2013 and final approval is pending.

This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a request by the Division of Neurology Products (DNP) on June 11, 2014 for DMPP and OPDP to review the Applicant’s proposed review the Applicant’s proposed Medication Guide (MG) for BELSOMRA (suvorexant) tablets.

2 MATERIAL REVIEWED

• Draft BELSOMRA (suvorexant) tablets MG received on February 14, 2014, and received by DMPP on June 11, 2014.

• Draft BELSOMRA (suvorexant) tablets MG received on February 14, 2014, and received by OPDP on June 11, 2014.

• Draft BELSOMRA (suvorexant) tablets Prescribing Information (PI), received on February 14, 2014, revised by the Review Division throughout the review cycle, and received by DMPP June 12, 2014.

• Draft BELSOMRA (suvorexant) tablets Prescribing Information (PI) received on February 14, 2014, revised by the Review Division throughout the review cycle and received by OPDP on June 11, 2014.

3 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 MG the target reading level is at or below an 8th grade level.

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 MG document using the Verdana font, size 10.


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In our review of the MG we have:

• simplified wording and clarified concepts where possible

• ensured that the MG are consistent with the Prescribing Information (PI)

• removed unnecessary or redundant information

• ensured that the MG meets the Regulations as specified in 21 CFR 208.20

• ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006)

4 CONCLUSIONS

The MG is acceptable with our recommended changes.

5 RECOMMENDATIONS

• Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence.

• Our collaborative review of the MG 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 MG.

Please let us know if you have any questions.




TWANDA D SCALES06/18/2014

MELINDA W MCLAWHORN06/18/2014

MELISSA I HULETT06/18/2014

LASHAWN M GRIFFITHS06/18/2014


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Food and Drug Administration Center for Drug Evaluation and Research

Office of Medical Policy Initiatives Division of Medical Policy Programs

PATIENT LABELING REVIEW

Date: June 12, 2013

To: Russell Katz, M.D., Director Division of Neurology Products (DNP)

Through: LaShawn Griffiths, RN, MSHS-PH, BSN Associate Director, Patient Labeling Team Division of Medical Policy Programs (DMPP) Melissa Hulett, RN, BSN, MSBA Team Leader, Patient Labeling Team Division of Medical Policy Programs (DMPP) Mathilda Fienkeng, PharmD Team Leader (Acting) Office of Prescription Drug Promotion (OPDP)

From: Twanda Scales, RN, MSN/Ed. Patient Labeling Reviewer Division of Medical Policy Programs (DMPP) Melinda McLawhorn, PharmD, BCPS Regulatory Review Officer Office of Prescription Drug Promotion (OPDP)

Subject: Review of Patient Labeling: Medication Guide (MG)

Drug Name: Suvorexant

Dosage Form and Route: Tablets

Application Type/Number:

NDA 204569

Applicant: Merck, Sharp & Dohme Corp.


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1 INTRODUCTION

On August 30, 2012, Merck, Sharp & Dohme Corp., a subsidiary of Merck and Co., Inc. (Merck) submitted for the Agency’s review an Original New Drug Application (NDA) NDA 204569 for MK-4305 (Suvorexant) tablets. Suvorexant is indicated for the treatment of insomnia characterized by difficulties with sleep onset and/or sleep maintenance. Proprietary Name Review Request for Suvorexant was submitted by the Merck on April 23, 2013 and approval is pending.

This collaborative review is written by the Division of Medical Policy Programs (DMPP) and the Office of Prescription Drug Promotion (OPDP) in response to a request by the Division of Neurology Products (DNP) on October 22, 2012 for DMPP and OPDP to review the Applicant’s proposed review the Applicant’s proposed Medication Guide (MG) for Suvorexant tablets.

2 MATERIAL REVIEWED

• Draft Suvorexant tablets MG received on August 29, 2012, and received by DMPP on June 4, 2013.

• Draft Suvorexant tablets MG received on August 29, 2012, and received by OPDP on June 4, 2013.

• Draft Suvorexant tablets Prescribing Information (PI), received on August 29, 2012, revised by the Review Division throughout the review cycle, and received by DMPP June 4, 2013.

• Draft Suvorexant tablets Prescribing Information (PI) received on August 29, 2012, revised by the Review Division throughout the review cycle and received by OPDP on June 7, 2013.

• Approved Ambien (zolpidem tartrate) tablets C-IV comparator labeling approved April 19, 2013.

3 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 MG the target reading level is at or below an 8th grade level.

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 MG document using the Verdana font, size 10.


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In our review of the MG we have:

• simplified wording and clarified concepts where possible

• ensured that the MG are consistent with the Prescribing Information (PI)

• removed unnecessary or redundant information

• ensured that the MG meets the Regulations as specified in 21 CFR 208.20

• ensured that the MG meets the criteria as specified in FDA’s Guidance for Useful Written Consumer Medication Information (published July 2006)

• ensured that the MG is consistent with the approved comparator labeling where applicable

4 CONCLUSIONS

The MG is acceptable with our recommended changes.

5 RECOMMENDATIONS

• Please send these comments to the Applicant and copy DMPP and OPDP on the correspondence.

• Our collaborative review of the MG 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 MG.

Please let us know if you have any questions.




TWANDA D SCALES06/12/2013

MELISSA I HULETT06/12/2013

LASHAWN M GRIFFITHS06/12/2013


FOOD AND DRUG ADMINISTRATION Center for Drug Evaluation and Research Office of Prescription Drug Promotion ****Pre-decisional Agency Information****

Memorandum Date: June 11, 2013 To: Cathleen Michaloski, BSN, MPH Senior Regulatory Project Manager Division of Neurology Products (DNP) From: Melinda McLawhorn, PharmD, BCPS Regulatory Review Officer Office of Prescription Drug Promotion (OPDP) Through: Mathilda Fienkeng, PharmD, Group Leader (Acting), OPDP Subject: NDA 204569 suvorexant Background On October 17, 2012, DNP consulted OPDP to review the proposed package insert (PI) and medication guide (MG) for the original NDA submission for suvorexant. OPDP reviewed the PI from the proposed substantially complete version retrieved from the eRoom on June 7, 2013 and our comments are provided below. Combined OPDP and the Division of Medical Policy Programs (DMPP) comments on the proposed MG will be provided under a separate cover. Thank you for your consult. If you have any questions, please contact Melinda McLawhorn at 6-7559 or at [email protected].




MELINDA W MCLAWHORN06/11/2013



Food and Drug Administration Center for Drug Evaluation and Research Office of Surveillance and Epidemiology

Office of Medication Error Prevention and Risk Management

Label, Labeling and Packaging Review

Date: May 6, 2013

Reviewer: Julie Neshiewat, PharmD Division of Medication Error Prevention and Analysis

Team Leader: Jamie Wilkins Parker, PharmD Division of Medication Error Prevention and Analysis

Associate Director: Scott Dallas, RPh Division of Medication Error Prevention and Analysis

Drug Name and Strengths: Suvorexant Tablets 15 mg, 20 mg, 30 mg, 40 mg

Application Type/Number: NDA 204569

Applicant: Merck Sharp & Dohme Corp.

OSE RCM #: 2012-2028

*** This document contains proprietary and confidential information that should not be released to the public.***


Contents

1 Introduction................................................................................................................. 1 1.1 Background......................................................................................................... 1 1.2 Product Information ............................................................................................ 1

2 Methods and Materials Reviewed............................................................................... 2 2.1 Labels and Labeling............................................................................................ 2 2.2 Drug Administration Errors ................................................................................ 2

3 Medication Error Risk Assessment............................................................................. 3 3.1 Drug Administration Errors Assessment ............................................................ 3 3.2 Integrated Summary of Medication Error Risk Assessment............................... 5

4 Conclusions................................................................................................................. 6

5 Recommendations....................................................................................................... 7

Appendices........................................................................................................................ 11


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• How Supplied: 3-count blister professional sample; Carton containing three 10-count blister cards retail

• Storage: Store at 20°C to 25°C (68°F to 77°F), excursions permitted to 15 °C to 30°C (59°F to 86°F).

• Container and Closure Systems: Formable aluminum blister film with push through lidding foil packed inside a plastic case

2 METHODS AND MATERIALS REVIEWED We reviewed the Suvorexant labels and labeling submitted by the Applicant. Since the proposed product has a similar indication as the currently marketed insomnia product, Ambien (Zolpidem), and there is a potential concern for accidental redosing secondary to amnesia with Ambien, we reviewed the narratives of the drug administration errors submitted by the Applicant to determine if accidental redosing occurred with Suvorexant in the clinical studies.

2.1 LABELS AND LABELING Using the principles of human factors and Failure Mode and Effects Analysis,1 along with post marketing medication error data, the Division of Medication Error Prevention and Analysis (DMEPA) evaluated the following:

• Wallet Labels: (Professional Sample) submitted August 30, 2012 (Appendix A)

• Blister Card Label: (Retail) submitted August 30, 2012 (Appendix B)

• Blister Card Plastic Case Labeling: (Retail) submitted August 30, 2012 (Appendix C)

• Carton Labeling: (Retail) submitted August 30, 2012 (Appendix D)

• Patient Information Leaflet submitted August 30, 2012 (No image)

• Insert Labeling submitted August 30, 2012 (No image)

2.2 DRUG ADMINISTRATION ERRORS

DMEPA reviewed the narratives of the drug administration errors occurring in the Suvorexant clinical trials during the 12-month period for the high dose Suvorexant group and the 6-month period for the low dose Suvorexant group submitted December 14, 2012.

1 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.


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3 MEDICATION ERROR RISK ASSESSMENT The following section describes the risk assessment of the Suvorexant product design, the associated labels and labeling, and the drug administration errors that occurred during the clinical studies.

3.1 DRUG ADMINISTRATION ERRORS ASSESSMENT In the clinical studies, medication compliance was routinely monitored at each study visit in order to assess compliance and to identify potential events of medication diversion or misuse. Drug accountability of the expected number of remaining tablets was determined based on the amount of tablets dispensed, the number of expected treatment days, any dosing deviations reported by the patient, and the number of tablets remaining. If the equivalent of more than one pill per week was missing during the run-in, treatment, run-out, or discontinuation period (i.e. more than four pills over a month), then the event was reported as an Event of Clinical Interest (ECI) with the adverse event term “potential study medication misuse.” This event term was coded in the MedDRA dictionary to the lower level term of “drug maladministration” and the preferred term “drug administration error.” The events reported in the trials are below:

3.1.1 Low Dose Suvorexant: P028 and P029 There were 20 out of 493 patients (4.1%) whose therapy was coded as a drug administration error based on the Applicant’s definition of missing more than one tablet per week during the run-in, treatment, or run-out period (i.e. more than four tablets missing per month). Three of these 20 patients had two occurrences of a drug administration error resulting in a total of 23 drug administration errors in the low dose Suvorexant clinical study. Below is a summary of the responses from the patients regarding the discrepancy in pill count. These responses correlate to the 23 instances of drug administration error.

• Patient could not account for the missing tablets (n = 12)

• Patient stated that tablets or the bottle was dropped or lost, or patient forgot to bring the bottle to the study visit and did not return the bottle to subsequent study visits (n = 7)

• Patient intentionally disposed of tablets in order to have the site think she was taking the study medication (n = 2)

• Patient refused to return the study medication and the patient was discontinued from the study due to protocol violation (n = 1)

• Patient who could not remember if he had taken two extra doses (n = 1)

There were several instances when patients could not explain what happened to the missing tablets. In the case describing the patient who could not remember if he had taken two extra doses, it is unclear if the study medication caused an adverse event, such as amnesia, leading to the extra doses or if the patient simply forgot if he took a dose and subsequently administered extra doses. The study was designed to monitor medication compliance and help identify potential drug diversion or misuse, but the study was not


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adequately designed to capture and evaluate patients redosing with the medication during the night. Thus, we cannot exclude redosing as a potential cause of the missing tablets in instances where the patient could not account for the missing tablets or could not remember if an extra dose was administered.

3.1.2 High Dose Suvorexant: P009 and P028 There were 32 out of 1291 patients (2.5%) whose therapy was coded as a drug administration error based on the Applicant’s definition of missing more than one tablet per week during the run-in, treatment, run-out, or discontinuation period (i.e. more than four tablets missing per month). Six of these 32 patients had two occurrences of a drug administration error resulting in a total of 38 drug administration errors in the high dose Suvorexant clinical study. Below is a summary of the responses from the patients regarding the discrepancy in pill count. These responses correlate to the 38 instances of drug administration error.

• Patient stated that the tablets or bottle was dropped or lost, or patient forgot to bring the bottle to the study visit and did not return the bottle to subsequent study visits (n = 17)

• Patient could not account for the missing tablets; one patient was later discontinued from the study due to non-compliance (n = 15)

• Patient accidentally threw away tablets or bottle (n = 3)

• Patient intentionally threw away medication because he did not want the pill count to show non-compliance; the patient was later discontinued from the study due to non-compliance (n = 1)

• Patient gave his wife a few tablets (n = 1)

• Patient may have taken another dose (n = 1)

There were several instances when patients could not explain what happened to the missing tablets. We do note that in two of the 15 patients who could not account for the missing tablets, the patients were discontinued from the study due to memory impairment. It is unclear if the study medication caused the memory impairment or if this was an underlying condition. We also note that one patient may have taken another dose. The case stated that the patient recalled putting the tablets on the counter and then not remembering what happened so he may have taken another dose thinking the tablets fell or were never taken. In this case, it is unclear if the study medication caused an adverse event, such as amnesia, leading to another dose. The study was designed to monitor medication compliance and help identify potential drug diversion or misuse, but the study was not adequately designed to capture and evaluate patients redosing with the medication during the night. Thus, we cannot exclude redosing as a potential cause of the missing tablets in instances where the patient could not account for the missing tablets or could not remember if an extra dose was administered.


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5. Carton Labeling: Retail

a. Debold the net quantity statement and the “Rx only” statement since they are

overly prominent. Additionally, revise the net quantity statement to read, “This package contains 30 Tablets in 3 Blister Cards. Each Blister Card contains 10 Tablets.” for clarity.

If you have further questions or need clarifications, please contact Laurie Kelley, project manager, at 301-796-5068.



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JULIE V NESHIEWAT05/06/2013

JAMIE C WILKINS PARKER05/06/2013

SCOTT M DALLAS05/06/2013


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M E M O R A N D U M

Department of Health and Human Services Food and Drug Administration

Center for Drug Evaluation and Research

Date: April 29, 2013 To: Russell Katz, M.D.

Division of Neurology Products Through: Michael Klein, Ph.D., Director

Silvia Calderon, Ph.D., Team Leader Controlled Substance Staff

From: Chad J. Reissig, Ph.D., Pharmacologist

Controlled Substance Staff Subject: NDA204569 (suvorexant)

Indication: Insomnia characterized by difficulties with sleep onset and/or sleep maintenance Dosages: 15, 20, 30, and 40 mg colored, oval or round-shaped tablets Sponsor: Merck

Materials reviewed: Sponsor’s NDA submission

Table of Contents

A. BACKGROUND..................................................................................................................................................1 B. CONCLUSIONS:.................................................................................................................................................2 C. RECOMMENDATIONS:.......................................................................................................................................2

A. Background The Division of Neurology Products (DNP) consulted CSS to review a New Drug Application (NDA) for , also known as suvorexant or MK-4305. Suvorexant is an orally active, dual orexin receptor antagonist seeking an indication for the treatment of insomnia. Orexin is produced as a preprohormone and cleaved into two peptide neurotransmitters, orexin A and orexin B. These orexins bind with a high degree of selectivity to two different G-protein coupled receptors (GPCRs): orexin receptor 1(OX1R) and orexin receptor 2 (OX2R). The orexin receptors are broadly expressed in cortical, thalamic, and hypothalamic neuronal circuits and are implicated in numerous physiological functions including feeding behavior and the regulation of sleep/arousal transitions. By blocking the wakefulness promoting effects of orexin A and B, suvorexant is purported to facilitate naturally occurring sleep processes. The Sponsor believes that the novel mechanism of action of suvorexant has the potential to improve sleep induction,


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sleep maintenance, consolidate fragmented sleep architecture, and improve the duration of REM sleep. The Sponsor claims that tolerance to suvorexant will be limited and that post-dose, morning after effects will be minimal. The Sponsor has proposed that suvorexant be placed in Schedule of the Controlled Substances Act.

B. Conclusions: 1. Data from the human abuse potential study suggest that suvorexant produces

reinforcing effects and has a potential for abuse. In the human abuse potential study, suvorexant produced a level of “drug liking” that was indistinguishable from zolpidem (C-IV).

2. In the human abuse potential study, suvorexant produced cognitive and psychomotor

impairment that was similar to zolpidem (C-IV). This impairment may be clinically significant because of the suvorexant’s long half-life (~8-11 hours) and duration of effects.

3. In clinical trials, euphoria and other adverse events (AEs) suggestive of abuse were

observed infrequently.

4. In the self-administration study in Rhesus monkeys, suvorexant did not appear to be self-administered or produce reinforcing effects. However, the predictive validity of self-administration studies in assessing the abuse potential of orexin ligands is unknown. It is plausible that suvorexant may be self-administered under a different or restricted set of experimental conditions.

5. The results of the drug discrimination study suggest that suvorexant produces

stimulus effects that are dissimilar from morphine (C-II) and may have some degree of similarity to zolpidem (C-IV). The drug discrimination data might be expected given the pharmacological differences between suvorexant, zolpidem, and morphine. Drug discrimination is a sensitive and specific behavioral assay, and drugs with different mechanisms of action would not be expected to generalize to one another.

6. Suvorexant does not appear to produce signs of physical dependence and/or produce

withdrawal upon abrupt cessation in clinical trials. The absence of signs of withdrawal within the first three days after discontinuation of suvorexant might be explained by the long half-life of the drug. Based on comparable levels of drug liking reported by subjects in the human abuse potential study, suvorexant may have a psychic dependence liability that is similar to zolpidem (C-IV).

C. Recommendations:

1. Based primarily on the observed similarity to zolpidem (C-IV) in the human abuse potential study, CSS will recommend scheduling suvorexant as a Schedule IV substance under the Controlled Substances Act (CSA). Accordingly, CSS will


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proceed with the scheduling procedure. This procedure involves concurrence from the National Institute of Drug Abuse, clearance from CDER’s Center Director Office, clearance from the Office of Chief Counsel, endorsement of the recommendation by the FDA Commissioner and Assistant Secretary for Health (ASH). The ASH will submit the final scheduling determination to the Drug Enforcement Administration.

2. CSS will contact the Sponsor to convey the scheduling findings, and the Schedule IV

recommendation.



CHAD REISSIG04/29/2013

SILVIA N CALDERON04/29/2013

MICHAEL KLEIN04/29/2013


M E M O R A N D U M DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE

FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH

______________________________________________________________________________________________________________________________

CLINICAL INSPECTION SUMMARY

DATE: April 3, 2013 TO: Cathleen Michaloski, BSN, M.P.H., Regulatory Health Project Manager Kachikwu Illoh M.D., Medical Officer

Division of Neurology Products FROM: Antoine El-Hage, Ph.D. Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations THROUGH: Susan Leibenhaut, M.D. Acting Team Leader

Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations

Susan D. Thompson, M.D. Acting Branch Chief


SUBJECT: Evaluation of Clinical Inspections NDA: 204-569 APPLICANT: Merck & Co, Inc. DRUG: Suvorexant (MK-4305) NME: Yes THERAPEUTIC CLASSIFICATION: Standard review INDICATION: Treatment of Insomnia CONSULTATION REQUEST DATE: October 10, 2012 DIVISION ACTION GOAL DATE: June 29, 2013 PDUFA DATE: June 29, 2013 INSPECTION SUMMARY: April 29, 2013


Clinical Inspection Summary/NDA 204-569

I. BACKGROUND: The Applicant has conducted studies in support of approval for the use of MK-4305 (suvorexant) in the treatment of patients with primary insomnia. MK-4305 is an orally-administered potent and selective dual orexin receptor antagonist being studied for the treatment of insomnia. Orexinergic neurons of the lateral hypothalamus broadly control the transition between arousal and sleep. By transiently blocking the binding of the wake-promoting neurotransmitters orexin A and orexin B to orexin receptors OX1R and OX2R, suvorexant inhibits activation of wakefulness-promoting neurons of the arousal system. This binding facilitates the physiological process by which the brain transitions from wake to sleep, enabling sleep to occur. Suvorexant is formulated for oral administration as an immediate-release tablet. According to the applicant, MK-4305 is well tolerated and efficacious and may provide an improved safety profile in promoting sleep onset and sleep maintenance in adult patient (non-elderly and elderly) with primary insomnia. The sponsor has submitted data from two studies:

1. Protocol P028 entitled “A Phase III, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, Study to Evaluate the Safety and Efficacy of MK-4305 in Patients with Primary Insomnia –Study A” and

2. Protocol P 029-00 entitled “A Phase III, Multicenter, Randomized, Double-Blind,

Placebo-Controlled, Parallel Group, Study to Evaluate the Safety and Efficacy of MK-4305 in Patients with Primary Insomnia –Study B”

The two protocols are essentially the same; therefore, a single description of the key design features is presented. Two doses of MK-4305 were evaluated within the non-elderly and elderly populations. For non-elderly patients, the MK-4305 doses were 40 mg and 20 mg. The two doses for elderly patients were 30 mg and 25 mg. MK-4305 high dose evaluations combined non-elderly patients on 40 mg with elderly patients on 30 mg: and MK-4305 low dose evaluation combined non-elderly patients on 20 mg with elderly patients on 15 mg. The primary objective of these studies were to evaluate the efficacy of MK-4305 high dose compared to placebo in improving insomnia, as measured by the change from baseline in mean subjective total sleep time (TSTm) on the daily sleep e-diary at Month 1. The primary efficacy endpoints were derived form polysomnograaphic (PSG) measures and from responses in the patients’s daily e-diary. For example, MK-4305 dose: Change from baseline in TSTm on the daily e-diary at Month 1 and Month 3. The protocols were randomized, double –blind, placebo-controlled, parallel group, multicenter questionnaire and PSG studies to assess the safety, tolerability and efficacy of MK-4305 in the treatment of patients with primary insomnia. Overall the study was compromised of a screening period, a 3-month double-blind core treatment period, an optional 3-month double-blind extension, and a 1-week double-blind run-out period at the conclusion of a patient’s treatment. Patients were recruited to either the Questinaire-only (Q-cohort) or the PSG-plus-Questionaire cohort (PQ-cohort). Patients in



both cohorts will complete a daily sleep questionnaire via and electronic diary (e-diary). The review division requested inspection of four clinical investigators for the pivotal protocols Study 028-00 and Study 029-00 because data from the protocols are considered essential to the approval process. These sites were targeted for inspection due to 1) enrollment of a relatively large number of subjects with a treatment effect that was greater than average, and 3) the need to determine if sites conducted the trial ethically and were in compliance with GCP and local regulations. II. RESULTS (by protocol/site): Name of CI, location and site #

Protocol and # of subjects

Inspection Dates

Final Classification

Dirk Zuchner, M.D. Haus 85 Berlin Germany Site #070

Protocol 028-00 Number of subjects: 59

January 7 to11, 2013

NAI

Heike Benes, M.D. Schwerin 19053 Germany Site #094


March 11 to 15, 2013

Pending (Preliminary classification NAI)

David Mayleben, Ph.D. Crestview Hill, KY 41017 Site #016


November 5 to 14, 2012

NAI

Mark Gottfried, M.D Glendale AZ 85306 Site #010

Protocol 029-00 Number of Subjects: 33

November 15 to 20, 2012

NAI

Key to Classifications NAI = No deviations VAI = Deviation(s) from regulations OAI = Significant deviations for regulations. Data unreliable. Pending = Preliminary classification based on e-mail communication from the field; the Establishment Inspectional Report (EIR) has not been received from the field and complete review of EIR is pending. An inspection summary addendum will be generated if conclusions change upon receipt and review of the EIRs.



1. Dirk Zuchner, M.D. 13125 Berlin Germany

a. What Was Inspected: This inspection was performed as a data audit for NDA 204-569, Study Protocol 028 A. At this site, a total of 133 subjects were screened, 74 subjects were reported as screen failures, 59 subjects were randomized into the study, 53 subjects completed the study, and one subject continued into the extension phase of the study. Review of the Informed Consent Documents, for all subjects reviewed, verified that subjects signed informed consent prior to enrollment. The medical records/source data for 30 of the 59 subjects enrolled were reviewed and compared to data listings. The review included consent forms, drug accountability records, inclusion/exclusion criteria, vital signs, IRB records, sponsor correspondence, and adverse events. Source documents for 30 subjects were compared to case report forms and data listings including for primary efficacy endpoints and adverse events listings. For the efficacy endpoint, 100% source data verification of the e-source was performed. Inspection revealed that source documents for primary endpoint data were not available at the site because subjects entered data into a handheld electronic device which sent data directly to a vender’s data system. The clinical investigator (CI) would review the entered data through a read only web-based system. Because review of the endpoint data was cumbersome on the web-based system, the FDA field investigator requested a report of the dataset in tabular format from the vender to be sent to the clinical investigator site for review. The field investigator reviewed all the latency to onset persistent sleep (LPS) source documents and compared the scores to the data listings provided with the assignment and found no discrepancies. The lack of source documents for the efficacy endpoints at the site was discussed with the review division medical officer who stated that “if confirmed that the vendor and the clinical investigator remained blinded to the subjects’ treatment assignment there should be no problem with the reported information or site endpoint verification”. The field investigator stated that to the best of his knowledge the blind was not broken by either the CI or the vender. b. General Observations/Commentary: At the conclusion of the inspection, no Form FDA 483 was issued to Dr. Zuchner. The medical records reviewed were found to be in order, organized, and the data verifiable. There were no deaths and no evidence of under-reporting of adverse events. There were no known limitations to the inspection. c. Assessment of Data Integrity: The data generated in support of the clinical efficacy and safety at Dr. Zuchner’s site are considered reliable and acceptable in support of the pending application.

2. Heike Benes, M.D. Scherwin 19055, Germany

a. What Was Inspected: This inspection was performed as a data audit for NDA 204-569 Study Protocol 029 B. At this site, a total of 67 were screened, 26 subjects were



reported as screen failures, and 41 subjects were randomized into the study. Review of the Informed Consent Documents, for all subjects reviewed, verified that subjects signed consent forms prior to enrollment. The medical records/source data for 41 subjects were reviewed including drug accountability records, vital signs, IRB records, prior and current medications, and inclusion/exclusion criteria. Source documents for 41 subjects were compared to data listings for primary efficacy endpoints and adverse events listing. There was no evidence of under-reporting of adverse events at this site. There were no known limitations to the inspection. b. General Observations/Commentary: At the conclusion of the inspection, No Form FDA 483 was issued to Dr. Benes. Our investigation found minor protocol deviations, in that some subjects ingested caffeine after one pm on PSG visit day. Protocol states to avoid caffeine after four pm. The medical records reviewed were verifiable based on the information available at the site. There were no known limitations to the inspection. There were no deaths and no evidence of under-reporting of adverse events. c. Assessment of Data Integrity: Although minor regulatory deviations were noted, the findings are unlikely to affect integrity of the data as they appear to be isolated incidences and not systemic in nature. The data from Dr. Benes’s site are considered reliable and appear acceptable in support of the pending application. Note: Observations noted above are based on the Form FDA 483 and communications with the field investigator; an inspection summary addendum will be generated if conclusions change upon receipt and review of the EIR

3. David Mayleben, Ph.D. Crestview Hills, KY 41017

a. What Was Inspected: This inspection was performed as a data audit for NDA 204-569 Study Protocol 028A: At this site, a total 152 subjects were screened, 107 subjects were reported as screen failures. 45 subjects were randomized into the study, 43 completed the study, and two subjects continued on the extension phase of the study. Four subjects discontinued due to adverse events and the reason(s) were documented. Review of the Informed Consent Documents, for 45 subjects records reviewed, verified that all subjects signed consent forms prior to enrollment. Note: Dr. Mayleben has a Ph.D. For medically related issues, a sub-investigator, was the most responsible person. He and the other medical doctor sub-investigators performed the medically related procedures including physical examinations and review of adverse events and laboratory tests. The medical records/source documents for 23 subjects were reviewed for primary/secondary endpoints. The medical records/source documents for 23 subjects for


(b) (6)


certain visits were reviewed in depth, including drug accountability records, vital signs, IRB files, inclusion/exclusion criteria, prior and concomitant medications, and adverse events reporting. Note: The primary efficacy endpoint data (wakefulness after persistent sleep (WASO) and latency to onset of persistent sleep (LPS)) scores with the exception of the Visit 2 baseline scores to determine donor eligibility were not collected at the site. Subjects entered the data directly into an e-Diary provided by PHT Study Works, the CRO for e-diary. The data were maintained in the Study Works database. The clinical site had access to the PHT Study Works database. The field investigator compared the source documents/endpoint values to the data listings for primary efficacy endpoints, and no discrepancies were noted. b. General Observations/Commentary: At the conclusion of the inspection, no Form FDA 483 was issued to Dr. Mayleben. The medical records reviewed were found to be in order and the data verifiable. There were no deaths and no evidence of under-reporting of adverse events. There were no known limitations to the inspection. c. Assessment of Data Integrity: The data in support of the clinical efficacy and safety at Dr. Mayleben’s site are considered reliable and may be used in support of the pending application.

4. Mark Gotfried, M.D. Glendale, AZ 85306

a. What was Inspected: This inspection was performed as a data audit for NDA 204-569 Study Protocol 029 B. At this site, a total 98 subjects were screened, 65 subjects were reported as screen failures, 33 subjects were randomized into the study, and 27 subjects completed the study. Six subjects discontinued early from the study, and the reason(s) were documented. Review of the Informed Consent Documents for 33 subjects verified that all subjects signed consent forms prior to enrollment. The medical records/source documents for 33 subjects were reviewed for primary/secondary endpoints. The medical records for five subjects for certain visits were reviewed in depth, including drug accountability records, vital signs, IRB files, financial disclosures, inclusion/exclusion criteria, study procedures, monitoring procedures and use of concomitant medications. Source documents were compared to e-CRFs and data listings, to include primary efficacy endpoints and adverse events. b. General Observations/Commentary: At the conclusion of the inspection, no Form FDA 483 was issued to Dr. Gotfried. The medical records reviewed were found to be in order, organized and the data verifiable. There were no deaths and no evidence of under-reporting of adverse events. There were no known limitations to the inspection. c. Assessment of Data Integrity: The data generated in support of the clinical efficacy and safety at Dr. Gotfried’s site are considered reliable and appear acceptable in support of the pending application.



III. OVERALL ASSESSMENT OF FINDINGS AND GENERAL RECOMMENDATIONS

Four clinical investigator sites were inspected in support of this application. The inspection of Drs. Zuchner, Mayleben and Gotfried revealed no regulatory violations, and the final classification for these inspections is No Action Indicated (NAI). The pending classification for the inspection of Dr. Benes is No Action Indicated (NAI). An inspection summary addendum will be generated if conclusions change upon receipt and review of the EIR. Overall, the data submitted from these four sites are considered acceptable in support of the pending application.

{See appended electronic signature page}

Antoine El-Hage, Ph.D. Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations

CONCURRENCE: {See appended electronic signature page}

Susan Leibenhaut, M.D. Acting Team Leader


{See appended electronic signature page} Susan Thompson, M.D. Acting Branch Chief Good Clinical Practice Assessment Branch Division of Good Clinical Practice Compliance Office of Scientific Investigations



ANTOINE N EL HAGE04/05/2013

SUSAN LEIBENHAUT04/05/2013

SUSAN D THOMPSON04/05/2013


1

Interdisciplinary Review Team for QT Studies Consultation: Thorough QT Study Review

NDA 204569

Brand Name Suvorexant

Generic Name MK-4305

Sponsor Merck Sharp & Dohme

Indication For Treatment of Insomnia

Dosage Form Tablet

Drug Class Sedative-hypnotic

Therapeutic Dosing Regimen Suvorexant 60 mg

Duration of Therapeutic Use Chronic

Maximum Tolerated Dose Suvorexant 240 mg

Submission Number and Date SDN 001, 26 Feb 2013

Review Division DNP Note: Any text in the review with a light background should be inferred as copied from the sponsor’s document.

1 SUMMARY

1.1 OVERALL SUMMARY OF FINDINGS No significant QTc prolongation effect of Suvorexant was detected in this TQT study. The largest upper bounds of the 2-sided 90% CI for the mean difference between Suvorexant and placebo were below 10 ms, the threshold for regulatory concern as described in ICH E14 guidelines. The largest lower bound of the two-sided 90% CI for the ΔΔQTcF for moxifloxacin was greater than 5 ms, and the moxifloxacin profile over time is adequately demonstrated in Figure 5, indicating that assay sensitivity was established.

In this randomized, blinded, four-period crossover study, 53 healthy subjects received Suvorexant 60 mg, Suvorexant 150 or 240 mg, placebo, and a single oral dose of moxifloxacin 400 mg. The overall summary of findings is presented in Table 1.


3

3.3 PRECLINICAL INFORMATION Suvorexant binds to and inhibits hERG at a concentration that is many-fold the human expected exposure. In dogs, very high exposures produced no discernible effects on the ECG.

3.4 PREVIOUS CLINICAL EXPERIENCE Over 2000 subjects have received study drug in trials. Cardiovascular adverse events suggestive of arrhythmia are not prominent.

3.5 CLINICAL PHARMACOLOGY Appendix 6.1 summarizes the key features of Suvorexant (MK-4306) clinical pharmacology.

4 SPONSOR’S SUBMISSION

4.1 OVERVIEW The QT-IRT reviewed the protocol prior to conducting this study under IND 101847. The sponsor submitted the study report MK-4305 Prot. No. 022 for Suvorexant and a Thorough QT (TQT) study, including electronic datasets and waveforms to the ECG warehouse.

4.2 TQT STUDY

4.2.1 Title “A Randomized, Double-Blind Study to Assess the Effect of MK-4305 on corrected QT Intervals in Healthy Male and Female Subjects”

4.2.2 Protocol Number MK-4305 Prot. No. 022

4.2.3 Study Dates 16 Feb 2010 – 23 June 2010

4.2.4 Objectives “Primary: To evaluate effects of supra-therapeutic doses of Suvorexant on the QTc interval. “Secondary:

• To demonstrate sensitivity of a QTc assay using moxifloxacin as a positive control.

• To evaluate the safety and tolerability of Suvorexant after administration of single oral doses to healthy young adult subjects.”

Source: Sponsor’s study synopsis, page 2.


6

4.2.8 Sponsor’s Results

4.2.8.1 Study Subjects Fifty-three subjects (~50% female), 20 to 45 years old, were randomized.

4.2.8.2 Statistical Analyses

4.2.8.2.1 Primary Analysis The 240-mg and 150-mg dose data were pooled (hereafter referred to as “top” dose) for the primary analysis. A repeated measures mixed model appropriate for a four-period crossover design was used to analyze QTcF change from baseline. The model included fixed factors period, treatment ( Suvorexant 60 mg, Suvorexant top dose, moxifloxacin, placebo), time, treatment-by-time interaction, and subject as random factor. Carryover effect was investigated, and included in the final model if found to be significant at α=0.10. All other tests were performed at α=0.05. The same model was also applied to QTcP (population-specific correction), which was found to be a slightly more appropriate correction method for the study data. The primary hypothesis was evaluated using a step-wise closed testing procedure with the underlying assumption that the doses administered are associated with a monotonically increasing QTcF effect. Means and two-sided 90% confidence intervals (CIs) for the true differences ( Suvorexant – placebo) in QTcF change from baseline at all prespecified QTcF timepoints were calculated for each Suvorexant dose, and the primary hypothesis was evaluated using all the QTcF timepoints. If, at the low dose level, all the upper limits of the CIs were smaller than 10.0 ms, then it could be concluded that administration of a single low dose of Suvorexant did not prolong the QTc interval to a clinically significant degree compared to placebo. The testing procedure would then have been repeated for the high dose. If, at the high dose level, all the upper limits of the CI’s were smaller than 10.0 ms, then it could be concluded that the primary hypothesis was supported. Namely, administration of a single dose of Suvorexant did not prolong the QTc interval to a clinically significant degree. If any one of the upper limit of the CIs for the true differences at the low dose level exceeded 10.0 ms, then there would have been insufficient evidence to accept the primary hypothesis and the testing procedure would have stopped with no test provided for the high dose level of Suvorexant. Assay sensitivity was the secondary hypothesis. Source: Sponsor’s study synopsis, page 5.

The sponsor found that Suvorexant did not elongate the QT interval at either the therapeutic or the supratherapeutic levels. The upper limits of the 90% confidence intervals (CI) for ΔΔQTcF were below 10 ms at all dosage levels (see Figure 1).


7

Figure 1: Sponsor’s Mean and 90% CI ΔΔQTcF Timecourse


Reviewer’s Comments: Our analysis agrees with the sponsor’s results. See section 5.2.

4.2.8.2.2 Assay Sensitivity To address the secondary hypothesis (estimation), the true difference between moxifloxacin and placebo in mean QTcF change from baseline was estimated. Two-sided 90% CIs for the true mean difference (moxifloxacin – placebo) in QTcF change from baseline were provided at each of the following timepoints (predose and 0.5, 1, 2, 3, and 4 hours postdose) based on the above model. Source: Sponsor’s study synopsis, page 5.

The lower limits of the 90% CI ΔΔQTcF for moxifloxacin were above 5 ms, indicating that the sponsor found that assay sensitivity was established (see Figure 1).

Reviewer’s Comments: Our analysis agrees with the sponsor’s results. See section 5.2.

4.2.8.2.3 Categorical Analysis Counts were provided by treatment and timepoint for QTcF values falling in the following ranges: ≤ 450, > 450, > 480, and > 500 ms. Counts were also provided by treatment and timepoint for QTcF change from baseline values falling in the following ranges: < 30, ≥ 30, and ≥ 60 ms. Clinical and laboratory adverse experiences were tabulated.



8

4.2.8.3 Safety Analysis There were no cardiovascular adverse events of note.

4.2.8.4 Clinical Pharmacology

4.2.8.4.1 Pharmacokinetic Analysis The PK results for Suvorexant are presented in Table 2 and Figure 2. Following values seen administration of 240 mg Cmax and AUC values in the thorough QT study were 2.2- and 2.6-fold, respectively, with 60 mg. The intended clinical dose is 30 mg for elderly and 40 mg for non-elderly patients.

Table 2: Summary Suvorexant Pharmacokinetic Parameters for Subjects Following Singles Doses of 240-mg, 150-mg, or 60-mg Suvorexant in Healthy Subjects

Source: Sponsor’s report, page 8

Figure 2: Mean Plasma Concentrations in Linear Scale of Suvorexant Following Administration of a 240-mg, 150-mg, or 60-mg Single Dose of Suvorexant in Health Subjects

Source: Sponsor’s report, page 82 Figure 11-5


9

4.2.8.4.2 Exposure-Response Analysis The relationship between the Suvorexant concentrations and QTcF was assessed and the scatter plots of overall ΔΔQTcF versus Suvorexant concentration are shown in Figure 3. The slope was estimated to be 0.841 (90% CI 0.165-1.517) with y-intercept of -1.664.

Figure 3: Individual QTcF Change from Baseline Following Administration of a 240-mg, 150-mg, or 60-mg Single Dose of Suvorexant or Placebo in Healthy Subjects

Source: Sponsor’s report, page 87, Figure 11-8

Reviewer’s Analysis: A plot of ΔΔQTc vs. drug concentrations is presented in Figure 6.

5 REVIEWERS’ ASSESSMENT

5.1 EVALUATION OF THE QT/RR CORRECTION METHOD We evaluated the appropriateness of the correction methods (QTcF and QTcB). Baseline values were excluded in the validation. Ideally, a good correction QTc would result in no relationship of QTc and RR intervals. It is not surprising that QTcF performs better than QTcB (Table 3).


19

Figure 6: ΔΔ QTcF vs. Drug concentration

5.4 CLINICAL ASSESSMENTS

5.4.1 Safety assessments None of the events identified to be of clinical importance per the ICH E 14 guidelines i.e. syncope, seizure, significant ventricular arrhythmias or sudden cardiac death occurred in this study.

5.4.2 ECG assessments Waveforms from the ECG warehouse were reviewed. Overall ECG acquisition and interpretation in this study appears acceptable.

5.4.3 PR and QRS Interval No clinically relevant effects were seen on PR or QRS.


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6 APPENDIX

6.1 HIGHLIGHTS OF CLINICAL PHARMACOLOGY


21


22


24


25

6.2 TABLE OF STUDY ASSESSMENTS Study procedures are summarized in Tables 3-5 to 3-8 of the study report.



JANICE B BRODSKY04/04/2013

JOANNE ZHANG04/04/2013

JEE E LEE04/04/2013

KEVIN M KRUDYS04/05/2013

NORMAN L STOCKBRIDGE04/05/2013


RPM PLR Format Review of the PI: Last Updated May 2012 Page 1 of 9

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 204569 Application Type: New NDA Name of Drug: SUVOREXANT (MK-4305) 10, 20, 30, and 40 mg oral tablets Applicant: Merck Sharp and Dohme Corp. Submission Date: August 29, 2012 Receipt Date: August 30, 2012

1.0 Regulatory History and Applicant’s Main Proposals Suvorexant is an orally active and reversible antagonist for orexin receptors being developed for the treatment of insomnia. By transiently blocking the binding of the wake-promoting neurotransmitters orexin A and orexin B to orexin receptors OX1R and OX2R, suvorexant inhibits activation of wakefulness-promoting neurons of the arousal system. The binding facilitates the physiological process by which the brain transitions from wake to sleep, enabling sleep to occur. Suvorexant is formulated for oral administration as an immediate-release tablet. End-of-Phase 2 Meeting was held on November 05, 2009. Discussion focused on the design of two similar Phase 3 confirmatory efficacy trials that included both subjective and objective efficacy measurements and both non- elderly and elderly patients, with the entire study sample (combined age groups) serving as the primary analysis population. PreNDA Meeting was held on March 19, 2012. FDA noted that the nonclinical safety package, clinical pharmacology, and clinical development data packages appeared complete and that the adequacy of the package will be a matter of review. FDA accepted the proposed organization and presentation of the efficacy and safety results of the NDA as well as the plans for electronic deliverables and Statistical Review Aids. FDA provided recommendations regarding the need for the NDA to contain a pediatric development plan. The CSS advised that while an abuse liability assessment and a proposal for scheduling are required in the NDA, an 8-Factor Analysis is a legal document and is not included in NDA submissions.

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).


RPM PLR Format Review of the Prescribing Information

RPM PLR Format Review of the PI: Last Updated May 2012 Page 2 of 9

3.0 Conclusions/Recommendations

Minor SRPI format deficiencies were identified in the review of this PI. For a list of these deficiencies see the Appendix. All SRPI format deficiencies of the PI will be conveyed to the applicant in the 74-day letter/an advice letter. The applicant will be asked to correct these deficiencies and resubmit the PI in Word format by November 26, 2012. The resubmitted PI will be used for further labeling review. RPM: Cathleen Michaloski BSN, MPH Sr. RPM, CDER OND DNP November 5, 2012


SRPI version 2: Last Updated May 2012 Page 3 of 9

5.0 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) 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 drop-

down 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 Cross-Discipline 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: 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). Comment:

YES

YES

YES

YES

YES




6. Section headings are presented in the following order in HL: Section Required/Optional • Highlights Heading Required • Highlights Limitation Statement Required • Product Title Required • Initial U.S. Approval Required • Boxed Warning Required if a Boxed Warning is in the FPI • Recent Major Changes Required for only certain changes to PI* • Indications and Usage Required • Dosage and Administration Required • Dosage Forms and Strengths Required • Contraindications Required (if no contraindications must state “None.”) • Warnings and Precautions Not required by regulation, but should be present • Adverse Reactions Required • Drug Interactions Optional • Use in Specific Populations Optional • Patient Counseling Information Statement Required • Revision Date Required

* RMC only applies to the Boxed Warning, Indications and Usage, Dosage and Administration, Contraindications, and Warnings and Precautions sections.

Comment:

7. A horizontal line must separate HL and Table of Contents (TOC). Comment:

HIGHLIGHTS DETAILS 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:

Product Title 10. Product title in HL must be bolded.

Comment:

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:

YES

YES

YES

YES

YES

YES

N/A




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

N/A

YES

N/A

N/A

N/A

N/A

N/A

N/A

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: Add 'oral'

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: Will verify that sponsor stm is adequate/correct.

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:

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)

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:

NO

NO

N/A

YES

YES

YES

YES

YES

YES




30. The section headings and subheadings (including title of the Boxed Warning) in the TOC must match the headings and subheadings in the FPI. Comment:

31. 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:

32. All section headings must be bolded and in UPPER CASE. Comment:

33. All subsection headings must be indented, not bolded, and in title case. Comment:

34. When a section or subsection is omitted, the numbering does not change. Comment:

35. 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)

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

N/A

YES

YES

YES

YES

YES

YES

NO




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: 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”.

YES

N/A

N/A

N/A

N/A

N/A

NO




Comment: Need to verify that sponsor statemnt is accurate. Pending response from SEALD. 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:

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:

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: Sponsor numbered subsections.

Miscellaneous: Section 12.2 Pharmacodynamics: QT study negative? The FPI does not contain the full statement “At a dose X times the MRD, Drug Y did not prolong the QTc interval to any relevant extent”. Will refer to Medical Officer.

NO

N/A

NO



CATHLEEN B MICHALOSKI11/05/2012


Version: 6/26/12 11

Reviewer:

Social Scientist Review (for OTC products) TL:

Reviewer:

OTC Labeling Review (for OTC products) TL:

Reviewer:

Clinical Microbiology (for antimicrobial products) TL:


Version: 6/26/12 12

Reviewer:

Kristina Dimova Y Clinical Pharmacology

TL:

Angela Men Xinning Yang (acting)

Y

Reviewer:

Tristan Massie Y Biostatistics

TL:

Kun Jin Y

Reviewer:

Richard Siarey Y Nonclinical (Pharmacology/Toxicology)

TL:

Lois Freed Y

Reviewer:

Atiar Rahman Statistics (carcinogenicity)

TL:

Karl Lin

Reviewer:

Immunogenicity (assay/assay validation) (for BLAs/BLA efficacy supplements) TL:

Reviewer:

Mohan Sapru Akm Khairuzzaman

Y Y

Product Quality (CMC)

TL:

Ramesh Sood Y

Reviewer:

Quality Microbiology (for sterile products)

TL:

Reviewer:

CMC Labeling Review

TL:

Reviewer:

Vibhakar Shah PM Teshara Bouie

Facility Review/Inspection

TL:

Reviewer:

Julie Nesiewat OSE/DMEPA (proprietary name)

TL:

Irene Z Chan

Reviewer:

Kendra Worthy OSE/DRISK (REMS)

TL:

Reviewer:

OC/OSI/DSC/PMSB (REMS)

TL:


Version: 6/26/12 14

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 Comments:

Not Applicable X FILE

REFUSE TO FILE

Review issues for 74-day letter

• 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:

X Not Applicable YES NO

CLINICAL MICROBIOLOGY Comments:

X Not Applicable FILE REFUSE TO FILE


CLINICAL PHARMACOLOGY Comments:


REFUSE TO FILE

Review issues for 74-day letter • Clinical pharmacology study site(s) inspections(s)

needed?

YES NO

BIOSTATISTICS Comments:


REFUSE TO FILE


NONCLINICAL (PHARMACOLOGY/TOXICOLOGY) Comments:


REFUSE TO FILE



Version: 6/26/12 15

IMMUNOGENICITY (BLAs/BLA efficacy supplements only) Comments:

Not Applicable FILE REFUSE TO FILE


PRODUCT QUALITY (CMC) Comments:


REFUSE TO FILE


Environmental Assessment • Categorical exclusion for environmental assessment

(EA) requested? If no, was a complete EA submitted?

If EA submitted, consulted to EA officer (OPS)?

Comments:

Not Applicable X YES

NO

YES NO

YES NO

Quality Microbiology (for sterile products) • Was the Microbiology Team consulted for validation

of sterilization? (NDAs/NDA supplements only) Comments:

Not Applicable

YES NO

Facility Inspection • Establishment(s) ready for inspection? Establishment Evaluation Request (EER/TBP-EER)

submitted to OMPQ?

Comments:

Not Applicable

YES NO

YES (pending-V. Shah

ONDQA) NO

Facility/Microbiology Review (BLAs only) Comments:

Not Applicable FILE REFUSE TO FILE



Version: 6/26/12 17

filing letter; For NDAs/NDA supplements: see CST for choices) • notify OMPQ (so facility inspections can be scheduled earlier)

X Send review issues/no review issues by day 74

X Conduct a PLR format labeling review and include labeling issues in the 74-day letter

Update the PDUFA V DARRTS page (for NME NDAs in “the Program”) BLA/BLA supplements: Send the Product Information Sheet to the product reviewer and

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

Information current as of 10.24.12 C. Michaloski


Version: 6/26/12 18


APPEARS THIS WAY ON ORIGINAL


CATHLEEN B MICHALOSKI10/24/2012
