`
` CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
` APPLICATION NUMBER:
`
`
`
` 212640Orig1s000
`
`
`
`
` OTHER REVIEW(S)
`
`
`
`
`

`

`MEMORANDUM
`
`REVIEW OF REVISED LABEL AND LABELING
`
`
`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)
`
`
` Date of This Memorandum:
`
`October 31, 2019
`Requesting Office or Division:
`Division of Neurology Products (DNP)
`Application Type and Number: NDA 212640
`Product Name and Strength:
`Exservan (riluzole) oral film, 50 mg
`Applicant/Sponsor Name:
`Aquestive Therapeutics
`OSE RCM #:
`2019-339-3
`DMEPA Safety Evaluator:
`Chad Morris, PharmD, MPH
`DMEPA Team Leader (Acting):
`Briana Rider, PharmD, CPPS
`
`PURPOSE OF MEMORANDUM
`1
`Aquestive Therapeutics submitted revised carton labeling on October 25, 2019 for Exservan in
`response to a recommendation developed upon internal discussion with The Office of
`
`Prescription Drug Promotion (OPDP). We concurred with OPDP to recommend Aquestive add
`the statement “Do not administer with liquids” after the statement “Keep in place until film
`dissolves” under the “How to Use” section on the carton labeling. a The Division of Neurology
`
`
`Products (DNP) requested that we review the revised carton labeling for Exservan (Appendix A).
`
` CONCLUSION
`2
`Aquestive implemented the recommendation, and we have no additional recommendations at
`this time.
`
` a Recommendation submitted to Aquestive Therapeutics via email on October 23, 2019. Email available at:
`
`\\cdsesub1\evsprod\nda212640\0011\m1\us\112-other-corr\request-for-information-additional-labeling­
`
`comments.pdf
`
`1
`
`
`
`Reference ID: 4513835Reference ID: 4525554
`
`1 Page(s) of Draft Labeling has been Withheld in Full as B4 (CCI/TS) immediately
`following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`JOHN C MORRIS
`10/31/2019 09:12:30 AM
`
`BRIANA B RIDER
`10/31/2019 09:16:59 AM
`
`
`
`Reference ID: 4513835Reference ID: 4525554
`
`

`

`Department of Health and Human Services
`
`
`Public Health Service
`
`
`Food and Drug Administration
`
`
`Center for Drug Evaluation and Research
`
`
`Office of Medical Policy
`
`
`
`
`PATIENT LABELING REVIEW
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` October 23, 2019
`
` William Dunn, MD
`
` Director
`
` Division of Neurology Products (DNP)
`
`
`
` LaShawn Griffiths, MSHS-PH, BSN, RN
` Associate Director for Patient Labeling
`
`
` Division of Medical Policy Programs (DMPP)
`
`
` Sharon W. Williams, MSN, BSN, RN
`
`
` Senior Patient Labeling Reviewer
` Division of Medical Policy Programs (DMPP)
`
` Sapna Shah, PharmD
`
`
` Regulatory Review Officer
`
` Office of Prescription Drug Promotion (OPDP)
`
` Review of Patient Labeling: Instructions for Use
`
` EXSERVAN (riluzole)
`
` oral film
`
`
` NDA 212640
`
` Aquestive Therapeutics
`
`
`
`
` Date:
`
` To:
`
`
`
`
` Through:
`
`
`
`
`
` From:
`
`
` Subject:
`
`
`
`
` Drug Name (established
`
`name):
` Dosage Form and Route:
`
`
`Application
` Type/Number:
`
` Applicant:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4510215Reference ID: 4525554
`
`
`
`
`
`

`

`
`1
`
` INTRODUCTION
`
`
` On January 31, 2019, Aquestive Therapeutics. submitted for the Agency’s review an
` Orignal New Drug Application (NDA) for EXSERVAN (riluzole) oral film. The
`
`
`
` purpose of the submission is to seek approval for marketing EXSERVAN (riluzole)
`
`
` for the treatment of amyotrophic lateral sclerosis (ALS).
`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 April 3, 2019 for DMPP
`
`
`
`
` and OPDP respectively to review the Applicant’s proposed IFU for EXSERVAN.
`
`
`
`
`
`
`
`
`
`
`
`
`
`2 MATERIAL REVIEWED
`
`
` • Draft EXSERVAN (riluzole) IFU received on January 31, 2019, and received by
`
`
`
`
`DMPP and OPDP on October 17, 2019.
`
`
` • Draft EXSERVAN (riluzole) use Prescribing Information (PI) received on
`
`
`
`
`
`
` January 31, 2019, revised by the Review Division throughout the review cycle,
`
`
`
` and received by DMPP and OPDP on October 17, 2019.
`
`
`
`
`
`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.
`
`
`
` Additonally, 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.
`
`
`
`
` In our collaborative review of the IFU we:
`
`
` simplified wording and clarified concepts where possible
`
`
`•
`
`
`
` ensured that the IFU is consistent with the Prescribing Information (PI)
`
`•
` removed unnecessary or redundant information
`
`
`•
`
`
` ensured that the IFU is free of promotional language or suggested revisions to
`
`•
` ensure that it is free of promotional language
`
`
`
`
` ensured that the IFU meets the criteria as specified in FDA’s Guidance for
`
` Useful Written Consumer Medication Information (published July 2006)
`
`
`
`•
`
`
`
`
` 4 CONCLUSIONS
` The IFU is acceptable with our recommended changes.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4510215Reference ID: 4525554
`
`
`
`
`
`
`
`
`
`

`

`
`
` 5 RECOMMENDATIONS
`
` • Please send these comments to the Applicant and copy DMPP and OPDP on the
`
`
`
` correspondence.
`
`
`
`
` • Our collaborative review of the 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 IFU.
`
`
`
`Please let us know if you have any questions.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4510215Reference ID: 4525554
`
`5 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this
`page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`SHARON W WILLIAMS
`10/23/2019 02:29:42 PM
`
`SAPNA P SHAH
`10/23/2019 02:32:26 PM
`
`LASHAWN M GRIFFITHS
`10/23/2019 02:43:49 PM
`
`
`
`Reference ID: 4510215Reference ID: 4525554
`
`

`

`
`
`
`
`Michelle Mathers, Regulatory Project Manager, (DNP)
`
`
`
`
`Tracey Peters, Associate Director for Labeling, (DNP)
`
`
`
`Sapna Shah, PharmD, Regulatory Review Officer
`
`Office of Prescription Drug Promotion (OPDP)
`
`
`
`
`Aline Moukhtara, RN, MPH, Team Leader, OPDP
`
`
` FOOD AND DRUG ADMINISTRATION
`
`
` Center for Drug Evaluation and Research
`
` Office of Prescription Drug Promotion
`****Pre-decisional Agency Information****
`
`
`
`
` Memorandum
`
`
` Date:
`
` October 21, 2019
`
`
`
`
`
`To:
`
`
`
`
`
`
`
`
`
`Rainer Paine, M.D.
`
`
`Division of Neurology Products (DNP)
`
`
`
`
`From:
`
`
`
`
`
`CC:
`
`
`Subject:
`
`NDA:
`
`
`
`In response to the DNP consult request dated April 3, 2019, OPDP has reviewed the proposed
`
`
`
`
`
`
`
`product labeling (PI), Instructions for Use (IFU), and carton and container labeling for the
`
`
`
`
`
`
` original NDA submission for EXSERVANTM (riluzole) oral suspension (Exservan).
`
`
`
`
`
`PI: OPDP’s has reviewed the proposed labeling for the draft PI received by electronic mail
`
`
`
`
`
`
`
`
`
`from DNP (Michelle Mathers) on October 17, 2019, and we do not have any comments at this
`
`time.
`
`IFU: A combined OPDP and Division of Medical Policy Programs (DMPP) review will be
`
`
`
`
`
`completed, and comments on the proposed IFU will be sent under a separate cover.
`
`Carton and Container Labeling: OPDP has reviewed the attached proposed carton and
`
`
`
`
`
`container labeling submitted by the sponsor on September 25, 2019, and our comments are
`
`provided below.
`
`
`Thank you for your consult. If you have any questions, please contact Sapna Shah (240) 402­
`
`
`6068 or Sapna.Shah@fda.hhs.gov.
`
`
`OPDP Labeling Comments for EXSERVANTM (riluzole) oral film
`
`
`
`
`
`
`
`
`212640
`
`
`
`
`
`
`Reference ID: 4508862Reference ID: 4525554
`
`
`
` 1
`
`14 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately
`following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`SAPNA P SHAH
`10/21/2019 02:06:30 PM
`
`
`
`Reference ID: 4508862Reference ID: 4525554
`
`

`

`FROM:
`
`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
`
`____________________________________________________________________________
`DATE:
`October 4, 2019
`TO:
`Billy Dunn, MD
`Director
`Division of Neurology Products (DNP)
`Office of New Drugs
`Bing Li, Ph.D.
`
`Acting Director
`
`Office of Bioequivalence
`
`Office of Generic Drugs
`
`Sripal Reddy Mada, Ph.D.
`Pharmacologist
`Division of Generic Drug Study Integrity (DGDSI)
`Office of Study Integrity and Surveillance (OSIS)
`THROUGH: John A. Kadavil, Ph.D.
`Deputy Director
`Division of Generic Drug Study Integrity (DGDSI)
`Office of Study Integrity and Surveillance (OSIS)
`SUBJECT: Routine inspection of Syneos Health, Inc. (fka
`inVentiv Health Clinical Research Services), Miami,
`FL.
`1 Inspection Summary
`The Office of Study Integrity and Surveillance (OSIS) arranged
`an inspection of study 162020 (NDA 212640) conducted at Syneos
`Health, Inc. (fka inVentiv Health Clinical Research Services),
`Miami, FL.
`No objectionable conditions were observed, and Form FDA 483 was
`not issued at the inspection close-out. The final inspection
`classification is No Action Indicated (NAI).
`1.1. Recommendation
`After reviewing the inspectional findings, I conclude the data
`from the audited study is reliable to support a regulatory
`decision.
`
`
`
`
`
`Reference ID: 4502131Reference ID: 4525554
`
`

`

`
`
`Page 2 – Routine inspection of Syneos Health, Inc. (fka inVentiv
`Health Clinical Research Services), Miami, FL.
`
` 2 Inspected Study:
`NDA 212640
`Study Number: 162020
`Study Title: “A Pivotal, Open-Label, Randomized, Single Dose,
`Five-period, Replicate Crossover, Comparative
`Bioavailability Study of Riluzole 50 mg Oral
`Soluble Films and RILUTEK® 50 mg Tablets in
`Healthy Male and Female Volunteers under Fasting
`Conditions with Evaluation of Food Effect”
`Dates of conduct: 02/16/2017 – 04/07/2017
`Clinical site: Syneos Health, Inc. (fka inVentiv Health Clinical
`Research Services)
`1951 Northwest 7th Avenue, Suite 450
`Miami, FL 33136
`ORA investigator Ladislav Kermet inspected Syneos Health, Inc.
`(fka inVentiv Health Clinical Research Services), Miami, FL, on
`September 09-11, 2019.
`The inspection included a thorough examination of case report
`forms, medical records and worksheets, inclusion and exclusion
`criteria, randomization schedules, correspondence between the
`IRB and clinical investigator, correspondence between the
`sponsor and the clinical investigator, informed consent forms
`for all subjects screened, collection, processing, and storage
`of study samples, monitoring visits and electronic records, and
`test article records and reserve samples.
`3 Inspectional Findings
`At the conclusion of the inspection, investigator Ladislav
`Kermet did not observe any objectionable conditions and did not
`issue Form FDA 483 to the clinical site.
`4. Conclusion:
`After reviewing the inspectional findings, I conclude the data
`from study 162020 (NDA 212640) is reliable. In addition, the
`data from studies of similar design that were not audited but
`submitted to pending applications (Attachment 1) are reliable
`for Agency review.
`Based on the inspectional findings, studies of similar design
`conducted between the previous inspection (December 2016) and
`
`
`
`Reference ID: 4502131Reference ID: 4525554
`
`V. 2.4 Last Revised Date:08-16-2019
`
`

`

`Page 3 – Routine inspection of Syneos Health, Inc. (fka inVentiv
`Health Clinical Research Services), Miami, FL.
`the end of the current surveillance interval should be
`considered reliable without an inspection.
`
`Sripal Reddy Mada, Ph.D.
`Pharmacologist
`
`Final Classification:
`
` NAI - Syneos Health, Inc. (fka inVentiv Health Clinical
`Research Services)
`Miami, FL
`FEI#: 3011234940
`
`cc:
`OTS/OSIS/Kassim/Dasgupta/Mitchell/Fenty­
`Stewart/Taylor/Haidar/Mirza
`OTS/OSIS/DNDSI/Bonapace/Au/Ayala/Biswas
`OTS/OSIS/DGDSI/Cho/Kadavil/Choi/Skelly/Lewin/Mada
`
`ORA/OMPTO/OBIMO/ORABIMOE.Correspondence@fda.hhs.gov
`
`Draft: SRM 09/25/2019
`Edit: YMC 09/26/2019; JAC 10/3/2019
`ECMS: Cabinets/CDER_OTS/Study Integrity and
`Surveillance/INSPECTIONS/BE Program/CLINICAL/Syneos Health, Inc.
`(fka inVentiv Health Clinical Research Services), Miami, FL, USA
`
`OSIS File #: BE 8472 (NDA 212640)
`
`FACTS: 11924239
`
`
`
`Reference ID: 4502131Reference ID: 4525554
`
`V. 2.4 Last Revised Date:08-16-2019
`
`Non-Responsive
`
`

`

`Page 4 – Routine inspection of Syneos Health, Inc. (fka inVentiv
`Health Clinical Research Services), Miami, FL.
`
`Attachment 1
`
`Studies not audited but submitted to pending applications
`
`
`Application
`#
`
`Study #
`
`
`
`Study
`Type
`
`Drug Name
`
`Dates of
`conduct
`
`
`
`Reference ID: 4502131Reference ID: 4525554
`
`V. 2.4 Last Revised Date:08-16-2019
`
`Non-Responsive
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`SRIPAL R MADA
`10/04/2019 01:32:21 PM
`
`YOUNG M CHOI
`10/04/2019 01:34:57 PM
`
`JOHN A KADAVIL
`10/04/2019 01:48:35 PM
`
`
`
`Reference ID: 4502131Reference ID: 4525554
`
`

`

`MEMORANDUM
`
`REVIEW OF REVISED LABEL AND LABELING
`
`
`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)
`
`
` Date of This Memorandum:
`
`October 2, 2019
`Requesting Office or Division:
`Division of Neurology Products (DNP)
`Application Type and Number: NDA 212640
`Product Name and Strength:
`Exservan (riluzole) oral film, 50 mg
`Applicant/Sponsor Name:
`Aquestive Therapeutics
`FDA Received Date:
`September 25, 2019
`OSE RCM #:
`2019-339-2
`DMEPA Safety Evaluator:
`Chad Morris, PharmD, MPH
`DMEPA Team Leader (Acting):
`Briana Rider, PharmD, CPPS
`
`PURPOSE OF MEMORANDUM
`1
`
`The Applicant submitted revised container label and carton labeling received on September 25,
`
`
`2019 for Exservan. The Division of Neurology Products (DNP) requested that we review the
`revised container label and carton labeling for Exservan (Appendix A) to determine if they are
`acceptable from a medication error perspective. The revisions are in response to
`
`
`recommendations that we made during a previous label and labeling review.a
`
` CONCLUSION
`2
` The Applicant implemented all of our recommendations, and we have no additional
`recommendations at this time.
`
`
`
`
`
`
`
` a Morris, C. Label and Labeling Review MEMO for Exservan (riluzole) NDA 212640. Silver Spring (MD): FDA, CDER,
`OSE, DMEPA (US); 2019 SEP 06. RCM No.: 2019-339-1.
`
`1
`
`
`
`Reference ID: 4500392Reference ID: 4525554
`
`2 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately
`following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`JOHN C MORRIS
`10/02/2019 11:28:04 AM
`
`BRIANA B RIDER
`10/02/2019 10:50:20 PM
`
`
`
`Reference ID: 4500392Reference ID: 4525554
`
`

`

`MEMORANDUM
`
`REVIEW OF REVISED LABEL AND LABELING
`
`
`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)
`
`
` Date of This Memorandum:
`
`September 6, 2019
`Requesting Office or Division:
`Division of Neurology Products (DNP)
`Application Type and Number: NDA 212640
`Product Name and Strength:
`Exservan (riluzole) oral film, 50 mg
`Applicant/Sponsor Name:
`Aquestive Therapeutics
`FDA Received Date:
`
` August 28, 2019
`OSE RCM #:
`2019-339-1
`DMEPA Safety Evaluator:
`Chad Morris, PharmD, MPH
`DMEPA Team Leader (Acting):
`Briana Rider, PharmD
`
`PURPOSE OF MEMORANDUM
`1
`
`The Applicant submitted revised container label and carton labeling received on August 28,
`
`2019 for Exservan. The Division of Neurology Products (DNP) requested that we review the
`revised container label and carton labeling for Exservan (Appendix A) to determine if they are
`acceptable from a medication error perspective. The revisions are in response to
`
`
`recommendations that we made during a previous label and labeling review.a
`
` CONCLUSION
`2
`
` The revised container label and carton labeling are unacceptable from a medication error
` perspective. We provide recommendations for Aquestive Therapeutics in Section 3.
`
`
`
`
`3 RECOMMENDATIONS FOR AQUESTIVE THERAPEUTICS
` We recommend the following be implemented prior to approval of this NDA:
`
`
`
`a Morris, C. Label and Labeling Review for Exservan (riluzole) NDA 212640. Silver Spring (MD): FDA, CDER, OSE,
`DMEPA (US); 2019 JUL 24. RCM No.: 2019-339.
`
`1
`
`
`
`Reference ID: 4487539Reference ID: 4525554
`
`

`

`Table 1. Identified Issues and Recommendations for Aquestive Therapeutics (entire table to be
`
`conveyed to Applicant)
`RATIONALE FOR CONCERN
`IDENTIFIED ISSUE
`Container Label(s) and Carton Labeling
`The affirmative statement
` Lacks clarity.
`
`
`
`” was
`added to the principal
`
`display panel. However,
`the statement does not
`clearly instruct what should
`be dissolved.
`
` The phrase
`
`RECOMMENDATION
`
`Consider revising the statement
`to read “Place film on top of
`
`tongue until film dissolves” for
`clarity and consistency with the
`instructions on the back panel.
`
`The product does not have a
`.
`
`Remove all references to “
`.”
`
`
`
`Consider relocating the warning
`Prominence can be improved
`“Keep product in foil pouch until
`to reduce the risk for
`
`ready to use” to the principal
`improper storage medication
`display panel.
`errors.
`Prominence can be improved. We recommend you relocate the
`usual dose statement to the
`
`“How to Use” section, similar to
`how it appears on the carton
`labeling.
`
`1.
`
`2.
`
`1.
`
`2.
`
`
`” is
`
`included on the label and
`labeling.
`Container Label
`The warning “Keep product
`in foil pouch until ready to
`use” is located on the back
`panel.
`The usual dose statement
`is not located in the “How
`to Use” section.
`
`1.
`
`Carton Labeling
`The human-readable
`portion of the product
`identifier and the 2D data
`matrix barcode, required
`
`
`under the Drug Supply
`Chain Act (DSCSA), are not
`
`located near each other.
`
` Not in alignment with
`
` recommendations found
`
` within the FDA draft guidance
`on product identifiers b.
`
`
`
`The human-readable product
`
`identifier contains the NDC, serial
`
`number, lot, and expiration date.
`The DSCSA guidance on product
`identifiers recommends the
`format below for the human-
`readable portion of the product
`identifier. The guidance also
`recommends that the human-
`readable portion be located near
`
`
`
` b Guidance for Industry: Product Identifiers Under the Drug Supply Chain Security Act Questions and
` Answers. 2018. Available from
`
`https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM62
`
`1044.pdf
`
`
`
`2
`
`
`
`Reference ID: 4487539Reference ID: 4525554
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Table 1. Identified Issues and Recommendations for Aquestive Therapeutics (entire table to be
`
`conveyed to Applicant)
`IDENTIFIED ISSUE
`
`RATIONALE FOR CONCERN
`
`RECOMMENDATION
`the 2D data matrix barcode.
`
`NDC: [insert product’s NDC]
`SERIAL: [insert product’s serial
`number]
`LOT: [insert product’s lot
`number]
`EXP: [insert product’s expiration
`
`date]
` Readability can be improved. We note, you added the usual
`
`dosage statement to the side and
`back panels. Since the statement
`
`is now on the back panel, it can
`be removed from the side panel.
`
`2.
`
`The usual dosage
`
`
`statement clutters the side
`panel.
`
`
`
`Reference ID: 4487539Reference ID: 4525554
`
`3
`
`2 Page(s) of Draft Labeling have been Withheld in Full as B4 (CCI/TS) immediately following this page
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`JOHN C MORRIS
`09/06/2019 07:51:03 AM
`
`BRIANA B RIDER
`09/06/2019 08:37:39 PM
`
`
`
`Reference ID: 4487539Reference ID: 4525554
`
`

`

`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 24, 2019
`Requesting Office or Division:
`Division of Neurology Products (DNP)
`Application Type and Number: NDA 212640
`Product Name and Strength:
`Exservan (riluzole) oral film, 50 mg
`Product Type:
`Single Ingredient Product
`Rx or OTC:
`Prescription (Rx)
`Applicant/Sponsor Name:
`Aquestive Therapeutics
`FDA Received Date:
`January 31, 2019
`OSE RCM #:
`2019-339
`DMEPA Safety Evaluator:
`Chad Morris, PharmD, MPH
`DMEPA Team Leader (Acting):
`Briana Rider, PharmD
`
`1
`
`
`
`Reference ID: 4466983Reference ID: 4525554
`
`

`

`1 REASON FOR REVIEW
`
`
`As part of the approval process for Exservan (riluzole) oral film, the Division of Neurology
`
`
`Products (DNP) requested that we review the proposed Exservan Prescribing Information
`
`
`(PI), Instructions for Use (IFU), Container label, and Carton labeling for areas of
`vulnerability that may lead to medication errors.
`
`
`2 REGULATORY HISTORY
`
`NDA 212640 is a 505(b)(2), developed under IND 130939. The listed drug product is Rilutek,
`NDA 020599.
`
`3 MATERIALS REVIEWED
`Table 1. Materials Considered for this Label and Labeling Review
`Material Reviewed
`
`
`
`Product Information/Prescribing Information
`Previous DMEPA Reviews
`ISMP Newsletters*
` FDA Adverse Event Reporting System (FAERS)*
`Other
`Labels and Labeling
`N/A=not applicable for this review
`*We do not typically search FAERS for our label and labeling reviews unless we are aware of
`
`
` medication errors through our routine postmarket safety surveillance
`
`Appendix Section
`(for Methods and Results)
`A
`B
`C (N/A)
`D (N/A)
`E (N/A)
`F
`
`FINDINGS AND RECOMMENDATIONS
`4
`We note, clinical manifestations of amyotrophic lateral sclerosis (ALS) may affect the ability of
`
`patients to successfully open the pouch containing the oral film. We discussed this risk with
`
`DNP, and find the benefit of adding this dosage form to the current treatment options in its
`
`
`current packaging outweighs the risk that patients may experience difficulty opening the pouch
`
`
`
`for the following reasons. First, the oral film dosage form may offer advantage over other
`forms of riluzole because patients with ALS may have difficulties swallowing the currently
`
`marketed dosage forms (tablet or oral solution). Next, we anticipate patients with ALS will have
`
`a caregiver to assist with medication administration, which will help to mitigate the risk
`associated with a patient’s difficulty opening the pouch. Lastly, if prescribers determine the
`
`
`
`patient’s disease state limitations preclude them from using the proposed product, then the
`tablets and oral solution may be safe and effective alternatives.
`Tables 2 and 3 below include the identified medication error issues with the submitted
`
`Prescribing Information (PI), Instructions for Use (IFU), Container label, and Carton labeling, our
`
`2
`
`
`
`
`Reference ID: 4466983Reference ID: 4525554
`
`

`

`
`
` rationale for concern, and the proposed recommendation to minimize the risk for medication
`error.
`
`Table 2. Identified Issues and Recommendations for Division of Neurology Products (DNP)
`
`RATIONALE FOR CONCERN
`IDENTIFIED ISSUE
`RECOMMENDATION
`Instructions for Use
`1.
`The orientation and format
`of the expiration date as
`
`presented in Step 1 are
`inconsistent with the
`proposed pouch label.
`The images are not labeled.
`
`Can be improved for clarity.
`
`2.
`
`Inconsistent with current
`practice.
`
`
` We recommend all images of the
`
` packaging/labeling in the IFU are
`
` consistent with the commercial
`presentation.
`
`We recommend you label each
`
`image as Figure 1, 2, etc. and
`refer to that image with a
`statement such as “see Figure” in
`the respective sentence.
`
`RECOMMENDATION
`
`Table 3. Identified Issues and Recommendations for Aquestive Therapeutics (entire table to be
`
`conveyed to Applicant)
`RATIONALE FOR CONCERN
`IDENTIFIED ISSUE
`Container Label(s) and Carton Labeling
`
`1.
` There is a warning
`Post-marketing reports
`
`containing a negative
`suggest negative statements
`
`
`
`
`statement (that is,
`may be misinterpreted as an
`
`
`) on the
`affirmative action.
`
`principal display panel
`
`(PDP) of the carton
`labeling.
`The usual dose statement
`is not present.
`
`
`
`
`
` We recommend you revise the
`negative statement “
`” to an affirmative
`statement. We recommend the
`revised statement should also be
`placed on the PDP of the
`container label.
`We recommend you add the
`
`statement “Recommended
`Dosage: See prescribing
`information” to the side panel of
`the carton labeling and the back
`
`panel of the foil pouch.
`Ensure the linear barcodes are
`
`surrounded by sufficient white
`space.
`
`2.
`
`Not in alignment with 21 CFR
`201.55.
`
`3.
`
` There may not be sufficient
`
`
` white space surrounding
`the linear barcodes.
`
`
`
`Specifically, the proprietary
`and established names are
`close to the linear barcode
`
`The barcode should be
`
`surrounded by sufficient white
`space to allow scanners to
`
`correctly read the barcode in
`
`accordance with 21 CFR
`201.25(c)(i).
`
`3
`
`
`
`Reference ID: 4466983Reference ID: 4525554
`
`(b) (4)
`
`(b) (4)
`
`

`

`RATIONALE FOR CONCERN
`
`RECOMMENDATION
`
`Table 3. Identified Issues and Recommendations for Aquestive Therapeutics (entire table to be
`
`conveyed to Applicant)
`IDENTIFIED ISSUE
`on the carton labeling.
`Similarly, the black area for
`
`the lot/exp date is close to
`the linear barcode on the
`container label.
`Container Label(s)
`1.
`The "Rx only" and net
`quantity statements are
`
`more prominent than the
`established name.
`
`Not in alignment with our
`draft guidancea.
`
` Ensure the proprietary name,
`
` established name, and strength
`
`are the most prominent
`information on the container
`
`label. Consider decreasing the
`
`
`prominence of the "Rx only" and
`net quantity statements as this
`information appears more
`prominent than the established
`name.
`
` Ensure the barcode on the pouch
`
` contains the required
`information per 21CFR
`
`201.25(c)(2).
`
`2.
`
`
`
` It is unclear if the barcode
`
` contains the required
`information to correctly
`identify the product in
`
`settings where individual
`pouches may be dispensed
`(for example, hospitals).
`
` The drug barcode is often
`
`used as an additional
`verification before drug
`
`
`administration in the hospital
`setting; therefore, it is an
`important safety feature that
`
`should be part of the label
`whenever possible.
`Can be improved for clarity.
`
`3.
`
` The numbers in the “TO
`
`OPEN:” statement do not
`make it immediately clear
`that the pouch is to be torn
`open with the pouch
`folded.
`Carton Labeling
`1.
`The net quantity statement Not in alignment with our
`
`We recommend revising the
`
`statement to read: “Fold along
`the solid line and tear down at
`the slit along the arrow.”
`
`Revise the net quantity
`
`a Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize
`Medication Errors. Food and Drug Administration. 2013. Available from
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM349009.pdf
`
`4
`
`
`
`
`Reference ID: 4466983Reference ID: 4525554
`
`

`

`Table 3. Identified Issues and Recommendations for Aquestive Therapeutics (entire table to be
`
`conveyed to Applicant)
`IDENTIFIED ISSUE
`does not contain the
`package type.
`
`RECOMMENDATION
`statement to include the package
`type. Consider revising to read:
`“60 pouches each containing 1
`
`oral film”, or a similar statement.
`
`RATIONALE FOR CONCERN
`draft guidanceb. It is important
`
` to include the package type on
`
` the carton labeling in
`situations where it is unclear
`
`how the medication should be
`safely handled and used
`
`simply by viewing the
`container.
`
` The SN is required on the
`
` smallest saleable unit in
`accordance with the Drug
`Supply Chain Security Act
`(DSCSA)c.
`
`2.
`
`It is unclear if the serial
`number (SN) is represented
`
`by the number
`”
`positioned below the 2D
`data matrix barcode.
`
` Please clarify what the number
`
`“
`” represents. If it is not a
`placeholder for the SN, then we
`recommend you identify a
`
`placeholder for the SN in
`accordance with the DSCSA.
`
` CONCLUSION
`5
`
`Our evaluation of the proposed Exservan Prescribing Information (PI), Instructions for Use (IFU),
`
`Container label, and Carton labeling identified areas of vulnerability that may lead to
`medication errors. Above, we have provided recommendations in Table 2 for the Division and
`
`
`Table 3 for the Applicant. We ask that the Division convey Table 3 in its entirety to Aquestive
`Therapeutics so that recommendations are implemented prior to approval of this NDA.
`
` b Guidance for Industry: Safety Considerations for Container Labels and Carton Labeling Design to Minimize
`
`Medication Errors. Food and Drug Administration. 2013. Available from
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM349009.pdf
`
`c Guidance for Industry: Product Identifiers Under the Drug Supply Chain Security Act Questions and Answers.
`2018. Available from
`https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM621044.pdf
`
`5
`
`
`
`
`Reference ID: 4466983Reference ID: 4525554
`
`(b) (4)
`
`(b) (4)
`
`

`

`APPENDICES: METHODS & RESULTS FOR EACH MATERIAL REVIEWED
`APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION
`
`Table 4 presents relevant product information for Exservan that Aquestive Therapeutics
`
`submitted on January 31, 2019, and the listed drug (LD).
` Table 4. Relevant Product Information for L