CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`210455Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`****Pre-decisional Agency Information****
`
`
`
`
`Memorandum
`
`Date:
`May 31, 2018
`
`
`To:
`
`
`
`
`From:
`
`
`
`CC:
`
`Subject:
`
`Myung-Joo Patricia Hong, Regulatory Project Manager
`Division of Antiviral Products (DAVP)
`
`Wendy Lubarsky, Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`Sam Skariah, Team Leader, OPDP
`
`OPDP Labeling Comments for SYMTUZA™ (darunavir, emtricitabine, and
`tenofovir alafenamide) tablets, for oral use
`
`
`NDA:
`
`
`
`In response to DAVP consult request dated September 25, 2017, OPDP has reviewed the
`proposed product labeling (PI), patient package insert (PPI), and carton and container labeling
`for the original NDA submission for SYMTUZA™ (darunavir, emtricitabine, and tenofovir
`alafenamide) tablets, for oral use (Symtuza).
`
`PI and PPI: OPDP’s comments on the proposed labeling are based on the draft PI and PPI
`received by electronic mail from DAVP (Myung-Joo Patricia Hong) on May 17, 2018, and are
`provided below.
`
`210455
`
` A
`
` combined OPDP and Division of Medical Policy Programs (DMPP) review was completed,
`and comments on the proposed PPI were sent under separate cover on May 31, 2018.
`
`Carton and Container Labeling: OPDP has reviewed the attached proposed carton and
`container labeling received by electronic mail from DAVP (Myung-Joo Patricia Hong) on May
`30, 2018, and we have no comments at this time.
`
`Thank you for your consult. If you have any questions, please contact Wendy Lubarsky at
`(240) 402-7721 or wendy.lubarsky@fda.hhs.gov .
`
`
`
`
`Reference ID: 4271034
`
`1
`
`49 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`WENDY R LUBARSKY
`05/31/2018
`
`Reference ID: 4271034
`
`

`

`
`Date:
`
`To:
`
`
`Through:
`
`From:
`
`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
`
`
`
`May 30, 2018
`
`Debra Birnkrant, MD
`Director
`Division of Antiviral Products (DAVP)
`
`LaShawn Griffiths, MSHS-PH, BSN, RN
`Associate Director for Patient Labeling
`Division of Medical Policy Programs (DMPP)
`
`Morgan Walker, PharmD, MBA, CPH
`Senior Patient Labeling Reviewer
`Division of Medical Policy Programs (DMPP)
`
`Wendy Lubarsky, PharmD
`Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`
`Subject:
`
`Review of Patient Labeling: Patient Package Insert (PPI)
`
`
`Drug Name (established
`name):
`
`SYMTUZA (darunavir, cobicistat, emtricitabine, and
`tenofovir alafenamide)
`
`
`Dosage Form and
`Route:
`
`Application
`Type/Number:
`
`tablets, for oral use
`
`210455
`
`Applicant:
`
`Jassen Products, LP
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4270589
`
`
`
`
`
`

`

`INTRODUCTION
`
`
`
`
`
` 1
`
`
`
`On September 22, 2017, Jassen Products, LP submitted for the Agency’s review an
`original New Drug Application (NDA) 210455 for SYMTUZA (darunavir,
`cobicistat, emtricitabine, and tenofovir alafenamide) tablets. The proposed indication
`is for the treatment of HIV-1 infection in adults and pediatric patients 12 years of age
`and older.
`
`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 Antiviral Products (DAVP) on September 25, 2017 for
`DMPP and OPDP to review the Applicant’s proposed Patient Package Insert (PPI)
`for SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir alafenamide)
`tablets.
`
` 2
`
` MATERIAL REVIEWED
` Draft SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir
`alafenamide) tablets PPI received on September 22, 2017, and received by DMPP
`and OPDP on May 17, 2018.
` Draft SYMTUZA (darunavir, cobicistat, emtricitabine, and tenofovir
`alafenamide) tablets Prescribing Information (PI) received on September 22,
`2017, revised by the Review Division throughout the review cycle, and received
`by DMPP and OPDP on May 17, 2018.
`
`
`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.
`
`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.
`
`In our collaborative review of the PPI we:
`
`
`
`
`simplified wording and clarified concepts where possible
`
`ensured that the PPI is consistent with the Prescribing Information (PI)
`
`removed unnecessary or redundant information
`
`
`
`
`
`
`
`Reference ID: 4270589
`
`

`

`
`
`ensured that the PPI is free of promotional language or suggested revisions to
`ensure that it is free of promotional language
`
`
`
`ensured that the PPI meets the criteria as specified in FDA’s Guidance for
`Useful Written Consumer Medication Information (published July 2006)
`4 CONCLUSIONS
`The PPI 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 PPI is appended to this memorandum. Consult
`DMPP and OPDP regarding any additional revisions made to the PI to determine
`if corresponding revisions need to be made to the PPI.
`
` Please let us know if you have any questions.
`
`
`
`
`
`
`
`Reference ID: 4270589
`
`7 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MORGAN A WALKER
`05/30/2018
`
`WENDY R LUBARSKY
`05/31/2018
`
`LASHAWN M GRIFFITHS
`05/31/2018
`
`Reference ID: 4270589
`
`

`

`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:
`March 5, 2018
`Requesting Office or Division:
`Division of Antiviral Products (DAVP)
`Application Type and Number: NDA 210455
`Product Name and Strength:
`Symtuza (darunavir, cobicistat, emtricitabine, and tenofovir
`alafenamide) Tablet, 800 mg/150 mg/200 mg/10 mg
`Multi-ingredient Product
`Rx
`Janssen Research & Development, LLC.
`September 22, 2017 and October 23, 2017
`2017-1955
`Valerie S. Wilson, PharmD
`Otto L. Townsend, PharmD
`
`Product Type:
`Rx or OTC:
`Applicant/Sponsor Name:
`Submission Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`Reference ID: 4229610
`
`1
`
`

`

`1 PURPOSE OF REVIEW
`As part of the approval process for Symtuza (darunavir, cobicistat, emtricitabine, and
`tenofovir alafenamide) 800mg/150 mg/200 mg/10 mg tablet, the Division of Antiviral
`Products (DAVP) requested that we review the proposed labels and labeling for areas that
`may lead to medication errors.
`
`2 MATERIALS REVIEWED
`
`Table 1. Materials Considered for this Label and Labeling Review
`Appendix Section
`Material Reviewed
`(for Methods and Results)
`A
`B (N/A)
`C (N/A)
`D (N/A)
`E (N/A)
`F
`
`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
`
`FINDINGS AND RECOMMENDATIONS
`3
`Table 2 below includes identified medication error issues with the submitted Prescribing
`Information, DMEPA’s rationale for concern, and the proposed recommendations to minimize
`the risk for medication error for DAVP’s consideration. Table 3 includes an identified
`medication error issue with the submitted container label, along with a general comment about
`the container label, DMEPA’s rationale for concern, and recommendations to the Applicant to
`minimize the risk for medication error.
`
`Reference ID: 4229610
`
`2
`
`

`

`Table 2: Identified Issues and Recommendations for Division of Antiviral Products
`Prescribing Information
`IDENTIFIED ISSUE
`
`RECOMMENDATION
`
`RATIONALE FOR
`CONCERN
`
`Full Prescribing Information (FPI)
`1. We note the unit of
`measurement of
`temperature (i.e. °C and
`°F) does not follow each
`numerical expression
`within the storage
`statement in Section 16
`of the FPI. The format
`also does not align with
`the format used in the
`Patient Package Insert or
`container label.
`2. We note important
`storage information such
`as, “Keep Symtuza in the
`original container” and
`“Keep the bottle tightly
`closed” is missing from
`the Patient Package
`Insert (PPI).
`
`The acceptable storage
`temperature could be
`misinterpreted and
`pose a risk for
`improper storage,
`which could affect the
`integrity of the tablets.
`
`To mitigate possible storage errors
`and to promote alignment across
`the label and labeling, we
`recommend the storage statement
`is revised to read:
`“Store at 20°C-25°C (68°F-77°F);
`with excursions permitted to 15°C-
`30°C (59°F-86°F).”
`
`This missing
`information poses a
`risk for improper
`storage of Symtuza by
`patients, which could
`affect the integrity of
`the tablet.
`
`We recommend additional storage
`instructions, for example, “Keep
`Symtuza in the original container”
`and “Keep the bottle tightly
`closed” be included in the PPI. We
`defer to the Patient Labeling Team
`to determine the appropriate
`language to use to convey the
`additional storage instructions.
`
`Reference ID: 4229610
`
`3
`
`

`

`Table 3: Identified Issues and Recommendations for Janssen Research & Development, LLC
`(***entire table to be conveyed to Applicant***)
`
`Container Labels
`IDENTIFIED ISSUE
`
`1. The storage statement
`includes instruction to
`
`
`
`”
`
`which does not align
`with the storage
`statement, “Dispense
`only in original
`container,” located in the
`Full Prescribing
`Information.
`2. We note the inclusion of
`
`
`
`
`
`
`
`
`
`RATIONALE FOR
`CONCERN
`Discrepancy between
`the storage statements
`could result in
`dispensing or storage
`errors which may
`affect the quality of
`the product.
`
`RECOMMENDATION
`
`For consistency and to mitigate
`possible dispensing or storage
`errors, we recommend you ensure
`the storage statement on the
`container label aligns with the
`storage statement in the
`Prescribing Information.
`
`We recommend you revise the
`establish name to read:
`“Symtuza
`(darunavir, cobicistat,
`emtricitabine, and tenofovir
`alafenamide) tablets
`800 mg/ 150 mg/ 200 mg/ 10 mg”
`
`CONCLUSION
`4
`DMEPA’s evaluation of the proposed label and labeling identified areas of vulnerability that
`may lead to medication errors. We have provided recommendations in Table 3 above and ask
`that the Division conveys the entire table to the Applicant so that recommendations are
`implemented prior to approval of this NDA.
`
`Reference ID: 4229610
`
`4
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`APPENDICES: METHODS & RESULTS FOR EACH MATERIALS REVIEWED
`APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION
`Table 4 presents relevant product information for Symtuza that Janssen Research &
`Development, LLC submitted on October 23, 2017.
`
`Table 4. Relevant Product Information for Symtuza
`N/A
`Initial Approval Date
`Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
`Active Ingredient
`A complete regimen for the treatment of HIV-1 infection in
`Indication
`adults and pediatric patients 12 years of age and older
`
`
`
`Route of Administration Oral
`Tablet
`Dosage Form
`800 mg/150 mg/200 mg/10 mg
`Strength
`1 tablet once daily with food
`Dose and Frequency
`Bottles of 30 tablets
`How Supplied
`Store at 20-25°C (between 68-77°F); with excursions permitted
`Storage
`to 15-30°C (59-86°F).
`Keep container tightly closed.
`Dispense only in original container.
`Bottle with child-resistant closure.
`
`Container Closure
`System
`
`Reference ID: 4229610
`
`5
`
`(b) (4)
`
`

`

`APPENDIX F. LABELS AND LABELING
`
`F.1
`
`List of Labels and Labeling Reviewed
`
`Using the principles of human factors and Failure Mode and Effects Analysis,a along with
`
`postmarket medication error data, we reviewed the following Symtuza labels and labeling
`
`submitted by Janssen Research & Development, LLC on September 22, 2017.
`
`Container label
`
`Professional Sample Container Label
`
`0
`
`Prescribing Information (Image not shown)
`
`F.2
`
`Label and Labeling Images
`
`
`
`" Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.
`
`Reference ID: 4229610
`
`

`

`
`
`Reference ID: 4229610
`Reference ID: 4229610
`
`7
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`VALERIE S WILSON
`03/05/2018
`
`OTTO L TOWNSEND
`03/05/2018
`
`Reference ID: 4229610
`
`