CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`214187Orig1s000
`
`
`OTHER REVIEW(S)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`Division of Antivirals
`
`REGULATORY PROJECT MANAGER LABELING REVIEW
`
`
`
`Applications:
`NDA 214187
`NDA 208341/S-17
`
`
`Name of Drug:
`
`Epclusa (sofosbuvir and velpatasvir), tablets, 400 mg/100 mg and 200 mg/50 mg
`
`Epclusa (sofosbuvir and velpatasvir), oral pellets, 200 mg/50 mg and 150 mg/37.5 mg
`
`
`Applicant: Gilead Sciences, Inc.
`
`
`Labeling Reviewed
`
`
`Submission Dates: Prescribing Information (PI) (May 7, 2021)
`
`
` Patient Package Insert (PPI) (May 17, 2021)
`
`
` Instructions for Use (IFU), oral pellet only (May 17, 2021)
`
`Background and Summary Description:
`
`On December 15, 2020, Gilead Sciences, Inc., submitted original NDA 214187, for Epclusa
`(sofosbuvir and velpatasvir) oral pellets and an efficacy supplement, NDA 208341/S-17, for
`Epclusa (sofosbuvir and velpatasvir) tablets that proposed updating the labeling with dosing
`recommendations for the Epclusa pellets in patients 3 years and older. The submissions included
`data from study GS-US-342-1143, “A Phase 2, Open-Label, Multicenter, Multi-cohort Study to
`Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir in Adolescents and Children with
`Chronic HCV Infection”, cohort 3, which enrolled patients 3 to less than 6 years of age. In
`addition, the sponsor conducted a BE/BA study that showed the pellets are bioequivalent to the
`tablet formulation. The submissions were submitted to fulfill the requirements of the Written
`Request. In addition, the submissions were submitted to fulfill the following PREA PMR that
`was included in the June 28, 2016 Approval letter for NDA 208341/0:
`
`3092-2
`
`Conduct a study to evaluate the pharmacokinetics, safety and treatment response
`(using sustained virologic response) of sofosbuvir and velpatasvir in pediatric
`subjects 3 through less than 12 years of age with chronic hepatitis C virus
`infection.
`
`
`
`
`
`
`Reference ID: 4805993
`
`1
`
`

`

`
`Review
`
`
`For the purposes of this review, the last approved PI and PPI (NDA 208341/S-15, approved on
`July 14, 2020) was compared to the draft PI received on May 7, 2021, and the draft PPI received
`on May 17, 2021.
`
`GLOBAL EDITORIAL CHANGES
`• Minor editorial and formatting revisions were made throughout the PI and PPI.
`• Subsections were renumbered throughout the PI as an additional subsection was added to
`the label.
`• Revised date will be updated to reflect Month and Year the action is taken in the PI and
`PPI.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`PRODUCT TITLE
`• New dosage form was added
`
`RECENT MAJOR CHANGES
`The following sections were added under this heading
`Indications and Usage
`•
`• Dosage and Administration
`o Recommended Treatment Regimen and Duration in Patients 3 years of Age and
`Older (2.2).
`o Recommended Dosage in Pediatric Patients 3 Years of Age and Older (2.4)
`o Preparation and Administration of Oral Pellets (2.5).
`
`INDICATIONS AND USAGE
`• Expanded the patient population to include pediatric patients 3 years of age and removed
`the minimum patient weight requirement of 17 kg.
`
`
`DOSAGE AND ADMINISTRATION
`• Updated subsections 2.2, 2.3, and 2.4 with Epclusa oral pellets dosing information for
`patients 3 years of age and older and removed the minimum weight requirement of 17 kg.
`• Added new subsection, 2.5 “Preparation and Administration of Oral Pellets”.
`
`
`DOSAGE FORMS AND STRENGTHS
`• Added information for Epclusa oral pellets: 200mg of sofosbuvir and 50 mg of
`velpatasvir; 150 mg of sofosbuvir and 37.5 mg of velpatasvir.
`
`
`ADVERSE REACTIONS
`• Adverse reactions updated to list the adverse reactions specific to the age group in which
`they were observed.
`
`
`
`Reference ID: 4805993
`
`2
`
`

`

`o Adverse reaction listed for adults and pediatric subjects 6 years of age and older
`as headache and fatigue
`o The most common adverse reactions in pediatric subjects less than 6 years of age
`has been added and listed as vomiting and product use issue (spitting up the drug)
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`DOSAGE AND ADMINISTRATION
`• Updated subsection 2.2 to remove the minimum weight limit for the patient and to update
`the minimum patient age to 3 years of age
`• Updated subsection 2.4 to revise the minimum pediatric patient age from 6 to 3 years of
`age.
`• Added subsection 2.5: Preparation and Administration of Oral Pellets
`
`
`CLINICAL STUDIES
`• Specified the subjects for the clinical trial summarized in subsection 14.5 were adults.
`
`
`FULL PRESCRIBING INFORMATION (FPI)
`
` 1
`
` 2
`
`
`
` INDICATIONS AND USAGE
`• Revised the minimum patient age from 6 to 3 years of age.
`• Removed the minimum patient body weight requirement.
`
` DOSAGE AND ADMINISTRATION
`• 2.2 Recommended Treatment Regimen and Duration in Patients 3 Years of Age and
`Older
`o Revised the minimum patient age from 6 to 3 years of age.
`o Removed the requirement of a minimum patient body weight.
`o Updated Table 1 to capture the above two revisions (e.g., age and body weight).
`
`• 2.4 Recommended Dosage in Pediatric Patients 3 Years of Age and Older
`o Revised the minimum patient age from 6 to 3 years of age.
`o Removed the requirement of a minimum patient body weight.
`o Specified that in pediatric patients less than 6 years of age, to administer the oral
`pellets with food to increase the tolerability related to palatability.
`o Two columns added to Table 2 to
` specify the EPCLUSA daily dose, and
`list dosing via the oral pellet.
`
`• Addition of subsection 2.5, entitled, “Preparation and Administration of Oral Pellets”.
`
` 3
`
` 6
`
`
`
` DOSAGE FORMS AND STRENGTHS
`• Added information for the Epclusa, oral pellets
`
` ADVERSE REACTIONS
`• 6.1 Clinical Trials Experience
`
`3
`
`Reference ID: 4805993
`
`

`

`o Adverse Reactions in Pediatric Subjects
` Added adverse reaction data for pediatric subjects 3 to less than 6 years of
`age.
`
`
`8 USE IN SPECIFIC POPULATIONS
`• 8.4 Pediatric use
`o Updated with data from pediatric patients 3 years of age and older, with no
`minimum weight limit.
`
`11 DESCRIPTION
`• Added header for the description of Epclusa tablets.
`• Added a new header and section describing the Epclusa pellet.
`
`
`12 CLINICAL PHARMACOLOGY
`• 12.3 Pharmacokinetics
`o Under Specific Populations: Pediatric Patients subsection, added the PK data
`from patients 3 to 6 years of age and older.
`• 12.4 Microbiology
`o Under the Pediatric subsection, added data from patients 3 to less than 6 years of
`age.
`
`
`14 CLINICAL STUDIES
`• 14.1 Description of Clinical Trials
`o Updated Table 12 to include information from the trial (NCT03022981) in
`pediatric subjects 3 to less than 6 years of age.
`o Added a footnote to Table 12 to define treatment-experience (TE) subjects as
`those who have failed an interferon-based regimen with or without ribavirin and
`with or without an HCV protease inhibitor (boceprevir, simeprevir, or telaprevir).
`• 14.7 Clinical Trials in Pediatric Subjects
`o Updated to include data from pediatric subjects 3 to less than 6 years of age.
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`o Added a header to identify the tablet specific information.
`o Added a new section to provide for the supplied/storage and handling information for the
`new oral pellet formulation.
`
`
`17 PATIENT COUNSELLING INFORMATION
`o Added new text to refer the patient to the new Instructions for Use, which is a new
`component of the FDA-approved patient labeling.
`
`PATIENT INFORMATION
`• Updated header to add the oral pellets.
`• Under the description, “What is EPCLUSA”, updated to provide for information
`regarding the oral pellet.
`o The minimum patient age has been revised from 6 years to 3 years of age.
`
`
`
`Reference ID: 4805993
`
`4
`
`

`

`o The lower weight limit of 17kg has been removed.
`o Added a statement to note that Epclusa contains both sofosbuvir and velpatasvir.
`• Under the description, “How should I take EPCLUSA,” updated to provide information
`regarding the oral pellet and revised patient population,
`o Added oral pellet as a formulation that can be taken by mouth.
`o The minimum patient age has been revised from 6 to 3 years of age.
`o An additional statement advising the patient to tell their healthcare provider if
`their child has problems with swallowing tablets.
`o Added reference to the new section to, “How should I give EPCLUSA oral pellets
`to my child?”
`• Added a new section to provide information on how the EPCLUSA oral pellets should be
`given to a child.
`• Updated the Possible Side Effects section to include the new data in children 3 to less
`than 6 years of age.
`o The already listed side effects are specified to be for adults and children 6 years
`an older.
`o Added the side effects for children younger than 6 years of age.
`• Storage of EPCLUSA has been updated to list the storage information for Oral Pellets
`o The oral pellets are stored in cartons and packets, and directions have been added
`to not use EPCLUSA if the carton-tamper evident seal or the packet has been
`opened or damaged.
`• Added the ingredients for the Oral Pellet.
`
`
`Recommendations
`
`
`The changes as proposed in the original NDA 214187 and supplemental NDA 208341/S-17 for
`Epclusa are acceptable and an approval letter will be sent. Please refer to the CDTL, division
`director, clinical, clinical pharmacology, clinical virology, CMC, DMEPA, OPDP, DMPP
`reviews for further information.
`
`
`
`
`
`
`
`
`
`Talia Lindheimer, 06/03/2021
`Regulatory Project Manager
`
`Karen Winestock, 6/3/2021
`Chief, Project Management Staff
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Date
`
`Date
`
`
`
`Reference ID: 4805993
`
`5
`
`49 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/
`------------------------------------------------------------
`
`TALIA A LINDHEIMER
`06/03/2021 05:05:34 PM
`
`KAREN D WINESTOCK
`06/06/2021 10:21:49 PM
`
`Reference ID: 4805993
`
`

`

`
`Date:
`
`To:
`
`
`Through:
`
`
`From:
`
`Subject:
`
`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 11, 2021
`
`Talia Lindheimer
`Regulatory Project Manager
`Division of Antivirals (DAV)
`
`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)
`Nima Ossareh, PharmD
`Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`Review of Patient Labeling: Patient Package Insert (PPI)
`and Instructions for Use (IFU)
`
`EPCLUSA (sofosbuvir and velpastavir)
`
`tablets, for oral use, NDA 208341/S-017
`oral pellets, for oral use, NDA 214187
`
`Drug Name (established
`name):
`Dosage Form and
`Route, Application
`Type/Number,
`Supplement Number:
`Applicant:
`
`Gilead Sciences, Inc.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4793618
`
`

`

`INTRODUCTION
`On December 14, 2020, Gilead Sciences, Inc. submitted for the Agency’s review an
`original New Drug Application (NDA) 214187 for EPCLUSA (sofosbuvir and
`velpatasvir) oral pellets. The Applicant also submitted a Prior Approval Supplement
`(PAS) to their NDA 208341/S-017 for EPCLUSA (sofosbuvir and velpatasvir)
`tablets. The purpose of the original NDA and PAS is in support of proposed labeling
`changes to the Prescribing Information (PI) to include a new formulation, oral
`pellets, for use in the treatment of hepatitis C virus (HCV) infection in pediatric
`patients. Both NDAs will share the same PI and Patient Package Insert.
`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 Antivirals (DAV) on December 18, 2020 for DMPP and
`OPDP to review the Applicant’s proposed Patient Package Insert (PPI) and
`Instructions for Use (IFU) for EPCLUSA (sofosbuvir and velpastavir) tablets and
`EPCLUSA (sofosbuvir and velpastavir) oral pellets.
`DMPP conferred with the Division of Medication Error, Prevention, and Analysis
`(DMEPA) and a separate DMEPA review of the IFU will be forthcoming.
`
` MATERIAL REVIEWED
`• Draft EPCLUSA (sofosbuvir and velpastavir) tablets and EPCLUSA (sofosbuvir
`and velpastavir) oral pellets PPI and IFU received on December 14, 2020, and
`received by DMPP and OPDP on April 28, 2021.
`• Draft EPCLUSA (sofosbuvir and velpastavir) tablets and EPCLUSA (sofosbuvir
`and velpastavir) oral pellets PI received on December 14, 2020, revised by the
`Review Division throughout the review cycle, and received by DMPP and OPDP
`on April 28, 2021.
`
`1
`
` 2
`
`
`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 and IFU we:
`simplified wording and clarified concepts where possible
`•
`•
`ensured that the PPI and IFU are consistent with the Prescribing Information
`(PI)
`
`
`
`
`
`
`
`Reference ID: 4793618
`
`

`

`•
`•
`
`•
`
`removed unnecessary or redundant information
`ensured that the PPI and IFU are free of promotional language or suggested
`revisions to ensure that it is free of promotional language
`ensured that the PPI and IFU meet the criteria as specified in FDA’s Guidance
`for Useful Written Consumer Medication Information (published July 2006)
`
`
`4 CONCLUSIONS
`The PPI and IFU are acceptable with our recommended changes.
`
` 5
`
` RECOMMENDATIONS
`• Please send these comments to the Applicant and copy DMPP and OPDP on the
`correspondence.
`• Our collaborative review of the PPI and IFU is appended to this memorandum.
`Consult DMPP and OPDP regarding any additional revisions made to the PI to
`determine if corresponding revisions need to be made to the PPI and IFU.
` Please let us know if you have any questions.
`
`
`
`
`
`
`
`Reference ID: 4793618
`
`12 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/
`------------------------------------------------------------
`
`MORGAN A WALKER
`05/11/2021 04:30:36 PM
`
`NIMA OSSAREH
`05/11/2021 07:29:15 PM
`
`Reference ID: 4793618
`
`

`

`FOOD AND DRUG ADMINISTRATION
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`****Pre-decisional Agency Information****
`
`
`
`
`Memorandum
`
`Date:
`5/10/2021
`
`
`To:
`
`
`
`
`Talia Lindheimer
`Regulatory Project Manager
`Division of Regulatory Operations for Infectious Disease
`
`Nima Ossareh, Regulatory Review Officer
`Office of Prescription Drug Promotion (OPDP)
`
`Sam Skariah, Team Leader, OPDP
`
`From:
`
`
`
`CC:
`
`Subject:
`
`
`
`
`OPDP Labeling Comments for EPCLUSA (sofosbuvir and velpatasvir)
`tablets, for oral use; EPCLUSA® (sofosbuvir and velpatasvir) oral pellets
`
`208341/S-17; 214187
`
`
`NDA:
`
`
`
`In response to DAVP consult request dated December 18, 2020, OPDP has reviewed the
`proposed product labeling (PI) and patient package insert (PPI) for EPCLUSA (sofosbuvir and
`velpatasvir) tablets, for oral use and EPCLUSA® (sofosbuvir and velpatasvir) oral pellets.
`
`PI: OPDP’s comments on the proposed labeling are based on the draft PI and PPI received by
`electronic mail from Division of Antiviral Products (DAVP) on April 28, 2021 and are provided
`below.
`
`PPI, IFU: A combined OPDP and Division of Medical Policy Programs (DMPP) review of the
`PPI will be completed under a separate cover.
`
`Thank you for your consult. If you have any questions, please contact Nima Ossareh at (240)
`402-2769 or nima.ossareh@fda.hhs.gov.
`
`
`
`
`
`
`Reference ID: 4793215
`
`1
`
`50 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/
`------------------------------------------------------------
`
`NIMA OSSAREH
`05/10/2021 03:34:26 PM
`
`Reference ID: 4793215
`
`

`

`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:
`April 14, 2021
`Requesting Office or Division:
`Division of Antivirals (DAV)
`Application Type and Number: NDA 214187
`NDA 208341/S-17
`
`Product Name and Strength:
`
`Epclusa (sofosbuvir and velpatasvir) oral pellets,
`150 mg/37.5 mg and 200 mg/50 mg
`Epclusa (sofosbuvir and velpatasvir) tablets,
`200 mg/50 mg and 400 mg/100 mg
`
`Applicant/Sponsor Name:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`Gilead Science
`2020-2642-1
`Melina Fanari, RPh
`Sevan Kolejian, PharmD, MBA, BCPPS
`
`PURPOSE OF MEMORANDUM
`1
`The Applicant submitted revised container labels and carton labeling received on April 7, 2021
`for Epclusa. The Division of Antivirals (DAV) requested that we review the revised Instruction
`for Use (IFU), container labels and carton labeling for Epclusa (Appendix A) to determine if it is
`acceptable from a medication error perspective. The revisions are in response to
`recommendations that we made during a previous label and labeling review.a
`2
` CONCLUSION
`The Applicant implemented all of our recommendations and we have no additional
`recommendations at this time.
`
`a Fanari, Melina Label and Labeling Review for Epclusa (NDA 214187 and NDA 208341/S-17), Silver Spring (MD):
`FDA, CDER, OSE, DMEPA (US); 2021 Mar 26. RCM No.: 2020-2642.
`1
`
`Reference ID: 4778941
`
`1 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/
`------------------------------------------------------------
`
`MELINA N FANARI
`04/14/2021 10:02:39 AM
`
`SEVAN H KOLEJIAN
`04/14/2021 10:22:45 AM
`
`Reference ID: 4778941
`
`

`

`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 26, 2021
`Requesting Office or Division:
`Division of Antivirals (DAV)
`Application Type and Number: NDA 214187
`NDA 208341/S-17
`Epclusa (sofosbuvir and velpatasvir) oral pellets,
`150 mg/37.5 mg and 200 mg/50 mg
`Epclusa (sofosbuvir and velpatasvir) tablets,
`200 mg/50 mg and 400 mg/100 mg
`
`Product Name and Strength:
`
`Product Type:
`Rx or OTC:
`Applicant/Sponsor Name:
`FDA Received Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`Multi-Ingredient Product
`Prescription (Rx)
`Gilead Science
`December 15, 2020
`2020-2642
`Melina Fanari, RPh
`Sevan Kolejian, PharmD, MBA, BCPPS
`
`1
`
`Reference ID: 4768714
`
`

`

`REASON FOR REVIEW
`1
`As part of the approval process for Epclusa (sofosbuvir and velpatasvir) oral pellets (NDA
`214187) and 208341/S-17, the Division of Antivirals (DAV) requested that we review the
`proposed Epclusa prescribing information (PI), patient prescribing information (PPI),
`instruction for use (IFU), container labels, and carton labeling for areas of vulnerability that
`may lead to medication errors.
`
`BACKGROUND
`2
`Epclusa tablet was approved June 28, 2016 (NDA 208341). Gilead has submitted a new NDA
`(214187) for an oral pellet formulation in addition to an efficacy supplement (NDA 208341/S-
`17) to revise the minimum patient age in labeling from 6 years to 3 years.
`
`3 MATERIALS REVIEWED
`Table 1. Materials Considered for this Label and Labeling Review
`Appendix Section
`Material Reviewed
`(for Methods and Results)
`
`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 or ISMP Newsletters for our label and labeling
`reviews unless we are aware of medication errors through our routine postmarket
`safety surveillance
`
`A
`B
`C-N/A
`D-N/A
`E-N/A
`F
`
`FINDINGS AND RECOMMENDATIONS
`4
`Tables 2 and 3 below include the identified medication error issues with the submitted
`prescribing information (PI), patient prescribing information (PPI), instruction for use (IFU),
`container labels, and carton labeling, our rationale for concern, and the proposed
`recommendation to minimize the risk for medication error. DMEPA will collaborate with DAV
`to provide edits related to below recommendations to sharepoint.
`
`2
`
`Reference ID: 4768714
`
`

`

`Table 2. Identified Issues and Recommendations for Division of Antivirals (DAV)
`IDENTIFIED ISSUE
`RATIONALE FOR CONCERN
`RECOMMENDATION
`Full Prescribing Information – Section 2 Dosage and Administration
`1.
`Table 2 combines
`Dosing recommendations
`Revise table 2 to include a
`recommended doses of
`are confusing and could
`separate column for the
`both formulations and
`lead to wrong dose
`recommended dosages of
`available strengths
`medication errors.
`each weight band for each
`within one column.
`formulation (tablet and oral
`pellets)
`Add the following sentence as
`the 2nd sentence in the 2nd
`paragraph of section 2.5:
`
`Administration method
`without food is not
`stated.
`
`Administration options are
`incomplete and could lead
`to confusion.
`
`2.
`
`Patient Package Insert (PPI)
`1.
`‘Do not chew warning is
`missing” under the ‘
`
`’
`
`section.
`
`
`
`Avoid chewing of pellets
`during patient
`administration.
`
`“EPCLUSA oral pellets can be
`taken right in the mouth or
`with food. See Instructions for
`use”
`
`Add the below statement as
`bullet #2 under the section
`entitled:
`’:
`
`
`
`“Pellets should be swallowed
`whole. Do not chew pellets.”
`
`RATIONALE FOR CONCERN
`
`RECOMMENDATION
`
`Table 3. Identified Issues and Recommendations for Gilead Science (entire table to be
`conveyed to Applicant)
`IDENTIFIED ISSUE
`Container Label(s)
`1.
`Container labels for oral
`pellets Epclusa 150
`mg/37.5 mg per packet
`and Epclusa 200 mg/50
`
`Mitigate risk of wrong
`strength medication errors.
`
`Revise the color scheme of the
`available packets so that each
`strength appears well
`differentiated.
`
`3
`
`Reference ID: 4768714
`
`(b) (4)
`
`(b) (4)
`
`

`

`RATIONALE FOR CONCERN
`
`RECOMMENDATION
`
`Table 3. Identified Issues and Recommendations for Gilead Science (entire table to be
`conveyed to Applicant)
`IDENTIFIED ISSUE
`mg per packet looks
`similar.
`Container label(s) and Carton Labeling
`2.
`Active ingredient
`Improve clarity.
`presentation
`incorporates a ‘/’.
`
`Revise the presentation of the
`active ingredients to read as
`follows:
`‘Sofosbuvir and Velpatasvir’
`We note this is consistent with
`the currently marketed tablet
`formulation labels and
`labeling.
`Add the following statement
`to the principle display panel:
`‘Pellets should be swallowed
`whole. Do not chew pellets.’
`
`Consider streamlining IFU to
`include the 1st step to Gather
`Supplies and 2nd step to
`Prepare and Administer a
`Dose which would include
`figures A-E followed by the 2
`available options to
`administer Epclusa oral pellets
`(with food or pouring contents
`in mouth).
`Add the below statement as
`bullet #2 under the section
`entitled: ‘Important
`Information You need to Know
`Before taking Epclusa oral
`Pellets’:
`
`“Pellets should be swallowed
`whole. Do not chew pellets.”
`
`3. Warning to not chew
`pellets missing.
`
`Avoid chewing of pellets
`during patient
`administration.
`
`Instruction for Use (IFU)
`1.
`Figures G, H, I, J and K
`are repeated.
`
`Remove redundancy and
`streamline IFU
`presentation.
`
`2. Do not chew warning is
`missing under the
`important information
`section.
`
`Avoid chewing of pellets
`during patient
`administration.
`
`4
`
`Reference ID: 4768714
`
`

`

`CONCLUSION
`5
`Our evaluation of the proposed Epclusa prescribing information (PI), patient prescribing
`information (PPI), instruction for use (IFU), container labels, 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 Gilead Science so that recommendations are
`implemented prior to approval.
`
`5
`
`Reference ID: 4768714
`
`

`

`APPENDICES: METHODS & RESULTS FOR EACH MATERIAL REVIEWED
`APPENDIX A. PRODUCT INFORMATION/PRESCRIBING INFORMATION
`Table 4 presents relevant product information for Epclusa that Gilead Science submitted on
`December 15, 2020.
`
`Table 4. Relevant Product Information for Epclusa
`Epclusa Pellets
`
`Initial Approval
`Date
`
`Active
`Ingredient
`
`Indication
`
`Route of
`Administration
`
`Dosage Form
`Strength
`
`Dose and
`Frequency
`
`N/A
`
`sofosbuvir and velpatasvir
`
`Epclusa tablet
`
`June 28, 2016
`
`EPCLUSA is indicated for the treatment of
`adults and pediatric patients 3 years of age and
`older with chronic hepatitis C virus (HCV)
`genotype 1, 2, 3, 4, 5, or 6 infection.
`
`EPCLUSA is indicated for the treatment of
`adults and pediatric patients 6 years of age
`and older or weighing at least 17 kg with
`chronic hepatitis C virus (HCV) genotype 1,
`2, 3, 4, 5, or 6 infection.
`
`Oral
`
`Oral pellets
`
`Oral tablets
`
`150 mg/37.5 mg and 200 mg/50 mg
`
`200 mg/50 mg and 400 mg/100 mg
`
`Recommended Dosage in Pediatric Patients
`3 Years and Older
`
`Less than 17 kg- One 150 mg/37.5 mg packet
`of pellets once daily
`
`17 kg to less than 30 kg- One 200 mg/50 mg
`tablet or one 200 mg/50 mg packet of pellets
`once daily.
`
`At least 30 kg- One 400 mg/100 mg tablet (or
`two 200 mg/50 mg tablets or two 200 mg/50
`mg packets of pellets) once daily
`
`Recommended Dosage in Adult and
`Pediatric Patients 6 Years and Older or
`Weighing at Least 17 kg
`
`17 kg to less than 30 kg- One 200 mg/50
`mg tablet once daily
`
`30 kg and up- One 400 mg/100 mg tablet
`(or two 200 mg/50 mg tablets) once daily
`
`(How Supplied
`
`Cartons of 28 packets
`
`Bottles of 28 tablets
`
`Storage
`
`Store below 30℃ (86℉)
`
`6
`
`Reference ID: 4768714
`
`

`

`APPENDIX B. PREVIOUS DMEPA REVIEWS
`On March 5, 2021, we searched for previous DMEPA reviews relevant to this current review
`using the terms, Epclusa. Our search identified no relevant reviews related to these
`submissions.
`
`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 Epclusa labels and labeling
`submitted by Gilead Science.
`
` Container label(s) received on December 15, 2020
` Carton labeling received on December 15, 2020
`Instructions for Use, Patient Prescribing Information and Prescribing Information
`
`(Images not shown) received on \\CDSESUB1\evsprod\NDA214187\0001\m1\us\114-
`labeling\draft\labeling
`
`Label and Labeling Images
`F.2
`Container label(s)
`
`a Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.
`
`7
`
`Reference ID: 4768714
`
`1 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`

`

`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/
`------------------------------------------------------------
`
`MELINA N FANARI
`03/26/2021 08:41:12 AM
`
`SEVAN H KOLEJIAN
`03/29/2021 09:29:25 AM
`
`Reference ID: 4768714
`
`

`

`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:
`
`2/18/2021
`
`TO:
`
`
`FROM:
`
`
`
`Division of Antivirals (DAV)
`Office of Infectious Diseases (OID)
`
`Division of New Drug Study Integrity (DNDSI)
`Office of Study Integrity and Surveillance (OSIS)
`
`SUBJECT:
`
`Decline to conduct an on-site inspection
`
`RE:
`
`NDA 214187
`
`The Division of New Drug Study Integrity (DNDSI) within the Office of Study Integrity and
`Surveillance (OSIS) determined that inspections are not warranted at this time for the site listed below.
`The rationale for this decision is noted below.
`
`Rationale
`, which falls within the surveillance interval. The inspection
`OSIS inspected the site in
`was conducted under the following submissions:
`, and
` and
`.
`The final classification for the inspection was No Action Indicated (NAI).
`Therefore, based on the rationale provided above, an inspection is not warranted at this time.
`
`Inspection Site
`
`Facility Type
`
`Facility Name
`
`Facility Address
`
`Reference ID: 4748911
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`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/
`------------------------------------------------------------
`
`KIMBERLY A MILLER
`02/18/2021 02:24:47 PM
`
`Reference ID: 4748911
`
`