CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
`
` APPLICATION NUMBER:
`
`
` 212477Orig1s000
`
`
`
`
` OTHER REVIEW(S)
`
`
`
`
`

`

`
`Application:
`
`
`
`
`
`Name of Drug:
`
`
`
`
`
`
`
`
`
`
`Applicant:
`
`
`
`NDA 205834/S-29, tablets (SDN 835)
`NDA 212477, oral pellets (SDN 1)
`
`HARVONI® (ledipasvir/sofosbuvir) tablet, 90 mg/400 mg, 45 mg/200 mg
`HARVONI® (ledipasvir/sofosbuvir) oral pellets, 45 mg/200 mg,
`33.75 mg/150 mg
`
`Gilead Sciences, Inc.
`
`
`
`Labeling Reviewed
`
`
`
`Division of Antiviral Products
`
`
`REGULATORY PROJECT MANAGER LABELING REVIEW
`
`
`
`
`
`
`Labeling Item: August 12, 2019, US Package Insert (USPI)
`
`
`Submission Date and Receipt Date: February 28, 2019
`
`Amendments: March 18, 2019; July 10, 2019; August 12, 2019
`
`Reviewed Items: The proposed labeling submitted by the applicant on August 12, 2019, was
`compared to the last approved labeling dated November 9, 2017 (NDA 205834/S-24).
`
`Background:
`Harvoni is a fixed dose combination of ledipasvir, a hepatitis C virus (HCV) NS5A inhibitor and
`sofosbuvir, a nucleotide analog HCV NS5B polymerase inhibitor. The FDA approved Harvoni
`on October 10, 2014 and is currently marketed as an oral tablet (ledipasvir and sofosbuvir), 90
`mg/ 400 mg for the treatment of chronic HCV infection in patients 12 years of age and older
`with genotypes 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis.
`
`PREA post-marketing requirements were issued during the initial approval of Harvoni under
`NDA 205834, and in subsequent prior approval supplements approved on, November 12, 2015
`(supplement 3, 5, and 6). The PMRs required Gilead to conduct a pediatric study to evaluate the
`pharmacokinetics, safety and treatment response (using sustained virologic response) of
`ledipasvir/sofosbuvir in pediatric subjects 3 to 17 years of age with chronic hepatitis C, PREA
`PMRs requirements 2780-1, 2983-1, and 2985-1.
`
`On February 8, 2014, Gilead submitted a Proposed Pediatric Study Request (PPSR) to the
`Agency and the Division concluded a Written Request was appropriate. A Written Request was
`issued September 2, 2016, and revised on December 1, 2016, January 30, 2017, and February 10,
`2017. Amendment 3 of the Written Request asked the Sponsor to conduct studies to assess the
`following:
`
`
`Reference ID: 4482917
`
`1
`
`

`

`
`
`
`1. Multiple dose pharmacokinetics (PK) of SOF, GS-331007, and LDV in pediatric patients
`with chronic HCV infection with genotypes 1, 4, 5 or 6, and compensated liver disease.
`
`2. Safety and effectiveness (SVR12 rate) of LDV/SOF in pediatric patients with chronic
`HCV infection with genotype 1, 4, 5 or 6 and compensated liver disease.
`
`
`Gilead submitted Supplement 17 on October 7, 2016, to expand the patient population to include
`the treatment of pediatric patients 12 years of age and older and weighing at least 35 kg with
`chronic hepatitis C virus genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated
`cirrhosis based upon the data from Trial GS-US-334-1116. On October 12, 2016, the Office of
`Orphan Product Development granted Gilead orphan designation for HARVONI for the
`treatment of chronic hepatitis C virus (HCV) infection in pediatric patients 3 to less than 18
`years of age. Upon approval of the Harvoni sNDA for pediatric patients 12 to less than 18 years
`of age, Gilead was granted Orphan exclusivity on April 7, 2017 for the treatment of pediatric
`patients 12 years of age and older or weighing at lease 35kg with chronic HCV genotype 1, 4, 5
`or 6 infection without cirrhosis or with compensated cirrhosis.
`
`On February 28, 2019, the Applicant submitted an original NDA (NDA 212477) and a prior
`approval supplement (S-29) to NDA 205834. The data from the clinical trial GS-US-337-1116,
`entitled “A Phase 2, Open-Label, Multicenter, Multi-cohort Study to Investigate the Safety and
`Efficacy of Ledipasvir/Sofosbuvir Fixed Dose Combination +/- Ribavirin in Adolescents and
`Children with Chronic HCV-Infection” was submitted to support the fulfillment of the PREA
`PMRs and Written Request issued to the Harvoni NDA (NDA 205834).
`
`NDA 212477 will have data on the new dosage form and strength of Harvoni, oral pellets, 45
`mg/200mg and 33.75mg/150 mg. NDA 205834/S- 29 will add a new dosage strength of Harvoni
`tablet 45 mg/ 200 mg.
`
`These original NDA and supplement proposes to update the USPI and Patient Information with:
`
`Information on dosing, administration, storage, and descriptions of the new 45 mg/ 200
`
`mg tablet; 45 mg/ 200 mg and 33.75 mg/ 150, oral pellet
`
` Data to support the use of HARVONI for patients 3 years of age and older
`
` Update the Patient Information with corresponding information
`
`
`The Division accepted the proposed changes with additional proposed modifications outlined
`below in the review.
`
`Key changes made within the USPI will be detailed in this review. For more additional details
`and information, reference the attached labeling and discipline reviews.
`
`
`
`
`
`
`
`
`Reference ID: 4482917
`
`2
`
`

`

`
`
`1.
`
`
`2.
`
`
` Review
`
`
`
`GENERAL
`
` Minor editorial changes were made throughout the label (i.e. spacing, grammar and
`
`capitalization).
`
` Table numbers, subsections and their references were renumbered throughout as
`
`additional tables and subsections were added to the label in this supplement.
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`
` HARVONI® (ledipasvir and sofosbuvir) oral pellets formulation was added
`
` The date was revised from 11/2018 to 8/2019 to reflect the present approval month
`and year
`
`
`
`
`
`
`RECENT MAJOR CHANGES
`
` This section was updated to reflect the following modifications to the label sections:
`o
`
`Removed Boxed Warning 02/2017 and Warnings and Precautions (2.1)
`02/2017 since this information has been in the label for more than one
`year
`o Updated Indications and Usage (1) to update to the month and year of the
`
`action
`o Updated Dosage and Administration,
`
`
`Recommended Treatment Regimen and Duration in Patients 3
`
`Years of Age and Older with Genotype 1, 4, 5, or 6 HCV (2.2)
`8/2019
`
`Recommended Dosage in Pediatric Patients 3 Years of Age and
`
`
`Older (2.4) 8/2019
`o Added Preparation and Administration of Oral Pellets (2.5) 8/2019
`
`
`INDICATIONS AND USAGE
`
` Revised indication statement to add “Adults and pediatric patients 3 years of age and
`older” and adults removed from the bulleted items
`
` The bulleted item referencing pediatric patients 12 years of age and older removed
`
`DOSAGE AND ADMINISRATION
`
` Recommended treatment regimen and duration information updated to include
`patients 3 years and older
`
` Consolidated tables containing regimen and duration information for adult patients
`and for pediatrics into one table
`
` Recommended dosage information updated to include patients ages 3 years of and
`older, and referencing the weight-based dosing Table 2, Dosing for Pediatric Patients
`3 Years and Older Using HARVONI Tablets or Oral Pellets
`
`
` Removed bullet item for recommended adult treatment regimen and duration
`
`
`
`
`Reference ID: 4482917
`
`3
`
`

`

`DOSAGE FORMS AND STRENGTHS
`
` Added Harvoni tablet strength of 45 mg of ledipasvir and 200 mg of sofosbuvir
`
` Added Harvoni oral pellets strengths of 45 mg of ledipasvir and 200 mg of
`sofosbuvir; and 33.75 mg of ledipasvir and 150 mg of sofosbuvir
`
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
` Added subsection, 2.2 Recommended Treatment Regimen and Duration in
`Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV
`
` Revised subsection header 2.3 to recommended dosage in adults
`
` Revised subsection header 2.4 to include patients ages 3 years of age and removed
`
`weight requirement of at least 35 kg
`
`
` Added subsection, 2.5 Preparation and Administration of Oral Pellets
`
`FULL PRESCRIBING INFORMATION
`
`The following substantive changes were made to the Full Prescribing Information of the
`labeling:
`
`1 INDICATIONS AND USAGE
`
` Adult Patients, heading removed to include pediatric patients 3 years and older
`
` Removed Pediatric Patients indication information
`
`2 DOSAGE AND ADMINISTRATION
`
` Revised subsection 2.2, Recommended Treatment Regimen and Duration in
`Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV
`
`o This new subsection was included to add information on the treatment and
`
`duration of HARVONI to include patients 3 years of age and older
`o Table 1, Recommended Treatment Regimen and Duration for HARVONI
`
`in Patients 3 Years of Age and Older with Genotype 1, 4, 5, or 6 HCV, for
`dosing information, was revised to include patients 3 years of age and
`older
`
` 2.3 Recommended Dosage in Adults
`o Language revised to include HCV genotypes 1, 4, 5 or 6
`
`
`
` Added subsection 2.4, Recommended Dosage in Pediatric Patients 3 Years of Age
`and Older
`
`o Added information on the dosing of HARVONI to include patients 3 years
`
`of age and older
`o Removed the original Table 2 titled, Recommended Regimen and
`
`Duration for HARVONI in Pediatric Patients 12 Years of Age or Older or
`Weighing at Least 35 kg with Genotype 1, 4, 5, or 6 HCV without
`Cirrhosis or with Compensated Cirrhosis, as the information is contained
`in Table 1.
`
`4
`
`
`
`3.
`
`
`
`4.
`
`
`
`Reference ID: 4482917
`
`

`

`o Revised Table 2 as, Dosing for Pediatric Patients 3 Years and Older Using
`
`HARVONI Tablets or Oral Pellets, to add dosing information on the use
`of HARVONI tablets and oral pellets based on body weight
`o Added Table 3, Recommended Dosing for Ribavirin in Combination
`
`Therapy with HARVONI for Pediatric Patients 3 Years and Older
`
`
` Subsection 2.5, Preparation and Administration of Oral Pellets
`
`
`o Added information on the preparation of HARVONI oral pellets regarding
`
`food and directions for administration
`
`3 DOSAGE FORMS AND STRENGTHS
`
` Added description of Harvoni tablet strength of 45 mg of ledipasvir and 200 mg of
`sofosbuvir, including shape, size, and number markers
`
` Added descriptions of Harvoni oral pellets strengths of 45 mg of ledipasvir and 200
`mg of sofosbuvir; and 33.75 mg of ledipasvir and 150 mg of sofosbuvir, including
`shape, size, and number markers
`
`
`6 ADVERSE REACTIONS
`6.1 Clinical Trials Experience
`
` Adverse Reactions in Pediatric Subjects 3 Years of Age and Older section
`
`updated to include number of subjects for patients 3 years and older
`
`
`8 USE IN SPECIFIC POPULATIONS
`8.4 Pediatric Use
`
`Included HCV genotype 4 regarding data for treatment-naïve and treatment-
`
`experienced pediatric patients from Study 1116
`
` Updated the numbering of study participants from Study 1116 and included
`pediatric patients 3 years and older
`
` Updated the established safety and efficacy statement of Harvoni with the
`removal of “less than 35 kg” and modification of the age to less than 3 years of
`age in pediatric patients from the previous 12 years of age
`
` Added information on rationale to support dosing recommendation for pediatric
`patients with genotype 1 HCV with decompensated cirrhosis and/or pediatric
`patients, genotypes 1 and 4, who are liver transplant recipients with cirrhosis or
`without compensated cirrhosis
`
` Updated the established safety and efficacy statement of Harvoni to only pediatric
`patients less than 3 years of age, including removing the “weighing less than 35
`kg, in pediatric patients with decompensated cirrhosis, or in pediatric liver
`transplant recipients” language
`
`11 DESCRIPTION
`
` Added the ingredients of the tablet and film-coating material from the 45 mg of
`ledipasvir and 200 mg sofosbuvir tablets
`
`
`
`Reference ID: 4482917
`
`5
`
`

`

`
` Added the ingredients of the oral pellet containing either 45 mg ledipasvir and
`200 mg sofosbuvir or 33.75 mg ledipasvir and 150 mg sofosbuvir, contained in
`packets
`
`12 CLINICAL PHARMACOLOGY
`12.3 Pharmacokinetics
`
` Pediatric Patients subsection updated to include HCV genotypes 1, 3, or 4
`infected pediatric subjects 3 years of age and older
`
` Table 7, Pharmacokinetic Properties of the Components of HARVONI in
`HCV-Infected Pediatric Subjects 3 Years of Age and Older, modified to include
`information on dosing, PK Parameters as geometric means categorized by weight
`groups less than 17 kg, 17 to less than 35 kg, and greater than or equal to 35 kg
`
` Added GS-331007 as unestablished pharmacokinetics with patients to less than 3
`years, updated from less than 12 years of age
`
`12.4 Microbiology
`
` Effect of Baseline HCV Polymorphisms on Treatment Response
`o Pediatrics subsection was updated to reflect additional pediatric data for
`
`
`reported numbers of resistance-associated polymorphism
`
`14 CLINICAL STUDIES
`14.1 Description of Clinical Trials
`
` Genotype 4 added, and age updated to 3 years of age and older to reflect new data
`from Study 1116
`
` Table 10, Trials Conducted with HARVONI with or without Ribavirin in Subjects
`with Chronic HCV Genotype 1, 4, 5, or 6 Infection
`o Trial 1116 updated to reflect ages 3 years of age and older, and
`
`referencing genotype 4 and treatment duration of HARVONI for 24 weeks
`to reflect one new subject
`o Number of patients updated to 223 from 100 from new Study 1116 data
`
`
`14.6 Clinical Trial in Pediatric Subjects
`
`Information from Study 1116 added to this section, lowered the age of pediatric
`
`patients to 3 years old and including information on the dose and duration of
`treatment studied
`
` Additional information on the SVR12 from Study 1116 added on to patients 6
`years to less than 12 years and patients 3 years to less than 6 years of age
`
`
`16 HOW SUPPLIED/STORAGE AND HANDLING
`
` Added description of HARVONI tablets
`
` Storage of tablets revised to “below 30 °C (86 °F) for consistency with the carton
`labeling
`
` Added description, storage, and handling information of HARVONI oral pellets
`
`6
`
`
`
`
`
`Reference ID: 4482917
`
`

`

`17 PATIENT COUNSELING INFORMATION
`
`
` ATRIPLA added as trademark of Gilead and removing reference of Bristol Myers
`
`Squibb
`
`Patient Information
`
` Added HARVONI© oral pellets
`
`
`
` Revised date to 08/2019
`
`What is HARVONI?
`
`
` Added children 3 years of age and older
`
` Removed language regarding the treatment of children 12 years of age and older
`and weighing at least 77 pounds
`
`How should I take HARVONI?
`
` Revised to include pellets and dose strength tablet
`
`
` Provided directions for children 3 years of age and older
`
`
` Added warning about missing a dose of HARVONI
`
`
`How should I give HARVONI oral pellets to my child?
`
` This section was added to provide caregivers directions on how to administer
`
`HARVONI oral pellets to children 3 years and older
`
`How should I store HARVONI?
`
` Removed “at room temperature” to match the carton labeling storage
`requirements
`
` Added warning about the use of HARVONI oral pellets and tamper-evident seals
`
`What are the ingredients in HARVONI?
`
` Added ingredient information for HARVONI oral pellets and tablets 45 mg /200
`
`mg
`
`Recommendations
`
`
`
`5.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Based upon the changes highlighted in this review and the reviews from the clinical
`pharmacology and clinical disciplines, this original NDA and this supplement should be
`
` approved. Please see the individual reviews for additional information.
`
`
`
`
`Philip Villasurda
`Regulatory Project Manager
`
`Karen Winestock
`
`Chief, Project Management Staff
`
`
`
`
`
`
`
`
`
`
`
`Date
`
`
`Date
`
`
`
`Reference ID: 4482917
`
`7
`
`56 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/
`------------------------------------------------------------
`
`PHILIP R VILLASURDA
`08/27/2019 11:55:52 AM
`
`LINDA C ONAGA
`08/27/2019 02:38:04 PM
`Signing of behalf of Karen Winestock, CPMS
`
`Reference ID: 4482917
`
`

`

`
`
`
` FOOD AND DRUG ADMINISTRATION
`
`
` Center for Drug Evaluation and Research
`
` Office of Prescription Drug Promotion
`****Pre-decisional Agency Information****
`
`
`
`
` Memorandum
`
`
` Date:
`
`
` 8/15/19
`
`
`
`
`To:
`
`
`
`
`Philip Villasurda
`
`Regulatory Project Manager
`
`
`
`Division of Antiviral Products (DAVP)
`
` Nima Ossareh, Regulatory Review Officer
`
` Office of Prescription Drug Promotion (OPDP)
`
`
`
`
` Sam Skariah, Team Leader, OPDP
`
`
`
`
`From:
`
`
`
`
`
` CC:
`
` Subject:
`
`
`
` OPDP Labeling Comments for HARVONI® (ledipasvir and sofosbuvir)
`
`
`
` tablets, for oral use, HARVONI® (ledipasvir and sofosbuvir) oral granules,
`
`
` SOVALDI® (sofosbuvir) tablets, for oral use, and SOVALDI® (sofosbuvir)
`
`
`
`
`
` oral granules
`
`
`NDA/BLA: 205834/Supplement 29 and 212477 204671 Supplement 14
`
`
`
`
`
`
`
`
`
`
`In response to DAVP consult request dated March 19, 2019, OPDP has reviewed the
`
`
`
`
`proposed product labeling (PI) and patient package insert (PPI) for HARVONI® (ledipasvir and
`
`
`
`
`
`sofosbuvir) tablets, for oral use, HARVONI® (ledipasvir and sofosbuvir) oral granules,
`
`
`
`
`
`SOVALDI® (sofosbuvir) tablets, for oral use, and SOVALDI® (sofosbuvir) oral granules.
`
`
`
`
`
`
`These supplements revise the label to provide information on the efficacy in patients 3 years of
`
`age and older.
`
`
`
`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 August 12, 2019 and are
`
`
`provided below.
`
`
`PPI: 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: 4478120
`
`
`
` 1
`
`88 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
`08/15/2019 04:01:08 PM
`
`Reference ID: 4478120
`
`

`

` 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
`
`
` August 13, 2019
`
`
` 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)
`
`
` Nima Ossareh PharmD, RAC
`
`
` Regulatory Review Officer
` Office of Prescription Drug Promotion (OPDP)
`
`
`Morgan Walker, PharmD, MBA, CPH
`
`Senior Patient Labeling Reviewer
`
`
`
`Division of Medical Policy Programs (DMPP)
`
`
`
`
`Review of Patient Labeling: Patient Package Insert (PPI)
`
`
` HARVONI (ledipasvir and sofosbuvir)
`
` oral granules
`
`
` NDA 212477 and NDA 205834/S-029
`
`
`
`
`
`
`
` Drug Name (established
`
` name):
`
` Dosage Form and Route:
`Application
` Type/Number/Supplement
`
`Number:
` Applicant:
`
`
`
`
`
`
`
`
` Gilead Sciences, Inc.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Date:
`
` To:
`
`
`
`
` Through:
`
`
`
`
`
` From:
`
`
`Subject:
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4476472
`
`
`
`
`
`

`

`
`
`1
`
` INTRODUCTION
`
`
`
`
` On February 28, 2019, Gilead Sciences, Inc. submitted for the Agency’s review an
` original New Drug Application (NDA) 212477 for HARVONI (ledipasvir and
`
`
` sofosbuvir) oral granules. This original NDA references NDA 205834/S-029
`HARVONI (ledipasvir and sofosbuvir) tablets. This application is intended to
`support the approval to market HARVONI (ledipasvir and sofosbuvir) oral granules
`
`
`
`for use in the treatment of hepatitis C virus (HCV) infection in pediatric patients.
`
`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 March 19, 2019 for DMPP
`and OPDP to review the Applicant’s proposed Patient Package Insert (PPI) for
`
`
`
`HARVONI (ledipasvir and sofosbuvir) oral granules.
`
`
`
`
`
`2 MATERIAL REVIEWED
`
`
`• Draft HARVONI (ledipasvir and sofosbuvir) oral granules PPI received on
`
`
`
`February 28, 2019, revised by the Review Division throughout the review cycle,
`
`and received by DMPP and OPDP on August 2, 2019.
`
`
`
`
`• Draft HARVONI (ledipasvir and sofosbuvir) oral granules Prescribing
`
`
`
`Information (PI) received on February 28, 2019, revised by the Review Division
`
`throughout the review cycle, and received by DMPP and OPDP on August 2,
`
`
`
`
`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.
`
`
`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
`•
`
`
`ensured that the PPI is free of promotional language or suggested revisions to
`•
`
`ensure that it is free of promotional language
`
`
`
`
`
`
`
`
`
`Reference ID: 4476472
`
`

`

`
`•
`
` 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: 4476472
`
`6 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
`08/13/2019 11:34:44 AM
`
`NIMA OSSAREH
`08/13/2019 12:43:02 PM
`
`LASHAWN M GRIFFITHS
`08/13/2019 01:16:54 PM
`
`Reference ID: 4476472
`
`

`

` 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:
`
`
`
` July 15, 2019
` Requesting Office or Division:
`
` Division of Antiviral Products (DAVP)
`
`
` Application Type and Number: NDA 212477
`
`
` Product Name and Strength:
` Harvoni (ledipasvir and sofosbuvir) Oral Pellets,
`
` 45 mg/200 mg; 33.75 mg/150 mg
`
`
` Gilead Sciences, Inc.
`
`
` July 10, 2019
`
` 2019-471-1
` Valerie S. Wilson, PharmD
`
`
`
` Sevan Kolejian, PharmD, MBA
`
`
`
`
` Applicant/Sponsor Name:
`
` FDA Received Date:
`
` OSE RCM #:
` DMEPA Safety Evaluator:
`
` DMEPA Team Leader:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`1
` PURPOSE OF MEMORANDUM
` The Applicant submitted revised container labels and carton labeling received on July 10, 2019
`
`
`
` for Harvoni . The Division of Antiviral Products (DAVP) requested that we review the revised
` labels and labeling for Harvoni (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 previous recommendations. However, we note the
`
`
`
`
`
`applicant’s use of oral granules to describe this product’s dosage form. We defer to the Office
`
`
`
`of Pharmaceutical Quality (OPQ) to determine the appropriate dosage form for this product
`
`and recommend the carton and container labels are updated accordingly to prevent confusion.
`
`
`
` a Wilson, V. Label and Labeling Review for Harvoni (NDA 212477). Silver Spring (MD): FDA, CDER, OSE, DMEPA
` (US); 2019 JUN 21. RCM No.: 2019-471.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 4462330
`
`
`
` 1
`
`3 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/
`------------------------------------------------------------
`
`SEVAN H KOLEJIAN on behalf of VALERIE S WILSON
`07/15/2019 03:28:57 PM
`
`SEVAN H KOLEJIAN
`07/15/2019 03:30:29 PM
`
`Reference ID: 4462330
`
`

`

`LABEL, LABELING, AND PACKAGING 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:
`
` June 21, 2019
`
`Requesting Office or Division:
`Division of Antiviral Products (DAVP)
`Application Type and Number: NDA 205834/S-029 and NDA 212477
`Product Name and Strength:
`Harvoni (ledipasvir and sofosbuvir),
`
` Tablets: 90 mg/400 mg; 45 mg/200 mg
`Oral Pellets: 45 mg/200 mg; 33.75 mg/150 mg
`Multi-Ingredient Product
`Prescription (Rx)
`Gilead Sciences, Inc
`
` February 28, 2019 and March 18, 2019
`2019-482 and 2019-471
`Valerie S. Wilson, PharmD
`Sevan Kolejian, PharmD, MBA
`
`Product Type:
`Rx or OTC:
`Applicant/Sponsor Name:
`FDA Received Date:
`OSE RCM #:
`DMEPA Safety Evaluator:
`DMEPA Team Leader:
`
`1
`
`Reference ID: 4452745
`
`

`

`1 REASON FOR REVIEW
`
`Gilead submitted an efficacy supplement for Harvoni (ledipasvir and sofosbuvir) tablets (NDA
`205834/S-029) to support expansion of the patient population and the addition of a new
`strength of Harvoni tablets (45 mg/200 mg). Additionally, Gilead submitted New Drug
`
`Application (NDA) 212477 to support the addition of Harvoni oral pellets, 45 mg/200 mg and
`33.75 mg/150 mg, to the Harvoni product line. Subsequently, the Division of Antiviral Products
`
`
`requested that we review the proposed labels and labeling for areas that may lead to
`
`medication errors.
`
`
`These applications are intended to share a single U.S. Prescribing Information. Thus, this review
`includes our combined assessment of both NDA 205834/S-029 and NDA 212477.
`
`2 MATERIALS REVIEWED
`
`We considered the materials listed in Table 1 for this review. The Appendices provide the
`methods and results for each material reviewed.
`Table 1. Materials Considered for this Label and Labeling Review
`Appendix Section
`Material Reviewed
`(for Methods and Results)
`A
`B
`C (N/A)
`D
`E
`F (N/A)
`G
`
`Product Information/Prescribing Information
`Previous DMEPA Reviews
`Human Factors Study
`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
`
`2
`
`
`Reference ID: 4452745
`
`

`

`FINDINGS AND RECOMMENDATIONS
`3
`Tables 2 and 3 below include the identified medication error issues with the submitted
`
`prescribing information, container labels, and carton labeling, DMEPA’s rationale for concern,
`
`and the proposed recommendation to minimize the risk for medication error.
`
`Table 2: Identified Issues and Recommendations for Division of Antiviral Products
`Prescribing Information
`RATIONALE FOR CONCERN RECOMMENDATION
`IDENTIFIED ISSUE
`Highlights of Prescribing Information
`
` 1. The dosage and
`The recommended dosage
`administration section of
`for pediatric patients 3
`
`the HPI states that
`years
`
`
`
` We recommend including an
`
` abbreviated recommended
`dosage table for the pediatric
`patient population. For
`
`example, revise to read:
`“Recommended dosage in
`
`pediatric patients 3 years to
`less than 12 years of age:
`
` Body Weight
`Sofosbuvir Daily
`(kg)
`Dose
`90 mg/400 mg
`once daily
`45 mg/200 mg
`once daily
` 33.75 mg/150 mg
`
`once daily
`
`at least 35 kg
`
`17 to less than
`35 kg
`
`Less than 17 kg
`
` Refer to Table 2 of the full
`
`prescribing information for
`specific dosing guidelines.
`(2.3)”
`
`Alternatively, if there are
`space limitations, we
`recommend revising the
`associated bulleted point to
`read:
`“Recommended dosage in
`
`pediatric patients 3 years to
`less than 12 years of age:
`
`Refer to Table 2 of the full
`prescribing information for
`
`
`
`
`
`
` is based on kilogram
`body weight. As currently
`presented,
`
`
`
`
`
`
`
`
`could lead to
`misinterpretation of the
`recommended dosage.
`
`.
`
`
` could lead
`
`to misinterpretation or
`
`dosing errors.
`
`3
`
`Reference ID: 4452745
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`specific dosing guidelines
`based on body weight. (2.3)”
`
`Full Prescribing Information
`1. Section 2.3 includes
`examples of non-acidic
`foods in which Harvoni
`
`oral pellets can be
`administered but does
`not include examples of
`non-acidic liquids in
`which Harvoni oral
`pellets can be
`
`administered. We are
`concerned that this
`could lead to
`administration errors.
`
`.
`
`Section 2.3 indicates that
`Harvoni oral pellets is to be
`administered with non-
`acidic soft food
`Common household
`beverages include acidic
`
`
`liquids such as orange juice
`
`or soda and end users could
`inadvertently administer
`Harvoni oral pellets with an
`acidic liquid. Additionally,
`our Office of
`Pharmaceutical Quality
`
`colleagues believe acidic
`foods and liquids may affect
`
`
` To provide clarity, we
`
`recommend including at least
`3 examples of non-acidic
`liquids for which prescribers
`
`
`can use as guidance when
`
`instructing patients and
`caregivers on the proper
`administration of Harvoni oral
`pellets. Additionally, for
`consistency, we recommend
`
`
`the same non-acidic liquid
`
`examples be included in the
`
`How should I give HARVONI
`oral pellets to my child?
`section of the Patient Package
`Insert.
`
`Table 3: Identified Issues and Recommendations for Gilead Sciences, Inc. (entire table to be
`conveyed to Applicant)
`Container Labels, Carton Labeling, and Packaging
`IDENTIFIED ISSUE
`RATIONALE FOR CONCERN RECOMMENDATION
`2. The quantity statement
`
`
` The use of the phrase
`Revise the quantity statement
`
`” is
`on the cartons for
`“
`to read: “28 packets”.
`Harvoni oral pellets
`inconsistent with the
`includes the phrase
`Harvoni oral pellets 90
`“
`,”
`mg/400 mg dosage regimen
`
`
`which could result in
`that requires administration
`
`
`
`administration errors.
`of two 45 mg/200 mg
`packets of pellets once
`daily.
` We are unable to evaluate
`
`
` whether the p