`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`203284Orig1s000
`
`RAVICTI Oral Liquid, 1.1 grams/ml.
`
`Trade Name:
`
`Generic Name:
`
`Sponsor:
`
`Approval Date: February 1, 2013
`
`
`glycerol phenylbutyrate
`
`Hyperion Therapeutics Inc.
`
`
`Indications:
`
` This new drug application provides for the use of
`RAVICTI (glycerol phenylbutyrate) Oral Liquid, 1.1
`grams/ml, for use as a nitrogen-binding adjunctive
`therapy for chronic management of adult and pediatric
`patients ≥2 years of age with urea cycle disorders
`(UCDs) that cannot be managed by dietary protein
`restriction and/or amino acid supplementation alone.
`RAVICTI must be used with dietary protein
`restriction and, in some cases, dietary supplements
`(eg, essential amino acids, arginine, citrulline, protein-
`free calorie supplements).
`
`

`

`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`203284Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`X
`X
`
`X
`X
`X
`
`X
`X
`
`X
`X
`X
`X
`X
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203284Orig1s000
`APPROVAL LETTER
`
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`NDA 203284
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`Hyperion Therapeutics Inc.
`601 Gateway Boulevard
`Suite 200
`South San Francisco, CA 94080
`
`Attention: Klara Dickinson
`Sr. VP Regulatory Affairs
`
`Dear Ms. Dickinson:
`
`Please refer to your New Drug Application (NDA) dated December 23, 2011, received
`December 23, 2011, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for RAVICTI (glycerol phenylbutyrate) Oral Liquid, 1.1 grams/ml.
`
`We acknowledge receipt of your amendments dated February 22, 2012; March 13, 23, and 27,
`2012; April 20, 2012; June 29, 2012; July 3 and 5, 2012; August 23, 2012; December 7, 13, 28,
`and 31, 2012; January 1, 8, and 23, 2013.
`
`This new drug application provides for the use of RAVICTI (glycerol phenylbutyrate) Oral
`Liquid, 1.1 grams/ml, for use as a nitrogen-binding adjunctive therapy for chronic management
`of adult and pediatric patients ≥2 years of age with urea cycle disorders (UCDs) that cannot be
`managed by dietary protein restriction and/or amino acid supplementation alone. RAVICTI must
`be used with dietary protein restriction and, in some cases, dietary supplements (eg, essential
`amino acids, arginine, citrulline, protein-free calorie supplements).
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`
`
`Reference ID: 3254236
`
`

`

`NDA 203284
`Page 2
`
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling (text for the package insert and Medication
`Guide). Information on submitting SPL files using eLIST may be found in the guidance for
`industry SPL Standard for Content of Labeling Technical Qs and As, available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE-CONTAINER LABELS
`
`We acknowledge your December 31, 2012, submission containing final printed carton and
`container labels.
`
`ADVISORY COMMITTEE
`
`Your application for Ravicti (glycerol phenylbutyrate) was not referred to an FDA advisory
`committee because this drug is not first in class; the application did not raise significant safety or
`efficacy issues that were unexpected for a drug of this class; outside expertise was not necessary
`and there were no controversial issues that would benefit from advisory committee discussion.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
`
`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
`
`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess a signal of a serious risk
`of neurologic toxicity related to the use of Ravicti (glycerol phenylbutyrate) in pediatric patients
`
`Reference ID: 3254236
`
`

`

`NDA 203284
`Page 3
`
`
`and in treatment-naïve patients, and as a result of exposure through breast milk in infants whose
`mothers are treated with Ravicti (glycerol phenylbutyrate), and to assess a signal of a serious risk
`of carcinogenicity as a result of exposure through breast milk in infants whose mothers are
`treated with Ravicti (glycerol phenylbutyrate).
`
`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess these serious risks.
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess a signal of a serious risk of neurologic toxicity related to the
`use of Ravicti (glycerol phenylbutyrate) in pediatric patients and in treatment-naïve patients, and
`as a result of exposure through breast milk in infants whose mothers are treated with Ravicti
`(glycerol phenylbutyrate), and to assess a signal of a serious risk of carcinogenicity as a result of
`exposure through breast milk in infants whose mothers are treated with Ravicti (glycerol
`phenylbutyrate).
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`2013-1
`
`A clinical trial to assess the safety, efficacy, and pharmacokinetics of Ravicti
`(glycerol phenylbutyrate) and its metabolites (PBA, PAA and PAGN) during
`Ravicti (glycerol phenylbutyrate) treatment in pediatric patients with Urea Cycle
`Disorders who are under 2 months of age.
`
`
`The timetable you submitted on January 30, 2013, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Protocol Submission: August 2013
`Trial Completion:
`
`August 2017
`Final Report Submission: March 2018
`
`
`The timetable you submitted on January 30, 2013, states that you will conduct this trial
`according to the following schedule:
`
`
`A clinical trial to assess the safety, efficacy, and pharmacokinetics of Ravicti
`(glycerol phenylbutyrate) and its metabolites (PBA, PAA and PAGN) during
`Ravicti (glycerol phenylbutyrate) treatment in pediatric patients with Urea Cycle
`Disorders who are ages 2 months to less than 2 years.
`
`July 2013
`Final Protocol Submission:
`July 2016
`Trial Completion:
`
`Final Report Submission: December 2016
`
`A milk-only lactation trial in lactating female patients with Urea Cycle Disorders
`receiving Ravicti (glycerol phenylbutyrate) to assess the pharmacokinetics of
`
`
`2013-2
`
`
`2013-3
`
`Reference ID: 3254236
`
`

`

`Ravicti (glycerol phenylbutyrate) and its active metabolites in breast milk using
`an assay that has been validated in milk.
`
`
`The timetable you submitted on January 30, 2013, states that you will conduct this trial
`according to the following schedule:
`
`
`NDA 203284
`Page 4
`
`
`
`2013-4
`
`Final Protocol Submission: December 2013
`Trial Completion:
`
`June 2015
`Final Report Submission: December 2015
`
`A randomized, controlled clinical trial to assess the safety and efficacy of Ravicti
`(glycerol phenylbutyrate) in patients with Urea Cycle Disorders who are treatment
`naïve to phenylbutyrate.
`
`
`The timetable you submitted on January 30, 2013, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Protocol Submission: August 2013
`Trial Completion:
`
`June 2016
`Final Report Submission: March 2017
`
`Submit the protocol(s) to your IND 073480, with a cross-reference letter to this NDA. Submit all
`final report(s) to your NDA. Prominently identify the submission with the following wording in
`bold capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21
`CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR
`314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also
`include a report on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o)
`on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could
`result in enforcement action.
`
`
`Reference ID: 3254236
`
`

`

`NDA 203284
`Page 5
`
`
`POSTMARKETING COMMITMENT SUBJECT TO THE REPORTING
`REQUIREMENTS UNDER SECTION 506B
`
`We remind you of your postmarketing commitment:
`
`
`2013-5
`
`To conduct an in vivo drug interaction study to evaluate the effect of Ravicti
`(glycerol phenylbutyrate) on the pharmacokinetics of a drug that is a sensitive
`substrate of CYP3A4/5 (e.g., midazolam).
`
`
`The timetable you submitted on January 5, 2013, states that you will conduct this study
`according to the following schedule:
`
`
`Final Protocol Submission: September 2013
`Study Completion:
`
`March 2014
`Final Report Submission:
`July 2014
`
`
`Submit clinical protocols to your IND 073480 for this product. Submit nonclinical and
`chemistry, manufacturing, and controls protocols and all postmarketing final reports to this
`NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a
`status summary of each commitment in your annual report to this NDA. The status summary
`should include expected summary completion and final report submission dates, any changes in
`plans since the last annual report, and, for clinical studies/trials, number of patients entered into
`each study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
`
`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
`
`We acknowledge receipt of your submission dated December 23, 2011, of a proposed risk
`evaluation and mitigation strategy (REMS). We have determined that, at this time, a REMS is
`not necessary for Ravicti (glycerol phenylbutyrate) to ensure that its benefits outweigh its risks.
`We will notify you if we become aware of new safety information and make a determination that
`a REMS is necessary.
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`Reference ID: 3254236
`
`

`

`NDA 203284
`Page 6
`
`
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
`information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`If you have any questions, call Jessica Benjamin, Regulatory Project Manager, at (301) 796-
`3924.
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Donna Griebel, M.D.
`Director
`Division of Gastroenterology and Inborn
`Errors Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
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`
`
`Enclosure(s):
`Content of Labeling
`Carton and Container Labeling
`
`
`Reference ID: 3254236
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DONNA J GRIEBEL
`02/01/2013
`
`Reference ID: 3254236
`
`