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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
`Silver Spring MD 20993
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` NDA 203284/S-005
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`SUPPLEMENT APPROVAL/
`FULFILLMENT OF POSTMARKETING
`REQUIREMENT
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`Horizon Therapeutics, LLC
`Attention: Jeffrey W. Sherman, M.D.
`Chief Medical Officer and Executive Vice President
`150 S. Saunders Road
`Lake Forrest, IL 60045
`
`
`Dear Dr. Sherman:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated and received, June 28,
`2016, received June 28, 2016, and your amendments, 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.
`
`This Prior Approval supplemental new drug application provides for the use of RAVICTI
`(glycerol phenylbutyrate) oral liquid, 1.1 grams/ml, for use as a nitrogen-binding agent for
`chronic management of pediatric patients ≥2 months and <2 years of age with urea cycle
`disorders (UCDs) who cannot be managed by dietary protein restriction and/or amino acid
`supplementation alone.
`
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`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
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`CONTENT OF LABELING
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`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
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`Guide, with the addition of any labeling changes in pending “Changes Being Effected” (CBE)
`supplements, as well as annual reportable changes not included in the enclosed labeling.
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`Reference ID: 4091177
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`

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`NDA 203284/S-005
`Page 2
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`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf
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`The SPL will be accessible from publicly available labeling repositories.
`
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`Also within 14 days, amend all pending supplemental applications that include labeling changes
`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
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`REQUIRED PEDIATRIC ASSESSMENTS
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`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.
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`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`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.
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`Since RAVICTI (glycerol phenylbutyrate) was approved on February 1, 2013, we have become
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`aware of the potential for a reduced drug dosage delivery due to adherence of RAVICTI
`(glycerol phenylbutyrate) to nasogastric or gastric tubes when delivered in volumes of less than
`1 milliliter. The results of your in vitro testing suggest drug loss when Ravicti (glycerol
`phenylbutyrate) is administered via gastric tube at volumes of 0.5 ml (70% drug recovery).
`Given the lack of information for doses between 0.5 ml and 1.0 ml, there is a potential serious
`risk of hyperammonemia in infants who receive volumes <1ml when administered via gastric or
`nasogastric tube. We consider this information to be “new safety information” as defined in
`section 505-1(b)(3) of the FDCA.
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`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 identify this unexpected serious
`risk.
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`Reference ID: 4091177
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`

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`NDA 203284/S-005
`Page 3
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
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` 505(k)(3) of the FDCA will not be sufficient to assess this serious risk.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following study:
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`3214-1 In vitro study to assess the amount of Ravicti (glycerol phenylbutyrate) delivered
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`through nasogastric and gastric tubes for dosing volumes less than 1 mL.
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`The timetable you submitted on April 20, 2017, states that you will conduct this study according
`to the following schedule:
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`07/17
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`08/17
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`Study Completion:
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`Final Report Submission:
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`Submit nonclinical and chemistry, manufacturing, and controls protocols and 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
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`Postmarketing Correspondence Under 505(o).”
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`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
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`trials.
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`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.
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`FULFILLMENT OF POSTMARKETING REQUIREMENT
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`We have received your submission dated June 28, 2016, containing the final report for the
`following postmarketing requirement listed in the February 1, 2013, letter.
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`2013-2: A clinical trial to assess the safety, efficacy, and pharmacokinetics of Ravicti
`(glycerol phenylbutyrate) and its metabolites (PBA, PAA and PAGN) during Ravicti
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`Reference ID: 4091177
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`

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`NDA 203284/S-005
`Page 4
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`(glycerol phenylbutyrate) treatment in pediatric patients with Urea Cycle Disorders,
`who are 2 months to <2 years of age.
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` We have reviewed your submission and conclude that the above requirement was fulfilled.
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`Additionally, we remind you of your post-marketing requirements (PMRs) 2013-1 and 2013-4
`listed in your February 2, 2013, approval letter that are still open.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
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`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
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`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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` You must submit final promotional materials and package insert(s), accompanied by a Form
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` FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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`FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. 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.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`Reference ID: 4091177
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`

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`NDA 203284/S-005
`Page 5
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`If you have any questions, contact Kelly Richards, Senior Regulatory Health Project Manager, at
`(240) 402-4276.
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`Sincerely,
`
`{See appended electronic signature page}
`
`
`Donna Griebel, MD
`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 Label
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`Reference ID: 4091177
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`DONNA J GRIEBEL
`04/28/2017
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`Reference ID: 4091177
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`