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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 203284/S-10
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Horizon Therapeutics, LLC
`Attention: Susan Telliard, MBA, MS
`Senior Director Regulatory Affairs
`150 S. Saunders Road
`Lake Forest, IL 60045
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`Dear Ms. Telliard,
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`Please refer to your Supplemental New Drug Application (sNDA) dated February 27, 2018,
`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 proposed to expand the approved
`indication to include patients less than 2 months of age. The indication is for the use of
`RAVICTI (glycerol phenylbutyrate) oral liquid, 1.1 grams/ml, as a nitrogen-binding agent for
`chronic management of patients with urea cycle disorders (UCDs) who 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.
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`APPROVAL & LABELING
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`We have completed our review of this supplemental application. 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 (Prescribing Information, Medication
`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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`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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`Reference ID: 4367866
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`

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`NDA 203284/S-10
`Page 2
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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 Microsoft Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes. To
`facilitate review of your submission(s), 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 Federal Food, Drug, and Cosmetic Act (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
`aware of a signal suggesting an increased risk of serious neurological adverse reactions in
`patients with UCDs treated with RAVICTI who have elevated phenylacetic acid (PAA) blood
`concentrations. This signal is based on a published study of the use of Ravicti in healthy adults
`and in patients with hepatic impairment, in which a dose-dependent increase in the incidence of
`neurological adverse events was noted in those who received RAVICTI and who had elevated
`PAA blood concentrations. 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 assess the signal of the serious
`risk of neurological adverse events associated with elevated PAA concentration in patients with
`urea cycle disorders.
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`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 this serious risk.
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`Reference ID: 4367866
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`

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`NDA 203284/S-10
`Page 3
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to:
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`3527-1
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`Conduct analyses of clinical data (from clinical trials of Ravicti, patient
`registry(ies), or other sources) to evaluate associations between elevations in
`plasma PAA concentration (above pre-defined thresholds) and plasma PAA to
`PAGN ratio (above pre-defined thresholds) with: (a) the development of serious
`neurological adverse reactions, and (b) the risk of hyperammonemia in patients
`with urea cycle disorders (UCDs; both treatment-naïve and non-treatment-naïve)
`treated with glycerol phenylbutyrate (Ravicti). Associations should be assessed in
`UCD patients of all ages and compared to potential associations observed in
`healthy adults and in patients with non-UCD diagnoses treated with Ravicti.
`Correlate these data with potential dosage adjustment strategies of Ravicti in
`treatment-naïve and non-treatment-naïve UCD patients of different ages/age
`groups and in the context of: (a) normal plasma ammonia, and (b) elevated plasma
`ammonia (over a pre-specified threshold).
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`The timetable you submitted on November 14, 2018, states that you will conduct this study
`according to the following schedule:
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`Draft Protocol Submission: 03/2019
`Final Protocol Submission: 09/2019
`Final Report Submission:
`03/2020
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`Submit the protocol(s) to your IND 073480, with a cross-reference letter to this NDA. Submit
`nonclinical and chemistry, manufacturing, and controls protocols and all postmarketing 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).”
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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
`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
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`Reference ID: 4367866
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`

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`NDA 203284/S-10
`Page 4
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`FULFILLMENT OF POSTMARKETING REQUIREMENT(S)/COMMITMENT(S)
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`We have received your submission dated February 27, 2018, containing the final report for the
`following postmarketing requirement listed in the February 1, 2013, letter.
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`2013-1: A clinical trial to assess the safety, efficacy, and PK 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.
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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 requirement (PMR) 2013-4 listed in your
`February 2, 2013, approval letter that is 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 Prescribing Information 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 ).
`You must submit final promotional materials and Prescribing Information, accompanied by a
`Form FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)].
`Form 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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`Reference ID: 4367866
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`

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`NDA 203284/S-10
`Page 5
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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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`If you have any questions, call Jenny Doan, Regulatory Project Manager, at 301-796-1023.
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`Sincerely,
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`{See appended electronic signature page}
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`Lisa Soule, M.D.
`Associate 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):
`Prescribing Information
`Medication Guide
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`Reference ID: 4367866
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`Signature Page 1 of 1
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`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.
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`/s/
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`LISA M SOULE
`12/21/2018
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`Reference ID: 4367866
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