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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 021196/S-023
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`Food and Drug Administration
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` Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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` Jazz Pharmaceuticals
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` Attention: Jennifer Ekelund
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` Vice President, US Regulatory Affairs
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` 3180 Porter Drive
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` Palo Alto, CA 94304
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`Dear Ms. Ekelund:
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`Please refer to your Supplemental New Drug Application (sNDA) dated April 1, 2015, received
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`April 1, 2015, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
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`(FDCA) for Xyrem® (sodium oxybate).
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`This supplemental application, submitted as a “Changes Being Effected” supplement, proposes
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`the following change(s): Prescribing Information and Medication Guide to be consistent with the
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`approved REMS program, as requested by the Division. Because the Medication Guide is an
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`element of the REMS, the supplement also constitutes a proposed REMS modification.
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`APPROVAL & LABELING
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`We have completed our review of this supplemental application, as amended. It is approved,
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`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
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`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
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described at
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`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
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`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)
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`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
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`“SPL Standard for Content of Labeling Technical Qs and As” at
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`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`Reference ID: 3791440
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` NDA 021196/S-023
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` 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
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`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
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`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
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`changes approved in this supplemental application, as well as annual reportable changes and
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`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
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`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
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`should provide appropriate annotations, including supplement number(s) and annual report
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`date(s).
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`We request that the labeling approved today be available on your website within 10 days of
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`receipt of this letter.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`The REMS for Xyrem (sodium oxybate) was approved on February 27, 2015. The REMS
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`consists of a Medication Guide, elements to assure safe use, an implementation system, and a
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`timetable for submission of assessments of the REMS.
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`In order to ensure that the benefits of Xyrem outweigh its risks, we determined that the following
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`REMS modifications to the Medication Guide, which is a part of the approved REMS and
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`product labeling, were necessary to be consistent with the approved REMS document and the
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`rest of the approved REMS for Xyrem:
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`• Change of the name of the REMS from the “Xyrem Success Program” to “Xyrem REMS
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`Program”
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`Your proposed modified REMS, which is appended to this letter and includes the revised
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`Medication Guide submitted on April 1, 2015, is approved.
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`The modified REMS consists of a Medication Guide, elements to assure safe use, an
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`implementation system, and a timetable for submission of assessments of the REMS.
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`The timetable for submission of assessments of the REMS remains the same as that approved on
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`February 27, 2015.
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`There are no changes to the REMS assessment plan described in our February 27, 2015, letter.
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`We remind you that in addition to the REMS assessments submitted according to the timetable in
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`the approved REMS, you must include an adequate rationale to support a proposed REMS
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`modification for the addition, modification, or removal of any goal or element of the REMS, as
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`described in section 505-1(g)(4) of the FDCA.
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`Reference ID: 3791440
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` NDA 021196/S-023
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` Page 3
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` We also remind you that you must submit a REMS assessment when you submit a supplemental
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` application for a new indication for use as described in section 505-1(g)(2)(A). This assessment
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` should include:
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`a) An evaluation of how the benefit-risk profile will or will not change with the new
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`indication;
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`b) A determination of the implications of a change in the benefit-risk profile for the current
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`REMS;
`c) If the new indication for use introduces unexpected risks: A description of those risks
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`and an evaluation of whether those risks can be appropriately managed with the currently
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`approved REMS.
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`d) If a REMS assessment was submitted in the 18 months prior to submission of the
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`supplemental application for a new indication for use: A statement about whether the
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`REMS was meeting its goals at the time of that the last assessment and if any
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`modifications of the REMS have been proposed since that assessment.
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`e) If a REMS assessment has not been submitted in the 18 months prior to submission of the
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`supplemental application for a new indication for use: Provision of as many of the
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`currently listed assessment plan items as is feasible.
`f) If you propose a REMS modification based on a change in the benefit-risk profile or
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`because of the new indication of use, submit an adequate rationale to support the
`modification, including: Provision of the reason(s) why the proposed REMS
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`modification is necessary, the potential effect on the serious risk(s) for which the REMS
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`was required, on patient access to the drug, and/or on the burden on the health care
`delivery system; and other appropriate evidence or data to support the proposed change.
`Additionally, include any changes to the assessment plan necessary to assess the
`proposed modified REMS. If you are not proposing REMS modifications, provide a
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`rationale for why the REMS does not need to be modified.
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`If the assessment instruments and methodology for your REMS assessments are not included in
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`the REMS supporting document, or if you propose changes to the submitted assessment
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`instruments or methodology, you should update the REMS supporting document to include
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`specific assessment instrument and methodology information at least 90 days before the
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`assessments will be conducted. Updates to the REMS supporting document may be included in a
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`new document that references previous REMS supporting document submission(s) for
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`unchanged portions. Alternatively, updates may be made by modifying the complete previous
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`REMS supporting document, with all changes marked and highlighted. Prominently identify the
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`submission containing the assessment instruments and methodology with the following wording
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`in bold capital letters at the top of the first page of the submission:
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`NDA 021196 REMS CORRESPONDENCE
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`(insert concise description of content in bold capital letters, e.g.,
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`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
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`METHODOLOGY)
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`Reference ID: 3791440
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` NDA 021196/S-023
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` Page 4
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` An authorized generic drug under this NDA must have an approved REMS prior to marketing.
` Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
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` contact us to discuss what will be required in the authorized generic drug REMS submission.
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`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved covered
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`application with elements to assure safe use from using any element to block or delay approval
`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
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` result in enforcement action.
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`Prominently identify any submission containing the REMS assessments or proposed
` modifications of the REMS with the following wording in bold capital letters at the top of the
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` first page of the submission as appropriate:
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`NDA 021196 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 021196
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`CHANGES BEING EFFECTED IN 30 DAYS
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`< other supplement identification >
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`PROPOSED MINOR REMS MODIFICATION
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`or
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`NEW SUPPLEMENT FOR NDA 021196
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`PRIOR APPROVAL SUPPLEMENT
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`< other supplement identification >
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`PROPOSED MAJOR REMS MODIFICATION
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`or
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`NEW SUPPLEMENT FOR NDA 021196
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`PRIOR APPROVAL SUPPLEMENT
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`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
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`SUBMITTED IN SUPPLEMENT XXX
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 021196 REMS ASSESSMENT
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`< other supplement identification >
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`PROPOSED REMS MODIFICATION (if included)
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`Should you choose to submit a REMS revision, prominently identify the submission containing
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`the REMS revisions with the following wording in bold capital letters at the top of the first page
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`of the submission:
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`REMS REVISIONS FOR NDA 021196
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`Reference ID: 3791440
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` NDA 021196/S-023
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` Page 5
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` To facilitate review of your submission, we request that you submit your proposed modified
` REMS and other REMS-related materials in Microsoft Word format. If certain documents, such
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` as enrollment forms, are only in PDF format, they may be submitted as such, but the preference
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` is to include as many as possible in Word format.
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
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`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
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`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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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion (OPDP)
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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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
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
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`more information about submission of promotional materials to the Office of Prescription Drug
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`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
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`(21 CFR 314.80 and 314.81).
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`If you have questions, call Vandna Kishore, Regulatory Project Manager, at (301) 796-4193.
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`Sincerely,
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`{See appended electronic signature page}
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`Billy Dunn, MD
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`Director
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`Division of Neurology Products
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`Office of Drug Evaluation I
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`Center for Drug Evaluation and Research
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`Reference ID: 3791440
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` NDA 021196/S-023
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` Page 6
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` ENCLOSURE(S):
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` Content of Labeling
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` REMS
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`Reference ID: 3791440
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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/
`----------------------------------------------------
`
`WILLIAM H Dunn
`07/15/2015
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`Reference ID: 3791440
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