` NDA 021196/S-46
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`NDA 212690/S-16
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`SUPPLEMENT APPROVAL
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` Jazz Pharmaceuticals Ireland Limited
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` Attention: Arthur Merlin d’Estreux
` Sr. Director, Regulatory Affairs Neurosciences
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` Jazz Pharmaceuticals
` 2005 Market Street, 21st Floor, Philadelphia, PA 19103
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`Dear Mr. d’Estreux:
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`Please refer to your supplemental new drug applications (sNDAs) dated and received
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`September 19, 2024, and your amendments, submitted under section 505(b) of the
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`Federal Food, Drug, and Cosmetic Act (FDCA) for Xywav (calcium, magnesium,
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`potassium, and sodium oxybates) oral solution 0.5 g/mL and Xyrem (sodium oxybate)
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`oral solution 0.5 g/ml.
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`These “Changes Being Effected” sNDAs provide for proposed modifications to the
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`approved Xywav and Xyrem Risk Evaluation and Mitigation Strategy (REMS).
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`We have completed our review of these supplemental applications, as amended. They
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`are approved effective on the date of this letter.
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`RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
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`The REMS for Xyrem was originally approved on February 27, 2015. Xywav was
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`approved on July 21, 2020, and joined the Xyrem REMS to form the Xywav and Xyrem
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`REMS. The most recent REMS modification was approved on May 22, 2024. The
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`REMS consists of 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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`Your proposed modification to the REMS consists of removal of REMS Website
`screenshots to remove screenshots related to the ePrescribe Platform Healthcare
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`Provider Registration, ePrescribe Prescription Summary, electronic prescription
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`application and ePrescribe Platform Support Website pages; and user redirection
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`through a new window to a website outside of the REMS website for the ePrescribe
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`Platform Healthcare Provider Registration and ePrescribe Platform Support.
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`Your proposed modified REMS, submitted on September 19, 2024, amended and
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`appended to this letter, is approved.
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`The timetable for submission of assessments of the REMS remains the same as that
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`approved on August 12, 2021.
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`Reference ID: 5480975
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`

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`NDA 021196/S-46
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`NDA 212690/S-16
`Page 2
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`There are no changes to the REMS assessment plan described in our January 16,
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`2024, letter.
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`We remind you that in addition to the REMS assessments submitted according to the
`timetable in the approved REMS, you must include an adequate rationale to support a
`proposed REMS modification for the addition, modification, or removal of any goal or
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`element of the REMS, as described in section 505-1(g)(4) of the FDCA.
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`We also remind you that you must submit a REMS assessment when you submit a
`supplemental application for a new indication for use, as described in section 505-
`1(g)(2)(A) of the FDCA. This assessment 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
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`current REMS;
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`c) If the new indication for use introduces unexpected risks: A description of those
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`risks and an evaluation of whether those risks can be appropriately managed
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`with the currently 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
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`the REMS was meeting its goals at the time of that 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
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`submission of the supplemental application for a new indication for use: Provision
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`of as many of the currently listed assessment plan items as is feasible.
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`If you propose a REMS modification based on a change in the benefit-risk profile
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`or because of the new indication of use, submit an adequate rationale to support
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`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
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`REMS 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
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`the proposed change. Additionally, include any changes to the assessment plan
`necessary to assess the proposed modified REMS. If you are not proposing
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`REMS modifications, provide a 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
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`included in the REMS supporting document, or if you propose changes to the submitted
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`assessment instruments or methodology, you should update the REMS supporting
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`document to include specific assessment instrument and methodology information at
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`f)
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 5480975
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`

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`NDA 021196/S-46
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`NDA 212690/S-16
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`Page 3
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`least 90 days before the assessments will be conducted. Updates to the REMS
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`supporting document may be included in a new document that references previous
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`REMS supporting document submission(s) for unchanged portions. Alternatively,
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`updates may be made by modifying the complete previous REMS supporting document,
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`with all changes marked and highlighted.
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`Prominently identify the submission containing the assessment instruments and
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`methodology 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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` NDA 212690; NDA 021196 REMS ASSESSMENT METHODOLOGY
` (insert concise description of content in bold capital letters, e.g.,
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` ASSESSMENT METHODOLOGY, PROTOCOL, SURVEY METHODOLOGIES,
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` AUDIT PLAN, DRUG USE STUDY)
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` An authorized generic drug under this NDA must have an approved REMS prior to
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` marketing. Should you decide to market, sell, or distribute an authorized generic drug
` under this NDA, contact us to discuss what will be required in the authorized generic
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` drug REMS submission.
`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved
` covered application with elements to assure safe use from using any element to block
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` or delay approval of an application under section 505(b)(2) or (j). A violation of this
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` provision in 505-1(f) could result in enforcement action.
`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
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`the first page of the submission as appropriate:
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`NDA 212690; NDA 021196 REMS ASSESSMENT
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`or
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`NEW SUPPLEMENT FOR NDA 212690/S-000; NDA 021196/S-000
`CHANGES BEING EFFECTED IN 30 DAYS
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`PROPOSED MINOR REMS MODIFICATION
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`NEW SUPPLEMENT FOR NDA 212690/S-000; NDA 021196/S-000
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`PRIOR APPROVAL SUPPLEMENT
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`PROPOSED MAJOR REMS MODIFICATION
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`or
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`or
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`Reference ID: 5480975
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`

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` NDA 021196/S-46
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`NDA 212690/S-16
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` Page 4
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`NEW SUPPLEMENT FOR NDA 212690/S-000; NDA 021196/S-000
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` PRIOR APPROVAL SUPPLEMENT
` PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABELING
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` CHANGES SUBMITTED IN SUPPLEMENT XXX
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 212690/S-000; NDA 021196/S-000
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`REMS ASSESSMENT
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`PROPOSED REMS MODIFICATION (if included)
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` or
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`Should you choose to submit a REMS revision, prominently identify the submission
`containing the REMS revisions with the following wording in bold capital letters at the
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`top of the first page of the submission:
`REMS REVISIONS FOR NDA 212690; NDA 021196
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`To facilitate review of your submission, we request that you submit your proposed
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`modified REMS and other REMS-related materials in Microsoft Word format. If certain
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`documents, such as enrollment forms, or website screenshots are only in PDF format,
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`they may be submitted as such, but Word format is preferred.
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`SUBMISSION OF REMS DOCUMENT IN SPL FORMAT
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`As soon as possible, but no later than 14 days from the date of this letter, submit the
`REMS document in Structured Product Labeling (SPL) format using the FDA automated
`drug registration and listing system (eLIST). Content of the REMS document must be
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`identical to the approved REMS document. The SPL will be publicly available.
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`Information on submitting REMS in SPL format may be found in the guidance for
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`industry Providing Regulatory Submission in Electronic Format – Content of the Risk
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`Evaluation and Mitigation Strategies Document Using Structured Product Labeling.
`For more information on submitting REMS in SPL format, please email
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`FDAREMSwebsite@fda.hhs.gov.
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`PATENT LISTING REQUIREMENTS
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`Pursuant to 21 CFR 314.53(d)(2) and 314.70(f), certain changes to an approved NDA
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`submitted in a supplement require you to submit patent information for listing in the
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`Orange Book upon approval of the supplement. You must submit the patent information
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`required by 21 CFR 314.53(d)(2)(i)(A) through (C) and 314.53(d)(2)(ii)(A) and (C), as
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`applicable, to FDA on Form FDA 3542 within 30 days after the date of approval of the
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 5480975
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`

`

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` NDA 021196/S-46
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`NDA 212690/S-16
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` Page 5
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`supplement for the patent information to be timely filed (see 21 CFR 314.53(c)(2)(ii)).
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`You also must ensure that any changes to your approved NDA that require the
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`submission of a request to remove patent information from the Orange Book are
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`submitted to FDA at the time of approval of the supplement pursuant to 21 CFR
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`314.53(d)(2)(ii)(B) and 314.53(f)(2)(iv).
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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 any questions, call Ermias Zerislassie, Associate Director for Postmarket
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`Regulatory Science, at (301) 796-2770.
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`Sincerely,
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`{See appended electronic signature page}
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`
`Marc Stone, M.D.
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`Deputy Director for Safety
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`Division of Psychiatry
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`Office of Neuroscience
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`Center for Drug Evaluation and Research
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`ENCLOSURE(S):
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`• REMS
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 5480975
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`

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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.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MARC B STONE
`11/18/2024 04:20:55 PM
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`Reference ID: 5480975
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`(
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