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` NDA 212690/ S-008
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` NDA 21196/ S-038
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`SUPPLEMENT APPROVAL
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` Jazz Pharmaceuticals Ireland Ltd
`
` Attention: Arthur Merlin d’Estreux
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` Sr. Director, Regulatory Affairs Neurosciences
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` Jazz Pharmaceuticals
` 2005 Market St 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 (sNDA) dated October 14,
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`2021, received October 14, 2021, submitted under Section 505(b) of the Federal Food,
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`Drug, and Cosmetic Act (FDCA) for XYWAV (calcium, magnesium, potassium, and
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`sodium oxybates) oral solution 0.5 g/mL and XYREM (sodium oxybate) oral solution 0.5
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`g/mL.
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`These “Changes Being Effected – 30 days” sNDAs provide proposed modifications to
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`the approved XYWAV and XYREM risk evaluation and mitigation strategy.
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`APPROVAL & LABELING
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`We have completed our review of these supplements. They are approved, effective on
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`the date of this letter, for use as recommended in the enclosed agreed-upon labeling.
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`We request that the labeling approved today be available on your website within 10
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`days of receipt 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, and the REMS
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`for XYWAV was approved on July 21, 2020. The two drugs are subject to the same
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`REMS, known as the XYWAV and XYREM REMS. The most recent REMS
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`modification was approved on August 12, 2021. The REMS consists of elements to
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`assure safe use, an implementation system, and a timetable for submission of
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`assessments of the REMS. Your proposed modification to the REMS consists of
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`changes to the dosing table structure on the XYWAV Prescription Form to prevent
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`confusion when the prescriber fills out the form.
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`Your proposed modified REMS, submitted on October 14, 2021, and appended to this
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`letter, is approved.
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`Reference ID: 4901893
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`

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`NDA 212690/ S-008
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`NDA 21196/ S-038
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`Page 2
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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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`There are no changes to the REMS assessment plan described in our August 12, 2021,
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`letter.
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`We remind you that in addition to the REMS assessments submitted according to the
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`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
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`supplemental application for a new indication for use, as described in section 505­
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`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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`f)
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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
`REMS was required, on patient access to the drug, and/or on the burden on the
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`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
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`necessary to assess the proposed modified REMS. If you are not proposing
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
`www.fda.gov
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`Reference ID: 4901893
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`

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`NDA 212690/ S-008
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`NDA 21196/ S-038
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`Page 3
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`REMS modifications, provide a rationale for why the REMS does not need to be
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`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
`assessment instruments or methodology, you should update the REMS supporting
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` document to include specific assessment instrument and methodology information at
` 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
` 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,
` with all changes marked and highlighted. Prominently identify the submission containing
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` the assessment instruments and methodology with the following wording in bold capital
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` letters at the top of the first page of the submission:
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` NDA ###### REMS ASSESSMENT METHODOLOGY
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`(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
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`under this NDA, contact us to discuss what will be required in the authorized generic
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`drug REMS submission.
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`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved
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`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.
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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
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`the first page of the submission as appropriate:
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`NDA ###### REMS ASSESSMENT
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`or
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`NEW SUPPLEMENT FOR NDA ######/S-000
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`CHANGES BEING EFFECTED IN 30 DAYS
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`PROPOSED MINOR 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
`www.fda.gov
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`Reference ID: 4901893
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`

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` NDA 212690/ S-008
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` NDA 21196/ S-038
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` Page 4
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` NEW SUPPLEMENT FOR NDA ######/S-000
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` PRIOR APPROVAL SUPPLEMENT
` PROPOSED MAJOR REMS MODIFICATION
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` or
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`NEW SUPPLEMENT FOR NDA ######/S-000
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`PRIOR APPROVAL SUPPLEMENT
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`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABELING
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`CHANGES SUBMITTED IN SUPPLEMENT XXX
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`or
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA ######/S-000
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`REMS ASSESSMENT
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`PROPOSED REMS MODIFICATION (if included)
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`REMS REVISIONS FOR NDA ######
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`Should you choose to submit a REMS revision, prominently identify the submission
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`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:
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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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`FDA can accept the REMS document in Structured Product Labeling (SPL) format. If
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`you intend to submit the REMS document in SPL format, as soon as possible, but no
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`later than 14 days from the date of this letter, submit the REMS document in SPL format
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`using the FDA automated drug registration and listing system (eLIST).
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`For more information on submitting REMS in SPL format, please email
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`FDAREMSwebsite@fda.hhs.gov.
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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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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
`www.fda.gov
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`Reference ID: 4901893
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`

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` NDA 212690/ S-008
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` NDA 21196/ S-038
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` Page 5
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`If you have any questions, contact Teresa Wheelous, Regulatory Project Manager, at
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`teresa.wheelous@fda.hhs.gov.
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`Sincerely,
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` {See appended electronic signature page}
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`
`Teresa Buracchio, MD
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`Director (Acting)
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`Division of Neurology 1
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`Office of Neuroscience
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`Center for Drug Evaluation and Research
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`ENCLOSURE:
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`• REMS
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
`www.fda.gov
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`Reference ID: 4901893
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`

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`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`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/
`------------------------------------------------------------
`
`TERESA J BURACCHIO
`12/09/2021 11:59:42 AM
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`Reference ID: 4901893
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`(
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