SUPPLEMENT APPROVAL
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` NDA 212690/S-001/S-002
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`NDA 021196/S-035
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`Reference ID: 4745184
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` Jazz Pharmaceuticals Ireland Limited
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` Attention: Arthur Merlin d’Estreux
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` Director, Global Regulatory Lead – Neurosciences
` One Commerce Square, 2005 Market Street, Suite 2100
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` 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 October 19,
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`2020, and November 24, 2020, and your amendments, submitted under Section 505(b)
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`of the Federal Food, Drug, and Cosmetic Act (FDCA) for NDA 212690 Xywav (calcium,
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`magnesium, potssium, and sodium oxybates) oral solution and NDA 21196 Xyrem
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`(sodium oxybate) oral solution.
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`The October 19, 2020, NDA 212690/S-001, Changes Being Effected Supplemental New
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`Drug Application provides for changes to the Xywav Prescribing Information [Highlights;
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`Warnings and Precautions (Section 5), Adverse Reactions (Section 6), Use in Specific
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`Populations (Section 8)], and the Medication Guide, to align with revisions in the prior
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`approval supplement Xyrem S-032 approval that included pediatric safety information.
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`The November 24, 2020, Prior Approval supplemental new drug applications NDA
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`22690/S-002 and NDA 21196/S-035 provide for changes to align the Xywav and Xyrem
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`REMS Document to conform with the recently approved prior approval supplement NDA
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`21196/S-032, and the addition of an authorized generic for Xyrem to the Xywav and
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`Xyrem REMS.
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`We also refer to the February 1, 2021, amendments to NDA 212690 and NDA 21196,
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`which provide your response and agreement to our January 27, 2021, labeling requests.
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`APPROVAL & LABELING
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`We have completed our review of these applications, as amended. They are approved,
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`effective on the date of this letter, for use as recommended in the enclosed agreed-
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`upon labeling.
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`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
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`Please note that we have previously granted a waiver of the requirements of 21 CFR
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`201.57(d)(8) regarding the length of Highlights of Prescribing Information.
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` NDA 212690/S-001/S-002
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` NDA 021196/S-035
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` Page 2
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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
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` content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
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` the FDA automated drug registration and listing system (eLIST), as described at
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` FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
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`Prescribing Information, Patient Package Insert, Instructions for Use, and Medication
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`Guide), with the addition of any labeling changes in pending “Changes Being Effected”
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`(CBE) supplements, as well as annual reportable changes not included in the enclosed
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`labeling.
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`Information on submitting SPL files using eList may be found in the guidance for
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`industry SPL Standard for Content of Labeling Technical Qs and As.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
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`changes for this NDA, including CBE supplements for which FDA has not yet issued an
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`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
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`format, that includes the changes approved in this supplemental application, as well as
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`annual reportable changes. To facilitate review of your submission(s), provide a
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`highlighted or marked-up copy that shows all changes, as well as a clean Microsoft
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`Word version. The marked-up copy should provide appropriate annotations, including
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`supplement number(s) and annual report date(s).
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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 25, 2015, and the most
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`recent REMS modification was approved on July 21, 2020. The REMS consists of
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`elements to assure safe use, an implementation system, and a timetable for submission
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`of assessments of the REMS. Your proposed modifications to the REMS consists of:
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`• Revisions to the most common side effects in pediatric patients listed in the
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`Patient Counseling Checklist, Prescriber Brochure, the Xyrem and Xywav
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`Brochures for Pediatric Patients and their Caregivers, and the REMS Supporting
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`Document to conform with a recently approved prior approval supplement.
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`• Revisions to the REMS document, REMS supporting document, and appended
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`REMS materials to allow for the addition of an authorized generic for Xyrem
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` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
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` 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
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` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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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: 4745184
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`NDA 212690/S-001/S-002
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`NDA 021196/S-035
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`Page 3
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`Your proposed modified REMS, submitted on November 24, 2020, amended and
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`appended to this letter, is approved.
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`There are no changes to the REMS assessment plan described in our July 21, 2020,
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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
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`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
`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: 4745184
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`NDA 212690/S-001/S-002
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`NDA 021196/S-035
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`Page 4
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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
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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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`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. 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: 4745184
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` NDA 212690/S-001/S-002
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` NDA 021196/S-035
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` Page 5
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` NEW SUPPLEMENT FOR NDA ######/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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`NEW SUPPLEMENT FOR NDA ######/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 ######/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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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and
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`promotional labeling. For information about submitting promotional materials, see the
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`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
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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: 4745184
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` NDA 212690/S-001/S-002
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` NDA 021196/S-035
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` Page 6
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`Electronic Format-Promotional Labeling and Advertising Materials for Human
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`Prescription Drugs.3
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`You must submit final promotional materials and Prescribing Information, accompanied
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`by a Form FDA 2253, at the time of initial dissemination or publication
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`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
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`Instructions for completing the form can be found at FDA.gov.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
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`(21 CFR 314.80 and 314.81).
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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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`
` Eric Bastings, MD
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` Director (Acting)
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` Division of Neurology 1
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` Office of Neuroscience
` Center for Drug Evaluation and Research
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` ENCLOSURES:
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` • Content of Labeling
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` o Prescribing Information
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` o Medication Guide
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` o Instructions for Use
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` • REMS
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` 3 For the most recent version of a guidance, check the FDA guidance web page at
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` https://www.fda.gov/media/128163/download.
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` 4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
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` 5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
`www.fda.gov
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`Reference ID: 4745184
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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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`ERIC P BASTINGS
`02/11/2021 09:13:05 AM
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`Reference ID: 4745184
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