NDA 212690/S-006
`NDA 021196/S-036
`
`
`
`SUPPLEMENT APPROVAL
`
`
`Jazz Pharmaceuticals Ireland Limited
`Attention: Arthur Merlin d'Estreux, M.Sc.
`Director, Global Regulatory Lead – Neurosciences
`One Commerce Square
`2005 Market Street
`Philadelphia, PA 19103
`
`
`Dear Mr. d’Estreux:
`
`Please refer to your supplemental new drug applications (sNDAs) dated February 12,
`2021, received February 12, 2021, and your amendments, submitted under section
`505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for XYWAV™ (calcium,
`magnesium, potassium, and sodium oxybates) oral solution and NDA 21196 Xyrem
`(sodium oxybate) oral solution.
`
`We acknowledge receipt of your risk evaluation and mitigation strategy (REMS)
`assessment dated February 26, 2021.
`
`The Prior Approval supplemental new drug application 212690/S-006 provides for the
`new indication of Idiopathic Hypersomnia (IH) for XYWAV. NDA 212690/S-006 and
`NDA 021196/S-036 provide for modifications to the approved XYWAV and XYREM risk
`evaluation and mitigation strategy (REMS) to align with the revisions to the XYWAV
`prescribing information.
`
`APPROVAL & LABELING
`
`We have completed our review of these applications, as amended. They are approved,
`effective on the date of this letter, for use as recommended in the enclosed agreed-
`upon labeling.
`
`
`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
`
`Please note that we have previously granted a waiver of the requirements of 21 CFR
`201.57(d)(8) regarding the length of Highlights of Prescribing Information.
`
`
`Reference ID: 4840646
`
`

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`CONTENT OF LABELING
`
`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
`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
`Prescribing Information, Instructions for Use, and 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.
`
`Information on submitting SPL files using eList may be found in the guidance for
`industry SPL Standard for Content of Labeling Technical Qs and As.2
`
`The SPL will be accessible from publicly available labeling repositories.
`
`Also within 14 days, amend all pending supplemental applications that include labeling
`changes for this NDA (NDA 212690), 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).
`
`We request that the labeling approved today be available on your website within 10
`days of receipt of this letter.
`
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
`
`The REMS for XYREM was originally approved on February 27, 2015, and the REMS
`for XYWAV was approved on July 21, 2020. The two drugs are subject to the same
`REMS, known as the XYWAV and XYREM REMS. The most recent REMS modification
`was approved on February 11, 2021. The REMS consists of elements to assure safe
`use, an implementation system, and a timetable for submission of assessments of the
`REMS. Your proposed modifications to the REMS consist of:
`• Changes to the REMS materials to align with the new indication of Idiopathic
`Hypersomnia for XYWAV
`• Changes to the REMS assessment timetable
`
`1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
`2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
`Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
`
`

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`• Change of the reporting interval for the Knowledge, Attitude, and Behavior
`Surveys from annually to every other year.
`
`
`In accordance with section 505-1 of the FDCA, we have determined that the following
`REMS modifications are necessary to ensure the benefits of the drug outweigh the
`risks:
`
`
`• Changes to the Patient Counseling Checklist to capture additional information
`regarding concomitant medication and alcohol use.
`
`Your proposed modified REMS, submitted on February 12, 2021, amended and
`appended to this letter, is approved.
`
`The timetable for submission of assessments of the REMS has been revised. Jazz
`Pharmaceuticals must submit a REMS Assessment on April 26, 2022, and annually
`thereafter.
`
`The revised REMS assessment plan must include, but is not limited to, the following:
`Program Implementation and Operations
`
`
`1. REMS Enrollment Statistics (per reporting period and cumulatively)
`a. Patients:
`i. Number and percentage of newly enrolled patients
`stratified by age, geographic region (defined by US
`Census), indication, and gender
`ii. Number and percentage of active patients enrolled (patients who
`received at least one shipment of XYWAV or XYREM during the
`reporting period) stratified by age, geographic region (defined by
`US Census), and gender
`iii. Number and percentage of patients who have discontinued
`XYWAV or XYREM after receiving at least one shipment of
`XYWAV or XYREM. Include demographics of discontinued
`patients and reasons for discontinuation.
`iv. Number and percentage of patients who transitioned from
`XYREM to XYWAV
`v. Number and percentage of patients who transitioned from
`XYWAV to XYREM.
`b. Healthcare Providers:
`i. Number and percentage of newly certified healthcare providers
`stratified by professional designation (i.e. MD, DO, PA, NP),
`medical specialty, and geographic region (defined by US
`Census)
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
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`

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`ii. Number and percentage of active certified healthcare providers
`(healthcare providers who have written at least one prescription
`for XYWAV or XYREM during the reporting period) stratified by
`professional designation (i.e. MD, DO, PA, NP), medical
`specialty, and geographic region (defined by US Census)
`iii. Number of patients by current enrolled prescriber.
`c. Certified Pharmacy
`i. If the Certified Pharmacy was decertified during the reporting
`period and reasons for decertification.
`2. Utilization Data (per reporting period and cumulatively)
`a. Number and percentage of XYREM prescriptions (new and refills)
`dispensed
`b. Number and percentage of XYWAV prescriptions (new and refills)
`dispensed
`c. Number and percentage of XYREM bottles and shipments sent
`d. Number and percentage of XYWAV bottles and shipments sent.
`3. REMS Program Operation and Performance Data (per reporting
`period and cumulatively)
`a. REMS Program Central Database Report
`i. Number and percentage of contacts by stakeholder type (e.g.
`patients, healthcare providers, pharmacy, other)
`ii. Summary of reasons for contacts (e.g., enrollment questions)
`by reporter (authorized representative, patient, healthcare
`provider, other)
`iii. Call center report with number of calls received and a
`summary of reasons for calls by stakeholder type
`iv. Summary of frequently asked questions by stakeholder type
`and topic
`v. Summary of any REMS-related problems identified and a
`description of any corrective actions taken
`If the summary reason for the calls indicates a complaint,
`provide details on the nature of the complaint(s) and whether
`they indicate potential REMS burden or patient access issues
`vii. Summary of program or system problems and a description of
`any corrective actions taken.
`4. REMS Program Compliance (per reporting period and cumulatively)
`a. Audits: Summary of audit activities including but not limited to:
`i. A copy of the audit plan for each audited stakeholder.
`ii. The number of audits expected, and the number of audits
`performed
`iii. The number and type of deficiencies noted
`
`vi.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
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`iv. For those with deficiencies noted, report the status of
`corrective and preventative action (CAPA) proposed to
`address the deficiencies. The status to include completion
`status.
`v. For any that did not complete the CAPA within the timeframe
`specified in the audit plan, describe actions taken
`vi. Provide details on deviations for the CAPA proposed,
`including timelines, and mitigating steps to address the
`deviations
`vii. Confirm documentation of completion of training for relevant
`staff
`viii. Review of accumulative findings to identify any trends of
`potential repeat issues, and steps to be taken to address
`these findingsA summary report of the processes and
`procedures that are implemented to be in compliance with the
`REMS requirements.
`b. A summary report of noncompliance, associated corrective and
`preventive actions (CAPA) plans, and the status of CAPA plans
`including but not limited to:
`i. A copy of the Noncompliance Plan which addresses the
`criteria for noncompliance for each stakeholder, actions
`taken to address noncompliance for each event, and under
`what circumstances a stakeholder would be suspended or
`de-certified from the REMS
`ii. The number of instances of noncompliance accompanied
`by a description of each instance and the reason for the
`occurrence (if provided). For each instance of
`noncompliance, report the following information:
`1) The unique ID(s) of the stakeholder(s)
`associated with the noncompliance event or
`deviation to enable tracking over time
`2) The source of the noncompliance data
`3) The results of root cause analysis
`4) What action(s) were taken in response.
`c. Healthcare Providers
`i. Number and percentage of certified prescribers who were
`disenrolled during the reporting period and reasons for
`disenrollment. Include if any prescribers were re-certified.
`ii. Number of disenrolled prescribers who were associated
`with a XYWAV and XYREM prescription and number of
`disenrolled prescribers associated with a XYWAV and
`XYREM shipment
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
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`iii. Number and percentage of XYWAV prescriptions filled
`from a prescriber who was not enrolled.
`iv. Number and percentage of XYREM prescriptions filled
`from a prescriber who was not enrolled.
`d. Certified Pharmacy
`i. Number and percentage of XYWAV prescriptions dispensed
`for more than a 30 days’ supply (first fill) or more than a 90
`days’ supply (refills) and reasons
`ii. Number and percentage of XYREM prescriptions dispensed
`for more than a 30 days’ supply (first fill) or more than a 90
`days’ supply (refills) and reasons
`iii. Number and percentage of XYWAV shipments lost in
`delivery (and unrecovered) with number of DEA 106
`Forms and Risk Management Reports (RMRs)
`completed
`iv. Number and percentage of XYREM shipments lost in
`delivery (and unrecovered) with number of DEA 106
`Forms and Risk Management Reports (RMRs)
`completed
`v. Number and percentage of initial XYWAV shipments sent to
`patients without completion of the XYWAV and XYREM
`REMS Patient Counseling Checklist.
`vi. Number and percentage of initial XYREM shipments sent to
`patients without completion of the XYWAV and XYREM
`REMS Patient Counseling Checklist.
`
`e. Patients
`i. Number and percentage of patients who were
`disenrolled from the program and reasons for
`disenrollment
`ii. Number and percentage of patients associated with
`more than one prescriber during their therapy
`iii. Number and percentage of patients prescribed a daily dose of
`XYWAV of >9 g
`iv. Number and percentage of patients prescribed a daily dose of
`XYREM of >9 g
`v. Number and percentage of patients with overlapping
`prescriptions (more than one active prescription shipped)
`vi. Number and percentage of patients with concurrent XYWAV
`and XYREM prescriptions
`vii. Number of duplicate patients detected by the Certified
`Pharmacy
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
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`viii. Number and percentage of duplicate patients who were
`shipped XYWAV or XYREM under more than one name or
`identifier
`ix. Number and percentage of patients who were shipped
`XYWAV or XYREM after being disenrolled
`x. Number and percentage of patients who requested
`an early refill of XYWAV and reason for the request
`1) Number and percentage of requests approved
`2) Number and percentage of requests denied by
`the prescriber
`3) Number and percentage of requests denied by
`the Certified Pharmacy
`4) Number and percentage of patients with multiple
`requests for early refills.
`xi. Number and percentage of patients who requested
`an early refill of XYREM and reason for request
`1) Number and percentage of requests approved
`2) Number and percentage of requests denied by the
`prescriber
`3) Number and percentage of requests denied by the
`Certified Pharmacy
`4) Number and percentage of patients with multiple
`requests for early refills.
`
`Safe Use Behaviors
`5. Pharmacy Notifications (per reporting period and cumulatively, for both
`XYWAV and XYREM)
`a. A summary of the notifications by pharmacies to prescribers for both
`XYWAV and XYREM. For each of the following situations, include
`the number and percentage of notifications, number of unique
`patients, the outcome of the pharmacy notification (e.g. counseled
`patient, discussed with prescriber and prescriber’s designee) and
`outcome of XYWAV and XYREM prescription disposition (e.g.
`prescriber approved shipment, prescriber requested shipment hold,
`prescriber denied shipment, pharmacy approved shipment):
`i. Use with sedative-hypnotics indicated for sleep (e.g.,
`eszopiclone, zaleplon, zolpidem, temazepam, suvorexant,
`quazepam, estazolam, flurazepam, triazolam, tasimelteon,
`ramelteon). Indicate specific actions taken by the
`prescriber and the prescriber rationale for continuing
`treatment in response to the notification including the
`following:
`• Treatment with XYWAV /XYREM will discontinue
`• Sedative hypnotic will be discontinued
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
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`

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`• Dosage of sedative hypnotic has been/will be reduced
`• Information unavailable
`• No action (continue sedative hypnotic with XYWAV or
`XYREM)
`• Prescriber’s rationale for continued use of sedative hypnotic
`with XYWAV or XYREM
`o Sedative hypnotic will not be taken at the same time
`asXYWAV /XYREM
`o Sedative hypnotic will be taken at the same time as
`XYWAV /XYREM
`o Sedative hypnotic will be taken as a sleep aid
`o Sedative hypnotic will be taken for different
`indication per medical need
`o XYWAV /XYREM dose regimen changed
`o No rationale provided
`ii. Benzodiazepines (e.g., diazepam, alprazolam or any
`not listed in metric 5.a.i.). Indicate specific actions taken
`by the prescriber and the prescriber rationale for
`continuing treatment in response to the notification
`including the following:
`• Treatment with XYWAV /XYREM will discontinue
`• Benzodiazepine will be discontinued
`• Dosage of benzodiazepine has been/will be reduced
`• Information unavailable
`• No action (continue benzodiazepine with XYWAV or
`XYREM)
`• Prescriber’s rationale for continued use of benzodiazepine
`with XYWAV or XYREM
`o Benzodiazepine will not be taken at the same time
`as XYWAV /XYREM
`o Benzodiazepine will be taken at the same time as
`XYWAV /XYREM
`o Benzodiazepine will be taken as a sleep aid
`o Benzodiazepine will be taken for different indication
`per medical need
`o XYWAV /XYREM dose regimen changed
`o No rationale provided
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
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`

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`iii. Use with other concomitant CNS-depressant medications
`(sedating antidepressants or antipsychotics, sedating anti-
`epileptics, sedating antihistamines, general anesthetics,
`muscle relaxants, opioid analgesics, or illicit CNS
`depressants)
`iv. Patient report of alcohol use
`v. Patient report of diagnosis of sleep apnea
`vi. Patient report of diagnosis of asthma, COPD, or other
`conditions affecting breathing
`vii. Suspected abuse, misuse, or diversion
`viii. Alerts regarding potential abuse, misuse, or diversion on the
`patient profiles
`ix. Prescription error
`x. Early refill requests
`6. Risk Management Reports (RMRs) (per reporting period and cumulatively,
`for both XYWAV and XYREM)
`a. Number and percentage of RMRs submitted
`b. Number and percentage of unique patients with a RMR
`c. Number and percentage of unique patients with multiple RMRs
`d. Number and percentage of alerts generated from RMRs
`e. Number and percentage of RMRs generated from early refill requests
`f. Number and percentage of RMRs generated for other reasons (list
`reasons)
`g. Number and percentage of prescriber-related RMRs
`h. Number and percentage of RMRs that included an adverse event.
`7. REMS Program Patient Counseling Checklist (per reporting period and
`cumulatively, for both XYWAV and XYREM)
`a. Summary table for both XYWAV and XYREM from REMS Program
`Patient Counseling Checklists of the number and percentage of
`patients taking the following concomitant medications and who
`subsequently received at least one shipment of drug:
`i. Sedative hypnotics indicated for sleep (e.g.,
`eszopiclone, zaleplon, zolpidem, temazepam, suvorexant,
`quazepam, estazolam, flurazepam, triazolam, tasimelteon,
`ramelteon)
`ii. Alcohol
`iii. Other potentially interacting agents:
`• Benzodiazepines (e.g., diazepam, alprazolam or any not
`listed in metric 7.a.i.)
`• Sedating antidepressants or antipsychotics, sedating
`anti epileptics, and sedating antihistamines
`• General anesthetics
`• Muscle relaxants
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
`
`

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`•
`
`• Opioid analgesics
`• Divalproex sodium or other valproate drug
`(e.g.,valproic acid)
`Illicit CNS depressants (e.g., heroin or gamma-
`hydroxybutyrate [GHB]).
`b. Summary tables for both XYWAV and XYREM from REMS
`Program Patient Counseling Checklists of the number and
`percentage of patients who have been diagnosed with the
`following conditions and who subsequently received at least one
`shipment of drug:
`c. Sleep apnea
`d. Asthma, COPD, or other conditions affecting the respiratory system.
`
`Health Outcomes and/or Surrogates of Health Outcomes
`8. Pharmacovigilance/surveillance (per reporting period)
`a. Separate summary tables for XYWAV and XYREM of the number of
`reports of serious adverse events. The summary tables will include
`the following data fields (CIOMS II line listings): date, report ID, report
`type, notifier, age, gender, indication, start and stop date, dose,
`frequency, onset date, system organ class, outcome, and causality.
`All tables should include an overall narrative summary of the adverse
`events and data fields reported.
`i. All cases of death
`1) Number, percentage, and type of RMRs, notifications,
`and alerts associated with any reported deaths.
`ii. All outcomes of death, emergency department visits
`(when admitted to hospital), or hospitalizations resulting
`from or associated with the following:
`1) Use with concurrent sedative hypnotics and
`alcohol. Provide a breakdown of concomitant
`sedative hypnotics usage (ex. zolpidem=6%,
`eszopiclone=3%)
`2) Intentional misuse
`3) Abuse
`4) Overdose
`5) Medication error
`iii. Cases of sexual abuse
`iv. Proportion of discontinued patients who were associated with
`a report of a serious adverse event, including death.
`
`
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
`
`

`

`ii.
`iii.
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`Knowledge
`9. Knowledge, Attitude, and Behavior (KAB) Surveys of Patients,
`Caregivers, and Healthcare Providers (to be submitted every other year
`beginning with the April 2023 assessment)
`a. Assessment of patients'/caregivers' and healthcare providers'
`understanding of the following:
`i.
`The risk of significant CNS and respiratory depression
`associated with XYWAV and XYREM even at
`recommended doses
`The contraindicated uses of XYWAV and XYREM
`The potential for abuse, misuse, and overdose associated
`with XYWAV and XYREM
`The safe use, handling, and storage of XYWAV and XYREM
`iv.
`The XYWAV and XYREM REMS Program requirements.
`v.
`10. Knowledge, Attitude, and Behavior (KAB) Surveys of Pharmacists (to be
`submitted every other year beginning with the April 2023 assessment)
`a. Assessment of pharmacists' understanding of the following:
`i. The risk of significant CNS and respiratory depression
`associated with XYWAV and XYREM even at
`recommended doses
`ii. The contraindicated uses of XYWAV and XYREM
`iii. The potential for abuse, misuse, and overdose associated
`with XYWAV and XYREM
`iv. The safe use, handling, and storage of XYWAV and XYREM
`v. The XYWAV and XYREM REMS Program requirements.
`11. Certified Pharmacy knowledge assessments (per reporting period and
`cumulatively)
`a. Number of pharmacy staff who completed post-training knowledge
`assessments including method of completion and the number of
`attempts needed to complete.
`i. Provide a breakdown of scores within Module A and B
`b. Summary of the most frequently missed post-training knowledge
`assessment questions
`c. Summary of potential comprehension or perception issues
`identified with the post-training knowledge assessment by
`module
`d. Number of pharmacy staff who did not pass the knowledge
`assessments.
`
`
`
`12. The requirements for assessments of an approved REMS under section 505-
`1 (g)(3) include with respect to each goal included in the strategy, an
`assessment of the extent to which the approved strategy, including each
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
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`

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`element of the strategy, is meeting the goal or whether one or more such
`goals or such elements should be modified.
`
`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
`element of the REMS, as described in section 505-1(g)(4) of the FDCA.
`
`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:
`
`
`a) An evaluation of how the benefit-risk profile will or will not change with the new
`indication;
`
`b) A determination of the implications of a change in the benefit-risk profile for the
`current REMS;
`
`c) If the new indication for use introduces unexpected risks: A description of those
`risks and an evaluation of whether those risks can be appropriately managed
`with the currently approved REMS.
`
`d) If a REMS assessment was submitted in the 18 months prior to submission of the
`supplemental application for a new indication for use: A statement about whether
`the REMS was meeting its goals at the time of that last assessment and if any
`modifications of the REMS have been proposed since that assessment.
`
`e) If a REMS assessment has not been submitted in the 18 months prior to
`submission of the supplemental application for a new indication for use: Provision
`of as many of the 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 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
`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
`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 rationale for why the REMS does not need to be
`modified.
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
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`

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`If the assessment instruments and methodology for your REMS assessments are not
`included in the REMS supporting document, or if you propose changes to the submitted
`assessment instruments or methodology, you should update the REMS supporting
`document to include specific assessment instrument and methodology information at
`least 90 days before the assessments will be conducted. Updates to the REMS
`supporting document may be included in a new document that references previous
`REMS supporting document submission(s) for unchanged portions. Alternatively,
`updates may be made by modifying the complete previous REMS supporting document,
`with all changes marked and highlighted. Prominently identify the submission containing
`the assessment instruments and methodology with the following wording in bold capital
`letters at the top of the first page of the submission:
`
`
`NDA ###### REMS ASSESSMENT METHODOLOGY
`(insert concise description of content in bold capital letters, e.g.,
`ASSESSMENT METHODOLOGY, PROTOCOL, SURVEY METHODOLOGIES,
`AUDIT PLAN, DRUG USE STUDY)
`
`
`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, contact us to discuss what will be required in the authorized generic
`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
`or delay approval of an application under section 505(b)(2) or (j). A violation of this
`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
`the first page of the submission as appropriate:
`
`
`NDA ###### REMS ASSESSMENT
`
`
`or
`
`
`NEW SUPPLEMENT FOR NDA ######/S-000
`CHANGES BEING EFFECTED IN 30 DAYS
`PROPOSED MINOR REMS MODIFICATION
`
`
`or
`
`
`NEW SUPPLEMENT FOR NDA ######/S-000
`PRIOR APPROVAL SUPPLEMENT
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
`
`

`

`NDA 212690/S-006
`NDA 021196/S-036
`
`Page 14
`
`
`
`PROPOSED MAJOR REMS MODIFICATION
`
`or
`
`
`NEW SUPPLEMENT FOR NDA ######/S-000
`PRIOR APPROVAL SUPPLEMENT
`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABELING
`CHANGES SUBMITTED IN SUPPLEMENT XXX
`
`
`
`or
`
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA ######/S-000
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`REMS REVISIONS FOR NDA ######
`
`
`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
`top of the first page of the submission:
`
`
`
`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 as enrollment forms, or website screenshots are only in PDF format,
`they may be submitted as such, but Word format is preferred.
`
`SUBMISSION OF REMS DOCUMENT IN SPL FORMAT
`
`FDA can accept the REMS document in Structured Product Labeling (SPL) format. If
`you intend to submit the REMS document in SPL format, as soon as possible, but no
`later than 14 days from the date of this letter, submit the REMS document in SPL format
`using the FDA automated drug registration and listing system (eLIST).
`
`For more information on submitting REMS in SPL format, please email
`FDAREMSwebsite@fda.hhs.gov.
`
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and
`promotional labeling. For information about submitting promotional materials, see the
`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
`
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
`
`

`

`NDA 212690/S-006
`NDA 021196/S-036
`
`Page 15
`
`
`Electronic Format-Promotional Labeling and Advertising Materials for Human
`Prescription Drugs.3
`
`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 FDA.gov.4 Information and
`Instructions for completing the form can be found at FDA.gov.5
`
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`
`If you have any questions, contact Teresa Wheelous, Regulatory Project Manager, at
`teresa.wheelous@fda.hhs.gov.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Eric Bastings, MD
`Acting Director
`Division of Neurology 1
`Office of Neuroscience
`Center for Drug Evaluation and Research
`
`
`ENCLOSURES:
`• Content of Labeling
`o Prescribing Information
`o Medication Guide
`Instructions for Use
`o
`
`• REMS
`
`
`
`3 For the most recent version of a guidance, check the FDA guidance web page at
`https://www.fda.gov/media/128163/download.
`4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`U.S. Food and Drug Administration
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4840646
`
`

`

`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 on behalf of ERIC P BASTINGS
`08/12/2021 01:15:04 PM
`
`Reference ID: 4840646
`
`