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`
`AD M I N ISTR ATIO N
`
`SUPPLEMENT APPROVAL
`
`NOA 021196/S-033 and S-034
`
`Arthur Merlin d'Estreux
`Director, Global Regulatory Lead
`Jazz Pharmaceuticals, Inc.
`2005 Market Street, Suite 2100
`Philadelphia, PA 19103
`
`Dear Mr. Merlin d'Estreux:
`
`Please refer to your Supplemental New Drug Applications (sNDAs) submitted under
`Section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Xyrem (sodium
`oxybate) oral solution, 500 mg/ml:
`
`lication
`A
`NOA 021196/S-033
`
`Submitted and Received On
`Jul 15 2020
`
`lication
`A
`NOA 021196/S-034
`
`Submitted and Received On
`Jul 16,2020
`
`Labeling updates and proposed modifications to the approved Xyrem (sodium
`ox bate risk evaluation and miti ation strate
`REMS .
`
`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 1h 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: 4644307
`
`

`

`
`
` NDA 021196/S-033 and S-034
`
` Page 2
`
`
`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, 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 (sodium oxybate) was originally approved on February 27, 2015,
`
`
`
`and the most recent REMS modification was approved on October 26, 2018. The REMS
`
`
`
`consists of elements to assure safe use, an implementation system, and a timetable for
`
`
`submission of assessments of the REMS.
`
`
`
`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
`
`
`
`and minimize burden on the healthcare delivery system of complying with the REMS:
`
`
`
`
`• Changes to the REMS Document:
`
`
`
`
` 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: 4644307
`
`

`

`
`
` NDA 021196/S-033 and S-034
`
` Page 3
`
`
`
`o add an additional NDA number to include Xywav (NDA 212690)
`
`
`
`
`
`o change the name of the REMS to the ‘Xywav and Xyrem REMS’
`
`
`
`
`o update the REMS Document to include Xywav.
`
`
`
`
`
`
`In addition, this REMS modification updates the format and content of the REMS
`
`
`Document consistent with the October 2017 Draft Guidance: Format and Content of a
`
`
`
`
`REMS Document Guidance for Industry
`
`• Changes to the REMS materials:
`
`
`
`
`o add an additional NDA to include Xywav (NDA 212690)
`
`
`
`
`o addition of the following new REMS materials: Xywav REMS
`
`
`
`Prescription Form, Xywav REMS Patient Quick Start Guide, and
`
`Xywav REMS Brochure for Pediatric Patients and Their Caregivers,
`
`
`
`Your proposed modified REMS, submitted on July 16, 2020, amended and appended to
`
`this letter, is approved.
`
`
`The timetable for submission of assessments of the REMS remains the same as that
`
`
`approved on February 27, 2015.
`
`
`The XYWAV and XYREM REMS Assessment Plan must include, but is not limited to,
`
`
`the following information:
`
`
`Program Implementation and Operations
`
` 1. REMS Program Implementation (1st assessment after approval only)
`
`
`
`
`
` a. Date of first commercial distribution of XYWAV
`
`
`
` b. Date when the XYWAV and XYREM REMS website became live and fully
`
`
` operational
`
`
` c. Date when the REMS Call Center was operationalized to include both XYWAV
` and XYREM.
`
`
`
`2. 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), 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
`
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4644307
`
`

`

`NDA 021196/S-033 and S-034
`
`Page 4
`
`
`
`
`
`
`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)
`
`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
`
`
`If the Certified Pharmacy was decertified during the reporting period and
`i.
`
`
`reasons for decertification.
`
`3. 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.
`
`
`4. 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.
`
`
`
`vi.
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4644307
`
`

`

`v.
`
`
`vi.
`
`
`NDA 021196/S-033 and S-034
`
`Page 5
`
`
`
`5. 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
`
`
`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.
`
`For any that did not complete the CAPA within the timeframe specified in
`the audit plan, describe actions taken
`
`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 findings
`
`ix. A summary report of the processes and procedures that are implemented
`
`
`to be in compliance with the REMS requirements
`
`b. A summary report of non-compliance, associated corrective and preventive
`
`actions (CAPA) plans, and the status of CAPA plans including but not limited to:
`
`
`i. A copy of the Non-Compliance Plan which addresses the criteria for non­
`
`compliance for each stakeholder, actions taken to address non­
`compliance for each event, and under what circumstances a stakeholder
`
`would be suspended or de-certified from the REMS
`
`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
`
`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.
`
`
`
`
`ii.
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4644307
`
`

`

`NDA 021196/S-033 and S-034
`
`Page 6
`
`
`
`
`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
`
`
`
`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.
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4644307
`
`

`

`
`
` NDA 021196/S-033 and S-034
`
` Page 7
`
`
`
`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
`
`6. Pharmacy Notifications (per reporting period and cumulatively, for both XYWAV and
`
`
`
`XYREM)
`
`i. 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):
`
`1) Use with sedative-hypnotics indicated for sleep (e.g. zolpidem,
`
`
`
`eszopiclone, zaleplon, ramelteon)
`
`2) Use with other concomitant CNS-depressant medications (opioid
`
`analgesics, benzodiazepines, sedating antidepressants or
`
`antipsychotics, sedating anti-epileptics, sedating antihistamines,
`
`general anesthetics, muscle relaxants, opioid analgesics, or illicit CNS
`
`
`depressants)
`
`3) Patient report of alcohol use
`
`
`4) Patient report of diagnosis of sleep apnea
`
`
`5) Patient report of diagnosis of asthma, COPD, or other conditions
`
`
`affecting breathing
`
`6) Suspected abuse, misuse, or diversion
`
`
`7) Alerts regarding potential abuse, misuse, or diversion on the patient
`
`
`
`profiles
`
`
`8) Prescription error
`
`
`
`9) Early refill requests.
`
`
`
`7. Risk Management Reports (RMRs) (per reporting period and cumulatively, for both
`
`XYWAV and XYREM)
`
`
`i. Number and percentage of RMRs submitted
`
`
`ii. Number and percentage of unique patients with a RMR
`
`
`iii. Number and percentage of unique patients with multiple RMRs
`
`
`iv. Number and percentage of alerts generated from RMRs
`
`
`v. Number and percentage of RMRs generated from early refill requests
`
`
`
`vi. Number and percentage of RMRs generated for other reasons (list reasons)
`
`
`
`vii. Number and percentage of prescriber-related RMRs
`
`
`viii. Number and percentage of RMRs that included an adverse event.
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4644307
`
`

`

`
`
` NDA 021196/S-033 and S-034
`
` Page 8
`
`
`8. REMS Program Patient Counseling Checklist (per reporting period and cumulatively,
`
`
`for both XYWAV and XYREM)
`
`i. 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:
`
`
`1) Sedative hypnotics indicated for sleep (e.g. zolpidem, eszopiclone,
`
`
`
`
`zaleplon, ramelteon)
`
`
`2) Alcohol
`
`
`
`3) Other potentially interacting agents:
`
`
`
`• Benzodiazepines
`
`
`• Sedating antidepressants or antipsychotics, sedating anti-
`
`epileptics, and sedating antihistamines
`
`• General anesthetics
`
`
`• Muscle relaxants
`
`
`• Opioid analgesics
`
`
`• Divalproex sodium or other valproate drug (e.g., valproic acid)
`
`
`Illicit CNS depressants (e.g., heroin or gamma-hydroxybutyrate
`
`•
`[GHB]).
`
`ii. 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:
`
`1) Sleep apnea
`
`
`2) Asthma, COPD, or other conditions affecting the respiratory system.
`
`
`
`Health Outcomes and/or Surrogates of Health Outcomes
`
`9. 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, 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
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4644307
`
`

`

`
`
` NDA 021196/S-033 and S-034
`
` Page 9
`
`
`
`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.
`
`
`ii.
`
`iii.
`
`
`ii.
`
`iii.
`
`
`Knowledge
`
`10.Knowledge, Attitude, and Behavior (KAB) Surveys of Patients, Caregivers, and
`
`
`Healthcare Providers (to be submitted annually)
`
`
`a. Assessment of patients'/caregivers' and healthcare providers' understanding of
`
`
`the following:
`
`The risk of significant CNS and respiratory depression associated with
`i.
`
`
`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.
`
`
`11.Knowledge, Attitude, and Behavior (KAB) Surveys of Pharmacists (Beginning with
`
`the 5-year assessment and annually thereafter)
`
`
`a. Assessment of pharmacists' understanding of the following:
`
`
`The risk of significant CNS and respiratory depression associated with
`i.
`
`
`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.
`
`
`12.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.
`
`
`
`
`e. Summary of potential comprehension or perception issues identified with the
`
`post-training knowledge assessment by module
`
`f. Number of pharmacy staff who did not pass the knowledge assessments.
`
`
`
`
`13.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 element of the strategy, is
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4644307
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`

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`NDA 021196/S-033 and S-034
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`Page 10
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`meeting the goal or whether one or more such goals or such elements should be
`modified.
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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
`
`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
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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.
`
`
`d) If a REMS assessment was submitted in the 18 months prior to submission of the
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`supplemental application for a new indication for use: A statement about whether
`
`
`the 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.
`
`
`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
`
`
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`of as many of the currently listed assessment plan items as is feasible.
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`
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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
`
`
`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.
`
`
`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
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4644307
`
`

`

`NDA 021196/S-033 and S-034
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`Page 11
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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
`
`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 021196 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 021196 REMS ASSESSMENT
`
`
`
`or
`
`
`
`
`
`NEW SUPPLEMENT FOR NDA 021196/S-000
`
`CHANGES BEING EFFECTED IN 30 DAYS
`
`PROPOSED MINOR REMS MODIFICATION
`
`
`or
`
`
`
`NEW SUPPLEMENT FOR NDA 021196/S-000
`PRIOR APPROVAL SUPPLEMENT
`
`PROPOSED MAJOR REMS MODIFICATION
`
`or
`
`
`
`
`
`
`
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`Reference ID: 4644307
`
`

`

`
`
` NDA 021196/S-033 and S-034
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` Page 12
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`NEW SUPPLEMENT FOR NDA 021196/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 021196/S-000
` REMS ASSESSMENT
`
` PROPOSED REMS MODIFICATION (if included)
`
`
`
`
`
`
`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-
`
`
`Electronic Format-Promotional Labeling and Advertising Materials for Human
`
`Prescription Drugs.3
`
`
`REMS REVISIONS FOR NDA 021196
`
`
`
`
`
` 3 For the most recent version of a guidance, check the FDA guidance web page at
`
`
`
` https://www.fda.gov/media/128163/download.
`
`U.S. Food and Drug Administration
`
`
`
`Silver Spring, MD 20993
`
`
`
`www.fda.gov
`
`
`
`
`
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`
`
`
`
`Reference ID: 4644307
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`

`

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` NDA 021196/S-033 and S-034
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` Page 13
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`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 Vandna Kishore, Regulatory Project Manager, at
`
`Vandna.Kishore@fda.hhs.gov.
`
`
`
`Sincerely,
`
`
`{See appended electronic signature page}
`
`
`Eric Bastings, MD
`
`Director (Acting)
`
`Division of Neurology 1
`
`Office of Neuroscience
`
`
`Center for Drug Evaluation and Research
`
`
`ENCLOSURES:
`
`
`
`• Content of Labeling
`
`
`o Prescribing Information
`
`
`o Medication Guide
`
`
`o Instructions for Use
`
`
`• REMS
`
`
`
`
`
`
`
` 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: 4644307
`
`

`

`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/
`------------------------------------------------------------
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`ERIC P BASTINGS
`07/21/2020 05:40:59 PM
`
`Reference ID: 4644307
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`(
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`