` NDA 021196/S-43
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` NDA 212690/S-12
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` SUPPLEMENT APPROVAL
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` Jazz Pharmaceuticals Ireland Limited
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`Attention: Arthur Merlin d’Estreux
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` Sr. Director, Regulatory Affairs Neurosciences
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` Jazz Pharmaceuticals
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` 2005 Market Street, 21st Floor, Philadelphia, PA 19103
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`Dear Mr. d’Estreux:
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` Please refer to your supplemental new drug application (sNDA) dated and received
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` December 15, 2022, submitted under section 505(b) of the Federal Food, Drug, and
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` Cosmetic Act (FDCA) for Xywav (calcium, magnesium, potassium, and sodium
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` oxybates) oral solution 0.5 g/mL and Xyrem (sodium oxybate) oral solution 0.5g/ml.
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` This Prior Approval sNDA provides for proposed modifications to the approved Xywav
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` and Xyrem Risk Evaluation and Mitigation Strategy (REMS).
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` We have completed our review of this supplemental application, as amended. It is
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` approved effective on the date of this letter.
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` RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
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` The REMS for Xyrem was originally approved on February 27, 2015. Xywav was
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` approved on July 21, 2020 and joined the Xyrem REMS to form the Xywav and Xyrem
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` REMS. The most recent REMS modification was approved on February 9, 2022. The
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` REMS consists of elements to assure safe use, an implementation system, and a
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` timetable for submission of assessments of the REMS.
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` Your proposed modifications to the REMS consist of adding electronic prescribing
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` functionality to the REMS website to allow prescribers to register for the Drug
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` Enforcement Administration (DEA) Electronic Prescribing for Controlled Substances
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` (EPCS) and submit Xywav or Xyrem Prescription Forms electronically through the
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` REMS website directly to the Certified Pharmacy. The following materials are affected
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` by this proposed modification: REMS Document, Xywav Prescription Form, Xyrem
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` Prescription Form, and Prescriber Brochure, and REMS Website. The pharmacy
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` requirements were changed to verify and document the patient has no other active
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` prescriptions for oxybate products before dispensing Xywav and Xyrem by reviewing
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` the information received from other REMS for oxybate products. The Applicant
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` requirements were changed to include reporting patient and prescriber disenrollment in
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` the Xywav and Xyrem REMS due to suspected abuse, misuse, or diversion to all other
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` REMS for oxybate products and to maintain a process to provide Xywav and Xyrem
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`Reference ID: 5310690
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` NDA 021196/S-43
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` NDA 212690/S-12
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` Page 2
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` prescription information to other pharmacies upon request to verify that the named
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` patient has no other active, overlapping prescriptions for oxybate products and that the
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` patient and prescriber have not been disenrolled from the Xywav and Xyrem REMS for
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` suspected abuse, misuse, or diversion. Additionally, the REMS Document was revised
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` to align with the current Format and Content of a REMS Document Guidance for
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` Industry and the REMS Document Technical Conformance Guide. The Prescriber
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` Enrollment and Patient Enrollment Forms were also revised to align with the changes to
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` the REMS Document. The following materials were also revised to align with the
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` Instructions For Use: Xyrem Brochure for Pediatric Patients and their Caregivers, Xyrem
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` Patient Quick Start Guide, Xywav Brochure for Pediatric Patients and their Caregivers,
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` and the Xywav Patient Quick Start Guide.
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` Your proposed modified REMS, submitted on December 15, 2022, amended and
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` appended to this letter, is approved.
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` The timetable for submission of assessments of the REMS remains the same as that
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` approved on August 12, 2021.
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` The revised REMS assessment plan must include, but is not limited to, the following:
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` For each metric, provide the two previous, current, and cumulative reporting periods
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` (where applicable) unless otherwise noted.
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` iii.
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` Program Implementation and Operations
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` 1. REMS Enrollment and Certification Statistics
` a. Patients:
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` i.
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` Total number of enrolled patients
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` ii.
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` Number and percentage of newly enrolled patients
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` stratified by age, geographic region (defined by US
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` Census), indication, and gender
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` Number and percentage of active patients enrolled (patients
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` who received at least one shipment of Xywav or Xyrem
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` during the reporting period) stratified by age, geographic
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` region (defined by US Census), and gender
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` Number and percentage of patients who have
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` discontinued Xywav or Xyrem after receiving at least one
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` shipment of Xywav or Xyrem. Include demographics of
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` discontinued patients and reasons for discontinuation.
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` Number and percentage of patients who transitioned
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` from Xyrem to Xywav
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` Number and percentage of patients who transitioned
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` b. Healthcare Providers:
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` Total number of certified prescribers
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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: 5310690
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`

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` NDA 021196/S-43
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` NDA 212690/S-12
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` Page 3
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` ii.
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` Number and percentage of newly certified healthcare
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` PA, NP), medical specialty, and geographic region (defined
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` by US Census)
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` Number and percentage of active certified healthcare
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` providers (healthcare providers who have written at least
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` one prescription for Xywav or Xyrem during the reporting
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` period) stratified by professional designation (i.e. MD, DO,
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` PA, NP), medical specialty, and geographic region (defined
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` by US Census)
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` c. Certified Pharmacy
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` If the Certified Pharmacy was decertified during the
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` reporting period and reasons for decertification.
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` 2. Utilization Data
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` a. Number and percentage of Xyrem prescriptions (new and refills)
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` b. Number and percentage of Xywav prescriptions (new and refills)
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` c. Number and percentage of Xyrem bottles and shipments sent
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` d. Number and percentage of Xywav bottles and shipments sent.
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` 3. REMS Program Operation and Performance Data
` a. REMS Program Central Database Report
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` i. Number and percentage of contacts by stakeholder type
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` (e.g. patients, healthcare providers, pharmacy, other)
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` ii. Summary of reasons for contacts (e.g., enrollment
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` questions) by reporter (authorized representative, patient,
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` healthcare provider, other)
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` iii. Call center report with number of calls received and a
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` summary of reasons for calls by stakeholder type
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` iv. Summary of frequently asked questions by stakeholder type
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` and topic
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` v. Summary of any REMS-related problems identified and a
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` If the summary reason for the calls indicates a complaint,
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` provide details on the nature of the complaint(s) and
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` whether they indicate potential REMS burden or patient
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` access issues
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` vii. Summary of program or system problems and a
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` description of any corrective actions taken.
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` vi.
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` 4. REMS Program Compliance
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` a. Audits: Summary of audit activities including but not limited to:
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` i. A copy of the audit plan for each audited stakeholder.
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` ii. The number of audits expected, and the number of audits
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` performed
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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: 5310690
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`

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` NDA 021196/S-43
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` NDA 212690/S-12
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` Page 4
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` v.
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` iii. The number and type of deficiencies noted
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` iv. For those with deficiencies noted, report the status of
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` corrective and preventative action (CAPA) proposed to
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` address the deficiencies. The status to include
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` completion status.
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` For any that did not complete the CAPA within the
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` timeframe specified in the audit plan, describe actions
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` vi. Provide details on deviations for the CAPA proposed,
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` including timelines, and mitigating steps to address the
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` deviations
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` vii. Confirm documentation of completion of training for relevant
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` viii. Review of accumulative findings to identify any trends of
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` potential repeat issues, and steps to be taken to address
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` these findings
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` ix. A summary report of the processes and procedures that are
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` implemented to be in compliance with the REMS
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` b. A summary report of noncompliance, associated corrective and
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` preventive actions (CAPA) plans, and the status of CAPA plans
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` including but not limited to:
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` i. A copy of the Noncompliance Plan which addresses the
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` criteria for noncompliance for each stakeholder, actions
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` taken to address noncompliance for each event, and under
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` what circumstances a stakeholder would be suspended or
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` de-certified from the REMS
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` ii. The number of instances of noncompliance accompanied by
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` a description of each instance and the reason for the
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` occurrence (if provided). For each instance of
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` noncompliance, report the following information:
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` 1) The unique ID(s) of the stakeholder(s)
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` associated with the noncompliance event or
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` deviation to enable tracking over time
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` 2) The source of the noncompliance data
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` 3) The results of root cause analysis
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` 4) What action(s) were taken in response.
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` c. Healthcare Providers
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` i. Number and percentage of certified prescribers who were
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` disenrolled during the reporting period and reasons for
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` disenrollment. Include if any prescribers were re-certified.
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` ii. Number of disenrolled prescribers who were associated
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` with a Xywav and Xyrem prescription and number of
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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: 5310690
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`

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` NDA 021196/S-43
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` NDA 212690/S-12
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` Page 5
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` disenrolled prescribers associated with a Xywav and
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` Xyrem shipment.
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` iii. Number and percentage of Xywav prescriptions filled from
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` a prescriber who was not enrolled.
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` iv. Number and percentage of Xyrem prescriptions filled from
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` a prescriber who was not enrolled.
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` d. Certified Pharmacy
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` i. Number and percentage of Xywav prescriptions dispensed
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`for more than a 30 days’ supply (first fill) or more than a 90
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`days’ supply (refills) and reasons
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` ii. Number and percentage of Xyrem prescriptions dispensed
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`for more than a 30 days’ supply (first fill) or more than a 90
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`days’ supply (refills) and reasons
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` iii. Number and percentage of Xywav shipments lost in
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` delivery (and unrecovered) with number of DEA 106
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` Forms and Risk Management Reports (RMRs)
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` completed
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` iv. Number and percentage of Xyrem shipments lost in
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` delivery (and unrecovered) with number of DEA 106
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` Forms and Risk Management Reports (RMRs)
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` v. Number and percentage of initial Xywav shipments sent to
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` patients without completion of the Xywav and Xyrem REMS
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` Patient Counseling Checklist.
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` vi. Number and percentage of Xywav shipments sent to
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` patients without completion of the Xywav and Xyrem REMS
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` Patient Counseling Checklist for patients that reinitiated
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` therapy after lapse > 6 months
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` vii. Number and percentage of Xywav shipments sent to
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` patients without completion of the Xywav and Xyrem REMS
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` Patient Counseling Checklist when the patient notified the
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` pharmacy of a new medication or change in concomitant
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` medication or comorbidity
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` viii. Number and percentage of initial Xyrem shipments sent to
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` patients without completion of the Xywav and Xyrem REMS
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` Patient Counseling Checklist.
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` ix. Number and percentage of Xyrem shipments sent to
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` patients without completion of the Xywav and Xyrem REMS
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` Patient Counseling Checklist for patients that reinitiated
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` therapy after lapse > 6 months
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` Number and percentage of Xyrem shipments sent to
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` patients without completion of the Xywav and Xyrem REMS
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` Patient Counseling Checklist when the patient notified the
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` U.S. Food and Drug Administration
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` Silver Spring, MD 20993
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` www.fda.gov
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`Reference ID: 5310690
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`

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` NDA 021196/S-43
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` NDA 212690/S-12
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` Page 6
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`
`
` pharmacy of a new medication or change in concomitant
`
`
` medication or comorbidity
`
`
`
` 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 with overlapping
`
`
`
`
`
`
`
` prescriptions (more than one active prescription shipped)
`
`
`
`
`
`
`
` iv. Number and percentage of patients with concurrent Xywav
`
`
`
`
`
`
` and Xyrem prescriptions
`
`
`
` v. Number of duplicate patients detected by the Certified
`
`
`
` Pharmacy
`
`
`
`
`
`
`
`
` vi. Number and percentage of duplicate patients who were
`
`
` shipped Xywav or Xyrem under more than one name or
`
`
`
`
`
`
`
`
`
`
` identifier
`
`
`
`
`
`
` vii. Number and percentage of patients who were shipped
`
` Xywav or Xyrem after being disenrolled
`
`
`
`
`
` viii. 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.
`
`
`
`
`
` ix. 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`
`
`
`
`
`
`
`
`
`
`
`
` Safe Use Behaviors
`
`
` 5. Pharmacy Notifications 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
`
`
`
`
`
`
`
`
`
`
`
`
` U.S. Food and Drug Administration
`
`
` Silver Spring, MD 20993
`
` www.fda.gov
`
`Reference ID: 5310690
`
`

`

`
` NDA 021196/S-43
`
` NDA 212690/S-12
`
` Page 7
`
`
`
`
`
`
`
`
`
`
`
`
`
` 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 prescription 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 be discontinued
`
`
`
`
`
`
`• Sedative hypnotic will be discontinued
`
`
`
`
`
`• 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
`
`
`
`
`
`
`
`
`
`
` as Xywav/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 be discontinued
`
`
`
`
`
`
`• 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
`
`
`
`
`
` U.S. Food and Drug Administration
`
`
` Silver Spring, MD 20993
`
` www.fda.gov
`
`Reference ID: 5310690
`
`

`

`
` NDA 021196/S-43
`
` NDA 212690/S-12
`
` Page 8
`
`
`
`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
`
`
`
`
`
`
`
`
`
`
`
` 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
`
`
`
`
`
`
` Risk Management Reports (RMRs) 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.
`
`
`
`
` REMS Program Patient Counseling Checklist 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. Prescription sedative hypnotics indicated for sleep (e.g.,
`
`
`
`
`
`
`
`eszopiclone, zaleplon, zolpidem, temazepam, suvorexant,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 6.
`
`
`
` 7.
`
`
`
`
`
` U.S. Food and Drug Administration
`
`
` Silver Spring, MD 20993
`
` www.fda.gov
`
`Reference ID: 5310690
`
`

`

`
` NDA 021196/S-43
`
` NDA 212690/S-12
`
` Page 9
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`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
`
`
`
`• 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. Analysis of serious adverse events and 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
`
`
`
`
`
`
`
`
`
`
` date, case report ID, age, gender, serious adverse event(s)
`
`
`
`
`
`
`
` reported, outcome (hospitalization or death), associated factor (i.e.,
`
`
`
`
`
` concurrent use with sedative hypnotics or alcohol, intentional
`
`
`
`
`
`
` misuse, abuse, overdose, diversion, or medication error) and if
`
`
`
`
`
`
`
` cases are considered related or not related to Xywav or Xyrem. All
`
`
`
`
`
`
`
`
` tables should include an overall narrative summary and analysis of
`
`
`
`
`
`
`
`
`
` the adverse events and data fields reported.
`
`
`
`
`
`
`
`i. All cases of death – include narrative summary of each death
`
`
`
`
`
`
`
`
`
`
`
`
` 1) Number, percentage, and type of RMRs, notifications,
`
`
`
`
`
`
`
` and alerts associated with any reported deaths.
`
`
`
`
`
`
`
` 2) Calculation of the overall, and age- and gender-specific
`
`
`
`
`
`
`
`
` mortality rates.
`
`
`
`
` 3) Calculation of the standardized mortality rates, adjusted
`
`
`
`
` for age and gender, using both the point estimates and
`
`
`
`
`
`
`
` the lower bounds of the 95% confidence intervals as the
`
`
`
`
`
` reference rates.
`
`
`
`
`
`
`
`
`
`
`
` U.S. Food and Drug Administration
`
`
` Silver Spring, MD 20993
`
` www.fda.gov
`
`Reference ID: 5310690
`
`

`

`
` NDA 021196/S-43
`
` NDA 212690/S-12
`
`
` Page 10
`
`
`
`
`
` Knowledge
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` ii. Serious adverse events with 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
`
`
` 2) Use with alcohol.
`
`
`
` 3) Intentional misuse
`
`
`
` 4) Abuse
`
`
`
` 5) Overdose
`
`
`
` 6) Medication error
`iii. Cases of sexual abuse – include narrative summary of each
`
`
`
`
`
`
`
`
`
`
`
` case
`
`
`
`
`
`
` iv. Proportion of discontinued patients who were associated with
`
`
` a report of a serious adverse event, including death
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 9. Knowledge, Attitude, and Behavior (KAB) Surveys of Patients,
`
`
`
` Caregivers, Pharmacists, and Healthcare Providers (to be
`
`
`
`
` submitted every other year beginning with the April 2023
`
`
`
`
`
`
` assessment)
`
`a. Assessment of patients'/caregivers', pharmacists’, 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
`
`
`
`
`
`
`
` 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.
`
`
`
`
`
`
` 10. 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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` U.S. Food and Drug Administration
`
`
` Silver Spring, MD 20993
`
` www.fda.gov
`
`Reference ID: 5310690
`
`

`

`
` NDA 021196/S-43
`
` NDA 212690/S-12
`
`
` Page 11
`
`
` Overall Assessment of REMS Effectiveness
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` 11. 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 meeting the goal or whether one or
`
`
`
`
`
`
`
`
`
`
`
`
`
` more such goals or such elements should be modified
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`
`
`
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`
`
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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.
`
`
`
`
`
`
`
`
`
`
`
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` We also remind you that you must submit a REMS assessment when you submit a
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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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` b) A determination of the implications of a change in the benefit-risk profile for the
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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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` 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) If you propose a REMS modification based on a change in the benefit-risk profile
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` or because of the new indication of use, submit an adequate rationale to support
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` the modification, including: Provision of the reason(s) why the proposed REMS
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` modification is necessary, the potential effect on the serious risk(s) for which the
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` REMS was required, on patient access to the drug, and/or on the burden on the
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` health care delivery system; and other appropriate evidence or data to support the
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` 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 REMS
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` modifications, provide a rationale for why the REMS does not need to be modified.
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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: 5310690
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`

`

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` NDA 021196/S-43
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` NDA 212690/S-12
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` Page 12
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` If the information provided in an assessment is insufficient to allow FDA to determine
` whether the REMS is meeting its goals or whether the REMS must be modified, FDA
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` may require the submission of a new assessment plan that contains the metrics and/or
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` methods necessary to make such a determination. Therefore, FDA strongly
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` recommends obtaining FDA feedback on the details of your proposed assessment plan
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` to ensure its success. To that end, we recommend that methodological approaches,
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` study protocols, other analysis plans and assessment approaches used to assess a
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` REMS program be submitted for FDA review as follows:
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` Submit your proposed audit plan and noncompliance plan for FDA review within 30
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` Prominently identify the submission with the following wording in bold capital letters at
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` the top of the first page of the submission:
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` NDA 212690; NDA 021196 REMS ASSESSMENT METHODOLOGY- AUDIT PLAN
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` and NONCOMPLIANCE PLAN.
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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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