CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
` NDA 21196/S-030
`
`
`
`
` Xyrem
`Trade Name:
`Sodium Oxybate
`Generic or Proper
`Name:
`
`
`Sponsor:
`
`Approval Date:
`
`Indication:
`
`
`Jazz Pharmaceuticals
`October 26, 2018
`For the treatment of cataplexy or excessive daytime
`sleepiness to pediatric patients 7 years of age and older
`with narcolepsy.
`
`

`

`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`NDA 21196/S-030
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Clinical Review(s)
`Product Quality Review(s)
`Non-Clinical Review(s)
`Statistical Review(s)
`Clinical Microbiology / Virology Review(s)
`Clinical Pharmacology Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`X
`X
`X
`
`
`
`
`X
`
`
`X
`
`X
`X
`
`
`
`
`

`

`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`APPLICATION NUMBER:
`
`NDA 21196/S-030
`NDA 21196/S-030
`
`APPROVAL LETTER
`APPROVAL LETTER
`
`

`

`  
`

 

 

   
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`
`

`

`NDA 021196/S-030
`Page 2
`
`CONTENT OF LABELING
`
`Information on submitting SPL files using eList may be foundin the guidancefor industrytitled
`“SPL Standard for Content of Labeling Technical Qs and As”at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UC
`M072392.pdf.
`
`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 hasnotyet issued an action letter, with
`the content of labeling [21 CFR 314.50()(1)G)] 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 copythat showsall
`changes, as well as a clean Microsoft Word version. The marked-up copy should provide
`appropriate annotations, including supplement number(s) and annualreport date(s).
`
`Werequest that the labeling approved today be available on your website within 10 days of receipt
`of this letter.
`
`Assoon aspossible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(1)] in structured product labeling (SPL) format using the FDA automated
`drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. 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 enclosedlabeling.
`
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`RISK EVALUATION AND MITIGATION STRATEGY
`
`MS) REQUIREMENTS
`
`The REMSfor Xyrem wasoriginally approved on February 27, 2015, and the most recent
`modification was approved on July 15, 2015. The REMSconsists of a Medication Guide,
`elements to assure safe use, an implementation system, and a timetable for submission of
`assessments of the REMS. Your proposed modifications to the REMSconsist primarily of
`modifications to the REMS document and appended materials to align with labeling changes
`related to the new pediatric indication.
`
`In accordance with section 505-1 of the FDCA, we have determinedthat the following additional
`REMSmodifications are necessary to minimize burden on the healthcare delivery system of
`complying with the REMS:
`
`Medication Guide: We have determined that maintaining the Medication Guideaspart of the
`approved labeling is adequate to address the serious and significant public health concern and
`meets the standard in 21 CFR 208. Therefore,it is no longer necessary to include the Medication
`
`Reference ID: 4341394
`
`

`

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`

`NDA 021196/S-030
`Page 4
`
`o Numberofpatients by current enrolled prescriber.
`
`Certified Pharmacy
`
`o
`
`Ifthe Certified Pharmacy was decertified during the reporting period and
`reasons for decertification.
`
`1.b. Dispensing and compliance data (totals for the current REMSassessment reporting
`period and cumulative totals from approvalof the finalized REMS)
`
`Jazz Pharmaceuticals will monitor and track shipping and handling of XYREMandreport to
`FDAthefollowing:
`
`Total numberof prescriptions
`
`Total numberof bottles and shipments sent
`
`Total numberoffirst-time fills and refills
`
`Numberof shipments lost in delivery (and unrecovered) with number of DEA 106 Forms
`and RMRscompleted
`
`Numberofpatients prescribed a daily dose greater than 9 g
`
`Numberofprescriptionsfilled from a prescriber who was not enrolled
`
`Numberofprescriptions for more than a 30 days’ supply (first fill) or more than a 90
`days’ supply (refills) and reasons
`
`o Numberof disenrolled prescribers who were associated with a XYREM
`prescription and numberof disenrolled prescribers associated with a XYREM
`shipment
`
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`
`Number of RMRssubmitted to the sponsor
`
`o Numberof patients with an RMR
`
`o Numberofpatients with multiple RMRs
`
`o Numberof alerts generated from RMRs
`
`o Number of RMRsgenerated from early refill requests
`
`o Number of RMRsgenerated for other reasons(list reasons)
`
`o Numberof prescriber-related RMRs
`
`Numberof patients with overlapping prescriptions (more than oneactive prescription)
`
`Numberof duplicate patients who were shipped XYREM under morethan one name or
`identifier
`
`Numberof patients who were shipped XYREMafter being disenrolled
`
`Numberof patients who requested an early refill and reason for the request
`
`o Numberof requests approved
`
`o Numberof requests denied by the prescriber
`
`Reference ID: 4341394
`
`

`

`NDA 021196/S-030
`Page 5
`
`o Number of requests denied by the Certified Pharmacy
`
`o Numberofpatients with multiple requests for early refills
`
`Numberofinitial shipments sent to patients without completion of the XYREM REMS
`Program Patient Counseling Checklist
`
`Summary table from XYREM REMSProgram Patient Counseling Checklists of the
`numberof patients taking the following concomitant medications and who
`subsequently received at least one shipment of XYREM:
`
`o Sedative hypnotics
`
`o Alcohol
`
`o Other potentially interacting agents:
`
`=
`
`Sedating antidepressants, antipsychotics, or anti-epileptics
`
`= General anesthetic
`
`=" Muscle relaxants
`
`" Opioid analgesics
`
`« Divalproex sodium or other valproate drug (e.g., valproic acid)
`
`=
`
`Illicit CNS depressants (e.g., heroin or gamma-hydroxybutyrate [GHB])
`
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`ÿÿÿ
`>?@?A?BC?ÿEFGÿHIHJIKH
`
`Summary table from XYREM REMSProgram Patient Counseling Checklists of the
`numberof patients who have been diagnosed with the following conditions and who
`subsequently received at least one shipment of XYREM:
`
`o Sleep apnea
`
`o Asthma, COPD,or other conditions affecting the respiratory system
`
`Numberof notifications by pharmacists to prescribers for the following situations
`and the outcome of the notification (dispensed XYREM,counseled patient, and
`summary of other actions):
`
`o Use with contraindicated medications (concomitant sedative hypnotics)
`
`o Use with other concomitant CNS-depressant medications (sedating
`antidepressants or antipsychotics, sedating anti-epileptics, general anesthetics,
`muscle relaxants, opioid analgesics, or illicit CNS depressants)
`
`o Patient report of alcohol use
`
`o Patient report of diagnosis of sleep apnea
`
`o Patient report of diagnosis of asthma, COPD,or other conditions affecting breathing
`
`o Suspected abuse, misuse, or diversion
`
`o Alerts regarding potential abuse, misuse, or diversion on the patient profiles
`
`o Prescription error
`
`o Early refill requests
`
`Reference ID: 4341394
`
`

`

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`

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`
`

`

`NDA 021196/S-030
`Page 7
`
`For the 12-month assessmentafter approvalof the finalized REMSandall subsequent
`REMSassessments submitted thereafter:
`
`1.g- Assessment of patients’and prescribers’ understandingof the following:
`
`Therisk of significant CNS and respiratory depression associated with
`XYREMeven at recommendeddoses
`
`The contraindicated uses of XYREM
`
`The potential for abuse, misuse, and overdose associated with XYREM
`
`Thesafe use, handling, and storage of XYREM
`
`The XYREM REMSProgram requirements.
`
`Patient and prescriber knowledge assessments are described in Sections 5.j and 5.k and provided
`in Appendix 2 of the REMSsupporting document.
`
`patient access or the healthcare system the company will submit a prior approval supplementto
`FDAproposing a revised REMSprior to implementing any changesto the approved REMS.
`
` ÿ
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`
`1.h. Certified Pharmacy knowledge assessments
`
`Assessmentof the understanding ofall Certified Pharmacystaff involved in the
`XYREM REMSProgram ofthe following:
`
`o The approved indications for XYREM
`
`o The abuse potential of XYREM
`
`o The contraindication of use of XYREM with sedative hypnotics and alcohol
`
`o The risk of significant CNS and respiratory depression associated with
`XYREMeven at recommendeddoses
`
`o The XYREM REMSProgram requirements
`
`o The types of information in the Central Database
`
`o Monitoring patients for signs of inappropriate prescribing, abuse, misuse, and
`diversion
`
`o The requirementto report all potential adverse events
`
`Assessment of pharmacists’ understanding of the following:
`
`o Requirements for limiting the first prescription to a one-month supply and
`subsequent prescriptions to no more than a three-month supply
`
`o Prescriber notification requirements
`
`o Requirements for validating the prescriber’s and patient’s enrollment
`
`o The ability to disenroll a prescriber or patient for noncompliance with the
`XYREM REMSProgram
`
`o Requirements for validating a XYREMprescription
`
`o Requirement for completing the XYREM REMSProgram Patient Counseling
`Checklist
`
`Reference ID: 4341394
`
`

`

`NDA 021196/S-030
`Page 8
`
`o Actions takenif the patient is using a contraindicated medication or other
`potentially interacting agent
`
`o Patient counseling information
`
`o Requirements to consult with the prescriber whenclarification is needed for a
`prescription and/or for an early refill request
`
`o Requirements for completing XYREM REMSProgram RMRs
`
`o Requirements for shipment of XYREMto the patient
`
`The XYREM REMSProgram Certified Pharmacy Knowledge Assessments are described in
`Section 5.1 and provided in Appendix 1 of the REMSsupporting document.
`
`1.i. A summary report of audits of the Certified Pharmacy conducted during the
`assessmentperiod
`
`Jazz Pharmaceuticals will provide a summary ofthe audits of the Certified Pharmacy that were
`conducted during the assessmentperiod, including the topics covered during the audit and the
`number of significant observations.
`
`1.j. Patient knowledge survey
`
`A representative sample of patients will be surveyed using a structured questionnaire annually
`following the first formal XYREM REMSProgram assessment. The objective is to assess their
`knowledge ofthe key risk information and REMSrequirements, including the seriousrisks
`associated with XYREM.The knowledgesurvey will be conducted according to industry
`standards and will assess patients and caregivers of pediatric patients who have received
`XYREMforat least one month.
`
` ÿ
`

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`
`The protocol includes details on the sample size and associated confidence intervals for various
`response rates: selection criteria for defining the sample, the expected numberofpatients or
`caregivers to be surveyed, recruitment strategies, how and whenthe surveyswill be
`administered, an explanation of controls used to minimize bias, an explanation of the controls
`used to compensate for the limitations associated with the methodology, the survey instruments
`(questionnaires and/or moderator’s guide), and any available background information on testing
`of survey questions andcorrelation to the information of the Medication Guide, the XYREM
`REMSProgram Patient Quick Start Guide, and the XYREM REMSProgram Brochure for
`Pediatric Patient and Their Caregivers.
`
`Survey data collection will be completed approximately 10 months after implementation of the
`REMS,thus enabling XYREM knowledge assessments to be submitted to the FDA at the
`12-month REMSassessment,at all subsequent REMSassessments, and as needed following
`substantive changes to the REMS-related educational materials. The protocol for the patient
`survey is provided in Appendix 2 of the REMSsupporting document.
`
`Data from the patient survey will be reported as descriptive statistics for the survey
`administration, study population, and survey questions. Results will include numbersofpatients,
`patient contacts by the Certified Pharmacy, patient demographics, and response data showing
`level of patient understanding of the risks associated with XYREMuse.
`
`Reference ID: 4341394
`
`

`

`NDA 021196/S-030
`Page 9
`
`1.k. Prescriber knowledge survey
`
`A representative sample of prescribers will be surveyed annually following the first formal
`XYREM REMSProgram assessment. The objective is to assess their knowledge of the XYREM
`REMSkeyrisk information and program requirements. The goal of this survey initiative will be
`to determine whether the XYREM REMSElements to Assure Safe Useare effective in
`educating prescribers about the key risk information and the procedures to be followed in the
`XYREM REMS. Thesurvey will be conducted according to industry standards and will assess
`prescribers who have prescribed XYREM.
`
`The protocol includes details on the sample size and the associated confidence intervals for
`response rates, selection criteria for defining the sample, the expected numberofprescribers to
`be surveyed, recruitment strategies, how and when the surveys will be administered, an
`explanation of the controls used to minimize bias, an explanation of the controls used to
`compensate for the limitations associated with the methodology, the survey instruments
`(questionnaires and/or moderator’s guide), and any available background information on testing
`of survey questions and correlation to the messagesofthe prescribing information and XYREM
`REMSProgram Prescriber Brochure.
`
`Surveydata collection will be completed approximately 10 months following implementation of
`the REMS,thus enabling XYREM knowledge assessments to be submitted to the FDA at the
`12-month REMSassessment,at all subsequent assessments, and as needed following substantive
`changes to the REMS-related educational materials. The protocol for the prescriber survey is
`provided in Appendix 2 of the REMSsupporting document. Results will include numbers of
`prescribers, prescriber contacts by the Certified Pharmacy, prescriber demographics, and
`response data showing level of prescriber understanding of safe use of XYREM,including
`approvedindications; contraindications; risk of severe CNS/respiratory depression; abuse,
`misuse, and diversion; and death.
`
` ÿ
`

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