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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 021196/S-030
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`Food and Drug Administration
`Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Jazz Pharmaceuticals
`Attention: Wheatley Spence, MS
`Associate Director, Regulatory Affairs
`1818 Market Street, Suite 2350
`Philadelphia, PA 19103
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`Dear Ms. Spence:
`
`Please refer to your Supplemental New Drug Application (sNDA) dated April 27, 2018, received
`April 27, 2018, and your amendments, submitted under section 505(b) of the Federal Food, Drug,
`and Cosmetic Act (FDCA) for Xyrem® (sodium oxybate) oral solution, 500 mg/mL.
`
`We acknowledge receipt of your risk evaluation and mitigation strategy (REMS) assessment dated
`May 18, 2018.
`
`This Prior Approval supplemental new drug application proposes to expand the use of Xyrem for
`the treatment of cataplexy or excessive daytime sleepiness to pediatric patients 7 years of age and
`older with narcolepsy, and proposes modifications to the approved Xyrem risk evaluation and
`mitigation strategy (REMS).
`
`APPROVAL & LABELING
`
`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
`
`We note that your April 27, 2018, submission includes final printed labeling (FPL) for your
`Prescribing Information, Instructions for Use, and Medication Guide. We have not reviewed this
`FPL. You are responsible for assuring that the wording in this FPL is identical to that of the
`approved content of labeling in the structured product labeling (SPL) format.
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`WAIVER OF ½ PAGE LENGTH REQUIREMENT FOR HIGHLIGHTS
`
`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`Prescribing Information. This waiver applies to all future supplements containing revised labeling
`unless we notify you otherwise.
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`Reference ID: 4341394
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`NDA 021196/S-030
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`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, submit the 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
`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 enclosed labeling.
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`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/UC
`M072392.pdf.
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications that include labeling 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.
`
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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, and the most recent
`modification was approved on July 15, 2015. The REMS consists 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 REMS consist primarily of
`modifications to the REMS document and appended materials to align with labeling changes
`related to the new pediatric indication.
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`In accordance with section 505-1 of the FDCA, we have determined that the following additional
`REMS modifications are necessary to minimize burden on the healthcare delivery system of
`complying with the REMS:
`
`Medication Guide: We have determined that maintaining the Medication Guide as part 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
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`Reference ID: 4341394
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`NDA 021196/S-030
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`Guide as an element of the approved REMS to ensure that the benefits of Xyrem outweigh its
`risks. The Medication Guide will continue to be part of the approved labeling in accordance with
`21 CFR 208. Like other labeling, Medication Guides are subject to the safety labeling change
`provisions of section 505(o)(4) of the FDCA.
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`Your proposed modified REMS, submitted on April 27, 2018, amended and appended to this
`letter, is approved. The modified REMS consists of elements to assure safe use, an implementation
`system, and a timetable for submission of assessments of the REMS.
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`The timetable for submission of assessments of the REMS remains the same as that approved on
`February 27, 2015.
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`The revised XYREM REMS Assessment Plan will include, but is not limited to, the following
`information:
`For the 6-month assessment after approval of the finalized REMS and all subsequent
`REMS assessments submitted thereafter:
`1.a. Program statistics (totals for the current REMS assessment reporting period and
`cumulative totals from approval of the finalized REMS, if feasible)
`Jazz Pharmaceuticals will report to FDA the following:
`• Patients:
`o Number of patients enrolled
`o Number of patients enrolled who received at least one shipment of XYREM
`o Number of duplicate patients detected by the Certified Pharmacy
`o Number of patients associated with more than one prescriber during their therapy
`o Number of patients who were disenrolled from the program and reasons for
`disenrollment
`o Number of patients who have discontinued XYREM after receiving at least one
`shipment of XYREM
` Proportion of discontinued patients who were associated with a report of a
`serious adverse event, including death
`o Age and gender of enrolled patients.
`• Prescribers:
`o Number of prescribers certified
`o Number of certified prescribers who have written at least one prescription for XYREM
`o Number of certified prescribers by specialty
`o Number of certified prescribers who were disenrolled during the reporting
`period and reasons for disenrollment
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`Reference ID: 4341394
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`o Number of disenrolled prescribers who were associated with a XYREM
`prescription and number of disenrolled prescribers associated with a XYREM
`shipment
`o Number of patients by current enrolled prescriber.
`• Certified Pharmacy
`If the Certified Pharmacy was decertified during the reporting period and
`o
`reasons for decertification.
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`1.b. Dispensing and compliance data (totals for the current REMS assessment reporting
`period and cumulative totals from approval of the finalized REMS)
`Jazz Pharmaceuticals will monitor and track shipping and handling of XYREM and report to
`FDA the following:
`• Total number of prescriptions
`• Total number of bottles and shipments sent
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`• Total number of first-time fills and refills
`• Number of shipments lost in delivery (and unrecovered) with number of DEA 106 Forms
`and RMRs completed
`• Number of patients prescribed a daily dose greater than 9 g
`• Number of prescriptions filled from a prescriber who was not enrolled
`• Number of prescriptions for more than a 30 days’ supply (first fill) or more than a 90
`days’ supply (refills) and reasons
`• Number of RMRs submitted to the sponsor
`o Number of patients with an RMR
`o Number of patients with multiple RMRs
`o Number of alerts generated from RMRs
`o Number of RMRs generated from early refill requests
`o Number of RMRs generated for other reasons (list reasons)
`o Number of prescriber-related RMRs
`• Number of patients with overlapping prescriptions (more than one active prescription)
`• Number of duplicate patients who were shipped XYREM under more than one name or
`identifier
`• Number of patients who were shipped XYREM after being disenrolled
`• Number of patients who requested an early refill and reason for the request
`o Number of requests approved
`o Number of requests denied by the prescriber
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`Reference ID: 4341394
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`o Number of requests denied by the Certified Pharmacy
`o Number of patients with multiple requests for early refills
`• Number of initial shipments sent to patients without completion of the XYREM REMS
`Program Patient Counseling Checklist
`• Summary table from XYREM REMS Program Patient Counseling Checklists of the
`number of 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])
`
`• Summary table from XYREM REMS Program Patient Counseling Checklists of the
`number of 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
`• Number of 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
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`Reference ID: 4341394
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`NDA 021196/S-030
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`1.c. Pharmacovigilance/surveillance (totals for the current REMS assessment reporting
`period and cumulative totals from start of program, if feasible)
`Jazz Pharmaceuticals will provide to FDA the following:
`• Summary tables of the number of reports of serious adverse events to include all
`outcomes of death, emergency department visits (when admitted to hospital), or
`hospitalizations resulting from or associated with the following:
`o Use with concurrent sedative hypnotics and alcohol
`Intentional misuse
`o
`o Abuse
`o Overdose
`o Medication error
`• Cases of Sexual Abuse.
`
`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.
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`1.d. Program infrastructure and performance surveillance (information for the current
`REMS assessment reporting period)
`Jazz Pharmaceuticals will provide to FDA the following:
`• Call center report with number of calls received
`• Summary of frequently asked questions
`• Summary of any REMS-related problems identified
`• Summary of program or system problems and a description of any corrective actions taken
`
`1.e. A report on periodic assessments of the dispensing of the Medication Guide in
`accordance with 21 CFR 208.24
`Jazz Pharmaceuticals will report to FDA on the dispensing of the Medication Guide as part of
`the REMS assessments.
`
`1.f. With respect to REMS goals, an assessment of the extent to which the Elements to
`Assure Safe Use are meeting the goals or whether the goals or such elements should
`be modified
`Jazz Pharmaceuticals will institute a system of oversight and review to evaluate whether the
`REMS is meeting its goals. If Jazz Pharmaceuticals determines, based on the results of the
`assessments, surveillance, and knowledge assessments, that modifications to the XYREM
`REMS program are needed (or that an element is no longer needed) to continue to ensure that
`the benefits of XYREM outweigh the risks and that the REMS is not unduly burdensome to
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`Reference ID: 4341394
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`NDA 021196/S-030
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`patient access or the healthcare system the company will submit a prior approval supplement to
`FDA proposing a revised REMS prior to implementing any changes to the approved REMS.
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`For the 12-month assessment after approval of the finalized REMS and all subsequent
`REMS assessments submitted thereafter:
`1.g. Assessment of patients’and prescribers’ understanding of the following:
`• The risk of significant CNS and respiratory depression associated with
`XYREM even at recommended doses
`• The contraindicated uses of XYREM
`• The potential for abuse, misuse, and overdose associated with XYREM
`• The safe use, handling, and storage of XYREM
`• The XYREM REMS Program requirements.
`Patient and prescriber knowledge assessments are described in Sections 5.j and 5.k and provided
`in Appendix 2 of the REMS supporting document.
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`1.h. Certified Pharmacy knowledge assessments
`• Assessment of the understanding of all Certified Pharmacy staff involved in the
`XYREM REMS Program of the 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
`XYREM even at recommended doses
`o The XYREM REMS Program requirements
`o The types of information in the Central Database
`o Monitoring patients for signs of inappropriate prescribing, abuse, misuse, and
`diversion
`o The requirement to 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 REMS Program
`o Requirements for validating a XYREM prescription
`o Requirement for completing the XYREM REMS Program Patient Counseling
`Checklist
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`Reference ID: 4341394
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`NDA 021196/S-030
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`o Actions taken if the patient is using a contraindicated medication or other
`potentially interacting agent
`o Patient counseling information
`o Requirements to consult with the prescriber when clarification is needed for a
`prescription and/or for an early refill request
`o Requirements for completing XYREM REMS Program RMRs
`o Requirements for shipment of XYREM to the patient
`The XYREM REMS Program Certified Pharmacy Knowledge Assessments are described in
`Section 5.l and provided in Appendix 1 of the REMS supporting document.
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`1.i. A summary report of audits of the Certified Pharmacy conducted during the
`assessment period
`Jazz Pharmaceuticals will provide a summary of the audits of the Certified Pharmacy that were
`conducted during the assessment period, including the topics covered during the audit and the
`number of significant observations.
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`1.j. Patient knowledge survey
`A representative sample of patients will be surveyed using a structured questionnaire annually
`following the first formal XYREM REMS Program assessment. The objective is to assess their
`knowledge of the key risk information and REMS requirements, including the serious risks
`associated with XYREM. The knowledge survey will be conducted according to industry
`standards and will assess patients and caregivers of pediatric patients who have received
`XYREM for at least one month.
`The protocol includes details on the sample size and associated confidence intervals for various
`response rates: selection criteria for defining the sample, the expected number of patients or
`caregivers to be surveyed, recruitment strategies, how and when the surveys will 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 and correlation to the information of the Medication Guide, the XYREM
`REMS Program Patient Quick Start Guide, and the XYREM REMS Program 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 REMS assessment, at all subsequent REMS assessments, 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 REMS supporting document.
`Data from the patient survey will be reported as descriptive statistics for the survey
`administration, study population, and survey questions. Results will include numbers of patients,
`patient contacts by the Certified Pharmacy, patient demographics, and response data showing
`level of patient understanding of the risks associated with XYREM use.
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`Reference ID: 4341394
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` 1.k. Prescriber knowledge survey
`A representative sample of prescribers will be surveyed annually following the first formal
`XYREM REMS Program assessment. The objective is to assess their knowledge of the XYREM
`REMS key risk information and program requirements. The goal of this survey initiative will be
`to determine whether the XYREM REMS Elements to Assure Safe Use are effective in
`educating prescribers about the key risk information and the procedures to be followed in the
`XYREM REMS. The survey 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 number of prescribers 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 messages of the prescribing information and XYREM
`REMS Program Prescriber Brochure.
`Survey data 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 REMS assessment, 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 REMS supporting 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
`approved indications; contraindications; risk of severe CNS/respiratory depression; abuse,
`misuse, and diversion; and death.
`1.l. Certified Pharmacy training knowledge assessments
`All Certified Pharmacy staff involved in the XYREM REMS Program will be required to
`complete Module A of the XYREM REMS Program Certified Pharmacy Training at least
`annually. In addition, all pharmacists involved in dispensing XYREM under the XYREM
`REMS Program will be required to complete Module B of the XYREM REMS Program
`Certified Pharmacy Training at least annually. A knowledge assessment must be successfully
`completed for each module as part of the training requirement. Successful completion of the
`knowledge assessments requires an 80% accuracy level. The Module A and Module B
`Knowledge Assessments are provided in Appendix 1 of the REMS supporting document.
`
`The following metrics will assess the post-training knowledge assessment:
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`A. Number of completed post-training knowledge assessments including method of
`completion and number of attempts to complete by module
`B. Summary of the most frequently missed post-training knowledge assessment questions
`by module
`C. A summary of potential comprehension or perception issues identified with the post-
`training knowledge assessment by module
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`NDA 021196/S-030
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`Reference ID: 4341394
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`NDA 21196/S-030
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`1.m. Surveillance and monitoring
`Jazz Pharmaceuticals will periodically monitor available safety databases, such as those
`established by), the American Association of Poison Control Centers (AAPCC) National
`Poison Data System (NPDS), the National Forensic Laboratory Information System, the
`National Drug Threat Assessment, and the for any information regarding abuse, misuse, or
`diversion of sodium oxybate. Any relevant information will be included in the REMS
`assessments.
`
`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 1 or more such
`goals or such elements should be modified.
`
`We remind you that in addition to the REMS assessments submitted according to the timetable in
`the approved REMS, you must include an adequate rationale to support a proposed REMS
`modification for the addition, modification, or removal of any goal or element of the REMS, as
`described in section 505-1(g)(4) of the FDCA.
`
`We also remind you that you must submit a REMS assessment when you submit a supplemental
`application for a new indication for use, as described in section 505-1(g)(2)(A) of the FDCA.
`This assessment should include:
`
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`a) An evaluation of how the benefit-risk profile will or will not change with the new
`indication;
`b) A determination of the implications of a change in the benefit-risk profile for the current
`REMS;
`c) If the new indication for use introduces unexpected risks: A description of those risks
`and an evaluation of whether those risks can be appropriately managed with the currently
`approved REMS.
`d) If a REMS assessment was submitted in the 18 months prior to submission of the
`supplemental application for a new indication for use: A statement about whether the
`REMS was meeting its goals at the time of that last assessment and if any modifications
`of the REMS have been proposed since that assessment.
`e) If a REMS assessment has not been submitted in the 18 months prior to submission of the
`supplemental application for a new indication for use: Provision of as many of the
`currently listed assessment plan items as is feasible.
`f) If you propose a REMS modification based on a change in the benefit-risk profile or
`because of the new indication of use, submit an adequate rationale to support the
`modification, including: Provision of the reason(s) why the proposed REMS
`modification is necessary, the potential effect on the serious risk(s) for which the REMS
`was required, on patient access to the drug, and/or on the burden on the health care
`delivery system; and other appropriate evidence or data to support the proposed change.
`Additionally, include any changes to the assessment plan necessary to assess the
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`Reference ID: 4341394
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`NDA 21196/S-030
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`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 assessment
`instruments or methodology, you should update the REMS supporting document to include
`specific assessment instrument and methodology information at least 90 days before the
`assessments will be conducted. Updates to the REMS supporting document may be included in a
`new document that references previous REMS supporting document submission(s) for
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
`REMS supporting document, with all changes marked and highlighted. Prominently identify the
`submission containing the assessment instruments and methodology with the following wording
`in bold capital letters at the top of the first page of the submission:
`
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`NDA 21196 REMS ASSESSMENT METHODOLOGY
`
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`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 21196 REMS ASSESSMENT
`
`
`or
`
`or
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`NEW SUPPLEMENT FOR NDA 21196/S-000
`CHANGES BEING EFFECTED IN 30 DAYS
`PROPOSED MINOR REMS MODIFICATION
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`
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`NEW SUPPLEMENT FOR NDA 21196/S-000 PRIOR APPROVAL
`SUPPLEMENT
`PROPOSED MAJOR REMS MODIFICATION
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`Reference ID: 4341394
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`NEW SUPPLEMENT FOR NDA 21196/S-000
`PRIOR APPROVAL SUPPLEMENT
`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
`SUBMITTED IN SUPPLEMENT XXX
`
`or
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`or
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 21196/S-000
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
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`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:
`
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`REMS REVISIONS FOR NDA 21196
`
`
`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.
`
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`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.
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`Reference ID: 4341394
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`NDA 21196/S-030
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the Prescribing Information to:
`
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion (OPDP)
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
`
`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
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`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, call Vandna Kishore, Regulatory Project Manager, at
`Vandna.Kishore@fda.hhs.gov.
`
`
`
`
`
`
`
`
`Reference ID: 4341394
`
`

`

`NDA 21196/S-030
`Page 14
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`
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`ENCLOSURE(S):
`Content of Labeling
`Prescribing Information
`Medication Guide
`Instructions for Use
`REMS
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Eric Bastings, MD
`Deputy Director
`Office of Drug Evaluation I
`Center for Drug Evaluation and Research
`
`Reference ID: 4341394
`
`

`

`Signature Page 1 of 1
`--------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`NICHOLAS A KOZAUER on behalf of ERIC P BASTINGS
`10/26/2018
`
`Reference ID: 4341394
`
`(
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`
`