`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 201655/S-024, S-025
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring, MD 20993
`
`SUPPLEMENT APPROVAL
`
`
`
`Endo Pharmaceuticals, Inc.
`1400 Atwater Drive
`Malvern, PA 19355
`
`
`Attention: Harris Rotman
`Vice President, Regulatory Affairs
`
`
`Dear Mr. Rotman:
`
`Please refer to the following Supplemental New Drug Applications (sNDAs) dated and received
`March 30, 2018, and June 26, 2018, and your amendments, submitted under section 505(b)of the
`Federal Food, Drug, and Cosmetic Act (FDCA) for OPANA ER (oxymorphone hydrochloride)
`Extended-Release Tablets.
`
`We also refer to our letter dated September 28, 2017, notifying you that under section 505-1 of
`the FDCA, we have determined that your approved Extended-Release and Long-Acting
`(ER/LA) Opioid Analgesics Risk Evaluation and Mitigation Strategy (REMS) must be modified
`to ensure that training is made available to healthcare providers involved in the treatment and
`monitoring of patients with pain, and to implement the FDA Education Blueprint for Health Care
`Providers Involved in the Treatment and Monitoring of Patients with Pain to ensure the benefits
`of the drugs outweigh the risks of adverse outcomes (addiction, unintentional overdose, and
`death) resulting from inappropriate prescribing, abuse, and misuse.
`
`Finally, we refer to our letter dated June 1, 2018, notifying you, under section 505(o)(4) of the
`FDCA, of new safety information that we believe should be included in the labeling for OPANA
`ER. This information pertains to the addition of the REMS program details to product labeling
`for the class of opioid analgesics intended for use in the outpatient setting.
`
`Supplement S-024 provides for the REMS modification required under section 505-1 of the
`FDCA, consistent with our September 28, 2017, letter.
`
`Supplement S-025 provides for revisions to the labeling for OPANA ER consistent with our June
`1, 2018, Safety Labeling Change Notification letter.
`
`
`
`
`
`Reference ID: 4321317
`
`

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`NDA 201655/S-024/S-025
`Page 2
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`APPROVAL & LABELING
`
`We have completed our review of these supplemental applications, as amended. They are
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text.
`
`WAIVER OF HIGHLIGHTS SECTION
`
`Please note that we have previously granted a waiver of the requirements of 21 CFR
`201.57(d)(8) regarding the length of Highlights of prescribing information.
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling, with the addition of any labeling changes
`in pending “Changes Being Effected” (CBE) supplements, as well as annual reportable changes
`not included in the enclosed labeling.
`
`Information on submitting SPL files using eList may be found in the guidance for industry titled
`“SPL Standard for Content of Labeling Technical Qs and As” at
`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.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 has not yet issued an action letter,
`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
`changes approved in this supplemental application, as well as annual reportable changes and
`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
`should provide appropriate annotations, including supplement number(s) and annual report
`date(s).
`
`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS)
`
`The REMS for Extended-Release and Long-Acting (ER/LA) opioid analgesics products, of
`which OPANA ER is a member, was originally approved on July 9, 2012, and the most recent
`REMS modification was approved on May 26, 2017. The REMS consists of a Medication
`Guide, elements to assure safe use, and a timetable for submission of assessments of the REMS.
`
`Reference ID: 4321317
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`

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`NDA 201655/S-024/S-025
`Page 3
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`In order to ensure the benefits of certain opioid analgesics intended for use in the outpatient
`setting outweigh their risks of adverse outcomes (addiction, unintentional overdose, and death)
`resulting from inappropriate prescribing, abuse, and misuse, we determined that you were
`required to make the REMS modifications outlined in our REMS Modification letter dated
`September 28, 2017.
`
` on March 26,
`Your proposed modified REMS, submitted to Drug Master File (DMF)
`2018, amended and appended to this letter, is approved. The modified REMS consists of a
`Medication Guide, elements to assure safe use, and a timetable for submission of assessments of
`the REMS.
`
`This REMS uses a shared system for the elements to assure safe use and the REMS assessments.
`This shared system, now known as the Opioid Analgesics REMS Program, includes the products
`listed on the FDA REMS website, available at
`https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm
`
`Other products may be added in the future if additional NDAs or ANDAs are approved.
`
`The revised REMS assessment plan must include, but is not limited to, the following:
`
`
`1. REMS Outreach and Communication
`
`
`a. For each healthcare provider (e.g., prescriber, pharmacist) to be sent information
`regarding REMS-compliant accredited continuing education (CE), provide the
`date when the letters were sent; the number of letters electronically sent, received,
`undeliverable, and opened; and the number of letters mailed and undeliverable
`
`b. For each professional society, association, and licensing board to be sent
`information regarding REMS-compliant accredited CE, provide the number of
`letters electronically sent, received, undeliverable, and opened; and the number of
`letters mailed and undeliverable
`
`
`
`2. REMS Implementation and Operations
`
`
`a. Status of grants
`
`
`i. The status of the request for proposals for grants for REMS-compliant
`accredited CE including:
`
`
`1. Request for Application (RFA) issued: date and number of
`applications submitted in response to each RFA
`2. RFAs awarded: date, number, and name of grantee
`3. Date/timeframe next RFA to be issued
`
`
`Reference ID: 4321317
`
`(b) (4)
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`NDA 201655/S-024/S-025
`Page 4
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`ii. The status of the requests for proposals for any grants to CE Providers or
`other CE organizations with expertise in assessing CE outcomes who
`agree to conduct evaluations of health care providers who have taken
`REMS-compliant accredited CE funded under this REMS.
`
`b. Grant review committee
`
`
`i. Individuals from the REMS Program Companies (RPC) reviewing grants
`will include the following clinical licensures: pharmacists, nurses,
`physicians. Additionally there will be involvement by individuals with
`regulatory and pharmacovigilance experience. The job title, licensure and
`professional degree of individuals will be provided for each grant review
`cycle.
`
`ii. Include any external members (non RPC) involved in the grant review,
`including those from the broad-based CE community. Provide the job
`title, licensure and professional degree of the individual for each grant
`review cycle.
`
`c. For CE programs awarded during the assessment period:
`
`
`i. Description of each grantee and projected number of completers
`
`ii. For the first assessment, the date the first program based upon the FDA
`Opioid Analgesic REMS Education Blueprint for Health Care Providers
`Involved in the Treatment and Monitoring of Patients with Pain (“FDA
`Blueprint”), became available
`
`iii. Description of CE program:
`
`1. Level of outcome the activity1 is designed to impact
`2. CE format (live, webinar, etc.)
`3. Duration of activity for live or webinar activities
`4. Average duration to complete for internet/enduring activities
`5. Education methods and tools (case-based, multimedia, didactic,
`interactive, adaptive, etc.)2,3
`
`iv. All reports submitted to the RPC by CE grantees during the assessment
`period.
`
`
`1 Stevenson R, Moore DE. Ascent to the Summit of the CME Pyramid. JAMA 2018;319(6):543-544
`2 Cervero R, Gaines J. The Impact of CME on Physician Performance and Patient Health Outcomes: An Updated
`Synthesis of Systematic Reviews J Contin Educ Health Prof 2015;35(2):131–138
`3 Agency for Research Health and Quality. (2007). Effectiveness of Continuing Medical Education. Retrieved May
`9, 2018, from https://archive.ahrq.gov/downloads/pub/evidence/pdf/cme/cme.pdf
`
`
`
`
`
`Reference ID: 4321317
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`

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`NDA 201655/S-024/S-025
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`d. Number of participants and completers during the assessment period; provide
`description of learners by standard learner category data4.
`
`e. Independent Audit: The results of independent audits of the CE. Audits must be
`conducted on a random sample of at least 10% of the REMS-compliant accredited
`CE funded under the Opioid Analgesic REMS and must include/evaluate:
`
`
`i. a description of the organization(s) conducting the audit(s)
`
`ii. whether the content of the REMS-compliant accredited CE covers all
`elements of the FDA Opioid Analgesic REMS Education Blueprint for
`Health Care Providers Involved in the Treatment and Monitoring of
`Patients with Pain (“FDA Blueprint”) approved as part of the REMS;
`
`
`
`
`
`
`
`iii. whether the integrated or post-course knowledge assessment measures
`knowledge of all sections of the FDA Opioid Analgesic REMS Education
`Blueprint for Health Care Providers Involved in the Treatment and
`Monitoring of Patients with Pain (“FDA Blueprint”); and
`
`iv. whether the REMS-compliant accredited CE was conducted in accordance
`with the Accreditation Council for Continuing Medication Education
`(ACCME) standards for CE or appropriate standards for accreditation
`bodies
`
`f. Concurrent Educational interventions
`
`
`i. For the year prior to the assessment period through the assessment period,
`provide an evaluation of the overall pain/opioid CE landscape including
`but not limited to:
`
`
`1. States requiring prescribers, pharmacists, or nurses to complete
`opioid or pain management continuing education for
`licensing/renewal of licensing:
`
`
`a. enumeration of these states and their requirements. for
`continuing education on either pain or safe opioid use,
`b. estimates of annual licensed prescribers in those states
`c. which, if any, opioid analgesic or ER/LA Opioid Analgesic
`REMS CE were permissible in which states, for prescribers
`to meet requirements
`
`
`4 Standard Continuing Education (CE) learner data to be captured by all CE Providers for Opioid Analgesic REMS
`includes geographic location (state of primary practice), DEA prescriber status (individual registration or
`institutional authorization), profession, practice area, and length of time in practice.
`
`Reference ID: 4321317
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`NDA 201655/S-024/S-025
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`2. Health systems, including government (DOD, VA, IHS, etc.), that
`require opioid or pain management continuing education; include
`number of completers if available
`
`3. Any additional available data on continuing education programs
`available during this time with a focus on pharmacological pain
`management or safe opioid use
`
`3. Health Outcomes and/or Surrogates of Health Outcomes
`
`
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`
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`Reference ID: 4321317
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`a. Surveillance and monitoring of data relating to opioid analgesic use, misuse,
`abuse, addiction, overdose, and death. Surveillance data should include the
`following:
`
`
`i. Nationally representative data or data from large stable populations on
`opioid analgesic misuse, abuse, addiction, overdose, and death, to allow
`reliable assessment of national trends and demographic patterns (e.g., age
`group specific rates and trends)
`
`ii. Both overall and drug-specific outcome rates, as available, in each data
`source
`
`iii. Data on trends and patterns of illicit opioid (e.g., heroin) use and related
`morbidity and mortality
`
`b. Evaluation of drug utilization patterns: Nationally-projected data on drug
`utilization trends and patterns, including an evaluation of trends in:
`
`
`i. Dispensing of opioid analgesics subject to the Opioid Analgesic REMS,
`by drug, age group, prescriber specialty
`
`ii. An evaluation of opioid tolerance for products that require patients to be
`opioid tolerant prior to use
`
`iii. An evaluation of concomitant prescribing of gabapentinoids,
`benzodiazepines, and other CNS depressants with opioid analgesics
`
`c. Evaluation of patient experiences around pain management
`
`d. An evaluation of patients’ experiences with acute and chronic pain management
`in various settings: this may include a survey, focus group, or other assessment of
`patient experience, including but not limited to access to coordinated pain
`management care, non-pharmacological options, and judicious and informed
`prescribing of opioids. The evaluation may also include an assessment of negative
`patient experiences, such as perceived overprescribing of opioids, providers’
`refusal to provide care, or forced rapid tapering or discontinuation
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`NDA 201655/S-024/S-025
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`e. Evaluation of prescriber behavior and patient outcomes: The results of an
`evaluation of the effect of REMS-compliant CE on prescriber behavior and
`patient outcomes. This evaluation should include the following:
`
`
`
`
`
`i. Development and use of metrics that assess prescriber behaviors and
`patient outcomes relating to key messages in the FDA Opioid Analgesic
`REMS Education Blueprint for Health Care Providers Involved in the
`Treatment and Monitoring of Patients with Pain (“FDA Blueprint”). The
`assessment should also include an evaluation of potential unintended
`adverse patient outcomes resulting from changes in prescribing practices
`(e.g., withdrawal symptoms or increased pain due to inappropriate rapid
`opioid tapering, patient abandonment, seeking of illicit opioids, suicide
`attempts/completion)
`
`
`ii. Use of an appropriate control group (i.e., providers who have not
`completed REMS-compliant accredited CE), and rigorous control for
`confounding, to allow an assessment of whether any observed changes in
`prescriber behaviors or patient outcomes can be attributed to the CE
`
`4. Knowledge
`
`
`a. Evaluation of CE participants: The results of evaluations to determine the impact
`of REMS-compliant accredited CE on participants’ knowledge, attitudes, and
`self-reported behavior around pain management and appropriate opioid
`prescribing. All evaluations should be representative and generalizable to the
`targeted health care professionals taking the REMS-compliant accredited CE and
`assess understanding of key elements from all sections of the FDA Opioid
`Analgesic REMS Education Blueprint for Health Care Providers Involved in the
`Treatment and Monitoring of Patients with Pain (“FDA Blueprint”). Multiple
`methodologies should be used, including but not limited to the following:
`
`
`i. Pre- and post-activity assessments using validated instruments. These
`assessments could be integrated into live, online, or multimedia formats
`using interactive approaches to enhance the educational value of the
`activity. Different versions or subsets of questions from a standardized
`assessment tool could be employed to cover all key messages and sections
`of the FDA Opioid Analgesic REMS Education Blueprint for Health Care
`Providers Involved in the Treatment and Monitoring of Patients with Pain
`(“FDA Blueprint”), in aggregate, while reducing the time burden for
`individual participants and allowing the assessment to be tailored for
`different types of healthcare professionals.
`
`ii. A long-term follow-up evaluation of participants to assess retention of
`knowledge and skills, application of learning to clinical practice, self-
`reported change in behavior, and barriers to change. Consider
`
`Reference ID: 4321317
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`

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`NDA 201655/S-024/S-025
`Page 8
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`
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`incentivizing participation in follow-up assessment, for example through
`additional CE credits.
`
`b. Evaluation of Patient Understanding: The results of an evaluation of patients’ and
`caregivers’ understanding of the serious risks of opioid analgesics and their
`understanding of how to use these products safely. This evaluation may include,
`for example, surveys of patients from a representative sample of patients taking
`opioid analgesics with respect to education level, insurance status, and geographic
`location.
`
`5. During transition from the ER/LA Opioid Analgesics REMS to Opioid Analgesic REMS,
`data to be included until the last enduring activity has been reported:
`
`
`a. For each CE activity released under the ER/LA Opioid Analgesics REMS that
`remains active, provide the name of the CE Provider, the title of the activity, and
`the date the activity will expire
`
`b. Aggregate data on participants and completers should be collected using original
`MEMS 2.0 definitions
`
`
`
`
`
`6. Methodologies: A timeline for submission of the assessment protocols, including data
`sources and the methodologies used to conduct all the above described analyses. Each
`assessment report should update the dates of submission for each component of the
`assessment.
`
`The first REMS assessment for the Opioid Analgesic REMS, due 6-months from the date of this
`letter, will include only information outlined in items 1, 2a, 2b, and 2c, and any additional
`information the REMS Program Companies (RPC) deems necessary to describe REMS
`implementation.
`
`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:
`
`
`a) An evaluation of how the benefit-risk profile will or will not change with the new
`indication;
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`Reference ID: 4321317
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`NDA 201655/S-024/S-025
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`b) A determination of the implications of a change in the benefit-risk profile for the current
`REMS;
`
`c) If the new indication for use introduces unexpected risks: A description of those risks
`and an evaluation of whether those risks can be appropriately managed with the currently
`approved REMS.
`
`d) If a REMS assessment was submitted in the 18 months prior to submission of the
`supplemental application for a new indication for use: A statement about whether the
`REMS was meeting its goals at the time of that last assessment and if any modifications
`of the REMS have been proposed since that assessment.
`
`e) If a REMS assessment has not been submitted in the 18 months prior to submission of the
`supplemental application for a new indication for use: Provision of as many of the
`currently listed assessment plan items as is feasible.
`
`
`
`
`
`
`
`
`
`f) If you propose a REMS modification based on a change in the benefit-risk profile or
`because of the new indication of use, submit an adequate rationale to support the
`modification, including: Provision of the reason(s) why the proposed REMS
`modification is necessary, the potential effect on the serious risk(s) for which the REMS
`was required, on patient access to the drug, and/or on the burden on the health care
`delivery system; and other appropriate evidence or data to support the proposed change.
`Additionally, include any changes to the assessment plan necessary to assess the
`proposed modified REMS. If you are not proposing REMS modifications, provide a
`rationale for why the REMS does not need to be modified.
`
`
`If the assessment instruments and methodology for your REMS assessments are not included in
`the REMS supporting document, or if you propose changes to the submitted assessment
`instruments or methodology, you should update the REMS supporting document to include
`specific assessment instrument and methodology information at least 90 days before the
`assessments will be conducted. Updates to the REMS supporting document may be included in a
`new document that references previous REMS supporting document submission(s) for
`unchanged portions. Alternatively, updates may be made by modifying the complete previous
`REMS supporting document, with all changes marked and highlighted. Prominently identify the
`submission containing the assessment instruments and methodology with the following wording
`in bold capital letters at the top of the first page of the submission:
`
`
`NDA 201655 REMS ASSESSMENT METHODOLOGY
`
`
`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
`
`Reference ID: 4321317
`
`

`

`NDA 201655/S-024/S-025
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`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 201655 REMS ASSESSMENT
`
`
`or
`
`
`NEW SUPPLEMENT FOR NDA 201655/S-000/
`CHANGES BEING EFFECTED IN 30 DAYS
`PROPOSED MINOR REMS MODIFICATION
`
`
`or
`
`
`NEW SUPPLEMENT FOR NDA 201655/S-000/
`PRIOR APPROVAL SUPPLEMENT
`PROPOSED MAJOR REMS MODIFICATION
`
`or
`
`
`NEW SUPPLEMENT FOR NDA 201655/S-000/
`PRIOR APPROVAL SUPPLEMENT
`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABEL CHANGES
`SUBMITTED IN SUPPLEMENT XXX
`
`
`
`or
`
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 201655/S-000/
`REMS ASSESSMENT
`PROPOSED REMS MODIFICATION (if included)
`
`REMS REVISIONS FOR NDA 201655
`
`
`Should you choose to submit a REMS revision, prominently identify the submission containing
`the REMS revisions with the following wording in bold capital letters at the top of the first page
`of the submission:
`
`
`
`To facilitate review of your submission, we request that you submit your proposed modified
`REMS and other REMS-related materials in Microsoft Word format. If certain documents, such
`as enrollment forms, or website screenshots are only in PDF format, they may be submitted as
`such, but Word format is preferred.
`
`
`Reference ID: 4321317
`
`

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`NDA 201655/S-024/S-025
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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.
`
`PROMOTIONAL MATERIALS
`
`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.
`
`All promotional materials that include representations about your drug product must be promptly
`revised to be consistent with the labeling changes approved in this supplement, including any
`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
`should include prominent disclosure of the important new safety information that appears in the
`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
`to comply with 21 CFR 314.70(a)(4) to the address above, by fax to 301-847-8444, or
`
`Reference ID: 4321317
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`NDA 201655/S-024/S-025
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`
`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 ).
`
`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 LCDR Mark A. Liberatore, PharmD, RAC, at (301) 796-2221.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Judith A. Racoosin, MD, MPH
`Deputy Director for Safety
`Division of Anesthesia, Analgesia,
` and Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`ENCLOSURES:
`Content of Labeling
`Medication Guide
`REMS
`
`Reference ID: 4321317
`
`

`

`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/
`------------------------------------------------------------
`
`JUDITH A RACOOSIN
`09/18/2018
`
`Reference ID: 4321317
`
`