;~ IQ ; . r.(,~ { ~ 11 U.S. FOOD & DRUG
`
`ADMINISTRATION
`
`\ :;:i~
`
`NDA 020732/S-026
`NDA 020733/S-030
`
`NDA 022410/S-045
`
`
`
`Indivior, Inc.
`10710 Midlothian Turnpike
`Suite 125
`North Chesterfield, VA 23235
`
`Attention:
`
`Alexis Williams, PharmD
`Global Regulatory Strategy & CMC Manager
`
`SUPPLEMENT APPROVAL
`
`
`
`
`Dear Dr. Williams:
`
`Please refer to your supplemental new drug applications (sNDAs) dated and received
`February 8, 2022, submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for the following products:
`
`
`NDA #
`
`Product
`
`Supplement
`#
`026
`
`030
`045
`
`
`020732
`Subutex (buprenorphine) sublingual tablets
`
`020733 Suboxone (buprenorphine and naloxone) sublingual tablets
`Suboxone (buprenorphine and naloxone) sublingual film
`022410
`
`
`
`
`These Prior Approval sNDAs provide for proposed modifications to the approved
`Suboxone/Subutex Risk Evaluation and Mitigation Strategy (REMS).
`
`We have completed our review of these supplemental applications, and are approved
`effective on the date of this letter.
`
`RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
`
`
`The REMS for Suboxone (buprenorphine and naloxone) sublingual film was originally
`
`approved on August 30, 2010. The REMS for Subutex (buprenorphine) sublingual
`tablets and the REMS for Suboxone (buprenorphine and naloxone) sublingual tablets
`were originally approved on December 22, 2011. Each REMS was modified on
`September 22, 2015, to consolidate the three product-specific REMS into a single
`REMS. The most recent modification was approved on November 19, 2021. 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.
`
`
`Reference ID: 4977797
`
`

`

`NDA 020732/S-026
`NDA 020733/S-030
`
`NDA 022410/S-045
`Page 2
`
`
`Your proposed modifications to the REMS consist of deactivating the Suboxone/
`Subutex REMS and joining the Buprenorphine Transmucosal Products for Opioid
`Dependence (BTOD) Shared System REMS.
`
`Your proposed modified REMS, referenced in Drug Master File (DMF) 031588,
`amended and appended to this letter, is approved. The following activities must be
`completed at the approval of modification, as you have proposed:
`
`
` Letters to inform key stakeholders of the incorporation of Suboxone and
`
`Subutex products into the BTOD REMS Program should be sent to
`prescribers certified to treat opioid dependence under the Drug Addiction
`Treatment Act of 2000 and retail pharmacies authorized by the DEA to handle
`Schedule III-controlled substances. Letters should include the website link
`and call center number of the BTOD REMS.
` The Suboxone/Subutex REMS website should be active for a period of four
`
`months after modification approval. A website pop-up message should inform
`stakeholders of the incorporation of Suboxone and Subutex products into the
`BTOD REMS Program and provide a link to the BTOD REMS website.
` The Suboxone/Subutex REMS toll-free information line should be active for a
`
`period of four months after modification approval. A pre-recorded message
`should inform callers of the incorporation of Suboxone and Subutex products
`into the BTOD REMS Program and the message should redirect callers to the
`BTOD REMS website and call center.
` A final close out report to document distribution of Suboxone/Subutex REMS
`
`mailings for the time period of July 2, 2021, through deactivation of the
`Suboxone/Subutex REMS.
`
`
`The BTOD REMS uses a shared system for the Medication Guide, elements to assure
`safe use, an implementation system, and a timetable for assessments of the REMS.
`The BTOD REMS currently includes the products listed on the FDA REMS website.1
`
`
`Other products may be added to the BTOD REMS in the future if additional BTOD
`
` NDAs or ANDAs are approved.
`
`Because Suboxone and Subutex products will be a member of the BTOD REMS, the
`assessment plan will be the same assessment plan required for the other products
`covered by this shared system REMS. The surveillance data on unintentional pediatric
`exposures and death (12.a.i.) must be submitted annually, beginning with the REMS
`
`
`1 https://www.accessdata.fda.gov/scripts/cder/rems/index.cfm
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4977797
`
`

`

`NDA 020732/S-026
`NDA 020733/S-030
`
`NDA 022410/S-045
`Page 3
`
`
`Assessment due August 30, 2022. All of the items below (1-13) must be submitted
`biennially, beginning with the REMS Assessment due August 30, 2023.
`
`Therefore, your REMS assessment plan must include, but is not limited to the following:
`
`
`Program Outreach and Communication (provide data for previous and current
`
`reporting periods (in yearly intervals within the reporting periods), and cumulatively)
`1. Medication Guide Distribution and Dispensing
`a. A report on periodic assessments of the distribution and dispensing of the
`Medication Guide in accordance with 21 CFR 208.24
`b. A report on failures to adhere to distribution and dispensing requirements,
`and corrective actions taken to address noncompliance
`2. Distribution of Stakeholder Letters
`a. Number of BTOD REMS Program materials (i.e., Dear Prescriber Letter,
`
`Dear Pharmacist letter, Prescriber Brochure, and Appropriate Use
`Checklist) sent via mail. Include the number of returned or undeliverable
`letters and the mailing success rates.
`3. REMS Website
`a. Number of visits and unique visits to the REMS Program website
`b. Number of Medication Guides accessed
`
`Program Implementation and Operations (provide data for previous and current
`
`reporting periods (in yearly intervals within the reporting periods), and cumulatively)
`4. REMS Contact Center
`a. Number of contacts by stakeholder type
`b. Summary of reasons for calls by reporter
`c. Summary of frequently asked questions (FAQs) by stakeholder type
`d. Summary report of REMS-related problems identified and resulting corrective
`actions
`
`5. BTOD REMS Specialists’ Activity
`Reports on the BTOD REMS specialists’ activity will include, but will not be
`limited to the following:
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4977797
`
`

`

`NDA 020732/S-026
`NDA 020733/S-030
`
`NDA 022410/S-045
`Page 4
`
`
`
`a. Number of REMS specialists available
`b. Number of prescribers contacted per specialist (stratified by the number of
`new prescribers vs. existing prescribers contacted)
`c. Number of prescribers who requested information about the REMS
`d. Number of prescribers who were provided with REMS materials during the
`visit/meeting/call
`6. REMS Compliance
`
`a. Prescriber adherence to ETASU
`7. Utilization Data
`a. An analysis to evaluate utilization patterns of BTOD products including
`frequency of office visits, amount dispensed in prescriptions to new patients,
`and other indicators of adherence to practices important for safe use
`
`Knowledge (provide data per reporting period)
`8. An evaluation of patients’ awareness and understanding of the serious risks
`associated with BTOD products
`9. An evaluation of prescribers’ awareness and understanding of the serious risks
`associated with BTOD products
`10. An evaluation of pharmacists’ awareness and understanding of the serious risks
`associated with BTOD products
`11. A proposal of specific measures to increase awareness if survey results of
`patients (metric 8), prescribers (metric 9), and pharmacists (metric 10) indicate
`
`that awareness is not adequate
`
`Health Outcomes and/or Surrogates of Health Outcomes (provide data for previous
`
`and current reporting periods (in yearly intervals within the reporting periods)
`12. Safety Surveillance
`a. An analysis and summary of surveillance and monitoring activities for abuse,
`misuse, overdose and addiction and any intervention taken resulting from
`signals of abuse, misuse, overdose and addiction. Surveillance will include,
`among other sources, reports of pediatric exposures (i.e., 12.a.i.).
`i. Surveillance data on unintentional pediatric (ages 0 through 5 years)
`exposures and deaths involving BTODs and comparators. Content
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4977797
`
`

`

`NDA 020732/S-026
`NDA 020733/S-030
`
`NDA 022410/S-045
`Page 5
`
`
`
`(i.e., tables, figures) and structure (i.e., organization of data sources
`and outcome measures) of these data must follow that of the data
`reported in the previous BTOD REMS Assessment reports.
`
`Overall Assessment
`
`13. The requirements for assessments of an approved REMS under section 505-
`1(g)(3) include with respect to each goal included in the strategy, an assessment
`of the extent to which the approved strategy, including each element of the
`strategy, is meeting the goal or whether one 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;
`
`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.
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4977797
`
`

`

`NDA 020732/S-026
`NDA 020733/S-030
`
`NDA 022410/S-045
`Page 6
`
`
`
`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 020732
`NDA 020733
`NDA 022410 REMS ASSESSMENT METHODOLOGY
`
`(insert concise description of content in bold capital letters, e.g.,
`
`ASSESSMENT METHODOLOGY, PROTOCOL, SURVEY METHODOLOGIES,
`AUDIT PLAN, DRUG USE STUDY)
`
`
`An authorized generic drug under this NDA must have an approved REMS prior to
`marketing. Should you decide to market, sell, or distribute an authorized generic drug
`under this NDA, contact us to discuss what will be required in the authorized generic
`drug REMS submission.
`
`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved
`covered application with elements to assure safe use from using any element to block
`or delay approval of an application under section 505(b)(2) or (j). A violation of this
`provision in 505-1(f) could result in enforcement action.
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4977797
`
`

`

`NDA 020732/S-026
`NDA 020733/S-030
`
`NDA 022410/S-045
`Page 7
`
`
`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 020732
`NDA 020733
`NDA 022410 REMS ASSESSMENT
`
`
`
`or
`
`
`NEW SUPPLEMENT FOR
`NDA 020732/S-000/ NDA 020733/S-000/ NDA 022410/S-000/
`CHANGES BEING EFFECTED IN 30 DAYS
`PROPOSED MINOR REMS MODIFICATION
`
`
`or
`
`
`NEW SUPPLEMENT FOR
`NDA 020732/S-000/ NDA 020733/S-000/ NDA 022410/S-000/
`PRIOR APPROVAL SUPPLEMENT
`
`PROPOSED MAJOR REMS MODIFICATION
`
`or
`
`
`NEW SUPPLEMENT FOR
`NDA 020732/S-000/ NDA 020733/S-000/ NDA 022410/S-000/
`PRIOR APPROVAL SUPPLEMENT
`
`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABELING
`CHANGES SUBMITTED IN SUPPLEMENTS NDA 020732/S-000/ NDA
`020733/S-000/ NDA 022410/S-000/
`
`
`
`
`
`or
`
`
`NEW SUPPLEMENT (NEW INDICATION FOR USE)
`FOR NDA 020732/S-000/ NDA 020733/S-000/ NDA 022410/S-000/
`REMS ASSESSMENT
`
`PROPOSED REMS MODIFICATION (if included)
`
`
`Should you choose to submit a REMS revision, prominently identify the submission
`containing the REMS revisions with the following wording in bold capital letters at the
`top of the first page of the submission:
`
`
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4977797
`
`

`

`NDA 020732/S-026
`NDA 020733/S-030
`
`NDA 022410/S-045
`Page 8
`
`
`
`REMS REVISIONS FOR
`NDA 020732
`NDA 020733
`NDA 022410
`
`
`To facilitate review of your submission, we request that you submit your proposed
`modified REMS and other REMS-related materials in Microsoft Word format. If certain
`documents, such as enrollment forms, or website screenshots are only in PDF format,
`they may be submitted as such, but Word format is preferred.
`
`SUBMISSION OF REMS DOCUMENT IN SPL FORMAT
`
`FDA can accept the REMS document in Structured Product Labeling (SPL) format. If
`you intend to submit the REMS document in SPL format, as soon as possible, but no
`later than 14 days from the date of this letter, submit the REMS document in SPL format
`using the FDA automated drug registration and listing system (eLIST).
`
`For more information on submitting REMS in SPL format, please email
`FDAREMSwebsite@fda.hhs.gov.
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and
`promotional labeling. For information about submitting promotional materials, see the
`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
`Electronic Format-Promotional Labeling and Advertising Materials for Human
`
`Prescription Drugs.2
`
`
`
`
` 2 For the most recent version of a guidance, check the FDA guidance web page at
`https://www.fda.gov/media/128163/download.
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4977797
`
`

`

`NDA 020732/S-026
`NDA 020733/S-030
`
`NDA 022410/S-045
`Page 9
`
`
`
`You must submit final promotional materials and Prescribing Information, accompanied
`by a Form FDA 2253, at the time of initial dissemination or publication
`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.3 Information and
`Instructions for completing the form can be found at FDA.gov.4
`
`
`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 labeling. Within 7 days of receipt of this
`letter, submit your statement of intent to comply with 21 CFR 314.70(a)(4).
`
`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 Jessica Voqui, PharmD, MS; Associate Director
`for Postmarket Regulatory Science, at 301-796-2915.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`
`CDR Mark A. Liberatore, PharmD, RAC
`Deputy Director for Safety
`Division of Anesthesiology, Addiction
`Medicine, and Pain Medicine
`Office of Neuroscience
`Center for Drug Evaluation and Research
`
`
`ENCLOSURE:
` REMS
`
`
`
`3 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
`
`
`4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
`
`
`
`U.S. Food and Drug Administration
`
`
`Silver Spring, MD 20993
`www.fda.gov
`
`Reference ID: 4977797
`
`

`

`Signature Page 1 of 1
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`This is a representation of an electronic record that was signed
`electronically. Following this are manifestations of any and all
`electronic signatures for this electronic record.
`--------------------------------------------------------------------------------------------
`/s/
`------------------------------------------------------------
`
`MARK A LIBERATORE
`05/03/2022 10:48:33 AM
`
`Reference ID: 4977797
`
`(
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`
`
`