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` NDA 021897/S-049
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` SUPPLEMENT APPROVAL
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`Divyani Patel, PharmD
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`Senior Associate, Regulatory Affairs
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`Alkermes, Inc.
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`852 Winter Street
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`Waltham, MA 02451
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`Attention:
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`Dear Dr. Patel:
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`Please refer to your supplemental new drug application (sNDA) dated and received
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`March 5, 2020, and your amendments, submitted pursuant to section 505(b)(2) of the
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`Federal Food, Drug, and Cosmetic Act (FDCA) for VIVITROL (naltrexone for extended-
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`release injectable suspension).
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`This “Changes Being Effected in 30 days” supplemental new drug application provides
`for changes to content of the labeling to include excipients used to adjust pH for the
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`diluents, revises the term “single-use” to “single-dose”, and proposed modification to the
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`approved Vivitrol (naltrexone for extended-release injectable suspension) risk
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`evaluation and mitigation strategy (REMS).
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`APPROVAL & LABELING
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`We have completed our review of this application, as amended. It is approved, effective
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`on the date of this letter, for use as recommended in the enclosed agreed-upon
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`labeling.
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`We note that your May 4, 2020, submission includes final printed labeling (FPL) for your
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`Prescribing Information and Medication Guide. We have not reviewed this FPL. You are
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`responsible for assuring that the wording in this printed labeling is identical to that of the
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`approved content of labeling in the structured product labeling (SPL) format.
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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
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`content of labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using
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`the FDA automated drug registration and listing system (eLIST), as described at
`FDA.gov.1 Content of labeling must be identical to the enclosed labeling (text for the
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`Prescribing Information and Medication Guide), with the addition of any labeling
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` 1 http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm
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`Reference ID: 4605456
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`

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` NDA 021897/S-049
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` Page 2
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`changes in pending “Changes Being Effected” (CBE) supplements, as well as annual
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`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
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` industry SPL Standard for Content of Labeling Technical Qs and As.2
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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
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`changes for this NDA, including CBE supplements for which FDA has not yet issued an
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`action letter, with the content of labeling [21 CFR 314.50(l)(1)(i)] in Microsoft Word
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`format, that includes the changes approved in this supplemental application, as well as
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`annual reportable changes. To facilitate review of your submission, provide a
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`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
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`supplement number(s) and annual report date(s).
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`CARTON AND CONTAINER LABELING
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`We acknowledge your May 4, 2020, submission containing final printed carton and
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`container labeling.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and
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`promotional labeling. For information aabout submitting promotional materials, see the
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`final guidance for industry Providing Regulatory Submissions in Electronic and Non-
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`Electronic Format – Promotional Labeling and Advertisign in Materials for Human
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`Prescription Drugs.3
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`You must submit final promotional materials and Prescribing Information, accompanied
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`by a Form FDA 2253, at the time of initial dissemination or publication
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`[21 CFR 314.81(b)(3)(i)]. Form FDA 2253 is available at FDA.gov.4 Information and
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`Instructions for completing the form can be found at FDA.gov.5
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` 2 We update guidances periodically. For the most recent version of a guidance, check the FDA Guidance
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` Documents Database https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.
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` 3 For the most recent version of a guidance, check the FDA guidance web page
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` athttps://www.fda.gov/media/128163/download.
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` 4 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf
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` 5 http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4605456
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`

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` NDA 021897/S-049
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` Page 3
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`RISK EVALUATION AND MITIGATION STRATEGY (REMS) REQUIREMENTS
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` The REMS for Vivitrol was originally approved on March 22, 2010, and the most recent
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` REMS modification was approved on June 7, 2019. The REMS consists of a Medication
` Guide, a communication plan, and a timetable for submission of assessments of the
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` REMS. Your proposed modifications to the REMS consists of a revised Medication
` Guide to include the addition of diluent ingredients sodium hydroxide and hydrochloric
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` acid as pH adjusters, in water for injection. This change was made to align with the
` changes made in the US package insert.
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`In accordance with section 505-1 of the FDCA, we have determined that the following
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`REMS modifications are necessary to ensure the benefits of the drug outweigh the
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`risks:
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`• Revision to the Medication Guide to include the addition of diluent ingredients
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`sodium hydroxide and hydrochloric acid as pH adjusters, in water for injection
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`The timetable for submission of assessments of the REMS remains the same as that
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`approved on July 29, 2013.
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`There are no changes to the REMS assessment plan described in our July 29, 2013,
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`letter.
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`We remind you that in addition to the REMS assessments submitted according to the
`timetable in the approved REMS, you must include an adequate rationale to support a
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`proposed REMS modification for the addition, modification, or removal of any goal or
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`element of the REMS, as described in section 505-1(g)(4) of the FDCA.
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`We also remind you that you must submit a REMS assessment when you submit a
`supplemental application for a new indication for use, as described in section 505­
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`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
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`indication;
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`b) A determination of the implications of a change in the benefit-risk profile for the
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`current REMS;
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`c) If the new indication for use introduces unexpected risks: A description of those
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`risks and an evaluation of whether those risks can be appropriately managed
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`with the currently approved REMS.
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`d) If a REMS assessment was submitted in the 18 months prior to submission of the
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`supplemental application for a new indication for use: A statement about whether
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4605456
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`

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`NDA 021897/S-049
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`Page 4
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`the REMS was meeting its goals at the time of that last assessment and if any
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`modifications of the REMS have been proposed since that assessment.
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`e) If a REMS assessment has not been submitted in the 18 months prior to
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`submission of the supplemental application for a new indication for use: Provision
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`of as many of the currently listed assessment plan items as is feasible.
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`f)
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`If you propose a REMS modification based on a change in the benefit-risk profile
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`or because of the new indication of use, submit an adequate rationale to support
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`the modification, including: Provision of the reason(s) why the proposed REMS
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`modification is necessary, the potential effect on the serious risk(s) for which the
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`REMS was required, on patient access to the drug, and/or on the burden on the
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`health care delivery system; and other appropriate evidence or data to support
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`the proposed change. Additionally, include any changes to the assessment plan
`necessary to assess the proposed modified REMS. If you are not proposing
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`REMS modifications, provide a rationale for why the REMS does not need to be
`modified.
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`If the assessment instruments and methodology for your REMS assessments are not
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`included in the REMS supporting document, or if you propose changes to the submitted
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`assessment instruments or methodology, you should update the REMS supporting
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`document to include specific assessment instrument and methodology information at
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`least 90 days before the assessments will be conducted. Updates to the REMS
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`supporting document may be included in a new document that references previous
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`REMS supporting document submission(s) for unchanged portions. Alternatively,
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`updates may be made by modifying the complete previous REMS supporting document,
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`with all changes marked and highlighted. Prominently identify the submission containing
`the assessment instruments and methodology with the following wording in bold capital
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`letters at the top of the first page of the submission:
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`NDA 021897 REMS ASSESSMENT METHODOLOGY
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`An authorized generic drug under this NDA must have an approved REMS prior to
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`marketing. Should you decide to market, sell, or distribute an authorized generic drug
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`under this NDA, contact us to discuss what will be required in the authorized generic
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`drug REMS submission.
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`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
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`the first page of the submission as appropriate:
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`NDA 021897 REMS ASSESSMENT
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`or
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4605456
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`

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` NDA 021897/S-049
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` Page 5
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` NEW SUPPLEMENT FOR NDA 021897 /S-000
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` CHANGES BEING EFFECTED IN 30 DAYS
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` PROPOSED MINOR REMS MODIFICATION
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` or
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`NEW SUPPLEMENT FOR NDA 021897 /S-000
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`PRIOR APPROVAL SUPPLEMENT
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`PROPOSED MAJOR REMS MODIFICATION
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`or
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`NEW SUPPLEMENT FOR NDA 021897 /S-000
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`PRIOR APPROVAL SUPPLEMENT
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`PROPOSED REMS MODIFICATIONS DUE TO SAFETY LABELING
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`CHANGES SUBMITTED IN SUPPLEMENT XXX
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`or
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 021897 /S-000
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`REMS ASSESSMENT
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`PROPOSED REMS MODIFICATION (if included)
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`REMS REVISIONS FOR NDA 021897
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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
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`top of the first page of the submission:
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`To facilitate review of your submission, we request that you submit your proposed
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`modified REMS and other REMS-related materials in Microsoft Word format. If certain
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`documents, such as enrollment forms, or website screenshots are only in PDF format,
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`they may be submitted as such, but Word format is preferred.
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`SUBMISSION OF REMS DOCUMENT IN SPL FORMAT
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`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
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`later than 14 days from the date of this letter, submit the REMS document in SPL format
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`using the FDA automated drug registration and listing system (eLIST).
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`For more information on submitting REMS in SPL format, please email
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`FDAREMSwebsite@fda.hhs.gov.
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`U.S. Food and Drug Administration
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`
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`Silver Spring, MD 20993
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`
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`www.fda.gov
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`Reference ID: 4605456
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`

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`NDA 021897/S-049
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`Page 6
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`We remind you that you must comply with the requirements for an approved NDA set
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`forth under 21 CFR 314.80 and 314.81.
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`If you have any questions, call Swati Patwardhan, Regulatory Project Manager, at 301­
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`796-4085.
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`Sincerely,
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`{See appended electronic signature page}
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`
`
` Rigoberto Roca, MD
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` Director (Acting)
`Division of Anesthesiology, Addiction Medicine
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` and Pain Medicine
` Office of Neuroscience
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` Center for Drug Evaluation and Research
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`ENCLOSURE(S):
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`• Content of Labeling
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`o Prescribing Information
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`o Medication Guide
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`• Carton and Container Labeling
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`• REMS
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`U.S. Food and Drug Administration
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`Silver Spring, MD 20993
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`www.fda.gov
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`Reference ID: 4605456
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`

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`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/
`------------------------------------------------------------
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`RIGOBERTO A ROCA
`05/08/2020 06:41:35 PM
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`Reference ID: 4605456
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`