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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 021897/S-020, S-023
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`Food and Drug Administration
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` Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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` Alkermes Inc,
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` 852 Winter Street
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` Waltham, MA 02451-1420
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`Attention:
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`Renee Howard
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`Senior Director, Regulatory Affairs
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`Dear Ms. Howard:
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`Please refer to your Supplemental New Drug Applications (sNDAs) dated April 13, 2012 (S­
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`020), and June 20, 2013 (S-023), received April 13, 2012, and June 20, 2013, respectively,
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`submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA)
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`for Vivitrol (naltrexone for extended-release injectable suspension).
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`We also refer to our letter dated February 17, 2012, notifying you, under Section 505-1(g)(2)(C)
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`of the FDCA, that your approved Risk Evaluation and Mitigations Strategy (REMS) must be
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`modified based on the review of your REMS assessment that showed that patients are not
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`adequately knowledgeable about the serious risks associated with Vivitrol (naltrexone for
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`extended-release injectable suspension) that are described in the Medication Guide. The REMS
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`modification notification letter indicated that the modified REMS must include a Medication
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`Guide revised to improve patient comprehension of the risks, a communication plan, and a
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`revised timetable for submission of REMS assessments.
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`We acknowledge receipt of your amendments dated August 20, 2012, May 17, June 11, and July
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`11, 2013.
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`Supplement S-020 proposed modifications to the approved REMS for Vivitrol (naltrexone for
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`extended-release injectable suspension) consistent with our February 17, 2012, letter.
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`Supplement S-023 proposed revisions to the BOXED WARNING, DOSAGE AND
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`ADMINISTRATION, CONTRAINDICATIONS, WARNINGS AND PRECAUTION, and
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`PATIENT COUNSELING INFORMATION sections of the Package Insert and revisions to
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`the Medication Guide and carton labeling.
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`We have completed our review of these supplemental applications, as amended, and they are
`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
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`upon labeling text and with the minor editorial revisions indicated in the enclosed labeling.
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`Reference ID: 3348450
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` NDA 021897/S-020, S-023
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` Page 2
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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
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described at
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`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
`of labeling must be identical to the enclosed labeling text for the package insert, and Medication
`Guide, with the addition of any labeling changes in pending “Changes Being Effected” (CBE)
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`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
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`“SPL Standard for Content of Labeling Technical Qs and As” at
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`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.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
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`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
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`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
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`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-
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`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
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`should provide appropriate annotations, including supplement number(s) and annual report
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`date(s).
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`We request that the labeling approved today be available on your website within 10 days of
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`receipt of this letter.
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`We acknowledge your June 20, 2013, submission containing the final printed carton label.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`The REMS for Vivitrol (naltrexone for extended-release injectable suspension) was originally
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`approved on March 22, 2010, and a REMS modification was approved on October 12, 2010.
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`The REMS consists of a Medication Guide, and a timetable for submission of assessments of the
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`REMS. Your response to the REMS modification notification letter consists of a REMS with a
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`revised Medication Guide, the addition of a communication plan to include information about the
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`serious risks associated with Vivitrol (naltrexone for extended-release injectable suspension),
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`and a revised timetable for submission of REMS assessments.
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`Your proposed modified REMS, submitted on July 11, 2013 and appended to this letter, is
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`approved. The modified REMS consists of a Medication Guide, communication plan, and a
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`revised timetable for submission of assessments of the REMS. The REMS assessments should
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`Reference ID: 3348450
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` NDA 021897/S-020, S-023
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` Page 3
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` be submitted to the Agency 2 years, 4 years, and 7 years from the date of the approval of the
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` modified REMS.
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`The revised REMS assessment plan should include, but is not limited to, the following:
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`1. Medication Guide
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`a. An evaluation of patients’ understanding of severe injection site reactions
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`associated with VIVITROL
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`i. Alkermes will submit the survey methodology and instrument(s) for
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`review at least 90 days before the next assessment is conducted. Alkermes
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`will submit both methods and instruments together, and clearly identify
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`any changes from the previous protocols.
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`ii. The protocols will include, at a minimum, the following:
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`1. The expected sample size
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`2. A description of the methodology for recruitment and selection of
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`the patient sample
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`3. The specific selection criteria for inclusion in each survey
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`4. A description of how and when the surveys will be administered
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`5. An explanation of the design features and controls that will be
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`included to minimize bias and compensate for any limitations in
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`the methodology
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`b. A report on periodic assessments of the distribution and dispensing of the
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`Medication Guide in accordance with 21 CFR 208.24
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`c. A report on failures to adhere to distribution and dispensing requirements, and
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`corrective actions taken to address noncompliance
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`2. Communication Plan
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`a. An evaluation of the distribution of the communication materials
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`i. The date(s) of mailing(s) and number of recipients of the DHCP Letters,
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`which include the Patient Counseling Tool and the Key Techniques to
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`Reduce Severe Injection Site Reactions Poster
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`1. Number of DHCP Letters sent electronically or via US Postal
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`service, and the number of letters returned undeliverable
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`(electronically or US Postal Service)
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`2. Number of DHCP Letters distributed by sales representatives or by
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`Medical Information
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`Reference ID: 3348450
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` NDA 021897/S-020, S-023
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` Page 4
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` ii. The number of Key Techniques to Reduce Severe Injection Site Reactions
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` posters and Patient Counseling Tools distributed by the sales force
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`1. The number of face-to-face interactions with healthcare providers
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`in which materials were provided
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`2. The number of calls on treatment centers during which materials
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`were presented
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`iii. Metrics associated with the REMS website for VIVITROL
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`1. Date the communication information is posted to the REMS
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`website for VIVITROL
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`2. Number of visits to the REMS website link for each reporting
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`period
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`b. An evaluation of prescribers’ understanding of severe injection site reactions
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`associated with VIVITROL
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`i. The survey will be conducted among a representative sample of healthcare
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`providers who are current or past prescribers or administrators of
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`VIVITROL.
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`ii. Alkermes will submit the survey methodology and instrument(s) for
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`review at least 90 days before the next assessment is conducted. Alkermes
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`will submit both methods and instruments together, and clearly identify
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`any changes from the previous protocols.
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`iii. The protocols will include, at a minimum, the following:
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`1. The expected sample size
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`2. A description of the methodology for recruitment and selection of
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`the healthcare provider sample
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`3. The specific selection criteria for inclusion in each survey
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`4. A description of how and when the surveys will be administered
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`5. An explanation of the design features and controls that will be
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`included to minimize bias and compensate for any limitations in
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`the methodology
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`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
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`strategy, including each element of the strategy, is meeting the goal or whether one or more such
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`goals or such elements should be modified.
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`In addition to the assessments submitted according to the timetable included in the approved
`REMS, you must submit a REMS assessment and may propose a modification to the approved
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`Reference ID: 3348450
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` NDA 021897/S-020, S-023
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` Page 5
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`REMS when you submit a supplemental application for a new indication for use as described in
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` section 505-1(g)(2)(A) of the FDCA.
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`If the assessment instruments and methodology for your REMS assessments are not included in
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`the REMS supporting document, or if you propose changes to the submitted assessment
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`instruments or methodology, you should update the REMS supporting document to include
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`specific assessment instrument and methodology information at least 90 days before the
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`assessments will be conducted. Updates to the REMS supporting document may be included in a
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`new document that references previous REMS supporting document submission(s) for
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`unchanged portions. Alternatively, updates may be made by modifying the complete previous
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`REMS supporting document, with all changes marked and highlighted. Prominently identify the
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`submission containing the assessment instruments and methodology with the following wording
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`in bold capital letters at the top of the first page of the submission:
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`NDA 021897 REMS CORRESPONDENCE
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`(insert concise description of content in bold capital letters, e.g.,
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`UPDATE TO REMS SUPPORTING DOCUMENT - ASSESSMENT
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`METHODOLOGY
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`An authorized generic drug under this NDA must have an approved REMS prior to marketing.
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`Should you decide to market, sell, or distribute an authorized generic drug under this NDA,
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`contact us to discuss what will be required in the authorized generic drug REMS submission.
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`Prominently identify the submission containing the REMS assessments or proposed
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`modifications of the REMS with the following wording in bold capital letters at the top of the
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`first page of the submission as appropriate:
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`NDA 021897 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 021897
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`PROPOSED REMS MODIFICATION
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 021897
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`REMS ASSESSMENT
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`PROPOSED REMS MODIFICATION (if included)
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
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`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
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`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
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`(3) the package insert(s) to:
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`Reference ID: 3348450
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` NDA 021897/S-020, S-023
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` Page 6
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` Food and Drug Administration
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` Center for Drug Evaluation and Research
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` Office of Prescription Drug Promotion (OPDP)
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` 5901-B Ammendale Road
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` Beltsville, MD 20705-1266
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`You must submit final promotional materials and package insert(s), accompanied by a Form
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`FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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`FDA 2253 is available at http://www.fda.gov/opacom/morechoices/fdaforms/cder.html;
`instructions are provided on page 2 of the form. For more information about submission of
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`promotional materials to the Office of Prescription Drug Promotion (OPDP), see
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`http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`All promotional materials that include representations about your drug product must be promptly
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`revised to be consistent with the labeling changes approved in this supplement, including any
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`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
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`should include prominent disclosure of the important new safety information that appears in the
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`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
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`to comply with 21 CFR 314.70(a)(4) to the address above or by fax to 301-847-8444.
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
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`(21 CFR 314.80 and 314.81).
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`If you have any questions, call Ayanna Augustus, Ph.D., Senior Regulatory Project Manager, at
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`(301) 796-3980.
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`Sincerely,
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`{See appended electronic signature page}
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`Judith A. Racoosin, M.D., M.P.H.
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`Deputy Director for Safety
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`Division of Anesthesia, Analgesia,
`and Addiction Products
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`Office of Drug Evaluation II
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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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`Carton Labeling
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`REMS
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`Reference ID: 3348450
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
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`JUDITH A RACOOSIN
`07/29/2013
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`Reference ID: 3348450
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