DEPARTMENT OF HEALTH & HUMAN SERVICES
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` NDA 021897/S-015
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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.
`852 Winter Street
`Waltham, MA 02451-1420
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`Attention: Dennis Bucceri
`Vice President, Regulatory Affairs
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`Dear Mr. Bucceri:
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`Please refer to your supplemental new drug application (sNDA) dated April 12, 2010, received
`April 12, 2010, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act, for
`Vivitrol (naltrexone for extended-release injectable suspension).
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`We acknowledge receipt of your amendments dated April 28, May 7, July 6, 9, and 29, August
`10, 13, 19 (2), and 26, September 7, 24, 28, and 30 (2), and October 4, 5 and 8, 2010. We also
`acknowledge receipt of your risk evaluation and mitigation strategy (REMS) assessment dated
`October 5, 2010.
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`This supplemental new drug application proposes a new indication for Vivitrol for the prevention
`of relapse to opioid dependence, following opioid detoxification, and a proposed modification to
`the approved REMS.
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`We have completed our review of this supplemental application, as amended. It is approved,
`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
`text.
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`We are waiving the requirements of 21 CFR 201.57(d)(8) regarding the length of Highlights of
`prescribing information. This waiver applies to all future supplements containing revised
`labeling unless we notify you otherwise.
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`CONTENT OF LABELING
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` As soon as possible, but no later than 14 days from the date of this letter, submit, using the FDA
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`automated drug registration and listing system (eLIST), the content of labeling
`[21 CFR 314.50(l)] in structured product labeling (SPL) format, as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed labeling text for the package insert, Medication Guide and include the
`labeling changes proposed in any pending “Changes Being Effected” (CBE) supplements.
`Information on submitting SPL files using eLIST may be found in the guidance for industry
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`titled “SPL Standard for Content of Labeling Technical Qs and As” at
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`ALKERMES EXHIBIT 2002
`Amneal Pharmaceuticals LLC v. Alkermes Pharma Ireland Limited
`IPR2018-00943
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`Page 1 of 9
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` NDA 021897/S-015
`Page 2
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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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`We request that the revised labeling approved today be available on your website within 10 days
`of receipt of this letter.
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`Also within 14 days, amend all pending supplemental applications for this NDA, including
`pending “Changes Being Effected” (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.
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed carton and container labels that are identical to the carton and immediate
`container labels submitted on September 30, and October 5, 2010, as soon as they are available,
`but no more than 30 days after they are printed.
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`Please submit these labels electronically according to the guidance for industry titled “Providing
`Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications
`and Related Submissions Using the eCTD Specifications (June 2008).” Alternatively, you may
`submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or
`similar material. For administrative purposes, designate this submission “Product
`Correspondence – Final Printed Carton and Container Labels for approved NDA 21897/S-
`015.” Approval of this submission by FDA is not required before the labeling is used.
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
`administration are required to contain an assessment of the safety and effectiveness of the
`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
`deferred, or inapplicable.
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`We are waiving the pediatric study requirement for ages 0 to 11 years because the necessary
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`studies are impossible or highly impracticable. This is because of the low prevalence of opioid
`addiction in this pediatric population that is appropriately treated with antagonist therapy.
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`We are deferring submission of your pediatric study for ages 12 to 16 years for this application
`because this product is ready for approval for use in adults and the pediatric study have not been
`completed.
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`Your deferred pediatric study required by section 505B(a) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) are required postmarketing study. The status of this postmarketing study
`must be reported annually according to 21 CFR 314.81 and section 505B(a)(3)(B) of the Federal
`Food, Drug, and Cosmetic Act. These required studies are listed below.
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` NDA 021897/S-015
`Page 3
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`To conduct a study to determine the multiple-dose pharmacokinetics (PK) of
`Vivitrol in pediatric patients in order to determine the appropriate doses for
`pediatric patients ages 12 through 16. The PK study will be conducted following a
`postmarketing assessment of the use of Vivitrol in pediatrics ages 12 through 16.
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`January 31, 2012
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`Final Protocol Submission:
`January 31, 2013
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`Study/Trial Completion:
`Final Report Submission: March 31, 2013
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`To conduct an efficacy study to determine the effectiveness of Vivitrol in
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`pediatric patients ages 12 through 16.
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`1694-1
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`1694-2
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`Final Protocol Submission: May 31, 2013
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`Study/Trial Completion:
`June 30, 2014
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`Final Report Submission:
`September 30, 2014
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`Submit all clinical protocols to your IND 061138. Submit final reports to this NDA. For
`administrative purposes, all submissions related to this required pediatric postmarketing study
`must be clearly designated “Required Pediatric Assessment(s)”.
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`POSTMARKETING REQUIREMENTS UNDER 505(o)
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`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
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`While the US population meeting criteria for alcohol dependence is approximately two-thirds
`male, the population meeting criteria for opioid dependence is more evenly distributed across
`genders. Therefore, after approval of this supplement, more female patients are expected to
`receive treatment with Vivitrol. Because serious injection site reactions appear to occur
`disproportionately in female patients, the number of such reactions may be expected to increase
`after marketing for the new indication. Specialized follow up and periodic analysis of the adverse
`event reports will provide information necessary to understand the factors contributing to these
`reactions to better characterize the population at risk.
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`In summary, since Vivitrol was approved on April 13, 2006, and with the approval of this
`supplemental application, we have become aware of the potential for an increased number of
`serious injection site reactions in female patients treated with Vivitrol, based on the broadening
`of the treatment population. We consider this information to be “new safety information” as
`defined in section 505-1(b)(3) of the FDCA.
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`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to assess a known serious risk of
`injection site reactions and to determine the characteristics of patients who are at risk for
`development of these reactions.
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA has not yet been established and is not sufficient to assess this serious
`risk.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
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`Semi-annual Report Submissions:
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`Annual Reports Submissions:
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`Final Report Submission:
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`04/2011
`10/2011
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`04/2012
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`10/2012
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`10/2013
`10/2014
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`10/2015
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`Patient:
`• Weight
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` • Waist and hip circumference
`• BMI
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`• Gender
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`Indication
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`•
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`Provider:
`• Medical qualifications
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`• Dedicated training on administration procedures
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`Administration technique:
`• Needle length selection
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`• Precise location of injection
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`1694-3 An assessment and analysis of spontaneous reports of injection site reactions
`associated with Vivitrol. Following approval, and according to the following
`timetable, submit the reports (containing both interval-based and comprehensive
`data) analyzing spontaneous adverse event reports received that describe serious
`skin reactions. Specialized follow-up should be obtained on these cases to collect
`additional information on the event. The summaries of reported cases of injection
`site reactions should include an analysis of patient factors, provider factors and
`administration technique factors, or any other information that may lead to
`improved directions for patient selection, needle selection, or administration
`technique to reduce the risk of serious injection site reactions. When available,
`provide summaries of pathology and surgical reports.
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`Patient, provider, and administration technique factors should include, but not be
`limited to, the following:
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`Submit all report(s) to your NDA. Prominently identify the submission with the following
`wording in bold capital letters at the top of the first page of the submission, as appropriate:
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`• Required Postmarketing Final Report Under 505(o)
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`• Required Postmarketing Correspondence Under 505(o)
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`investigation required under this section. This section also requires you to periodically report to
`FDA on the status of any study or clinical trial otherwise undertaken to investigate a safety issue.
`Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to report annually
`on the status of any postmarketing commitments or required studies or clinical trials.
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`FDA will consider the submission of your annual report under section 506B and 21 CFR
`314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section 505(o)(3)(E)(ii)
`provided that you include the elements listed in 505(o) and 21 CFR 314.81(b)(2)(vii). We
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`remind you that to comply with 505(o), your annual report must also include a report on the
`status of any study or clinical trial otherwise undertaken to investigate a safety issue. Failure to
`submit an annual report for studies or clinical trials required under 505(o) on the date required
`will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could result in enforcement
`action.
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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
`approved on March 22, 2010. The REMS consists of a Medication Guide and a timetable for
`submission of assessments of the REMS. Your proposed modification to the REMS consists of a
`revised Medication Guide with additional information about the risks associated with the use of
`Vivitrol for the treatment of opioid dependence.
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`The proposed modified REMS, submitted on October 5, 2010 and appended to this letter, is
`approved.
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`The timetable for submission of assessments of the REMS will remain the same as that approved
`on March 22, 2010.
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`There are no changes to the REMS assessment plan described in our March 22, 2010 letter.
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`Assessments of an approved REMS must include, under section 505-1(g)(3)(B) and (C),
`information on the status of any postapproval study or clinical trial required under section 505(o)
`or otherwise undertaken to investigate a safety issue. With respect to any such postapproval
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`study, you must include the status of such study, including whether any difficulties completing
`the study have been encountered. With respect to any such postapproval clinical trial, you must
`include the status of such clinical trial, including whether enrollment has begun, the number of
`participants enrolled, the expected completion date, whether any difficulties completing the
`clinical trial have been encountered, and registration information with respect to requirements
`under subsections (i) and (j) of section 402 of the Public Health Service Act. You can satisfy
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`these requirements in your REMS assessments by referring to relevant information included in
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`the most recent annual report required under section 506B and 21 CFR 314.81(b)(2)(vii) and
`including any updates to the status information since the annual report was prepared. Failure to
`comply with the REMS assessments provisions in section 505-1(g) could result in enforcement
`action.
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`We remind you that 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 REMS when you submit a supplemental application for a new indication for use as
`described in section 505-1(g)(2)(A) of FDCA.
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`If you currently distribute or plan to distribute an authorized generic product under this NDA,
`you will also need to submit a REMS, REMS supporting document, and any required appended
`documents for that authorized generic, to this NDA. In other words, you must submit a complete
`proposed REMS that relates only to the authorized generic product. Review and approval of the
`REMS is required before you may market your product.
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`Prominently identify the submission containing the REMS assessments or proposed
`modifications with the following wording in bold capital letters at the top of the first page of the
`submission as appropriate:
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`NDA 021897 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 021897
`PROPOSED REMS MODIFICATION
`REMS ASSESSMENT
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 021897
`REMS ASSESSMENT
`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
`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 package insert(s) to:
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`Food and Drug Administration
`Center for Drug Evaluation and Research
`Division of Drug Marketing, Advertising, and Communications
`5901-B Ammendale Road
`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.(b)(3)(i)]. Form 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 promotional
`materials to the Division of Drug Marketing, Advertising, and Communications (DDMAC), see
`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
`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 or by fax to 301-847-8444.
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`LETTERS TO HEALTH CARE PROFESSIONALS
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`If you decide to issue a letter communicating important safety-related information about this
`drug product (i.e., a “Dear Health Care Professional” letter), we request that you submit, at least
`24 hours prior to issuing the letter, an electronic copy of the letter to this NDA, to the following
`address:
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`MedWatch Program
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`Office of Special Health Issues
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`Food and Drug Administration
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`10903 New Hampshire Ave
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`Building 32, Mail Stop 5353
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`Silver Spring, MD 20993
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
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`If you have any questions, call Ayanna Augustus, Ph.D., Regulatory Project Manager, at (301)
`796-3980.
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`Sincerely,
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`{See appended electronic signature page}
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`
`Rigoberto Roca, M.D.
`Deputy Director
`Division of Anesthesia and Analgesia Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`ENCLOSURE(S):
`Content of Labeling
`Carton and Container Labeling
`REMS
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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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`RIGOBERTO A ROCA
`10/12/2010
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`Reference ID: 2848831
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