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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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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 202788/S-001
`NDA 202788/S-003
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`
`Lauren H. Wind, MPH
`Senior Consultant
`The Weinberg Group, Inc.
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` Insys Therapeutics, Inc.
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`(c/o) The Weinberg Group, Inc.
`1129 Twentieth Street, NW
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`Suite 600
`Washington, DC 20036
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`Attention:
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`
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`Dear Ms. Wind:
`
`Please refer to your Supplemental New Drug Applications (sNDA) dated January 18, and
`February 8, 2012, and received January 18, and February 8, 2012, and identified as S-001 and S-
`003, respectively. These sNDAs were submitted pursuant to section 505(b)(2) of the Federal
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`Food, Drug, and Cosmetic Act (FDCA) for Subsys (fentanyl sublingual spray).
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`We also acknowledge receipt of your risk evaluation and mitigation strategy (REMS) assessment
`dated February 8, 2012.
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`These “Prior Approval” supplemental new drug applications provide for the following:
`S-001: Addition of a 30-unit secondary package (i.e., shelf carton) for each strength as
`well as minor editorial changes to the full package insert.
`S-003: Modifications to the approved REMS for Subsys which are part of the single
`shared system REMS, the transmucosal immediate-release fentanyl (TIRF)
`REMS Access Program.
`
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`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.
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`CONTENT OF LABELING
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`
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`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 text for the package insert and Medication
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`
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`Reference ID: 3140097
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`

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`NDA 202788/S-001
`NDA 202788/S-003
`Page 2
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`Guide), 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.
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`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.
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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 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).
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`We request that the labeling approved today be available on your website within 10 days of
`receipt of this letter.
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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 enclosed carton labels,
`submitted on January 18, 2012, as soon as they are available, but no more than 30 days after they
`are printed.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`The REMS for Subsys was originally approved on January 4, 2012. 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. Your proposed modifications to the TIRF REMS
`consist of edits to the Patient-Prescriber Agreement Form, the addition of the Closed System
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`Pharmacy Enrollment Form and minor editorial changes. Additionally, the TIRF REMS Access
`Program “go-live” placeholder date has been updated with the actual "go-live" date of March 12,
`2012.
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`Your proposed modified REMS, submitted on February 8, 2012, and appended to this letter, is
`approved.
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` The TIRF REMS Access program includes the following products:
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`NDA 020747
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`Actiq (fentanyl citrate) oral transmucosl lozenge and its authorized
`generic
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`Fentora (fentanyl buccal tablets)
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`NDA 021947
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`
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`Reference ID: 3140097
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`

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`NDA 202788/S-001
`NDA 202788/S-003
`Page 3
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`NDA 022266
`NDA 022510
`NDA 022569
`NDA 202788
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`ANDA 077312
`ANDA 078907
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`Onsolis (fentanyl buccal soluble film)
`Abstral (fentanyl) sublingual tablets
`Lazanda (fentanyl) nasal spray
`Subsys (fentanyl) sublingual spray
`Fentanyl Citrate Oral Transmucosal Lozenge
`Fentanyl Citrate Oral Transmucosal Lozenge
`
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`Other products may be added in the future if additional NDAs or ANDAs are approved.
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`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.
`
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`The timetable for submission of assessments of the REMS was amended to correspond with the
`TIRF REMS Access Program timetable for submission of assessments approved on December
`28, 2011. The first assessment is due June 28, 2012, and the second assessment is due December
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`28, 2012, and assessments are due annually thereafter.
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`There are no changes to the REMS assessment plan described in our January 4, 2012, letter.
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`We remind you that 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
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`such postapproval 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 these requirements in your REMS assessments by referring to relevant
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`information included in the most recent annual report required under section 506B and 21 CFR
`314.81(b)(2)(vii) and including any material or significant 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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`In addition to the assessments submitted according to the timetable included in this 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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`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,
`contact us to discuss what will be required in the authorized generic drug REMS submission.
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`Reference ID: 3140097
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`

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`NDA 202788/S-001
`NDA 202788/S-003
`Page 4
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`Prominently identify any 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:
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`NDA 202788
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`REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 202788
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`PROPOSED REMS MODIFICATION
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`REMS ASSESSMENT
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`If you do not submit electronically, please send 5 copies of REMS-related submissions.
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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 Matthew Sullivan, Senior Regulatory Health Project Manager, at
`301-796-1245.
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`Sincerely,
`
`{See appended electronic signature page}
`
`
`Judith A. Racoosin, M.D., M.P.H.
`Deputy Director for Safety
`Division of Anesthesia, Analgesia, and
`Addiction Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`Enclosures:
`Content of Labeling
`Carton and Container Labeling
`REMS
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`Reference ID: 3140097
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`

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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
`06/05/2012
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`Reference ID: 3140097
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