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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 202788/S-009
`NDA 202788/S-011
`NDA 202788/S-012
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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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`Insys Therapeutics, Inc.
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`1333 South Spectrum Blvd., Suite 100
`Chandler, AZ 85286
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`Attention: Stephen Sherman
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`Vice President, Regulatory Affairs
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`Dear Mr. Sherman:
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`Please refer to your Supplemental New Drug Applications (sNDAs) dated and received February
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`25, 2013, (S-009), December 19, 2013, (S-011), and May 20, 2014 (S-012) submitted pursuant to
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`section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (FDCA) for Subsys (fentanyl
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`sublingual spray).
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`We also acknowledge receipt of your amendments dated September 12, 2013, and February 13,
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`March 11, and July 23, 2014, for S-009; February 20 and 26, and April 29, 2014, for S-011; and
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`November 26, and December 11, 2014 for Supplement S-012. Finally, we refer to the May 20,
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`, which contain the proposed
`November 25, and December 10, 2014, submissions to DMF
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`modifications to your shared risk evaluation and mitigation strategy (REMS) program.
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`S-009 is a “Prior Approval” supplemental new drug application which proposes revisions
`to the DOSAGE AND ADMINISTRATION, HOW SUPPLIED/STORAGE AND
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`HANDLING, and PATIENT COUNSELING INFORMATION sections of the package
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`insert, as well as to the Medication Guide, to provide for an alternate system for Subsys
`disposal.
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`S-011 is a “Changes Being Effected” supplemental new drug application which provides
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`for a new secondary packaging facility as well as a reduction in the size of the blister
`packages.
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`S-012 is a “Prior Approval” supplemental new drug application which proposes
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`modifications to the approved REMS for Subsys which is part of the single shared system
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`REMS, the Transmucosal Immediate-Release Fentanyl (TIRF) REMS Access Program.
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`Reference ID: 3677533
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`(b) (4)
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`

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` Revise the following line on the blister package labeling for the 1600 mcg dosage
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` strength:
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` Use two sprays (one spray from each device) to achieve a total of
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`This line should be revised to read:
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`Use two sprays (one spray from each device) to achieve a total of 1600 mcg.
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` NDA 202788/S-009
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` NDA 202788/S-011
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` NDA 202788/S-012
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` Page 2
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` APPROVAL & LABELING
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` We have completed our review of these supplemental applications, as amended. They are
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`approved, effective on the date of this letter, for use as recommended in the enclosed, agreed-
`upon labeling text and with the minor editorial revision listed below:
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` mcg.
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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
` automated drug registration and listing system (eLIST), as described at http://www.fda.gov/
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` ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content of labeling must be
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` 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) supplements, as
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`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/
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`DrugsGuidanceComplianceRegulatoryInformation/Guidances/UCM072392.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 includes 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
`changes approved in this supplemental application, as well as annual reportable changes and
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`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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`Reference ID: 3677533
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`(b) (4)
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` NDA 202788/S-009
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` NDA 202788/S-011
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` NDA 202788/S-012
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` Page 3
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` CARTON AND IMMEDIATE CONTAINER LABELS
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` Submit final printed carton and immediate container labels that are identical to the enclosed
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` immediate container labels submitted on April 29, 2014, except with the revision listed above, as
` soon as they are available, but no more than 30 days after they are printed. Please submit these
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` labels electronically according to the guidance for industry Providing Regulatory Submissions in
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` Electronic Format – Human Pharmaceutical Product Applications and Related Submissions
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` Using the eCTD Specifications (June 2008). Alternatively, you may submit 12 paper copies,
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` with 6 of the copies individually mounted on heavy-weight paper or similar material. For
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` administrative purposes, designate this submission “Final Printed Carton and Container
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` Labels for approved NDA 202788/S-011.” Approval of this submission by FDA is not
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` required before the labeling is used.
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` Marketing the product with FPL that is not identical to the approved labeling text may render the
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` product misbranded and an unapproved new drug.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`The REMS for TIRF Products, of which Subsys is a member, was originally approved on
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`December 28, 2011, and the most recent REMS modification was approved on November 7,
`2013. Subsys was approved and incorporated into the shared system REMS as result of approval
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`on January 4, 2012. The REMS consists of a Medication Guide, elements to assure safe use, an
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`implementation system, and a timetable for submission of assessments of the REMS.
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`Your proposed modifications to the REMS consist of revisions to the Medication Guide (MG)
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`for Subsys to include instructions for use of the new disposal system.
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`In addition, your proposed modifications to the TIRF REMS, including appended REMS
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`materials as applicable, consist of the following:
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`1. Removal of NDC Numbers from the following:
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`Independent Outpatient Pharmacy Enrollment Form
`i.
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`ii. Chain Outpatient Pharmacy Enrollment Form
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`iii.
`TIRF REMS Website
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`2. Removal of reference to generic equivalents of specific products and replacement with a
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`footnote in the following:
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`Education Program for Prescribers and Pharmacists
`i.
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`ii.
`TIRF REMS Website
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`Reference ID: 3677533
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`

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` NDA 202788/S-009
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` NDA 202788/S-011
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` NDA 202788/S-012
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` Page 4
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` 3. Removal of “Attachment 1: List of TIRF Medicines Available Only through the TIRF
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` REMS Access Program," and replacement with a hyperlink to the new TIRF REMS
` Webpage in the following:
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`i.
` TIRF REMS Document
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` ii. Overview for Prescribers
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`iii.
` Prescriber Enrollment Form
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` iv. Overview for Patients and Caregivers
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`v.
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` Independent Outpatient Pharmacy Overview
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` vi. Chain Outpatient Pharmacy Overview
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` vii. Closed System Outpatient Pharmacy Overview
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` Independent Outpatient Pharmacy Enrollment Form
`viii.
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` ix. Chain Outpatient Pharmacy Enrollment Form
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` x. Closed System Outpatient Enrollment Form
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`xi.
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` Inpatient Pharmacy Enrollment Form
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` xii. Distributor Enrollment Form
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`xiii.
` TIRF REMS Website and Website Landing Page
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` 4. Revised criteria for inactivation of Patient-Prescriber Agreement Form (PPAF) in the
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` TIRF REMS Document
` 5. Revisions to enhance knowledge about conversion of TIRF Medicines in the following:
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` Education Program for Prescribers and Pharmacists
`i.
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`ii.
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` TIRF REMS Website
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` 6. Information clarifying the process to electronically transmit TIRF REMS Cash Claims in
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` the following:
` TIRF REMS Document
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`i.
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` TIRF REMS Access Program Frequently Asked Questions (FAQ)
`ii.
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`iii.
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` Independent Outpatient Pharmacy Overview
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` iv. Chain Outpatient Pharmacy Overview
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` v. Closed System Outpatient Pharmacy Overview
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`We remind you that section 505-1(f)(8) of FDCA prohibits holders of an approved covered
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`application with elements to assure safe use from using any element to block or delay approval
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`of an application under section 505(b)(2) or (j). A violation of this provision in 505-1(f) could
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`result in enforcement action.
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`Reference ID: 3677533
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`

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` NDA 202788/S-009
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` NDA 202788/S-011
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` NDA 202788/S-012
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` Page 5
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` Your proposed modified REMS, submitted on May 21, 2014, and amended on December 11,
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` 2014, and appended to this letter, is approved.
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`The TIRF REMS Access Program currently includes the products listed on the FDA REMS
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`website, available at http://www.fda.gov/downloads/Drugs/DrugSafety/
`PostmarketDrugSafetyInformationforPatientsandProviders/UCM309784.pdf
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`Other products may be added to the TIRF REMS Access Program in the future if additional
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`TIRF NDAs or ANDAs are approved.
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` The timetable for submission of assessments of the REMS will remain the same as that approved
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` on June 5, 2012. There are no changes to the revised REMS Assessment Plan attached to our
` August 21, 2014, REMS Assessment Acknowledgment/REMS Assessment Plan Revisions letter.
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` In addition to the assessments submitted according to the timetable included in the approved
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` REMS, you must submit a REMS assessment when you submit a supplemental application for a
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` new indication for use as described in section 505-1(g)(2)(A) of the FDCA. Also, under section
` 505-1(g)(2)(C), FDA can require the submission of a REMS assessment if FDA determines an
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` assessment is needed to evaluate whether the REMS should be modified to ensure the benefits of
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` the drug outweigh the risks or to minimize the burden on the healthcare delivery system of
` complying with the REMS.
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` 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
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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 202788 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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`Reference ID: 3677533
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`

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` NDA 202788/S-009
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` NDA 202788/S-011
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` NDA 202788/S-012
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` Page 6
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`Prominently identify any 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
` first page of the submission as appropriate:
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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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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 202788
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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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`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 Matthew Sullivan, Supervisory Regulatory Health Project
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`Manager, at (301) 796-1245.
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`Sincerely,
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`{See appended electronic signature page}
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`
`Sharon Hertz, MD
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`Acting Director
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`Division of Anesthesia, Analgesia, and
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`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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`ENCLOSURES:
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`Content of Labeling
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`Carton and Container Labeling
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`REMS
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`Reference ID: 3677533
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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/
`----------------------------------------------------
`
`SHARON H HERTZ
`12/24/2014
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`Reference ID: 3677533
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`