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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 022410/S-004, S-017, S-018
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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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`FULFILLMENT OF POSTMARKETING
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`REQUIREMENT
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`Bruce Paolella
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`Director, Regulatory Affairs
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`Reckitt Benckiser Pharmaceuticals Inc.
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`10710 Midlothian Turnpike
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`Suite 430
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`Richmond, VA 23235
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`Attention:
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`Dear Mr. Paolella:
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`Please refer to your Supplemental New Drug Applications (sNDAs) dated June 1, 2011, received
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`June 2, 2011, which was refused to file on August 01, 2011, and resubmitted March 28, 2013,
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`(S- 004), December 13, 2013, received December 13, 2013 (S-017) and December 30, 2013,
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`received December 30, 2013, (S-018), submitted under section 505(b) of the Federal Food, Drug,
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`and Cosmetic Act (FDCA) for Suboxone (buprenorphine and naloxone) sublingual film.
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`We acknowledge receipt of your amendments dated June 15, and July 20, 22, and 27, 2011,
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`March 28, April 26, May 7 and 8, June 24, August 15, September 16, and October 28, 2013, and
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`January 24, 2014, (S-004), and January 28, 2014 (S-018), and your risk evaluation and
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`mitigation strategy (REMS) assessment dated April 21, 2014.
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`Supplement S-004 proposes a revised indication to include the use of Suboxone sublingual film
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`for the initiation of buprenorphine treatment of opioid dependence and a proposed modification
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`to the approved risk evaluation and mitigation strategy (REMS).
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`Supplement S-017 provides for revisions to the HIGHLIGHTS: USE IN SPECIFIC
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`POPULATIONS, 8.1: Pregnancy and 8.3: Nursing Mothers, and 17.1: Safe Use sections of
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`the Package Insert.
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`Supplement S-018 proposes revisions to Section 8: USE IN SPECIFIC POPULATIONS, and
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`Section 12: CLINICAL PHARMACOLOGY of the Package Insert to include results of the
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`recently completed study Pharmacokinetics of Buprenorphine and Naloxone in Subjects with
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`Mild to Severe Hepatic Impairment (Child-Pugh Classes A, B, and C), in HCV-Seropositive
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`Subjects, and in Healthy Volunteers, to fulfill the following Postmarketing Commitment listed in
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`the approval letter dated August 30, 2010.
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`Reference ID: 3496928
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` NDA 022410/S-004, 017, 018
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` Page 2
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` 1674-2
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` A clinical trial to determine the effect of hepatic impairment on the
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` pharmacokinetics of sublingual Suboxone, and to establish whether there is a
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` differential effect on buprenorphine as compared to naloxone
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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.
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` WAIVER OF HIGHLIGHTS SECTION
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` Please note that we have previously granted a waiver of the requirements of 21 CFR
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` 201.57(d)(8) regarding the length of Highlights of prescribing information.
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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
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`of labeling must be identical to the enclosed labeling (text for the package insert and Medication
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`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 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
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` 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
`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: 3496928
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` NDA 022410/S-004, 017, 018
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` Page 3
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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
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`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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`administration are required to contain an assessment of the safety and effectiveness of the
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`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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`deferred, or inapplicable.
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`Because this drug product for this indication has an orphan drug designation, you are exempt
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`from this requirement.
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`FULFILLMENT OF POSTMARKETING REQUIREMENT
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`Your January 28, 2014, submission contains the final report for the following postmarketing
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`requirement listed in the August 30, 2010, approval letter.
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`A clinical trial to determine the effect of hepatic impairment on the
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`1674-2
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`pharmacokinetics of sublingual Suboxone, and to establish whether there is a
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`differential effect on buprenorphine as compared to naloxone.
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`We have reviewed your submission and conclude that the above requirement was fulfilled.
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`We remind you that there is a postmarketing requirement listed in the August 30, 2010, approval
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`letter that has not been fulfilled.
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`RISK EVALUATION AND MITIGATION STRATEGY REQUIREMENTS
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`The REMS for Suboxone sublingual film was originally approved on August 30, 2010 and a
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`REMS modification was approved on August 10, 2012. The REMS consists of a Medication
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`Guide, elements to assure safe use, an implementation system, and a timetable for submission of
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`assessments of the REMS. Your proposed modification to the REMS consists of:
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`• Addition of the following information to the appended REMS materials:
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`o A revised indication to allow for buprenorphine to be used in both the initiation and
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`maintenance phases of opioid dependence.
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` Limitations of use to patients physically dependent on heroin or other short-acting
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`opioids.
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`o A new warning regarding use in patients with hepatic impairment.
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`o Updated language on use in pregnancy, nursing mothers, and patients with hepatic
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`impairment.
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`• Updates to the appended REMS materials to reflect information on how approved
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`buprenorphine/naloxone combination products differ from each other, how to switch
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`between products, and recommended dosing.
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`• Revisions to the appended REMS materials to convey information in a clearer, more
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`concise manner, provide greater emphasis on messages thought to be of most importance,
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`and remove information found to be unnecessary.
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`Reference ID: 3496928
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` NDA 022410/S-004, 017, 018
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` Page 4
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` • Removal of Appendix A: Obtaining Eligibility to Prescribe Suboxone
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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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`Your proposed modified REMS, submitted on April 21, 2014, and appended to this letter, is
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`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 August 30, 2010.
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`There are no changes to the REMS assessment plan described in our August 30, 2010, 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.
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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 022410 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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`Reference ID: 3496928
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` NDA 022410/S-004, 017, 018
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` Page 5
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` NDA 022410 REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 022410
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`PROPOSED REMS MODIFICATION
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`NEW SUPPLEMENT (NEW INDICATION FOR USE)
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`FOR NDA 022410
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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
`(3) the package insert(s) to:
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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
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
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`Information and Instructions for completing the form can be found at
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
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`more information about submission of promotional materials to the Office of Prescription Drug
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`Promotion (OPDP), 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
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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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`Reference ID: 3496928
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` Sincerely,
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`{See appended electronic signature page}
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`Bob A. Rappaport, M.D.
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`Director
`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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` NDA 022410/S-004, 017, 018
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` Page 6
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` If you have any questions, call Matt Sullivan, Senior Regulatory Project Manager, at
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` (301) 796-1245.
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`ENCLOSURES:
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`Content of Labeling
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`REMS
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`Reference ID: 3496928
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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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`BOB A RAPPAPORT
`04/28/2014
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`Reference ID: 3496928
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