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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`Food and Drug Administration
`Silver Spring MD 20993
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`NDA 022410
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`NDA APPROVAL
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`Reckitt Benckiser Pharmaceuticals Inc.
`10710 Midlothian Turnpike, Suite 430
`Richmond, VA 23235
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`Attention: John D. Pitts, R.Ph., Ph.D.
`Manager, Regulatory Affairs
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`Dear Dr. Pitts:
`
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`Please refer to your New Drug Application (NDA) submitted October 20, 2008, received
`October 21, 2008, under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA)
`for Suboxone (buprenorphine and naloxone) sublingual film.
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`We acknowledge receipt of your amendments dated October 22 and 30, and December 1, 3, 8,
`and 11, 2008, and January 8, February 4 (2), March 3, 20, 25, and 26, April 6, 20, 28, and 30,
`June 9, July 24, August 7 and 14, and November 2, 12, 24, 2009, and January 25, March 5 (2),
`April 29, May 17, July 21, and August 20, 23, 24, and 27, 2010.
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`The November 24, 2009, submission constituted a Complete Response to our August 21, 2009,
`Action Letter.
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`This new drug application provides for the use of Suboxone (buprenorphine and naloxone)
`sublingual film for use in the maintenance treatment of opioid dependence when used as part of a
`complete treatment plan to include counseling and psychosocial support.
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`We have completed our review of this 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, via the FDA
`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
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`NDA 022410
`Page 2
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`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm, that is
`identical to the enclosed labeling (text for the package insert and Medication Guide).
`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
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible via publicly available labeling repositories.
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`We acknowledge your April 29, 2010, submission containing final printed carton and container
`labels.
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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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`Because this drug product for this indication has an orphan drug designation, you are exempt
`from this requirement.
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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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`During the review of this NDA we have become aware of a placebo-controlled thorough QT
`study employing another buprenorphine containing product, Butrans, approved on June 30, 2010.
`The study indicated QT prolongation meeting the threshold for concern at buprenorphine plasma
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`concentrations similar to those that could be achieved with Suboxone sublingual film.
`Therefore, Suboxone sublingual film may have the potential to cause QT prolongation at
`therapeutic doses that could result in increased risk for serious cardiac events, including life-
`threatening arrhythmias. Further, we note that patients with hepatic impairment may have
`delayed clearance of, and increased exposure to, buprenorphine which could lead to an increase
`in adverse effects, including the potential for QT prolongation.
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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 identify the unexpected serious
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`NDA 022410
`Page 3
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`risk of cardiac events related to your product and whether presence of hepatic impairment
`increases this risk. 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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`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to identify an unexpected serious risk of cardiac events, including life-
`threatening arrhythmias, related to the use of Suboxone sublingual film.
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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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`1674-1.
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`A clinical trial to assess the risk of QT prolongation with sublingual
`buprenorphine, i.e., a thorough QT (tQT) trial. A comparison to methadone at
`typical treatment doses should be included. It is likely this trial will need to be
`conducted in opioid-tolerant volunteers or new entrants to opioid dependence
`treatment.
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`The timetable you submitted via email on August 6, 2010, states that you will conduct this trial
`according to the following schedule:
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`Final Protocol Submission:
`Trial Completion:
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`Final Report Submission:
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`September 30, 2011
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`December 31, 2014
`September 30, 2015
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`1674-2.
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`A clinical trial to determine the effect of hepatic impairment on the
`pharmacokinetics of sublingual Suboxone, and to establish whether there is a
`differential effect on buprenorphine as compared to naloxone.
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`The timetable you submitted via email on August 16, 2010, states that you will conduct this
`trial according to the following schedule:
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`Final Protocol Submission:
`Trial Completion Date:
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`Final Report Submission:
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`April 30, 2011
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`June 30, 2013
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`December 30, 2013
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`Submit the protocol to your IND, with a cross-reference letter to this NDA. Submit all final
`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 PROTOCOL UNDER 505(o)
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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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`NDA 022410
`Page 4
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial 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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`Section 505-1 of the FDCA authorizes FDA to require the submission of a risk evaluation and
`mitigation strategy (REMS), if FDA determines that such a strategy is necessary to ensure that
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`the benefits of the drug outweigh the risks (section 505-1(a)). The details of the REMS
`requirements were outlined in our complete response letter dated August 21, 2009.
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`Pursuant to 505-1(f)(1), we have determined that Suboxone sublingual film can be approved only
`if elements necessary to assure safe use are required as part of a REMS to mitigate the risks of
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`(1) exposure to Suboxone sublingual film in persons for whom it was not prescribed, including
`accidental exposure in children, and (2) risks of abuse and misuse, listed in the labeling. The
`elements to assure safe use will inform patients of the serious risks associated with Suboxone
`sublingual film and the appropriate conditions of safe use and storage of Suboxone sublingual
`film. The elements to assure safe use will also ensure adequate clinical monitoring of patients by
`healthcare providers.
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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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`Your proposed REMS, submitted on August 27, 2010, and appended to this letter, is approved.
`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.
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`The REMS assessment plan should include but is not limited to the following:
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`a. An evaluation of patients’ understanding of the serious risks of Suboxone sublingual
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` film
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`b. A report on periodic assessments of the distribution and dispensing of the 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
`corrective actions taken to address noncompliance
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`d. A survey of healthcare providers’ understanding of the serious risks of Suboxone
`sublingual film and the:
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`i. need for appropriate patient monitoring
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`ii. need for patient adherence to conditions of safe use
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`iii. need to check that patients are using the drug appropriately and making
`adequate progress towards treatment goals
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`iv. need to make sure prescriptions are provided in amounts commensurate with
`patient stability
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`v. importance of psychosocial support services
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`e. Specific measures that will be taken to increase awareness if surveys of prescribers
`indicate that prescriber awareness is not adequate
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`f. An analysis to evaluate Suboxone sublingual film utilization patterns including
`frequency of office visits/patient/prescriber, amount dispensed in prescriptions to new
`patients, and other indicators of adherence to practices important to safe use
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`g. An analysis and summary of surveillance and monitoring activities for abuse, misuse,
`overdose and addiction and any intervention taken resulting from signals of abuse,
`misuse, overdose and addiction. Surveillance will include, among other sources,
`reports from street ethnography programs and pediatric exposures
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`NDA 022410
`Page 5
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`The requirements for assessments of an approved REMS under section 505-1(g)(3) include, in
`section 505-1(g)(3)(A), an assessment of the extent to which the elements to assure safe use are
`meeting the goal or goals to mitigate a specific serious risk listed in the labeling of the drug, or
`whether the goal or goals or such elements should be modified.
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`Assessments of an approved REMS must also 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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`NDA 022410
`Page 6
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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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`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:
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`NDA 022410
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`REMS ASSESSMENT
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`NEW SUPPLEMENT FOR NDA 022410
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`PROPOSED REMS MODIFICATION
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`REMS ASSESSMENT
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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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`EXPIRATION DATING PERIOD
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`Your packaging configuration of 30 films per carton is granted a 12 month expiration dating
`period, stored at 25ºC (77ºF); excursions permitted to 15-30°C (59- 86°F).
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`NDA 022410
`Page 7
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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, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`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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`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`2253. For instruction on completing the Form FDA 2253, see page 2 of the Form. For more
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`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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`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
`CDERMedWatchSafetyAlerts@fda.hhs.gov, and 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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`NDA 022410
`Page 8
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`If you have any questions, call Matt Sullivan, Regulatory Project Manager, at 301-796-1245.
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`Sincerely,
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`{See appended electronic signature page}
`
`
`Rigoberto Roca, MD
`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
`Medication Guide
`Carton and Container Labeling
`REMS
`REMS materials
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`• REMS Introductory Letter to Prescribers
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`• REMS Introductory Letter to Pharmacists
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`• Appropriate Use Checklist
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`• Physician Brochure, “Important Information for Physicians-Frequently Asked
`Questions”
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`• Pharmacist Brochure, “Important Information for Pharmacists-Frequently Asked
`Questions”
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`Application
`Type/Number
`--------------------
`NDA-22410
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`Submission
`Type/Number
`--------------------
`ORIG-1
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`Submitter Name
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`Product Name
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`------------------------------------------
`--------------------
`SUBOXONE
`RECKITT
`(BUPRENORPHINE/NALOXONE
`BENCKISER
`PHARMACEUTICA ) sublingual film
`LS INC
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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/
`----------------------------------------------------
`
`RIGOBERTO A ROCA
`08/30/2010
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`