CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`022410Orig1s000
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`OTHER ACTION LETTERS
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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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`COMPLETE RESPONSE
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`NDA 022410
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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.
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`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, 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, and August 7 and 14, 2009.
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`We have completed the review of your application, as amended, and have determined that we
`cannot approve this application in its present form. We have described below our reasons for
`this action and, where possible, our recommendations to address these issues.
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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
`the benefits of the drug outweigh the risks (section 505-1(a)).
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`In accordance with section 505-1 of the FDCA, we have determined that a REMS is necessary
`for Suboxone sublingual film to ensure that the benefits of the drug outweigh the risks of (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. The REMS, once approved,
`will create enforceable obligations.
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`Your proposed REMS, included in your submission dated October 20, 2008, is not sufficient to
`ensure that the benefits of Suboxone sublingual film outweigh the risks associated with use of
`Suboxone sublingual film.
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`NDA 022410
`Page 2
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`Your proposed REMS must include the following:
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`Medication Guide: As one element of a REMS, FDA may require the development of a
`Medication Guide as provided for under 21 CFR Part 208. Pursuant to 21 CFR Part 208,
`FDA has determined that Suboxone sublingual film poses a serious and significant public
`health concern requiring the distribution of a Medication Guide. The Medication Guide is
`necessary for patients’ safe and effective use of Suboxone sublingual film. FDA has
`determined that Suboxone sublingual film is a product for which patient labeling could help
`prevent serious adverse events and that Suboxone sublingual film is a product that has
`serious risks (relative to benefits) of which patients should be made aware as information
`concerning the risks could affect patients’ decisions to use, or continue to use Suboxone
`sublingual film. Under 21 CFR Part 208, you are responsible for ensuring that the
`Medication Guide is available for distribution to patients who are dispensed Suboxone
`sublingual film.
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`Elements to Assure Safe Use: We have determined that elements to assure safe use are
`necessary to mitigate serious risks listed in the labeling of the drug. In addition, we have
`determined that the Medication Guide and a communication plan are not sufficient to
`mitigate the serious risks. Your REMS must include tools to manage these risks, including,
`at least, assurance that each patient using the drug is subject to certain clinical monitoring
`under section 505-1(f)(3)(E) of the FDCA to ensure that 1) each patient is receiving the
`psychosocial support necessary for safe and effective use buprenorphine, 2) each patient
`adheres to the conditions of safe use explained to him/her, and 3) each patient is using
`Suboxone sublingual film appropriately and making adequate progress towards treatment
`goals.
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`Timetable for Submission of Assessment: The proposed REMS must include a timetable
`for submission of assessments that shall be no less frequent than every six months for the
`first 1 year and annually thereafter after the REMS is initially approved. You should specify
`the reporting interval (dates) that each assessment will cover and the planned date of
`submission to the FDA of the assessment. To facilitate inclusion of as much information as
`possible while allowing reasonable time to prepare the submission, the reporting interval
`covered by each assessment should conclude no earlier than 60 days before the submission
`date for that assessment. For example, the reporting interval covered by an assessment that is
`to be submitted by July 31st should conclude no earlier than June 1st.
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`Each assessment must assess the extent to which the elements to assure safe use of your
`REMS are meeting the goals of your REMS and whether the goals or elements should be
`modified.
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`Your proposed REMS submission should include two parts: a “proposed REMS” and a “REMS
`supporting document.” Attached is a template for the proposed REMS that you should complete
`with concise, specific information (see Appendix A). Include information in the template that is
`specific to your proposed REMS for Suboxone sublingual film. Additionally, all relevant
`proposed REMS materials including any educational materials or forms should be appended to
`the proposed REMS. Once FDA finds the content acceptable and determines that the application
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`NDA 022410
`Page 3
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`can be approved, we will include these documents as an attachment to the approval letter that
`includes the REMS.
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`The REMS supporting document should be a document explaining the rationale for each of the
`elements included in the proposed REMS (see Appendix B).
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`The REMS assessment plan should include but may not be limited to, the following:
`1. A survey of healthcare providers’ understanding of the serious risks of Suboxone
`sublingual film and the need for appropriate patient monitoring and psychosocial support
`services.
`2. A report on the status of the monitoring of patients by healthcare professionals.
`3. An evaluation of the effectiveness of the REMS program through an analysis and
`summary of surveillance and monitoring activities for abuse and misuse and any
`intervention taken resulting from signals of abuse and misuse. This surveillance and
`monitoring should include substance abuse treatment programs, private practitioners,
`ethnographers, and media surveillance.
`4. A report on the frequency and consequences of accidental pediatric exposures to
`Suboxone sublingual film.
`5. An evaluation of patients’ understanding of the serious risks of Suboxone sublingual
`film.
`6. A report on periodic assessments of the distribution and dispensing of the Medication
`Guide in accordance with 21 CFR 208.24.
`7. A report on failures to adhere to distribution and dispensing requirements for the
`Medication Guide, and corrective actions taken to address noncompliance.
`8. Specification of proposed measures that could be taken to increase awareness if surveys
`of healthcare providers indicate that healthcare provider awareness is not adequate.
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`Under 21 CFR 208.24(d), you are responsible for ensuring that the label of each container or
`package includes a prominent and conspicuous instruction to authorized dispensers to provide a
`Medication Guide to each patient to whom the drug is dispensed, and states how the Medication
`Guide is provided. You should submit marked up carton and container labels of all strengths and
`formulations with the required statement alerting the dispenser to provide the Medication Guide.
`We recommend the following language dependent upon whether the Medication Guide
`accompanies the product or is enclosed in the carton (for example, unit of use):
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`(cid:131) “Dispense the enclosed Medication Guide to each patient.” or
`(cid:131) “Dispense the accompanying Medication Guide to each patient.”
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`NDA 022410
`Page 4
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`Prominently identify the proposed REMS submission with the following wording in bold capital
`letters at the top of the first page of the submission:
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`NDA 022410
`PROPOSED REMS
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`Prominently identify subsequent submissions related to the proposed REMS with the following
`wording in bold capital letters at the top of the first page of the submission:
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`NDA 022410
`PROPOSED REMS-AMENDMENT
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`If you do not submit electronically, please send 5 copies of your REMS-related submissions.
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`LABELING
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`We reserve comment on the proposed labeling until the application is otherwise adequate. If you
`revise labeling, your response must include updated content of labeling [21 CFR 314.50(l)(1)(i)]
`in structured product labeling (SPL) format as described at
`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm.
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`SAFETY UPDATE
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`When you respond to the above deficiencies, include a safety update as described at
`21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and
`clinical studies/trials of the drug under consideration regardless of indication, dosage form, or
`dose level.
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`1. Describe in detail any significant changes or findings in the safety profile.
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`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
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`a. Present new safety data from the studies for the proposed indication using the
`same format as the original NDA submission.
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`b. Present tabulations of the new safety data combined with the original NDA data.
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`c. Include tables that compare frequencies of adverse events in the original NDA
`with the retabulated frequencies described in the bullet above.
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`d. For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
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`NDA 022410
`Page 5
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`3. Present a retabulation of the reasons for premature study discontinuation by incorporating
`the drop-outs from the newly completed studies. Describe any new trends or patterns
`identified.
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`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical study or who did not complete a study because of an adverse event. In addition,
`provide narrative summaries for serious adverse events.
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`5. Describe any information that suggests a substantial change in the incidence of common,
`but less serious, adverse events between the new data and the original NDA data.
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`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
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`7. Provide a summary of worldwide experience on the safety of this drug. Include an
`updated estimate of use for drug marketed in other countries.
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`8. Provide English translations of current approved foreign labeling not previously
`submitted.
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`OTHER
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`Within one year after the date of this letter, you are required to resubmit or take one of the other
`actions available under 21 CFR 314.110. If you do not take one of these actions, we will
`consider your lack of response a request to withdraw the application under 21 CFR 314.65. A
`resubmission must fully address all the deficiencies listed. A partial response to this letter will
`not be processed as a resubmission and will not start a new review cycle.
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`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to
`discuss what steps you need to take before the application may be approved. If you wish to have
`such a meeting, submit your meeting request as described in the FDA’s Guidance for Industry -
`Formal Meetings Between the FDA and Sponsors or Applicants, May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
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`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
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`NDA 022410
`Page 6
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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}
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`Bob A. Rappaport, M.D.
`Director
`Division of Anesthesia, Analgesia
` and Rheumatology Products
`Office of Drug Evaluation II
`Center for Drug Evaluation and Research
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`Enclosure: REMS Template
`REMS Supporting Document
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`NDA 022410
`Page 7
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`Appendix A: REMS Template
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`If you are not proposing to include one of the listed elements, include a statement that the
`element is not necessary.
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`Application number TRADE NAME (DRUG NAME)
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`Class of Product as per label
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`Applicant name
`Address
`Contact Information
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`RISK EVALUATION AND MITIGATION STRATEGY (REMS)
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`I. GOAL(S):
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` List the goals and objectives of the REMS.
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`II. REMS ELEMENTS:
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`A. Medication Guide or PPI
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`If a Medication Guide is included in the proposed REMS, include the following:
`A Medication Guide will be dispensed with each [drug name] prescription. [Describe in detail
`how you will comply with 21 CFR 208.24.]
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`B. Communication Plan
`If a Communication Plan is included in the proposed REMS, include the following:
` [Applicant] will implement a communication plan to healthcare providers to support
`implementation of this REMS.
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`List elements of communication plan. Include a description of the intended audience, including
`the types and specialties of healthcare providers to which the materials will be directed. Include
`a schedule for when and how materials will be distributed. Append the printed material and web
`shots to the REMS Document.
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`C. Elements To Assure Safe Use
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`If one or more Elements to Ensure Safe Use are included in the proposed REMS, include the following:
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`List elements to assure safe use of Section 505-1(f)(3)(A-F) included in this REMS. Elements to
`assure safe use may, to mitigate a specific serious risk listed in the labeling, require that:
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`NDA 022410
`Page 8
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`A. Healthcare providers who prescribe [drug name] have particular training or experience, or
`are specially certified. Append any enrollment forms and relevant attestations/certifications
`to the REMS;
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`B. Pharmacies, practitioners, or healthcare settings that dispense [drug name] are specially
`certified. Append any enrollment forms and relevant attestations/certifications to the
`REMS;
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`C. [Drug name] may be dispensed to patients only in certain healthcare settings (e.g.,
`hospitals);
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`D. [Drug name] may be dispensed to patients with documentation of safe-use conditions;
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`E. Each patient using [drug name] is subject to certain monitoring. Append specified
`procedures to the REMS; or
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`F. Each patient using [drug name] be enrolled in a registry. Append any enrollment forms and
`other related materials to the REMS Document.
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`D. Implementation System
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`If an Implementation System is included in the proposed REMS, include the following:
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`Describe the implementation system to monitor and evaluate implementation for, and work to
`improve implementation of, Elements to Assure Safe Use (B), (C), and (D), listed above.
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`E. Timetable for Submission of Assessments
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`Specify the timetable for submission of assessments of the REMS. The timetable for submission
`of assessments shall be no less frequent than by 18 months, 3 years, and in the 7th year after the
`REMS is initially approved. You should specify the reporting interval (dates) that each
`assessment will cover and the planned date of submission to the FDA of the assessment. To
`facilitate inclusion of as much information as possible while allowing reasonable time to prepare
`the submission, the reporting interval covered by each assessment should conclude no earlier
`than 60 days before the submission date for that assessment. For example, the reporting interval
`covered by an assessment that is to be submitted by July 31st should conclude no earlier than
`June 1st.
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`NDA 022410
`Page 9
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`Appendix B: Supporting Document
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`This REMS Supporting Document should include the following listed sections 1 through 6. If
`you are not proposing to include one of the listed elements, the REMS Supporting Document
`should simply state that the element is not necessary. Include in section 4 the reason you believe
`each of the potential elements you are proposing to include in the REMS is necessary to ensure
`that the benefits of the drug outweigh the risks.
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`1. Table of Contents
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`2. Background
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`3. Goals
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`4. Supporting Information on Proposed REMS Elements
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`a. Additional Potential Elements
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`i. Medication Guide
` ii. Patient Package Insert
` iii. Communication Plan
`b. Elements to Assure Safe Use, including a statement of how the
` elements to assure safe use will mitigate the observed safety risk
`c. Implementation System
`d. Timetable for Submission of Assessments of the REMS
`5. REMS Assessment Plan
`6. Other Relevant Information
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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
`08/21/2009
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