CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`022410Orig1s000
`
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
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`

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`****Pre-decisional Agency Information****
`
`INTERIM REMS REVIEW COMMENTS
`
`
`Date: 8/6/10
`
`
`Comment Set # 1
`
`
`Drug Name:
`
`SUBOXONE Sublingual
`Film (buprenorphine HCL
`and naloxone)
`
`BLA/NDA:
`
`#22-410
`
`
`
`
`DRISK Scientific Leads:
`Jeanne Perla, Ph.D., Risk Management
`Analyst
`
`Megan Moncur, Risk Management Analyst
`
`
`
`RCM #: 2010-970
`
`
`
`Reviewers:
`DRISK
`Gita Toyserkani, Pharm.D., Acting Team
`Leader
`Marcia Britt, Ph.D., Health Education
`Reviewer
`Brian Gordon, MA., Social Science Reviewer
`DDMAC
`Mathilda Fienkeng, Pharm.D., Regulatory
`Review Officer
`OC
`Agnes Plante, BSN, RN, Consumer Safety
`Officer
`
`
`MATERIALS REVIEWED:
`• General Advise Letter to applicant dated March 29, 2010
`• SUBOXONE Sublingual Film NDA 22-410
`The following proposed REMS materials received April 30, 2010, were reviewed:
`1. Proposed REMS
`2. Proposed REMS Supporting Document
`3. REMS Instruction Letter to Prescribers
`4. REMS Introductory Letter to Pharmacists
`5. Appropriate Use Checklist
`6. Physician Brochure, “Important Information for Physicians- Frequently Asked
`Questions”
`7. Pharmacist Brochure, “Important Information for Pharmacists-Frequently Asked
`Questions”
`
`
`
`
`
`1
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`(b) (4)
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`****Pre-decisional Agency Information****
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`
`INTRODUCTION:
`This interim REMS review is to provide preliminary comments on the proposed REMS
`submitted on April 23, 2010 for SUBOXONE sublingual film (NDA 22-410),
`
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`
`
`On October 8, 2002 SUBUTEX and SUBOXONE sublingual tablets were approved for
`the treatment of opioid dependence with a Risk Management Plan. On October 20, 2008,
`Reckitt Benckiser submitted a REMS for NDA 22-410. The proposed indication for
`SUBOXONE sublingual film is for the maintenance treatment of opioid dependence.
`
`On August 21, 2009, Reckitt Benckiser received a Complete Response Letter for NDA
`22-410 stating the proposed REMS was not sufficient to ensure the benefits outweighed
`the risk. In the CR letter the sponsor was notified that each patient using the drug be
`subject to certain clinical monitoring under section 5050(f)(3)(E) of the FDCA to ensure
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`2
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`****Pre-decisional Agency Information****
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`
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`that 1) each patient is receiving the psychosocial support necessary for safe use and
`effective use of
` SUBOXONE, 2) each patient adheres to the conditions
`of safe use explained to him/her, and 3) each patient is using
`
`SUBOXONE appropriately and making adequate progress towards treatment goals.
`
`The sponsor requested a meeting and submitted questions in the meeting background
`package on October 5, 2009 to discuss their proposed REMS submitted on
` November 24, 2009, (NDA 22410). Based on
`the review of the proposed REMS, the Agency provided responses in a General Advice
`letter to the questions and provided additional comments on the proposed REMS
`documents.
`
`In the General Advice letter the sponsor was notified that based on the Agencies
`understanding of the risks of buprenorphine, it was determined that the REMS must
`include a Medication Guide, elements to assure safe use under 505-1(f)(3)(D) and 505-
`1(f)(3)(E), an implementation system, and a timetable for the submission of assessments
`of the REMS. A communication plan was not required as an element of the REMS.
`
`Furthermore, because the risks of buprenorphine for the treatment of opioid dependence
`are the same, the sponsor was informed that the REMS for the three applications can be
`the same; however, the Medication Guide may be product specific and not all three
`products have to share the same Medication Guide. Additionally, the sponsor was
`informed that the goals of the REMS should be changed to the following: 1) to mitigate
`the risk of accidental overdose, misuse and abuse and 2) to inform patients of the serious
`risks associated with the use of SUBOXONE sublingual film
`
`
`
`
`The comments below are OSE/OC/DDMAC’s preliminary review of the amended
`proposed REMS submitted by Reckitt Benckiser on April 23, 2010, which incorporates
`the goals and the elements as recommended in the General Advice letter of March 29,
`2010.
`
`COMMENTS FOR THE SPONSOR
`The following comments are on the proposed REMS, appended material and Supporting
`Document submitted for NDA 22-410.
` Please incorporate the changes for all three applications and submit all
`revised materials within 2 weeks.
`
`1. General Comments
`a. Comments are provided based on the draft Product Labeling (PI). Revise all
`REMS materials to be consistent with the final agreed upon PI.
`b. Ensure the approved name of each drug is consistent with the PI in all of the
`REMS material.
`c. Replace
` with Reckitt Benckiser throughout REMS and REMS
`Supporting Document.
`
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`3
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`****Pre-decisional Agency Information****
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`d. Once the REMS and appended material are agreed upon, submit a final REMS
`with all appended materials and the REMS Supporting Document for each
`application.
`e. Provide a track changes and clean version of all revised materials and
`documents.
`f. All REMS documents should be dated and paginated to facilitate reviewer
`document control.
`g. Remove the word
` from the final documents.
`h. Please submit your revised proposed REMS and other materials in WORD
`format. It makes review of these materials more efficient and it is easier for
`the web posting staff to make the document 508 compliant. If certain
`documents are only in PDF format, they may be submitted as such, but any
`revisions will need to be identified (e.g. using the PDF Comment & Markup
`Tool).
`
`
`2. REMS Goals and Objectives:
`The goals of the REMS have been reviewed and found to be acceptable. The separate
`section titled
` has been removed from the REMS document but may remain in
`the Supporting Document.
`
`3. Medication Guide:
`a. Detailed information on the
` dispensing of the Medication
`Guide has been deleted from your REMS document, and should be included
`in your Supporting Document.
`b. The Medication Guide for NDA 22-410 submitted on July 14, 2010 was
`reviewed and found to be acceptable.
`
`
`
`
`
`
`4. Elements to Assure Safe Use (ETASU):
`a. Revisions were made to the following documents. See appended redline and
`clean versions:
`i. Appendix A (Appendix B – clean version) for revisions to the proposed
`REMS document. Please incorporate the changes. The REMS document
`may continue to undergo revisions by the Agency as the REMS goes
`through the internal clearance process.
`ii. Attachment C (Appendix D – clean Copy) for revisions to the REMS
`Instruction Letter to Prescribers
`iii. Attachment E (Appendix F – clean Copy) for revisions to the REMS
`Introductory Letter to Pharmacists
`iv. Insert headings (e.g., Obtaining Eligibility to Prescribe Suboxone, REMS,
`The Impact of a REMS on Prescribing Tradename) in the prescriber and
`pharmacist brochure to delineate the different sections being described.
`As currently written, the guide does not flow well.
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`4
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`****Pre-decisional Agency Information****
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`v. Attachment G (Appendix H – clean Copy) for revisions to the Physician
`Brochure, “Important Information for Physicians- Frequently Asked
`Questions”
`vi. Attachment I (Appendix J – clean Copy) for revisions to the Pharmacist
`Brochure, “Important Information for Pharmacists-Frequently Asked
`Questions”
`b. Appropriate Use Checklist is acceptable, no revisions are necessary.
`
`5. Implementation System
`a. Revise the proposed implementation system to include the following:
`i. Reckitt Benckiser will verify that all DATA 2000-certified physicians
`receive the Introduction Letter with the appended materials.
`ii. Reckitt Benckiser will monitor compliance with the requirements to
`document safe use conditions through surveys of patients and
`prescribers, evaluations of health care utilization databases, and ongoing
`surveillance (sources including, but not limited to, internet, street
`ethnography, national databases, and surveys conducted at substance
`abuse treatment programs).
`iii. Reckitt Benckiser will monitor and evaluate the implementation of the
`elements to assure safe use provided for under Sections B1, above, and
`in the manner described in the REMS supporting document, and will
`take reasonable steps to improve implementation of these elements to
`meet the goals of the REMS.
`
`
`6. Timetable for Submission Assessment
`The Timetable for Assessment of the REMS have been reviewed and found to be
`acceptable. Please see track changes for minor editorial revisions.
`
`7. REMS Supporting Document
`a. All changes in REMS Document should be reflected in the REMS Supporting
`Document for consistency.
`b. Clarify and provide the “cover letter” mentioned on page 13 of the REMS
`Supporting Document. Although, this letter will not be part of the appended
`REMS materials, it should be included in your Supporting Document.
`c. The REMS Assessment Plan is to be summarized in the REMS Supporting
`Document and will be included in the approval letter. The REMS Assessment
`Plan will include, but is not limited to the following:
`i. An evaluation of patients’ understanding of the serious risks of the
`Suboxone film.
`ii. A report on periodic assessments of the distribution and dispensing of
`the Medication Guide in accordance with 21 CFR 208.24.
`iii. A report on failures to adhere to distribution and dispensing
`requirements for the Medication Guide, and corrective actions taken to
`address noncompliance.
`iv. A survey of healthcare providers’ understanding of the serious risks of
`Suboxone film and the need a) for appropriate patient monitoring, b) for
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`****Pre-decisional Agency Information****
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`patient adherence to conditions of safe use, c) to check that patients are
`using the drug appropriately and making adequate progress towards
`treatment goals, d) to make sure prescriptions are provided in amounts
`commensurate with patient stability and e) the importance of
`psychosocial support services. Include specification of measures that
`would be taken to increase awareness if surveys of healthcare providers
`indicate that healthcare provider awareness is not adequate.
`v. An analysis to evaluate Suboxone 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.
`vi. 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 should include, among other sources, reports from street
`ethnography programs and pediatric exposures.
`vii. With respect to REMS goals, an assessment of the extent to which the
`elements to assure safe use are meeting the goals or whether the goals or
`such elements should be modified.
`d. The methodologies and survey instruments for the proposed patient and
`prescriber surveys are under review. We will provide our comments once the
`review is completed. The proposed methodologies and survey instruments do
`not need to be approved at the time of the REMS approval.
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`6
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`123 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this
`page.
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`

`

`Application
`Type/Number
`--------------------
`
`Submission
`Type/Number
`--------------------
`
`Submitter Name
`
`Product Name
`
`--------------------
`
`------------------------------------------
`
`NDA-22410
`
`ORIG-1
`
`RECKITT
`BENCKISER
`PHARMACEUTICA
`LS INC
`
`SUBOXONE
`(BUPRENORPHINE/NALOXONE
`) sublingual film
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`GITA A AKHAVAN TOYSERKANI
`08/06/2010
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`(b) (4)
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`(b) (4)
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`