CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`022410Orig1s000
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`
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`SUMMARY REVIEW
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`

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`Food and Drug Administration
`CENTER FOR DRUG EVALUATION AND RESEARCH
`Division of Anesthesia and Analgesia Products
`10903 New Hampshire Ave.
`Silver Spring, MD 20993-0002
`
`Summary Review for Regulatory Action
`August 30, 2010
`Rigoberto Roca, M.D.
`Deputy Director
`Division of Anesthesia and Analgesia Products
`Deputy Division Director Summary Review
`022410
`Reckitt Benckiser
`October 21, 2008
`August 21, 2009
`November 30, 2009
`August 30, 2010
`(extended due to a submission of a major amendment)
`Suboxone (Buprenorphine/naloxone) sublingual film
`
`
`
`
`Date
`From
`
`
`
`Subject
`NDA Number
`Applicant Name
`Date of Original Submission
`Date of Complete Response
`Date of Re-Submission
`PDUFA Goal Date
`
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`
`Proposed Indication(s)
`
`Action
`
`Material Reviewed/Consulted
`OND Action Package, including:
`CDTL Review
`DDMAC
`
`OSE/DMEPA
`
`OSE/DRISK
`
`Sublingual film
`2 mg/0.5 mg and 8 mg/2 mg
`For the maintenance treatment of opioid dependence
`
`
`Approval
`
`Celia Winchell, M.D.
`Mathilda Fienkeng, Pharm.D., Regulatory Review Officer
`Twyla Thompson, Pharm.D., Regulatory Review Officer
`Zachary Oleszczuk, PharmD, Acting Team Leader
`Denise Toyer, PharmD, Deputy Director
`Jeanne Perla, Ph.D., Risk Management Analyst;
`Megan Moncur, Risk Management Analyst;
`Gita Toyserkani, Pharm.D., Acting Team Leader;
`Marcia Britt, Ph.D., Health Education Reviewer; and
`Brian Gordon, MA., Social Science Reviewer
`Agnes Plante, BSN, RN, Consumer Safety Officer
`
`Office of Compliance
`
`
`CDTL = Cross-Discipline Team Leader
`DDMAC = Division of Drug Marketing, Advertising and Communication
`DMEPA = Division of Medication Error Prevention and Analysis
`DRISK = Division of Risk Management
`
`
`DSI = Division of Scientific Investigations
`OND = Office of New Drugs
`OSE = Office of Surveillance and Epidemiology
`
`
`
`
`(b) (4)
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`

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`NDA 022410
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` Suboxone (buprenorphine/naloxone) sublingual film
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`1. Introduction
`The Applicant, Reckitt Benckiser, submitted an application on October 21, 2008, for a line
`extension of, and as an alternative to, their Suboxone tablets. The new formulation is a
`sublingual strip, in dosage strengths that are similar to the approved tablets; specifically,
`buprenorphine 2 mg/naloxone 0.5 mg and buprenorphine 8 mg/naloxone 2 mg. The
`application received a Complete Response on August 21, 2009, because it did not contain an
`adequate Risk Evaluation and Mitigation Strategy (REMS) to address the Agency’s concerns
`regarding misuse and abuse of the product. The Applicant’s submission of November 24,
`2009, constituted a Complete Response to the Action letter of August 21, 2009.
`
`This review will provide an overview of the regulatory and scientific facts of this application
`and issues that were identified during the course of the review of the submission. Aspects that
`will be touched upon include the regulatory history, the adequacy of the data to support the
`application, and the labeling requested by the Applicant.
`
`
`
`2. Background
`Buprenorphine is an opioid partial agonist which has been marketed as an injectable analgesic
`since 1982. Subutex (buprenorphine) and Suboxone (buprenorphine and naloxone) were
`approved in 2002 for the treatment of opioid dependence. These products may only be
`prescribed by health care professionals who have fulfilled certain training requirements
`defined in the Drug Abuse Treatment Act of 2002, which also limits the number of patients for
`whom a specific health care professional or group practice may prescribe these products. As
`noted in Dr. Rappaport’s memorandum from the first review cycle, due to its pharmacological
`properties, buprenorphine, with or without naloxone, has been thought to be useful only in
`patients with mild to moderate degrees of opioid dependence. Methadone remains the
`treatment of choice for patients with more severe forms of opioid addiction.
`
`Dr. Rappaport also noted that the Applicant purportedly created this formulation to minimize
`abuse and misuse, including unintended exposures in children. The Applicant also posited an
`increase in patient compliance, minimization of counterfeiting, minimization of illegal use and
`diversion, and a decrease in product damage during transport and storage compared to the
`sublingual tablets. These goals were based on the use of unit dose packaging and child-
`resistant packaging with improved coding.
`
`Support for the efficacy and safety of this product rested primarily on data from Phase 1
`pharmacokinetic studies evaluating bioavailability, dose proportionality, and comparisons to
`Suboxone tables, and reference to the sponsor’s NDAs for Suboxone and Subutex. A small
`open-label safety study of the buprenorphine/naloxone strip and a small laboratory study
`comparing the buprenorphine/naloxone strip to a buprenorphine-only strip supplemented these
`findings.
`
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`Summary Review for Regulatory Action
`
`2
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`

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`NDA 022410
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` Suboxone (buprenorphine/naloxone) sublingual film
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`3. Chemistry, Manufacturing, and Controls (CMC)
`All issues related to product quality, facilities review and inspections, as well as stability
`testing were addressed during the first review cycle. There were no outstanding issues that
`would have precluded approval, and no new information was submitted or reviewed with this
`submission.
`
`
`4. Nonclinical Pharmacology/Toxicology
`No new nonclinical pharmacology/toxicology information was submitted or reviewed in this
`submission. Label changes recommended by the pharmacology/toxicology reviewer based on
`the initial application are documented in the original reviews and will be incorporated in
`labeling.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`No new nonclinical clinical pharmacology/biopharmaceutics information was reviewed in this
`submission. Labeling changes recommended by the reviewer based on the initial application
`are documented in the original reviews and will be incorporated in labeling.
`
`Hepatic impairment:
`The Applicant has an outstanding post-marketing commitment under the NDAs for Subutex
`(NDA 020732) and Suboxone (NDA 020733) to study the effects of hepatic impairment on the
`pharmacokinetics of buprenorphine/naloxone. This study has not been initiated and it will be
`reiterated with this approval as a post-marketing requirement for this NDA.
`
`Thorough QT Study
`As noted in Dr. Winchell’s review, there were no new electrocardiographic data reviewed in
`the original submission. The Applicant had submitted data on electrocardiograms collected
`during the pharmacokinetic studies; however, these data were not expected to yield any
`information relevant to the application because they were collected from healthy volunteers
`and not in the same manner and degree were a determination could be made on the effect of
`the QT interval.
`
`Since the action was taken on August 21, 2009, the Agency has become aware of the results of
`a thorough QT (TQT) study conducted by Purdue Pharma with their transdermal
`buprenorphine product (BuTrans, NDA 021306). In this study, transdermal application of
`buprenorphine, 10 mcg/hr and 40 mcg/hr, were compared to a moxifloxacin control.
`
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`Dr. Winchell also noted in her review that there have been other studies reported in the
`literature, conducted with buprenorphine at typical addiction treatment doses and appropriate
`ECG measurements, which do not indicate a clinically significant effect on the QT interval.
`
`
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`Summary Review for Regulatory Action
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`3
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`(b) (4)
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`

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`NDA 022410
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`
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`
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`
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` Suboxone (buprenorphine/naloxone) sublingual film
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`
`Outstanding or Unresolved Issues
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`
`
` the Applicant will be required to conduct a thorough QT study. This can be
`accomplished as a post-approval study, and will be identified as a post-marketing requirement
`in the action letter.
`6. Clinical Microbiology
`The drug product, buprenorphine/naloxone, is not a therapeutic antimicrobial; therefore,
`clinical microbiology data were not required or submitted for this application.
`
`
`7. Clinical/Statistical-Efficacy
`There were no new efficacy data submitted in support of this application, and none were
`needed in support of the complete response submission.
`
`
`8. Safety
`As noted in Dr. Winchell’s review of the original submission, the safety review of the
`application consisted of:
`1. Data generated in the Applicant’s safety study, RB-US-07-0001.
`2. Data generated in the Applicant’s laboratory induction study, RB-US-07-0002.
`3. The Applicant’s comprehensive evaluation of hepatic safety issues, comprising their
`evaluation of sources such as postmarketing data, literature, and clinical trial data. This
`review was supplemented by a review of AERS data conducted by the Office of
`Surveillance and Epidemiology (OSE).
`4. The Applicant’s evaluation of issues related to the use of buprenorphine in pregnancy.
`5. The Applicant’s evaluation of information about accidental pediatric exposure, which
`was submitted to substantiate the public health importance of the individually-
`packaged strip product.
`
`
`Dr. Rappaport’s noted in his memorandum that there were no serious or unexpected safety
`signals identified during the first review cycle. However, three concerns were noted by the
`review team:
`• Potential for oral mucosal irritation;
`• Potential to precipitate withdrawal in the opioid dependent patients who would be
`treated by this product; and
`• Potential for hepatotoxicity.
`
`
`Dr. Rappaport noted that the incidence of withdrawal symptoms in the overall database was no
`higher than would be expected in this patient population, and, therefore, generally not
`concerning. He also noted that, while there was no new or increased hepatotoxicity signal
`noted in the database, the previous post-marketing commitment to evaluate the comparative
`effects of buprenorphine and methadone on the liver should be reiterated.
`
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`Summary Review for Regulatory Action
`
`4
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`(b) (4)
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`

`

`NDA 022410
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` Suboxone (buprenorphine/naloxone) sublingual film
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`During this review cycle, which included a safety update, the overall conclusion regarding the
`safety profile of the product was essentially unchanged from the conclusion reached during the
`first review cycle.
`
`Regarding the potential for oral mucosal irritation, the review team has concluded that routine
`pharmacovigilance of the post-marketing adverse event reports should be sufficient to
`determine whether a specific post-marketing study would be warranted and I concur.
`
`Regarding the potential for hepatic toxicity, it was noted that, at the time of this submission, a
`study was already underway to evaluate the comparative hepatic safety of buprenorphine and
`methadone. This was the study identified by Dr. Rappaport in his memorandum as one of the
`post-marketing commitments agreed to by the Applicant under the NDAs for Subutex and
`Suboxone (NDAs 020732 and 020733, respectively).
`
`Another outstanding post-marketing commitment under the NDAs for Subutex and Suboxone
`was a study to evaluate the effects of hepatic impairment on the pharmacokinetics of
`buprenorphine/naloxone. This study has not been initiated and will be reiterated as a post-
`marketing requirement with this action.
`
`Outstanding or Unresolved Issues
`The Applicant has a study underway comparing the hepatic safety of buprenorphine and
`methadone under the sponsorship of the National Institute on Drug Abuse. This study was a
`post-marketing commitment under the NDAs for Subutex (NDA 020732) and Suboxone
`(NDA 020733).
`
`The Applicant will have two post-marketing requirements imposed with this action: one to
`evaluate
`the
`effects
`of
`hepatic
`impairment
`on
`the
`pharmacokinetics
`of
`buprenorphine/naloxone, and one to conduct a thorough QT study (as described above, in the
`Clinical Pharmacology/Biopharmaceutics section of this memorandum).
`
`
`9. Advisory Committee Meeting
`As noted in Dr. Rappaport’s memo, the review team determined that an advisory committee
`meeting was unnecessary for this new formulation of buprenorphine/naloxone as there were no
`clinically serious new or unexpected safety concerns specific to this product.
`
`
`Pediatrics
`10.
`This product is exempt from the pediatric study requirements authorized by PREA as the
`sponsor received orphan designation for the active moiety of buprenorphine, with or without
`naloxone, for the treatment of opioid addiction.
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`Summary Review for Regulatory Action
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`5
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`

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`NDA 022410
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` Suboxone (buprenorphine/naloxone) sublingual film
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`Other Relevant Regulatory Issues
`11.
`The Complete Response action that was taken after the first review cycle was due to the lack
`of an adequate REMS submission. The action letter indicated that the REMS must include the
`following:
`1) Medication Guide
`2) Elements to Assure Safe Use
`a) 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
`i) each patient is receiving the psychosocial support necessary for safe and
`effective use buprenorphine,
`ii) each patient adheres to the conditions of safe use explained to him/her, and
`iii) each patient is using Suboxone sublingual film appropriately and making
`adequate progress towards treatment goals.
`3) Timetable for Submission of Assessment
`
`
`The final version of the REMS submitted by the Applicant has met these stipulations.
`
`4) Labeling
`The Applicant has submitted enough information to support their proposed labeling. As noted
`above, representatives from the Office of Surveillance and Epidemiology and the Division of
`Drug Marketing, Advertising and Communications were consulted and their recommendations
`were incorporated during the discussion of the label.
`
`The label has been revised in several ways to more strongly emphasize the drug, and the risk
`of accidental exposure. It also includes more explicit recommendations on clinical
`management in the Dosing and Administration section.
`
`5) Decision/Action/Risk Benefit Assessment
`Regulatory Action
`Approval.
`
`Risk:Benefit Assessment
`I concur with the review team that the Applicant has submitted sufficient evidence
`to demonstrate the effectiveness and safety of the new formulation when used
`according the labeled instructions. With the submission of an acceptable REMS,
`the Applicant has addressed the Agency’s concerns regarding misuse and abuse of
`the product, and, therefore, I find the risk:benefit assessment favorable.
`
`Recommendation for Postmarketing Risk Management Activities
`In order to assure that the benefits of this product outweigh the risks of abuse,
`misuse and accidental pediatric exposure, the Agency has determined that the
`product must have a REMS as described above. The REMS is comprised of a
`Medication Guide, an Element to Assure Safe Use (ETASU), and a timetable for
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`Summary Review for Regulatory Action
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`6
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`

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`NDA 022410
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` Suboxone (buprenorphine/naloxone) sublingual film
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`submission of assessments of the REMS. The ETASU falls under section 505-
`1(f)(3)(E) of the FDCA and is intended 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.
`
`
`Recommendation for other Postmarketing Study Requirements
`
`
`1. The Applicant will need to conduct a clinical trial to assess the risk of QT
`prolongation with their buprenorphine-containing product, i.e., a thorough TQT
`trial. This trial should include a methadone treatment arm, at typical treatment
`doses, for comparison. It is likely that this trial will need to be conducted in
`opioid-tolerant volunteers or new entrants to opioid dependence treatment.
`
`2. The Applicant will need to conduct a clinical trial to determine the effect of
`hepatic impairment on the pharmacokinetics of their buprenorphine-containing
`product, and to establish whether there is a differential effect on the buprenorphine
`as compared to naloxone.
`
`
`
`Recommendation for other Postmarketing Study Commitments
`None.
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`Summary Review for Regulatory Action
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`7
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`

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`Application
`Type/Number
`--------------------
`NDA-22410
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`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/
`----------------------------------------------------
`
`RIGOBERTO A ROCA
`08/30/2010
`
`