CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`022410Orig1s000
`
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
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`

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`Cross-Discipline Team Leader Review
`
`Cross Discipline Team Leader Review
`
`
`Date
`From
`Subject
`
`NDA #
`Applicant
`Date of Submission
`
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) names
`Dosage forms / Strength
`
`Proposed Indication(s)
`
`August 20, 2010
`Celia Winchell, M.D., Clinical Team Leader
`Cross-Discipline Team Leader Review and Review of
`Safety Update
`22-410
`Reckitt Benckiser
`Initial Submission: October 21, 2008
`Complete Response Received: November 24, 2009
`August 30, 2010 (extended due to major amendment)
`Suboxone (buprenorphine and naloxone) sublingual film
`
`Buprenorphine 2 mg with Naloxone 0.5 mg
`Buprenorphine 8 mg with Naloxone 2 mg
`Maintenance Treatment of Opioid Dependence
`
`
`
`
`Approval
`Recommended:
`1
`Introduction..........................................................................................................................3
`2 Background..........................................................................................................................4
`3 CMC/Device ........................................................................................................................4
`3.1
`Other notable issues .....................................................................................................4
`3.1.1
`Proprietary Name Review....................................................................................4
`4 Nonclinical Pharmacology/Toxicology ...............................................................................5
`5 Clinical Pharmacology/Biopharmaceutics...........................................................................5
`6 Clinical Microbiology..........................................................................................................5
`7 Clinical/Statistical- Efficacy................................................................................................5
`8
`Safety ...................................................................................................................................5
`8.1
`Safety Findings ............................................................................................................6
`8.1.1.1 Hepatic Safety..................................................................................................6
`8.1.1.2 Study Drug Accountability/Diversion .............................................................7
`8.1.1.3 Use in Pregnancy .............................................................................................7
`8.1.1.4 Common Adverse Events ................................................................................7
`8.1.2
`Electrocardiograms (ECGs).................................................................................8
`8.1.3
`Safety Update.......................................................................................................8
`8.2
`Safety Conclusions.......................................................................................................9
`8.2.1
`Overall safety profile ...........................................................................................9
`9 Advisory Committee Meeting..............................................................................................9
`10
`Pediatrics..........................................................................................................................9
`11
`Other Relevant Regulatory Issues....................................................................................9
`12
`Labeling .........................................................................................................................14
`12.1 Medication guide .......................................................................................................15
`12.2 Physician and Pharmacist Brochures.........................................................................15
`13
`Recommendations/Risk Benefit Assessment.................................................................15
`13.1 Recommended Regulatory Action.............................................................................15
`13.2 Risk Benefit Assessment............................................................................................15
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`13.3 Recommendation for Postmarketing Risk Management Activities...........................15
`13.4 Recommendation for other Postmarketing Study Commitments ..............................15
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`1 Introduction
`This New Drug Application for buprenorphine and naloxone soluble film for sublingual
`administration was initially received on 10/21/08 and a Complete Response letter was sent on
`8/21/09 citing the need for a Risk Evaluation and Mitigation Strategy (REMS) as the sole
`deficiency.
`
` is intended for the maintenance treatment of opioid dependence, and was
`Suboxone
`developed as an alternative to Suboxone sublingual tablets (NDA 20-733, approved October 8,
`2002). The dosage strengths of Suboxone
` for which marketing approval is being sought
`are the same as those currently approved for Suboxone sublingual tablets, and are as follows:
`
`
`• Buprenorphine 2mg With Naloxone 0.5mg (herein referred to as 2/0.5 or as 2 mg)
`• Buprenorphine 8mg With Naloxone 2mg (herein referred to as 8/2 or as 8 mg)
`
`
`
`The film formulation is intended by the Applicant to be similar in efficacy to Suboxone
`sublingual tablets, while offering additional safety and increased compliance. Reckitt
`Benckiser reports that the formulation was “created for the purpose of minimizing abuse and
`misuse of the product, including unintended and potentially dangerous exposure in children.”
`Other stated goals include increasing patient compliance, minimizing counterfeiting,
`minimizing illegal use and diversion, and decreased product damage during transport and
`storage compared to sublingual tablets. The achievement of these goals is based on the use of a
`unit dose product and package that is child-resistant, has enhanced physical integrity, and
`improved coding.
`
`The NDA rests primarily on a program of Phase 1 pharmacokinetic (PK) studies evaluating
`bioavailability, dose proportionality, and comparisons to Suboxone tablets, and on previous
`Reckitt Benckiser data submitted to the NDAs for Suboxone and Subutex tablets,
`encompassing data on safety and efficacy of buprenorphine sublingual solution, Suboxone and
`Subutex. A small open-label safety study of Suboxone
` and a small laboratory study
`comparing Suboxone
` to a buprenorphine-only film strip supplements these findings. No
`new efficacy studies were conducted for this NDA.
`
`
`1 n.b. the proposed proprietary name, “Suboxone
`was deemed unacceptable by the Office of Surveillance
`and Epidemiology (OSE); nevertheless the product will be referred to by that name in this review for convenience
`and clarity
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`2 Background
`
`Buprenorphine HCl is a narcotic analgesic which has been marketed since 1982 as Buprenex,
`an injectable formulation, for the treatment of moderate to severe pain. In 2002, two
`sublingual tablet formulations were approved for the treatment of opioid dependence: Subutex
`(buprenorpine only, NDA 20-732) and Suboxone (buprenorphine with naloxone intended to
`deter abuse2, NDA 20-733). The present NDA proposes a new dosage form of the
`buprenorphine/naloxone combination product, in a soluble strip intended for sublingual use.
`The application is based on pharmacokinetic studies in naltrexone-blocked healthy volunteers;
`a single open-label safety study in patients already using Suboxone; a small inpatient
`laboratory study comparing the initiation of dosing with Suboxone
` to initiation of dosing
`with a buprenorphine-only film strip; as well as reference to efficacy and safety information
`included in Reckitt Benckiser’s approved applications for Subutex and Suboxone and a review
`of post-marketing data and literature regarding buprenorphine products.
`
` 3
`
` CMC/Device
`General product quality considerations; facilities review and inspection; and stability data were
`deemed acceptable during the initial review of the application.
`3.1 Other notable issues
`3.1.1 Proprietary Name Review
`Three proprietary names have been evaluated for this product by the Division of Medication
`Error Prevention Analysis (DMEPA).
`
`
`
`
` DMEPA recommended that Reckitt Benckiser manage this product and the
`currently marketed Suboxone sublingual tablets under the name Suboxone.
`
`Upon resubmission of the NDA, Reckitt Benckiser submitted a request for a new proprietary
`name,
`
`
` Thus, DMEPA found the proposed name
` unacceptable, and reiterated the recommendation that both products could be
`managed under the same proprietary name Suboxone. Reckitt Benckiser submitted carton and
`container labels using this approach and DMEPA deemed them acceptable.
`
`
`
`
`
`
`2 Naloxone is poorly bioavailable by the sublingual route and expected to be inactive under usual conditions of
`use. The inclusion of naloxone with buprenorphine in the Suboxone product is designed to reduce the intravenous
`abuse potential of the product compared to a buprenorphine only product by precipitating withdrawal if used
`intravenously by individuals physically dependent on full agonists.
`
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`4 Nonclinical Pharmacology/Toxicology
`No new nonclinical pharmacology/toxicology information was reviewed in this resubmission.
`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
`resubmission. Labeling recommended by the reviewer based on the initial application are
`documented in the original reviews and will be incorporated in labeling.
`
` 6
`
` Clinical Microbiology
`(n/a)
`
` 7
`
` Clinical/Statistical- Efficacy
`No new efficacy studies were included in this application. There was no statistical review of
`the clinical data. The efficacy data and recommendations for dosing are based on the approved
`application for Suboxone.
`
`
`
`
`
`
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`
`
`8 Safety
`
`The safety review for this application focused on:
`1. Data generated in Reckitt Benckiser’s safety study, RB-US-07-0001
`2. Data generated in Reckitt Benckiser’s laboratory induction study, RB-US-07-0002
`3. Reckitt Benckiser’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. Reckitt Benckiser’s evaluation of issues related to the use of buprenorphine in
`pregnancy
`5. Reckitt Benckiser’s evaluation of information about accidental pediatric exposure,
`which was submitted to substantiate the public health importance of the individually-
`packaged strip product.
`
`
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`8.1 Safety Findings
`Overall, no major new safety findings concerning the combination of buprenorphine and
`naloxone were identified in this review.
`
`Almost all of the safety experience with the proposed new formulation was derived from a
`single study. This study had a number of flaws, including inadequate training of personnel
`conducting safety exams, inconsistent recording of findings, treatment of participants with
`dosing regimens not recommended in the proposed labeling, and a high drop-out rate. As a
`result, although no major safety concerns arose in this study, the quality of the data and their
`relevance to the proposed labeling are questionable. Therefore, the labeling emphasizes the
`experience with the approved formulations and does not include a separate tabulation of safety
`findings on the new formulation. Accidental Pediatric Exposure
`This new safety information, based on post-marketing experience with the approved
`formulations, was identified as an issue requiring a REMS, using a MedGuide to communicate
`with patients about medication safety in the home. Compared to other opioid analgesics, the
`number of accidental exposures of small children to buprenorphine is very high, considering
`the extent of distribution. Most patients had minor or moderate adverse events reported; no
`fatal cases were reported. Some authors observed that children may be inclined to suck on or
`chew tablets, rather than swallow them whole, which promotes buccal absorption. Because of
`buprenorphine’s poor oral bioavailability, tablets swallowed whole would be less harmful. It
`should be noted that the proposed filmstrip product cannot be spit out easily and dissolves
`quickly. Therefore, to the extent that some cases may be mitigated by the child spitting out the
`tablet before full absorption, the filmstrip product could be more hazardous than the tablet.
`However, the unit-dose packaging will help protect against this as long as the medication is
`not removed from the packaging and left out. (This may occur if patients use fractions of a
`strip, which is apparently common practice with tablets.)
`
`Reports of response to naloxone in pediatric exposure cases were provided. The current
`labeling does not provide guidance on the use of naloxone in overdose. Labeling should be
`revised to reflect the advice that naloxone, at higher-than-usual doses, and potentially repeated
`doses, may be useful in overdose.
`8.1.1.1 Hepatic Safety
`The potential hepatotoxicity has been a topic of concern for some time, and was identified as a
`deficiency in the 1/26/01 Approvable action on the NDAs for Subutex and Suboxone. A post-
`marketing study to define the role of buprenorphine in the development of hepatic
`abnormalities in opiate addicts was included as a post-marketing commitment at the time of
`approval. This study, being conducted by the National Institute on Drug Abuse, rather than by
`Reckitt Benckiser, has been slow to enroll and no results shedding light on hepatic safety are
`available.
`
`As part of the original submission of this NDA, Reckitt Benckiser was asked to do a
`comprehensive update on the question of hepatic safety, using any sources of available
`information. The reviewers concluded that the current labeling should be slightly revised to
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`reflect the existence of reports outside the population being treated for drug dependence, and
`the reports of fatal cases and cases with positive dechallenge.
`
` A
`
` study comparing hepatic safety of buprenorphine and methadone, included as a post-
`marketing commitment under NDAs 20-732 and 20-733, is underway under the sponsorship of
`the National Institute on Drug Abuse.
`
`There is an outstanding post-marketing commitment under NDAs 20-732 and 20-733 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.
`8.1.1.2 Study Drug Accountability/Diversion
`Reckitt Benckiser has implied that this product may represent an advantage over the current
`tablet products with respect to diversion. No information on accountability of drug supply for
`clinical trials of the tablet formulation is available, because the registration studies were done
`under supervised administration conditions (and in some cases used a liquid formulation).
`Therefore, there is no basis for comparison, but there does not appear to be any reason to
`conclude that this formulation rendered the study drug particularly resistant to diversion.
`8.1.1.3 Use in Pregnancy
`Current labeling identifies Suboxone and Subutex as Pregnancy Category C, and includes the
`CFR-mandated statement “There are no adequate and well-controlled studies of SUBOXONE
`or SUBUTEX in pregnant women. SUBOXONE or SUBUTEX should only be used during
`pregnancy if the potential benefit justifies the potential risk to the fetus.” The label describes
`non-clinical findings of increases in neonatal mortality in rat studies with no safety margin.
`
`The current language describing neonatal withdrawal in infants exposed to buprenorphine in
`utero did not fully capture the range of symptoms observed. The approved labeling for the
`sublingual tablet products, used as base copy, described “one case” of apnea, respiratory
`depression and bradycardia. Other cases of this nature have been reported and the label was
`revised to reflect this fact.
`8.1.1.4 Common Adverse Events
`Reckitt Benckiser proposed to include
`
`
`
`
`
`
`
` The film strip
`can be expected to be associated with systemic adverse events similar to those seen with other
`formulations, and, if anything, may be more irritating locally.
`
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`8.1.2 Electrocardiograms (ECGs)
`No new ECG data was reviewed in the original submission of this NDA; some ECGs were
`collected in the pharmacokinetic studies but were expected to offer little of interest because the
`population consisted of healthy volunteers under naltrexone blockade. However, since the CR
`action was taken, the Agency has become aware of data from a Thorough QT (TQT) study
`comparing transdermal buprenorphine, 10 mcg/hr or 40 mcg/hr, to a moxifloxacin control,
`undertaken in support of the approval of NDA 21-306 (BuTrans, Purdue Pharma).
`
`
`Scrutiny of the submitted tables of data from the ECGs collected in the healthy volunteer
`studies suggests that some subjects may have experienced QT prolongation in the PK program
`for this application.
`
`However, other studies have been conducted at typical addiction treatment doses, some using
`fairly sophisticated ECG measurements, which do not indicate a clinically significant effect of
`buprenorphine.
`
`It is not yet known what the effects would be at the exposures associated with typical addiction
`treatment doses. Because of the known risks of untreated opiate addiction and the inconsistent
`findings concerning the effects of buprenorphine on cardiac conduction in doses used in
`addiction treatment, it seems prudent to establish whether a true clinical concern about cardiac
`conduction exists prior to adding labeling language which may unduly dissuade patients and
`providers from using this treatment.
`
`Therefore, based on this new safety information, Reckitt Benckiser will be required to perform
`appropriate studies and to incorporate appropriate labeling language. Reckitt Benckiser has
`been informed of this and advised that one study, using the sublingual formulation of their
`choice, could support labeling for all three of the sublingual products in their product line.
`
`8.1.3 Safety Update
`A safety update consisting was included with this resubmission which corrected errors
`included in the previous submission. For example, 13 adverse events experienced by 11 patients
`were included in the Clinical Study Report for Study RB-US-07-0001 in the original NDA 22-410
`but were not included in the summary tabulations of all Treatment Emergent Adverse Events
`included in the 4-month Safety Update submitted to NDA 22-410 (submitted on March 3, 2009,
`Serial No. 0009). The nature of the AEs did not contribute new information or change the overall
`conclusions, and the labeling will not change because no AE table based on this study was
`included.
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`
`Updated information from pharmacovigilance, literature searches, and Poison Control Center data
`pertaining to the currently-marketed products did not change the overall safety conclusions of the
`original review.
`8.2 Safety Conclusions
`8.2.1 Overall safety profile
`The overall safety profile of this product is similar to that of the approved sublingual tablets.
`
` Advisory Committee Meeting
`
` 9
`
`
`No Advisory Committee meeting was held pertaining to this application.
`10 Pediatrics
`
`The active moiety of buprenorphine (with or without naloxone) has, and will retain, orphan
`designation for the treatment of opioid addiction. The sponsor's new formulation of
`buprenorphine falls under this designation and thus, pursuant to 21 U.S.C. 355c(g), is exempt
`from the pediatric study requirements under PREA.
`
`Reckitt Benckiser has indicated that they have no firm plans for conducting pediatric studies,
`
`11 Other Relevant Regulatory Issues
`Suboxone (buprenorphine/naloxone sublingual tablets) and Subutex (buprenorphine sublingual
`tablets) were approved in 2002 subject to a risk management program that encompassed:
`1. Targeted product distribution and sales monitoring
`2. Active surveillance for diversion and abuse (including an advisory group to
`recommend interventions if problems were identified). This program was extensive,
`and included surveys of patients, treatment programs, and physicians, as well as a
`network of “street ethnographers” who collected information about illicit use of
`buprenorphine directly from individuals involved in the street drug trade.
`3. Educational programs for patients, physicians, and pharmacists (n.b., this referred to
`specific labeling brochures for each of these audiences, approved as part of the
`labeling).
`
`
`The risk management program also made reference to a requirement, legislated under the Drug
`Abuse Treatment Act of 2000, that Suboxone and Subutex could be prescribed for addiction
`treatment only by physicians who had met certain requirements (specifically, a minimum of 8
`hours of training) and had obtained the proper waiver from the DEA via making appropriate
`notifications to the Substance Abuse and Mental Health Services Administration (SAMHSA).
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`Although considered an aspect of risk management for this product, aimed at ensuring safe and
`effective use and preventing abuse, misuse, and diversion, this feature was not administered by
`the manufacturer.
`
`Based on safety information showing a growing problem with misuse and abuse of sublingual
`buprenorphine tablets, reflected in reports from Reckitt Benckiser’s active surveillance
`program conducted as part of the current Risk Management Program for Suboxone and
`Subutex, REMS elements are required for this product to address the risk of misuse and abuse.
`The lack of an appropriate REMS was cited as the deficiency in the Complete Response letter.
`
`The original Risk Management Program was developed prior to the passage of the Food and
`Drug Administration Amendments Act (FDAAA) and therefore is not enforceable. Concurrent
`with the CR action on this application, a REMS letter was sent to Reckitt Benckiser requiring
`submission of a REMS for the approved sublingual tablet
`.
`
`The specific safety concerns to be addressed include:
`
`
`1. Accidental pediatric exposures:
`
`
`Accidental pediatric exposures to Suboxone and Subutex are reported at a prescription-
`volume-adjusted rate that exceeds that of other narcotic analgesics. A MedGuide
`strongly communicating the need to keep buprenorphine products out of reach of
`children is recommended as an appropriate strategy to manage this risk.
`
`
`2. Increasing reports of abuse, misuse and diversion attributed to patients who receive
`prescriptions with little supervision or ancillary support towards recovery from drug
`addiction:
`
`The post-marketing surveillance program, particularly the “street ethnography”
`interviews conducted as part of the risk management program note that it is easy to
`obtain buprenorphine on the street and that the source is usually patients who find it
`very easy to get excessive supplies of buprenorphine from physicians. Although both
`labeling and treatment guidelines recommend supervised administration and frequent
`face-to-face visits, progressing to less intense supervision as treatment progresses,
`there are reports that physicians provide prescriptions for large supplies of medication
`on the first visit and do not monitor progress, compliance, or ongoing illicit drug use.
`Buprenorphine products have not been shown to be safe or effective when used in this
`manner. Therefore, Elements to assure safe use requiring the sponsor to ensure that
`patients are monitored appropriately (i.e., in keeping with labeling and SAMHSA
`guidelines) is recommended as a strategy to ensure safe and effective use and to
`prevent abuse and misuse.
`
`Because physician certification is provided for under the Drug Abuse Treatment Act
`(DATA) and the responsibility for this certification has been delegated to the
`Substance Abuse and Mental Health Services Administration (SAMHSA) and the Drug
`Enforcement Administration (DEA), it does not seem appropriate to create a separate
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`education and certification program to be administered by Reckitt Benckiser. However,
`despite this provision, it appears apparent that there is widespread disregard of the
`recommendations for use of the product, in terms of frequency of face-to-face visits,
`counseling provided, monitoring of results, and also in dosing, with many (if not most)
`patients receiving multiple daily doses, which are pharmacologically illogical and
`unsupported by efficacy data, and promote diversion by, in many cases, giving patients
`more tablets per prescription than would be required with a single daily dose. The
`objectives of this element of the REMS should be to ensure that the products are used
`under conditions that ensure safe and effective use, specifically ensuring that patients
`are monitored carefully and frequently and provided with necessary counseling, and
`that medication is provided to patients in appropriate doses and quantities to prevent
`diversion.
`
`
`
`
`Because the active surveillance program already in place for Subutex and Suboxone has been
`useful and effective in detecting problems, this should be included as an aspect of the
`evaluation of the REMS.
`
`In addition to the above information conveyed in the Complete Response letter, after extensive
`internal discussion, Reckitt Benckiser was provided with the advice concerning the required
`REMS. Note that the original REMS memo of August 2009 called for elements to assure safey
`use (ETASU) under 505-1(f)(3)(E), each patient using the drug to be subject to certain
`monitoring. However, upon futher consideration and internal review, it became apparent that
`some of the recommended risk mitigation measures included aspects of 505-1(f)(3)(D), the
`drug being dispensed to patients with evidence or other documentation of safe-use conditions.
`In turn, this ETASU may be associated with a requirement for an implementation plan, which
`has been included. Therefore, per agreement between OND and OSE, the final version of the
`REMS will include:
`A.
`Medication Guide
`B.
`Elements to Assure Safe Use
`1. Safe use conditions
`a. SUBOXONE film will only be dispensed by the prescriber or prescribed to
`patients with documentation of the following safe use conditions:
`i. Verification that the patient meets the diagnostic criteria for opioid
`dependence.
`ii. Risks described in the professional labeling and the Medication Guide
`have been discussed with the patient.
`iii. Safe storage of the medication has been explained and reviewed with
`the patient.
`
`
`iv. After appropriate induction, the patient is prescribed a limited amount of
`medication at the first visit.
`b. Reckitt Benckiser Pharmaceuticals Inc. will perform the items outlined in
`Section C.
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`c. Prescribers will document safe use conditions for each patient by using the
`‘Appropriate Use Checklist,’ or by using another method (e.g. electronic
`health record) specific to the prescriber’s office practice.3
`d. Reckitt Benckiser Pharmaceuticals Inc. will ensure that within 30 days of
`FDA approval of the SUBOXONE REMS, a REMS Instruction Letter to
`Prescribers will be mailed to all physicians certified to treat opioid
`dependence under the Drug Addiction Treatment Act of 2000 (DATA
`2000). This letter is designed to convey and reinforce the risks of accidental
`overdose, misuse, and abuse of SUBOXONE, as well as the need to
`appropriately monitor patients and document safe use conditions.
`e. Reckitt Benckiser Pharmaceuticals Inc. will, on a monthly basis, identify
`any newly DATA 2000-certified physicians and mail the applicable
`documents to them. The following materials will be appended to the
`Prescriber Instruction Letter: Medication Guide, Full Prescribing
`Information, Physician Brochure, and the Appropriate Use Checklist.
`f. To further reinforce safe use conditions, Reckitt Benckiser Pharmaceuticals
`Inc. will ensure that within 30 days of FDA approval of the SUBOXONE
`REMS, a REMS Introductory Letter for Pharmacists will be mailed to all
`pharmacists on a national mailing list from the American Pharmacists
`Association. The following materials will be appended to the Introductory
`Pharmacist Letter: Medication Guide, Full Prescribing Information and the
`Pharmacist Brochure.
`g. Reckitt Benckiser Pharmaceuticals Inc. will make the letters and all
`materials that are appended to the letters available through its toll-free
`information line, through its field personnel, and on the product website.
`
`
`2. Each patient using SUBOXONE film will be subject to certain clinical
`monitoring
`a. Reckitt Benckiser Pharmaceuticals Inc. will assess the REMS to ensure that
`each patient using SUBOXONE film will be subject to the following
`monitoring:
`i. Return visits are scheduled at intervals commensurate with patient
`stability. Weekly, or more frequent, visits are recommended for the first
`month.
`ii. Assessment and reinforcement of patient’s compliance with the
`prescribed medication.
`iii. Assessment of appropriateness of dosage prescribed.
`iv. Assessment of whether patient is receiving the necessary psychosocial
`support.
`v. Assessment of whether patient is making adequate progress towards
`treatment goals.
`b. Reckitt Benckiser Pharmaceuticals Inc. will perform the items outlined in
`Section C.
`
`3 The Appropriate Use Checklist emphasizes best practices but is worded to permit clinical judgment. Both
`conditions necessary for safe use appropriate clinical monitoring are communicated/prompted by the Appropriate
`Use Checklist. See Appendix.
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`c. Prescribers will document that each patient has received the required
`clinical monitoring using the ‘Appropriate Use Checklist,’ or by using
`another method/system (e.g. electronic health record) specific to the
`prescriber’s office practice.
`The following materials are part of the REMS and are appended to the REMS
`document:
`• SUBOXONE film Medication Guide
`• REMS Instruction Letter to Prescribers
`• REMS Introductory Letter to Pharmacists
`• Appropriate Use Checklist
`• Physician Brochure, “Important Information for Physicians- Frequently
`Asked Questions”
`• Pharmacist Brochure, “Important Information for Pharmacists-Frequently
`Asked Questions”
`
`Implementation System
`The Implementation System includes the following:
`1. Reckitt Benckiser Pharmaceuticals Inc. will ensure that all DATA 2000-certified
`physicians receive the Instruction Letter with the appended materials.
`2. Reckitt Benckiser Pharmaceuticals Inc. will monitor compliance with the
`requirements to document prescribing and dispensing with documentation of 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).
`3. Reckitt Benckiser Pharmaceuticals Inc. will monitor and evaluate the
`implementation of the elements to assure safe use provided for under Se