CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`200533Orig1s000
`
`
`OTHER REVIEW(S)
`
`

`

`
`
`PMR/PMC Development Template
`
`
`This template should be completed by the PMR/PMC Development Coordinator and included for each
`PMR/PMC in the Action Package.
`
`
`NDA #/Product Name:
`
`PMR/PMC Description:
`
`NDA 200533/Nucynta ER (tapentadol) extended-release oral tablets
`
`Deferred pediatric study under PREA: a pharmacokinetic, efficacy, and safety
`study of Nucynta ER for the treatment of chronic pain in pediatric patients
`ages 7 to less than 17 years
`
` 05/28/2014
` 10/31/2017
` 03/26/2018
`
`
`
`
`PMR/PMC Schedule Milestones: Final Protocol Submission:
`
`Study/Trial Completion:
`
`Final Report Submission:
`
`Other: N/A
`
`1. During application review, explain why this issue is appropriate for a PMR/PMC instead of a
`pre-approval requirement. Check type below and describe.
` Unmet need
` Life-threatening condition
` Long-term data needed
` Only feasible to conduct post-approval
` Prior clinical experience indicates safety
` Small subpopulation affected
` Theoretical concern
` Other
`
`
`
`We are deferring submission of the required pediatric study for ages 7 to less than 17 years
`for this application because this product is ready for approval for use in adults and the
`pediatric study has not been completed.
`
`
`
`2. Describe the particular review issue and the goal of the study/clinical trial. If the study/clinical trial is
`a FDAAA PMR, describe the risk. If the FDAAA PMR is created post-approval, describe the “new
`safety information.”
`
`To obtain adequate data for the use of Nucynta ER in the pediatric population ages 7 to less than 17
`to inform dosing, efficacy, and safety.
`
`PMR/PMC Development Template
`
`Last Updated 8/25/2011
`
`Page 1 of 3
`
`Reference ID: 3006365
`
`

`

`
`3. If the study/clinical trial is a PMR, check the applicable regulation.
`If not a PMR, skip to 4.
`- Which regulation?
` Accelerated Approval (subpart H/E)
` Animal Efficacy Rule
` Pediatric Research Equity Act
` FDAAA required safety study/clinical trial
`
`
`
`- If the PMR is a FDAAA safety study/clinical trial, does it: (check all that apply)
` Assess a known serious risk related to the use of the drug?
` Assess signals of serious risk related to the use of the drug?
` Identify an unexpected serious risk when available data indicate the potential for a serious
`risk?
`
`
`- If the PMR is a FDAAA safety study/clinical trial, will it be conducted as:
` Analysis of spontaneous postmarketing adverse events?
`Do not select the above study/clinical trial type if: such an analysis will not be sufficient to
`assess or identify a serious risk
`
`
`
` Analysis using pharmacovigilance system?
`Do not select the above study/clinical trial type if: the new pharmacovigilance system that the
`FDA is required to establish under section 505(k)(3) has not yet been established and is thus
`not sufficient to assess this known serious risk, or has been established but is nevertheless not
`sufficient to assess or identify a serious risk
`
` Study: all other investigations, such as investigations in humans that are not clinical trials as
`defined below (e.g., observational epidemiologic studies), animal studies, and laboratory
`experiments?
`Do not select the above study type if: a study will not be sufficient to identify or assess a
`serious risk
`
`
`
`
`
` Clinical trial: any prospective investigation in which the sponsor or investigator determines
`the method of assigning investigational product or other interventions to one or more human
`subjects?
`4. What type of study or clinical trial is required or agreed upon (describe and check type below)? If the
`study or trial will be performed in a subpopulation, list here.
`The efficacy study must be a randomized double blind controlled superiority study of Nucynta ER
`in the pediatric population ages 7 to <17. Pharmacokinetic and safety data may also be obtained
`from this study.
`
`
`Required
` Observational pharmacoepidemiologic study
` Registry studies
` Primary safety study or clinical trial
` Pharmacogenetic or pharmacogenomic study or clinical trial if required to further assess safety
` Thorough Q-T clinical trial
` Nonclinical (animal) safety study (e.g., carcinogenicity, reproductive toxicology)
`
`PMR/PMC Development Template
`
`Last Updated 8/25/2011
`
`Page 2 of 3
`
`Reference ID: 3006365
`
`

`

`
`
`
`
`Continuation of Question 4
`
`
` Nonclinical study (laboratory resistance, receptor affinity, quality study related to safety)
` Pharmacokinetic studies or clinical trials
` Drug interaction or bioavailability studies or clinical trials
` Dosing trials
` Additional data or analysis required for a previously submitted or expected study/clinical trial
`(provide explanation)
`
` Meta-analysis or pooled analysis of previous studies/clinical trials
` Immunogenicity as a marker of safety
` Other (provide explanation)
`
`
`Agreed upon:
` Quality study without a safety endpoint (e.g., manufacturing, stability)
` Pharmacoepidemiologic study not related to safe drug use (e.g., natural history of disease,
`background rates of adverse events)
` Clinical trials primarily designed to further define efficacy (e.g., in another condition,
`different disease severity, or subgroup) that are NOT required under Subpart H/E
` Dose-response study or clinical trial performed for effectiveness
` Nonclinical study, not safety-related (specify)
`
` Other
`
`
`
`5. Is the PMR/PMC clear, feasible, and appropriate?
` Does the study/clinical trial meet criteria for PMRs or PMCs? Yes
` Are the objectives clear from the description of the PMR/PMC? Yes
` Has the applicant adequately justified the choice of schedule milestone dates? Yes
` Has the applicant had sufficient time to review the PMRs/PMCs, ask questions, determine
`feasibility, and contribute to the development process? Yes
`
`
`PMR/PMC Development Coordinator:
` This PMR/PMC has been reviewed for clarity and consistency, and is necessary to further refine
`the safety, efficacy, or optimal use of a drug, or to ensure consistency and reliability of drug
`quality.
`
`PMR/PMC Development Template
`
`Last Updated 8/25/2011
`
`Page 3 of 3
`
`Reference ID: 3006365
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DOMINIC CHIAPPERINO
`08/25/2011
`
`BOB A RAPPAPORT
`08/25/2011
`
`Reference ID: 3006365
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`MEMORANDUM
`
`
`PUBLIC HEALTH SERVICE
`
`
`
`
`
`FOOD AND DRUG ADMINISTRATION
`
`
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`
`___________________________________________________________
`
`DATE:
`August 04, 2011
`
`TO:
`Bob Rappaport, M.D.
`Director
`Division of Anesthesia, Analgesia, and Addiction
`Products(DAAAP)
`Office of Drug Evaluation II
`
`
`Chandrahas Sahajwalla, Ph.D.
`Director,
`Division of Clinical Pharmacology II (DCPII)
`Arindam Dasgupta, Ph.D., Staff Fellow
`Division of Bioequivalence and GLP Compliance
`(DBGC)
`Office of Scientific Investigations (OSI)
`
`THROUGH: Martin K. Yau, Ph.D.
`Acting Team Leader – Bioequivalence Branch
`Division of Bioequivalence and GLP Compliance
`Office of Scientific Investigations
`
`SUBJECT: Review of EIR Covering NDA 200533, NUCYNTA® ER
`(tapentadol hydrochloride) extended-release
`tablets, 250 mg sponsored by Johnson & Johnson
`Pharmaceutical Research & Development, L.L.C.(on
`behalf of Ortho-McNeil-Janssen Pharmaceuticals,
`Inc.)
`
`
`
`At the request of the Division of Anesthesia and Analgesic
`Products (DAAAP), Office of New Drugs (OND), DBGC audited
`the clinical and analytical portions of the following
`bioequivalence (BE) study.
`
`Study Number:
`R331333-PAI-1061; HP5503/84
`
`Study Title:
`
` Single-Dose, Open-Label, Randomized, Two-Way Crossover
`
` A
`
`Reference ID: 2984686
`
`
`
`
`FROM:
`
`

`

`
`
`Page 2 –NDA 200-533, NUCYNTA® ER (tapentadol hydrochloride)
`extended-release tablets, 250 mg
`
`Pivotal Study to Assess Bioequivalence of a New Tapentadol
`Extended-Release (TRF) 250-mg Tablet with Respect to a
`Tapentadol Extended-Release (PR2) 250-mg Tablet Under
`Fasted Conditions in Healthy Subjects
`Audit of the clinical portion of the study was conducted at
`Celerion Inc., Lincoln, NE. Following the inspection of
`the clinical site (June 20-24, 2011), no Form FDA-483 was
`issued and there were no significant findings. The audit
`of the analytical portion of this study was conducted at
`Following inspection of the analytical site (July 11-15,
`2011), Form FDA-483 was issued (Attachment 1). DBGC
`received the firm’s written response to the inspectional
`findings on August 3, 2011 (Attachment 2).
`The 483 observations for study R331333-PAI-1061; HP5503/84
`(analytical),
` response, and our evaluations follow:
`
`
`Analytical Site:
`
`
`
`1. Failure to accurately report the carry-over evaluation
`conducted during tapentadol prestudy method validation. For
`example, in blank 1 sample (sample number 0352) in prestudy
`validation run, VA-09-1a, carry-over was determined to be
`245.5% of the mean of the LLOQ. However, in source records
`the calculated carry-over in the blank 1 sample was
`actually 330% of that of the LLOQ.
`
`In their response,
` acknowledged the observation as an
`oversight and indicated that the lab staff would be
`retrained to prevent such oversights from occurring in
`future.
` also indicated that the validation report
`would be amended to reflect the correct carryover
`evaluation data and the corrected validation report would
`be sent to the sponsor. As the carry-over peaks were small
`or absent compared to the analyte peaks in carry-over
`evaluation samples in majority of the analytical runs, the
`above observation is not likely to affect the outcome of
`the study.
`
`
`
`
`Reference ID: 2984686
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`Page 3 –NDA 200-533, NUCYNTA® ER (tapentadol hydrochloride)
`extended-release tablets, 250 mg
`
`2. Failed to use freshly prepared calibrators in the
`validation of autosampler stability during the conduct of
`tapentadol pre-study validations.
`
`In their response,
` acknowledged the observation and
`indicated that since the study,
` has updated their
`procedures to use freshly prepared calibration standards
`for assessment of autosampler stability.
` plans to
`generate new data to demonstrate autosampler stability for
`tapentadol using freshly prepared calibrators by august 15,
`2011.
`
`The above observation is not likely to affect the outcome
`of the study.
`
`3. Failed to document all aspects of the study conduct. For
`example:
`
`a) In validation run VA-09-4a for tapentadol the 3rd blank
`sample (sample 0681) injected after the validation QCs
`exhibited carry-over of >20% of LLOQ. This validation run
`was accepted as it was determined that the carry-over had
`no influence on the run results. However the justification
`or objective criteria for this determination was not
`documented.
`
` acknowledged the observation
`In their written response,
`and indicated that they have implemented corrective actions
`since the conduct of the study.
` also presented
`justification for accepting the results of carry-over
`evaluation.
`
` response is adequate and the above finding is not
`likely to impact the outcome of the current study.
`
` b) Failure to maintain documentation for individual
`calibrators and QC sets used during sample processing for
`tapentadol study. Calibrator and QC samples were stored as
`multi-use aliquots. In absence of documentation for
`individual calibrators or QC sets used during analysis or
`of their disposal, it cannot be confirmed if the
`calibrators and QCs used were within their validated
`freeze/thaw stability cycles.
`
`
`Reference ID: 2984686
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`Page 4 –NDA 200-533, NUCYNTA® ER (tapentadol hydrochloride)
`extended-release tablets, 250 mg
`
` acknowledged the observation and stated that they will
`implement a new labeling procedure for future studies such
`that individual calibrators and QCs were uniquely
`identified and tracked along with study samples.
`
`The above finding is not likely to impact outcome of the
`current study.
`
`
`4. Failure to retain the audit trail for the initial
`results table during data processing for tapentadol study.
`This did not allow complete reconstruction of events during
`data processing.
`
`
` acknowledged the observation and
`In their response,
`indicated that they would implement new procedures where a
`single quantitation method would be created from default
`settings and would be used for processing each run in a
`study. Any changes made thereof was to be captured in the
`audit trail to allow complete reconstruction of events
`during data processing.
`
`reprocessed all their data
`To address the concerns,
`using the modified procedure. The results of the
`reprocessed data were comparable to the original data.
`Hence the above observation is not likely to affect the
`outcome of the current study.
`
`Conclusion:
`
`Following the above inspection, the Division of
`Bioequivalence and GLP Compliance recommends that the
`analytical data analytical data of the study R331333-PAI-
`1061; HP5503/84 be accepted for Agency review.
`
`
`After you have reviewed this transmittal memo, please
`append it to the original NDA submission.
`
`
`
`
`Arindam Dasgupta, Ph.D.
`
`Reference ID: 2984686
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`Page 5 –NDA 200-533, NUCYNTA® ER (tapentadol hydrochloride)
`extended-release tablets, 250 mg
`
`
`
`
`
`
`
`Final Classification:
`
`Clinical
`
`NAI- Celerion inc., Lincoln, NE
`
`Analytical
`
`VAI-
`cc: DARRTS
`OND/ODEII/DAAAP/Rappaport/Dominic Chiapperino
`OTS/OCP/DCPII/Sahajwala/David Lee
`
`OC/DSI/Salewski/Haidar/Ball/Dasgupta/Yau/Dejernett
`SW-FO/KAN-DO/LROB/OMA-NB/jessica.hensley@fda.hhs.gov
`
`
`cc: email
`CDER DSI PM TRACK
`Draft: AD 08/04/2011
`Edits: MKY 8/4/2011
`DSI: 6211; O:\BE\EIRCOVER\200533.jon.tap.doc
`FACTS:1284684
`
`
`
`
`
`
`
`Reference ID: 2984686
`
`131 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ARINDAM DASGUPTA
`08/05/2011
`
`MARTIN K YAU
`08/05/2011
`
`Reference ID: 2984686
`
`

`

`
`
`M E M O R A N D U M
`
`Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`Date:
`
`To:
`
`From:
`
`Subject:
`
`August 3, 2011
`
`Bob Rappaport, M.D., Director
`Division of Anesthesia, Analgesia and Addiction Products
`
`lVIichael Klein, Ph.D., Director
`Controlled Substance Staff
`
`ADDENDUM TO MEMOS of Sept 9, 2010, and July 12, 2011 by
`Alicja Lerner, MD, PhD Nucynta ER (Tapentadol HCl extended-
`release). NDA 200—533
`
`I am writing this addendum to clarify some issues addressed by Dr. Alicja Lerner in two reviews
`on the Nucynta ER NDA.
`
`The memo of July 12, 2011 concerned PK/PD issues that may affect the relative abuse potential
`of tapentadol extended release tablets Tamper Resistant Formulation (TRF). Possible
`interactions of food or alcohol with long acting opioid formulations and resultant safety and
`abuse potential effects are recognized. I discussed these issues in a July 29, 2011 meeting with
`Dr. Chandrahas Sahajwalla, Office of Clinical Pharmacology (OCP) and Dr. Lerner. Regarding
`Dr. Lerner’s conclusions from the July 12th memo, CSS and OCP concur on the following:
`
`1. Co-administration of tapentadol TRF with FDA recommended high fat/calorie meal resulted
`in increases in Cmax and AUC that are within the confidence interval of 80—125%. Thus, OCP
`concludes that there is no food effect for this product. PD effects of tapentadol TRF formulation
`are potentiated after intake of alcohol, but such effects were not observed with food.
`2. Co-administration of tapentadol TRF with alcohol resulted in increases in Cmax and AUC.
`In the first review cycle of this product, the team agreed that as with other opioid labels,
`including the label of Nucynta immediate release product, warnings and precautions of the
`interaction of tapentadol TRF with alcohol should be adequately described in its product label.
`3. The FDA recommended high fat/calorie meal was not used in the PK study in Japanese men
`with tapentadol TRF 0831333-PAI-1052). Therefore, results from this study are not pivotal for
`assessing the effect of food. The food effect should be labeled based on the result using the FDA
`recommended high fat/calorie meal.
`4. The PK studies contain insufficient data to override the analyses and conclusions of the
`clinical studies that the drug does not exhibit a gender effect.
`
`In her memo of Sept 9, 2010, Dr. Lerner concluded that the controlled release properties of the
`TRF formulation are overcome by simple physiochemical manipulations and that the drug
`product elicits typical mu opioid—like effects.
`
`CSS Review: Nucynta ER.nda200533.0803201l.addendum.doc
`1 of 2
`
`Reference ID: 2983568
`
`

`

`1. Because the recent bioequivalence study resolved that the PK and AE profiles of different
`formulations are similar, Dr. Lemer’s first recommendation in the memo is withdrawn.
`
`2. Dr. Lemer’s second recommendation is also withdrawn because her AE analysis covered a
`limited area of investigation. Thus, her conclusions are insufficient to override the analyses and
`conclusions of the reviewer of the full range of clinical studies.
`
`CSS Review: Nucynta ER.nda200533.0803201l.addendum.doc
`2 of 2
`
`Reference ID: 2983568
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`MICHAEL KLEIN
`08/03/2011
`
`Reference ID: 2983568
`
`

`

`
`
`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`
`Label and Labeling Review
`
`Date:
`
`August 1, 2011
`
`Jibril Abdus-Samad, PharmD, Safety Evaluator
`Reviewer(s):
`
`Division of Medication Error Prevention and Analysis
`Todd Bridges, RPh, Team Leader
`Team Leader
`Division of Medication Error Prevention and Analysis
`
`Carol Holquist, RPh, Director
`Division Director
`Division of Medication Error Prevention and Analysis
`
`Nucynta ER (Tapentadol) Extended-release Tablets
`Drug Name(s):
`50 mg, 100 mg, 150 mg, 200 mg, and 250 mg
`
`Application Type/Number: NDA 200533
`Applicant/sponsor:
`Ortho-McNeil-Janssen Pharmaceuticals, Inc.
`OSE RCM #:
`2009-2413
`
`*** This document contains proprietary and confidential information that should not be
`released to the public.***
`
`
`
`
`
`
`Reference ID: 2982076
`
`

`

`
`
`1
`INTRODUCTION
`This review evaluates the proposed container label, blister label, carton labeling, and
`insert labeling for Nucynta ER (NDA 200533) for areas of vulnerability that can lead to
`medication errors. Ortho-McNeil-Janssen Pharmaceuticals, Inc. submitted the proposed
`labels and labeling on December 1, 2009 and updated insert labeling on
`February 28, 2011.
`
`1.1 BACKGROUND OR REGULATORY HISTORY
`Nucynta (Tapentadol) is currently marketed in the United States. Nucynta tablets were
`approved by FDA on November 20, 2008, under NDA 022304. For this application, the
`Applicant is proposing an extended-release formulation of tapentadol to be marketed
`under the proprietary name, Nucynta ER. The original submission dated December 1,
`2009, received a Complete Response on October 1, 2010. Subsequently, the Applicant
`submitted an amendment on February 28, 2011.
`
`1.2 PRODUCT INFORMATION
`Nucynta ER has a proposed indication of use for the management of moderate to severe
`chronic pain in patients 18 years of age or older when a continuous, around-the-clock
`opioid analgesic is needed for an extended period of time. The recommended daily dose
`is 100 mg to 250 mg twice daily, taken approximately every 12 hours, with or without
`food. Patients currently not taking opioid analgesics should begin Nucynta ER therapy
`with 50 mg twice a day (approximately every 12 hours) and then be individually titrated
`to adjust to an optimal dose within the therapeutic range of 100 mg to 250 mg twice
`daily. Nucynta ER tablets will be available in five strengths: 50 mg, 100 mg, 150 mg,
`200 mg, and 250 mg. All five strengths will be marketed in bottles of 60 tablets and unit-
`dose blister packs of 10 tablets.
`
`2 METHODS, MATERIALS REVIEWED, AND RESULTS
`
`2.1 FAILURE MODE AND EFFECTS ANALYSIS AND POSTMARKETING MEDICATION
`ERROR DATA
`Using Failure Mode and Effects Analysis1 and postmarketing medication error data, the
`Division of Medication Error Prevention and Analysis (DMEPA) evaluated the
`following:
`• Container Labels submitted December 1, 2009 (Appendix A)
`• Carton Labeling submitted December 1, 2009 (Appendix B)
`• Hospital Unit Dose Blister Labels submitted December 1, 2009 (Appendix C)
`Insert Labeling submitted February 28, 2011 (no image)
`•
`
`
`
`1 Institute for Healthcare Improvement (IHI). Failure Modes and Effects Analysis. Boston. IHI:2004.
`
`
`
`
`
`Reference ID: 2982076
`
`1
`
`

`

`
`
`2.2 FDA ADVERSE EVENT REPORTING SYSTEM (AERS) DATABASE
`The following section describes DMEPA use of FDA Adverse Event Reporting System
`(AERS) database to identify medication errors relevant to this review.
`
`2.2.1 Nucynta (Tapendatol) Immediate-release Tablets
`Since Nucynta (Tapentadol) is currently marketed, DMEPA searched the FDA Adverse
`Event Reporting System (AERS) database to identify medication errors involving
`Tapentadol. The AERS search conducted on June 27, 2011 used the following search
`terms: active ingredient “Tapentadol”, trade name “Nucynta”, and verbatim terms
`“Tapen%” and “Nucy%%”. The reaction terms used were the MedDRA High Level
`Group Terms (HLGT) “Medication Errors” and “Product Quality Issues”. The time
`search was limited from July 21, 2010 to June 27, 2011. A previous OSE Review 2009-
`846 Nucynta (Tapentadol) NME 915 Review conducted an AERS search that searched up
`till July 21, 2010.
`The reports were manually reviewed to determine if a medication error occurred.
`Duplicate reports were combined into cases. The cases that described a medication error
`were categorized by type of error. We reviewed the cases within each category to
`identify factors that contributed to the medication errors. If a root cause was associated
`with the label or labeling of the product, the case was considered pertinent to this review.
`Reports excluded from the case series include those that described an intentional
`overdose, patients changing the frequency of administration, accidental ingestion, or
`cases that did not describe a medication error.
`Following exclusions, we evaluated a total of 3 cases relevant to this review. All three
`cases were classified as wrong technique, which involved patients cutting or splitting
`Nucynta tablets in half. The first case involved a patient that was told to cut Nucynta
`tablets in half and experienced hallucinations. There were no details explaining who told
`the patient to cut the tablet. The second case involved a patient that split Nucynta tablets
`and experienced problems breathing, throat closing, and swollen hands four days later
`requiring and emergency room visit. The third case involved a patient that required
`hospitalization due to problems breathing and hands swelling “like boxing gloves,” after
`cutting Nucynta tablets in half.
`
`2.2.2 Concomitant use of Tramadol Extended- and Immediate-release
`
`Since the proposed insert labeling states concomitant use of Tapentadol extended-release
`and other tapentadol and tramadol products is not recommended, DMEPA searched FDA
`AERS database to identify medication errors involving pharmacologically similar
`products, tramadol extended- and immediate-release products. DMEPA notes it is
`common practice to treat chronic pain with an extended-release opioid for around-the-
`clock pain management along with an immediate-release version of the same opioid for
`breakthrough pain.
`The AERS search conducted on June 23, 2011 used the following search terms: trade
`names “Ryzolt” and “Ultram ER”, and verbatim terms “Ryz%” and “Ultr%%”. The
`reaction terms used were the MedDRA High Level Group Terms (HLGT) “Medication
`Errors” and “Product Quality Issues.” No time limitation was set.
`
`
`
`
`
`Reference ID: 2982076
`
`2
`
`

`

`
`
`The reports were manually reviewed to determine if a medication error occurred.
`Duplicate reports were combined into cases. The cases that described a medication error
`were categorized by type of error. We reviewed the cases within each category to
`identify factors that contributed to the medication errors. If a root cause was associated
`with the label or labeling of the product, the case was considered pertinent to this review.
`Reports excluded from the case series include those that described an intentional
`overdose, wrong drug, overdoses with no details of causality, patients changing the
`frequency of administration, or did not describe a medication error.
`Following exclusions, we evaluated a total of 9 cases relevant to this review.
`Wrong Frequency of Administration (5)
`Theses cases involved patients taking tramadol extended-release tablets more than once
`daily such 1 tablet every 4 to 6 hours or three times daily. The first case involved a
`patient that was previously taking tramadol immediate-release and then “almost
`overdosed” on tramadol sustained-release tablets because she was taking them every 4 to
`6 hours. The patient received charcoal in the emergency and was kept for observation.
`The second case involved a physician that reported a patient received Ultram ER 10 mg
`twice daily instead of once daily, resulting in confusion and hallucinations. The
`physician discontinued Ultram ER. The third case involved another patient that was
`prescribed Ultram ER 100 mg once daily but was taking it twice daily. The patient was
`hospitalized because her “liver stopped.” The fourth case involved a patient that was
`taking Ultram ER 200 mg twice daily instead of once daily as prescribed. The patient
`resumed the correct dose and did not suffer any adverse events. The fifth case involved a
`patient hospitalized for severe mental change after taking Ryzolt 100 mg three times
`daily for 2 days. The physician did not provide causality assessment.
`Of these five cases, only was a prescribing error in which the physician prescribed
`Ultram ER twice daily. The other cases did not provide details for causality; however, in
`one case, the patient was previously receiving tramadol immediate-release tablets.
`Wrong Dose, resulting in overdose (2)
`The first case involved a patient took physician samples of Ultram ER 1 tablet every 4 to
`6 hours and also twice daily because no one explained what “ER” meant and she did not
`read the labeling provided. She experienced a grand mal seizure. The second case
`involved a patient whose physician increased the dose of Ultram ER 300 mg daily to
`400 mg daily resulting in auditory hallucinations, nervous breakdown and severe
`headache.
`Monitoring Error (2)
`The first case occurred in France and involved a patient taking tramadol sustained-release
`tablets 200 mg and tramadol immediate-release 50 mg for 3 days, resulting in
`hospitalization for hypoglycemia. The patient died in the hospital. The second case
`involved a patient taking Ultram ER 200 mg twice daily. The reporter thought Ultram
`ER was not working, as the patient supplemented with Ultracet (tramadol and
`acetaminophen) tablets which led to hospitalization for dizziness.
`
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`
`
`Reference ID: 2982076
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`3
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`3
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`DISCUSSION OF DEFICIENCIES IDENTIFIED
`
`3.1 PRODUCT DESIGN
`The product design introduces vulnerabilities that can lead to medication errors due to the
`overlapping product strengths. The following sections discuss these concerns.
`
`3.1.1 Overlapping Strengths
`The Applicant developed an extended-release formulation of tapentadol with product
`strengths that overlap with the currently marketed strengths of Tapentadol Immediate-
`release tablets (See Appendix D). By choosing to develop an extended-release
`formulation of tapentadol with product strengths that overlap with those of the currently
`marketed Tapentadol Immediate-release tablets, the Applicant has eliminated a
`potentially valuable error-reduction strategy that has been employed in other product line
`extensions. The Applicant should have developed product strengths slightly different
`than available strengths of immediate-release Nucynta Tablets as previously discussed at
`the Pre-NDA Meeting on June 5, 2007.
`Post-marketing experience has shown that the introduction of product line extensions
`result in medication errors if the modifier is omitted and product characteristics are
`similar or overlap. For example, if the modifier ‘ER’ is omitted or overlooked, the
`difference in strength would offer the opportunity for an error to be caught before it
`reaches the patient, provided it is a dose that could not be achieved with the current
`product strengths.
`Currently, the Applicant has not sufficiently differentiated the labels and labeling of the
`proposed Nucynta ER extended-release tablets from the currently marketed Nucynta
`immediate-release tablets (see Appendix E). This is of greater concern for the 50 mg and
`100 mg strengths for both Nucynta ER and Nucynta.
`
`
`
`3.1.2 Concomitant use of Tapentadol Extended- and Immediate-release Products
`Concomitant use of Tapentadol extended-release and other tapentadol and tramadol
`products is not recommended. This recommendation to avoid use of immediate- and
`extended-release tapentadol products is similar to the currently marketed tramadol
`immediate- and extended-release products. However, this recommendation differs from a
`common practice of using a long-acting opioid along with the short-acting opioid for
`breakthrough pain.
`Our AERS database search uncovered 2 reports of concomitant use of tramadol extended-
`and immediate-release products. In both cases, patients were using a tramadol extended-
`release and tramadol immediate release products for breakthrough pain. It is not clear
`whether the concomitant use of extended- and immediate-release tramadol was the result
`of a prescribing error or a patient initiated error. However, in both cases, the patients did
`not realize the concomitant use of Tramadol extended- and immediate-release products
`was not recommended.
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`Reference ID: 2982076
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`4
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`Nucynta ER insert labeling contains guidance to discontinue all other tapentadol and
`tramadol products when beginning and while taking Nucynta ER. If FDA receives
`reports of concomitant use tapentadol extended-release and other tapentadol or tramadol
`products, DMEPA will revisit this issue.
`
`3.2 CONTAINER LABELS AND CARTON LABELING
`The proposed Nucynta ER and currently marketed Nucynta container labels and carton
`labeling are similar in appearance, which can lead to product selection errors. The
`Applicant has not sufficiently differentiated the proposed Nucynta ER extended-release
`tablets from the currently marketed Nucynta immediate-release tablets. This is of greater
`concern for the overlapping 50 mg and 100 mg strengths for both Nucynta ER and
`Nucynta.
`Additionally, statements to help ensure proper dosing (twice daily) are lacking. The
`proposed Nucynta ER recommended dosing interval is twice daily approximately every
`12 hours. This is different from Nucynta’s recommended dosing interval of every 4 to 6
`hours. Our AERS search uncovered errors involving patie