CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`200533Orig1s000
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`SUMMARY REVIEW
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`”than
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`FDA CENTER FOR DRUG EVALUATION AND RESEARCH
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`DIVISION OF ANESTHESIA , ANALGESIA, AND ADDICTION PRODUCTS
`
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`Summary Review for Regulatory Action
`
`Bob A. Rappaport, MD.
`Director
`
`Division of Anesthesia, Analgesia, and Addiction
`Products
`
`Subject
`Division Director Summary Review
`NBA #
`200533 Class 2 Resubmission
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`Applicant Name
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`Johnson & Johnson Pharmaceutical Research and
`Development, LLC on behalf of Janssen
`Pharmaceuticals, Inc.
`
`extended period of time
`
`Date of Submission
`PDUFA Goal Date
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`Proprietary Name /
`Established
`S ‘
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`Name
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`Dosage Forms / Strength
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`Proposed Indication
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`28, 2011
`Feb
`Au st 26, 2011
`
`Nucynta ER
`Tan - ntadol
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`50 mg, 100 mg, 150 mg, 200 mg and 250 mg
`extended—release tablets
`
`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
`
`Reference ID: 3006373
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`Material Reviewed/Consulted
`OND Action Package, including:
`Ellen Fields, MD, MPH
`CDTL
`Elizabeth Kilgore, MD
`Medical Officer Review
`Alicja Lerner, MD, PhD, PhD/Michael Klein, PhD
`CSS
`ONDQA-Biopharmaceutics Review Sandra Suarez-Sharp, PhD/Angelica Dorantes,
`PhD/Patrick J. Marroum, PhD
`David Lee, PhD/Yun Xu, PhD
`Mathilda Fienkeng, PharmD, Twyla Thompson
`(analytical site): Arindam Dasgupta,PhD/ Martin K.
`Yau, PhD
`(clinical site): Susan Liebenhaut, MD/Tejashri Purohit-
`Sheth, MD
`Dominic Chiapparino, PhD/Parinda Jani
`Jibril Abdus-Samad, PharmD/Todd Bridges, RPh/Carol
`Holquist, RPh
`Jibril Abdus-Samad, PharmD/Todd Bridges, RPh/Carol
`Holquist, RPh
`Cynthia LaCivita, PharmD / Doris Auth, PharmD/
`Sharon R. Mills, BSN, RN, CCRP/ Barbara Fuller, RN,
`MSN, CWOCN/ LaShawn Griffiths, RN, MSHS-PH, BSN
`/Claudia Karwoski, Pharm.D.
`
`Clinical Pharmacology Review
`DDMAC
`OSI
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`Project Management
`OSE/DMEPA (C&C)
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`OSE/DMEPA (Trade Name)
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`OSE/DRISK
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`OND=Office of New Drugs
`CDTL=Cross Discipline Team Leader
`CSS=Controlled Substance Staff
`DDMAC=Division of Drug Marketing, Advertising and Communication
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=Division of Risk Management
`OSI=Office of Scientific Investigations
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`NDA 200533
`Nucynta ER
`Division Director’s Review and Summary Basis for Approval
`August 25, 2011
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`2
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`Reference ID: 3006373
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`1.
`
`Introduction
`
`
`Tapentadol is a centrally-acting analgesic which combines mu-receptor opioid agonist
`activity with inhibition of norepinephrine reuptake. It is pharmacologically similar to
`tramadol. Nucynta ER is an extended-release (ER) formulation of tapentadol and the
`proposed indication is “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 standard indication for ER opioid
`products. The application for immediate-release (IR) tapentadol, Nucynta, received
`approval for marketing “for the relief of moderate to severe acute pain in patients 18
`years or older” on November 20, 2008.
`2. Background
`
`The original application for Nucynta ER was submitted on November 30, 2009. Dr.
`Rigoberto Roca, Deputy Director of the Division of Anesthesia, Analgesia, and
`Addiction Products, was the signatory authority for that submission. His review and
`summary basis for a complete response action is appended to this review. While the
`review team for the first-cycle submission found that there was substantial evidence to
`support the safety and efficacy of the product, a complete response action was taken
`due to the deficiencies described in the following excerpt from the Complete Response
`(CR) Letter, issued on October 1, 2010:
`
`
`PRODUCT QUALITY/BIOPHARMACEUTICS
`
`
`1. Your proposed in vitro in vivo correlation (IVIVC) models do not support the
`bridging of the clinical study batches (PR2) to the to-be-marketed tamper resistant
`formulation (TBM TRF).
`
`
`2. The re-constructed IVIVC models using individual plasma concentrations are not
`acceptable for the following reasons:
`
`
`
`• The models submitted on July 23, 2010, still include a mathematical term that
`has no mechanistic foundation and, therefore, are not acceptable.
`
` •
`
` The models using the individual subject concentrations failed the external
`validation, indicating a lack of robustness.
`
`
`3. The proposed dissolution acceptance criteria for TBM TRF tapentadol ER tablets
`were based on the proposed IVIVC models. Because these models were not
`accepted, these dissolution acceptance criteria will need to be revised. You may
`refer to our advice letter dated August 12, 2010, for additional guidance concerning
`these acceptance criteria.
`
`4. Given that your proposed IVIVC models do not support the bridging of the clinical
`study batches to the TBM TRF, bioequivalence has not been demonstrated. Provide
`in vivo bioequivalence (BE) data comparing the PR2 and TBM TRF formulations.
`Because the compositions of your formulations are not proportional, you should
`provide bioequivalence (BE) data for the lowest, 50 mg, and highest, 250 mg,
`NDA 200533
`Nucynta ER
`Division Director’s Review and Summary Basis for Approval
`August 25, 2011
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`3
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`Reference ID: 3006373
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`strengths. You may request a biowaiver for the intermediate strengths. The
`biowaiver request should be supported with: l) acceptable in vivo BE data for the
`lowest and highest strengths and 2) in vitro comparative dissolution profile data and
`similar 12 values (using the highest and lowest strengths as references).
`
`CLINICAL
`
`5. For Protocols KFS 503/23 and KFS 503/36, data pertaining to subject eligibility,
`primary endpoint, and rescue medication use were direcfly submitted by subjects via
`eDiaries to eTrials, the contract research organization (CRO) responsible for this
`electronic data capture. Because the clinical investigator sites did not maintain
`independent source doctmrontation of the data that were transmitted directly to
`eTrials via eDiaries, verification of source data at the CRO, in conjunction with
`evaluation of findings from other completed inspections, is required before this
`application may be approved.
`
`The Applicant submitted this response to the CR Letter issued on October 1, 2010.
`This review will focus only on the new data and information submitted to address the
`deficiencies in the CR Letter. The reader is referred to Dr. Roca’s first-cycle summary
`review, which has been appended to this review, for discussion of the data from the
`original submission supporting the efficacy and safety ofNucynta ER.
`
`In this submission, rather than attempt to reconstruct their IVIVC model, the Applicant
`has provided the results of new bioequivalence studies between their Phase 3 PR2
`tablets and the to-be-marketed formulation, to support the bridging of the strengths
`(150 mg and 200 mg) which they had originally proposed to cover with the IVIVC
`model. In addition, inspections of the CR0 and the additional clinical pharmacology
`studies were performed by OSI during this review cycle to address the approvability
`issues in Item 5 of the CR Letter.
`
`A post-action meeting was held with the Applicant on November 9, 2010. At that
`meeting, two additional concerns were raised by the clinical review team. First, the
`fact that the to-be-marketed 50 mg tablet was not bioequivalent to the 50 mg PR2 tablet
`had been noted upon review of the meeting package submitted by the Applicant for the
`post-action meeting. During the meeting, the Applicant was asked to provide data or a
`rationale in their response to the CR Letter to justify the use of multiple 50 mg tablets
`in place of a tablet of a higher dose. The information that they have submitted to
`address this concern is discussed in Section 5 below. Second, the formulation of the
`Nuc
`ta ER tablets contains 01 eth lene oxide
`
`However, polyethylene oxide is an excipient that,
`
`
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`in certain approve pr ucts,
`een associated with swelling and stickiness upon
`contact with saliva or water, at times resulting in serious adverse events including
`choking, some requiring medical intervention. As such, the Applicant was asked to
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`NDA 200533
`Nucynta ER
`Division Director’s Review and Summary Basis for Approval
`August 25, 2011
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`4
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`Reference ID: 3006373
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`fully explore this concern in their response to the CR letter with appropriate analyses of
`their safety data. Those explorations were included in this submission.
`
`During this review cycle, Dr. Lerner raised a number of concerns based on her review
`of the clinical pharmacology study results. The clinical pharmacology and clinical
`review teams disagreed with Dr. Lerner’s conclusions and the matter was raised to the
`Division Director level for adjudication. Dr. Klein, Dr. Chandrahas Sahajwalla
`(Division Director in the Office of Clinical Pharmacology) and I discussed the issues
`raised by the reviewers and determined that Dr. Lerner’s conclusions and
`recommendations were not consistent with the data, and Dr. Klein wrote a supervisory
`memo rescinding her recommendations. See Section 11 for further discussion.
`
`3. CMC
`
`See appendix.
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`4. Nonclinical Pharmacology/Toxicology
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`See appendix.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`The following summary of the new clinical pharmacology data submitted in this
`response to the CR Letter has been reproduced from pages 5 through 8 of Dr. Fields’
`review:
`
`
`BE studies were conducted comparing all strengths of the TRF [tamper-resistent
`formulation] formulation (50mg, 100mg, 150mg, 200mg, and 250mg) with the PR2
`formulation used in the Phase 3 studies. All strengths except the 50mg strength were
`demonstrated to be bioequivalent. You are referred to Dr. Lee’s review for details
`regarding the studies of the 100mg, 150mg, 200mg, and 250mg.
`
`The results of the study assessing the bioequivalence of the 50mg tablet are of interest
`because bioequivalence was not demonstrated, and this raises concern regarding the use
`of the 50mg tablet. As stated in Dr. Lee’s review:
`
`“Study HP5503/82 evaluated tapentadol 50 mg tablets. Sixty-four subjects (32 men and
`32 women) were enrolled for the study. The batch numbers for test (TRF 50-mg tablet)
`and reference (PR2 50-mg tablet) products were 9EG9279-X and PD3137, respectively.
`Subjects were excluded from bioequivalence analyses if they did not complete both
`treatments and vomited anytime during the treatments. The mean serum concentration-
`time profiles were somewhat dissimilar between two formulations.
`
`The mean serum concentration-time profiles for 50 mg tablets are shown in the table
`below:
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`NDA 200533
`Nucynta ER
`Division Director’s Review and Summary Basis for Approval
`August 25, 2011
`
`5
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`Reference ID: 3006373
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`Reference ID: 3006373
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`The tapentadol pharmacokinetic parameters and a summary of statistical results are
`presented below:
`
`Summary Statistics on the Pharmacokinetic Parameters of Tapentadol
`(Study HP5503/82: Pharmacokinetic Data Analysis Set)
`
`
`
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`The corresponding 90% CI for AUC values were within the 80% to 125% range, but, not
`for the Cmax. Thus, the two formulations are not bioequivalent. However, 50 mg dose
`will be strictly used for a titration purpose. Therefore, the result is considered acceptable
`after discussion with the clinical team.”
`
`As stated in Dr. Lee’s review, the lack of bioequivalence between the two formulations
`based on the higher Cmax for the TRF formulation does not represent a safety concern
`because the Cmax is only approximately 30% higher, and because the 50mg is intended
`to be used only during titration.
`
`Dr. Lee also addressed the issue of the interchangeability of the 50mg tablets if they are
`administered as multiple units to achieve a particular dose instead of administering the
`higher dose unit. The following is taken from Dr. Lee’s review:
`
`The cross-study dose linearity assessment indicated that tapentadol 50 mg Cmax and
`AUC∞ values are in line with higher doses and do not expect to provide greater exposure
`when a smaller-dose unit is administered as multiple units. The observed serum
`tapentadol concentrations following administration of a particular dose as combinations
`of 50-mg and 100-mg TRF tablets, e.g., 200 mg: two 100 mg tablets or two 50 mg and
`one 100 mg tablets, in a Phase 3 study PAI-3027/KF56 were within the 90 percent
`confidence interval established by the population pharmacokinetic model. However, the
`NDA 200533
`Nucynta ER
`Division Director’s Review and Summary Basis for Approval
`August 25, 2011
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`6
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`observed data do not provide a robust comparison, e.g., five units of 50 nrg tablets
`compared to a single rmit of 250 nrg tablet, and can not be used as a strong supportive
`argument in the comparability discussion. In all, the resultsfrom the linearity assessment
`and the supportive information fiom the observed Phase 3 trial indicate that patients
`would not be at riskfor over—exposure to tapentadol ifmultiple tablets are administered.
`
`Food Effect
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`The determination regarding a food effect for tapentadol ER was made during the first
`cycle review, and the conclusion was that there is not a food effect for the to-be-marketed
`formulation based on a standard food effect study conducted in the United States. During
`her review of the complete response application, Dr. Alicja Lemer of the Controlled
`Substance Staff reviewed another food eflect study conducted in Japan that was included
`in the complete response submission, and concluded that there is a food efl'ect. Dr. Lee
`had the following comments in his clinical pharmacology review relative to the Japanese
`study.
`
`".....a cursory review was conducted for Study HP5503/51, a food eflect study (with a
`'standard Japanese meal - total calories are approximately 700 - 800 kcal,‘ percentages
`ofenergy ofcontents ofnreal are: carbohydrate 50— 70%, protein less than 20%, li id 20—
`.30% with 100 nr
`IRF ER orrrrulation Ja anese healthv men n=12 .
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` was reviewe
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`e resu ts indicated that the geometric nreansfor Cmax and AUC oftapentadol
`under fed conditions were approximately 54 and 12% higher compared to under fasted
`conditions. The observed arithmetic mean Cinax and AUC values for fed and fasted
`conditions were 65. 7 and 42.8 ng/mL, and, 585 and 520 ngh/mL, respectively. The
`provided information was considered not to be critical for this application simply
`because this study utilized a 'standard Japanese meal ’, not an Agency ’s recommended
`high-fat meal, and, thefact that the studiedpopulation does not represent the population
`majority in the US. Additionally, the high-fatfood efi'ect information was assessed in the
`original NDA submission, and, that study was considered as a pivotalfood efl'ect study;
`in that assessment, the AUC and Crnax increased by 6% and 17%, respectively, when
`TRF ER tablets were administered after a high—fat meal. The tmax was prolonged by
`about 1 hour with a median tmax of 6.00 hours (range: 2.98-12.0 hours) in thefed state
`and 5 hours (range: 2.00—12.0 hours) in the fasted state. In Phase 3 studies, tapentadol
`ER tablets were also administered without restriction to food. Therefore, we recommend
`that tapentadol ER tablets may be taken without restriction tofood. ”
`
`The Division’s conclusion regarding the food effect studies is that the results of the
`standard food efiect study reviewed by the Clinical Pharmacology team provide adequate
`evidence of a lack of food effect for tapentadol ER, and that while the study conducted in
`Japan did show an effect of food, the interpretation of the study is limited due to the fact
`that the meal administered during the study was not the standard meal for US studies, and
`the study population did not represent the US population as a whole. The clinical studies
`demonstrated that taking tapentadol ER without regard to food did not result in safety
`concerns. The labeling for tapentadol ER will reflect that it may be taken without regard
`to food intake.
`
`Biopharmaceutics
`Since the Applicant conducted five BE studies linking all of the proposed strengths, the
`biowaiver request for the intermediate strengths was no longer required. The Applicant
`did submit dissolution specifications for all strengths of tapentadol ER tablets which were
`agreed upon with the biopharmaceutics team. The dissolution specifications were based
`on the mean dissolution profiles for data from registration stability batches, commercial
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`NDA 200533
`
`Nucynta ER
`Division Director’s Review and Summary Basis for Approval
`August 25, 2011
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`Reference ID: 3006373
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`site stability batches, and clinical (pivotal BE) batches, and were deemed acceptable from
`the biopharmaceutics perspective.
`
`According to the Clinical Pharmacology and Biopharmaceutics review teams, there are
`no issues that preclude approval for tapentadol ER tablets at this time.
`
` I
`
` concur with the review team that the Applicant has provided adequate data to resolve
`the concerns related to the dissolution specifications for Nucynta ER. I also concur
`that the small increase in Cmax seen with the 50 mg tablets is not clinically relevant
`and that there are adequate data to support that the product may be taken with or
`without food without concern for an increased risk of toxicity.
`
`6. Clinical Microbiology
`
`No clinical microbiology data were necessary for this application.
`
`7. Clinical/Statistical-Efficacy
`
`See appendix.
`
`8. Safety
`
`The following summary of the updated safety data submitted in this response to the CR
`Letter has been reproduced from pages 8 and 9 of Dr. Fields’ review:
`
`
`The original NDA submission included safety data on more than 4,000 subjects who
`received tapentadol ER in 38 clinical studies. In this submission the Sponsor included
`safety data collected since the cut-off date for the 4-month safety update in the original
`NDA submission, October 1, 2009. This consisted of unblinded data on 1,700 study
`subjects from eight completed Phase 1 studies, and three completed Phase 2 and 3
`studies. Additional data was submitted for 11 ongoing Phase 2 and 3 studies that included
`only numbers of deaths and serious adverse events. Phase 2 and 3 studies were conducted
`in patients with chronic pain due to osteoarthritis, chronic low back pain, cancer,
`postherpetic neuralgia, and diabetic peripheral neuropathy.
`
`The updated safety profile of tapentadol ER as reviewed by Dr. Kilgore is consistent with
`that noted during the first cycle review. There were no new or concerning safety signals
`detected during her review. The review of laboratory tests, ECG findings, and vital sign
`measurements did not indicate any potential clinically relevant safety concerns. There
`were no new deaths reported for the completed studies, and the SAEs reported in the
`update did not lead to concern regarding any new safety issues. The most frequently
`reported
`treatment emergent adverse events (TEAEs)
`in
`this update
`included
`gastrointestinal and nervous system disorders such as nausea, constipation, headache, and
`somnolence, which is consistent with the findings from the first cycle review.
`
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`NDA 200533
`Nucynta ER
`Division Director’s Review and Summary Basis for Approval
`August 25, 2011
`
`8
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`Reference ID: 3006373
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`The following additional summary evaluation has been reproduced from pages 10 and
`11 of Dr. Fields’ review:
`
`
`Regarding the safety of the TRF tablets in terms of choking and sticking, the Applicant
`has stated that there were no Product Quality Complaints submitted for the Phase 1 and
`Phase 3 studies showing difficulty swallowing the TRF tablets, and there were no TEAEs
`that would suggest difficulty swallowing the tapentadol TRF tablets in the 845 subjects
`who took tapentadol TRF in the Phase 1 and Phase 3 studies. Dr. Kilgore also reviewed
`the adverse event data from studies utilizing the TRF formulation and did not detect any
`events likely associated with the tablets swelling or sticking in the throat or GI tract. This
`information appears adequate to address the choking/sticking issue from a premarketing
`perspective. The product label will include instructions to take one tablet at a time with
`adequate water to avoid choking or sticking, and the Applicant will be required to report
`to the Agency adverse events related to the stickiness of the tablets as 15-day expedited
`safety reports. If a safety signal appears in this regard during the postmarketing period,
`additional steps may be taken.
`
`Since the CR Action for this NDA, the required New Molecular Entity Post Marketing
`Evaluation (915 review) for Nucynta (NDA 22-304) was completed by OSE and DAAAP
`on November 22, 2010. As noted in this review, a Tracked Safety Application (TSI) was
`opened in May, 2010 to investigate events that may represent new safety signals for
`Nucynta as reported in Periodic Safety Reports to the Agency. These included events of
`hallucination, suicidal ideation, angioedema, and headache, and a higher than expected
`number of reports of seizure and serotonin syndrome (SS), that were included in the class
`labeling for tramadol and tapentadol products, but had not occurred during the clinical
`trials. Of note, it appears that the reports of serotonin syndrome included concomitant
`medications that would increase the SS risk. The following conclusions and
`recommendations were made:
`• Hallucination and seizure are adequately described in revised Nucynta labeling
`of 11/1/10.
`• Reports of headache have likely been confounded by underlying medical
`conditions, and routing postmarketing surveillance for these events should be
`continued.
`• Serotonin syndrome, suicidal ideation, angioedema and palpitations should be
`added to the Nucynta label as postmarketing events.
`• The Nucynta ER label will also reflect the above issues.
`
`9. Advisory Committee Meeting
`
`As this was a reformulation of an approved opioid and as the Agency has already
`received sufficient advice from our advisory committee on the development of
` opioid formulations, this application was not taken to an advisory committee
`for discussion.
`
`10. Pediatrics
`
`The following summary of the pediatric study requirements has been reproduced from
`pages 11 and 12 of Dr. Fields’ review:
`NDA 200533
`Nucynta ER
`Division Director’s Review and Summary Basis for Approval
`August 25, 2011
`
`9
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`Reference ID: 3006373
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`(b) (4)
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`The pediatric study requirements for drug products intended to treat chronic pain include
`studies in pediatric patients ages 7 to <17 years of age. Studies in patients under the age
`of 7 years are not required, since the population of pediatric patients with chronic pain in
`this age group is too small to study. The types of studies required include those assessing
`efficacy, safety, and pharmacokinetics. Although the Division’s current policy includes
`extrapolation of efficacy from adults to pediatric patients two years and older for opioids,
`tapentadol is not a pure mu-opioid agonist, having the additional mechanism of action
`related to norepinephrine reuptake inhibition. For products such as this, that currently
`include tramadol and tapentadol, efficacy may not be extrapolated from findings in
`adults.
`
`The Sponsor submitted a pediatric plan that included a waiver request for pediatric
`patients under 7 years, and a deferral request for pharmacokinetic, efficacy, and safety
`studies in patients ages 7-<17 years, with the appropriate justifications. A timeline was
`submitted as shown below:
`
`o Final protocol submission to Agency: May 28, 2014
`o Study completion date:
`
` October 31, 2017
`o Study report submission to Agency: March 26, 2018
`
`
`The Sponsor’s rationale for the study start date (three years from now) is that the
`determination of dosing in pediatric patients for tapentadol ER is dependent in part on the
`results of the PK studies of the IR formulation in pediatric patients.
`
`The pediatric plan was presented to the Pediatric Research Committee (PeRC) on July 6,
`2011, and was found acceptable by the Committee.
`
`11. Other Relevant Regulatory Issues
`
`The following summary reproduced from pages 12 through 15 of Dr. Fields’ review,
`addresses the concerns raised by Dr. Lerner, mentioned above in Section 2:
`
`
`Dr. Alicja Lerner of the Controlled Substance Staff (CSS), with secondary concurrence
`from Michael Klein, Ph.D., filed two reviews for this NDA in order to address abuse-
`related safety issues, one during the first cycle dated September 9, 2010, and another
`during the current review cycle, dated July 12, 2011. The issues in the September, 2010
`review were not addressed by the first cycle review team, and were deferred for internal
`discussion during the subsequent review cycle.
`
`The conclusions from Dr. Lerner’s first cycle review are summarized as follows:
`1. The controlled-release properties of the purported tamper-resistant formulation
`can be readily overcome by multiple simple physiochemical manipulations.
`2. The to-be-marketed formulation exhibits an increased frequency of abuse-
`related adverse events.
`3. Withdrawal symptoms, including insomnia, depressed mood, depression,
`suicidal ideation, and disturbance in attention, occurred after the extended-
`release formulation tapentadol was stopped. They noted that such withdrawal
`symptoms are typical of all μ-opioid receptor agonists.
`
`
`The CSS recommendations based on these conclusions are:
`
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`NDA 200533
`Nucynta ER
`Division Director’s Review and Summary Basis for Approval
`August 25, 2011
`
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`Reference ID: 3006373
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`1. The Sponsor must provide information and explanations of the pharmacokinetic
`and adverse event differences noted in the clinical trials using the tamper-
`resistant formulation and other extended-release formulations, because of pooled
`data that encompasses all formulations that were investigated. Linkage of the
`pharmacokinetic/pharmacodynamic data for the various formulations is needed.
`2. Because the drug product at the 250 mg dose level appears to result in a high
`percentage of euphoria and other opioid-like adverse events, the sponsor must
`provide an adequate rationale for marketing the dose, so that the benefits
`continue to outweigh the risks.
`3. Upon approval and marketing, the drug product should continue to be monitored
`for abuse, misuse, overdose, and withdrawal.
`
`
`Additional conclusions from the current cycle CSS review are summarized here:
`1. Review of the bioequivalence studies submitted during the second cycle with the
`TRF formulation indicates a possible gender effect, with nervous system,
`gastrointestinal and psychiatric adverse events occurring in females up to 8-12
`times more frequently than in males.
`2. Withdrawal symptoms occurred after Nucynta ER administration was stopped.
`The occurrence of withdrawal symptoms indicates development of dependency
`and a need to slowly taper when discontinuing the drug.
`3. Co-administration of tapentadol TRF with meals and alcohol resulted in
`increases in Cmax and AUC’s.
`4. Pharmacodynamic effects of tapentadol TRF formulation are potentiated after
`intake with alcohol, not food.
`
`
`CSS recommendations based on the above conclusions are:
`1.
`Include appropriate warning language in the label regarding susceptibility of
`females to development of adverse events. The extent of the relation of gender
`to adverse events should be further examined.
`2. All planned and ongoing clinical trials should include prospective assessment of
`suicidality, due to the appearance of suicidality in the post-marketing phase of
`Nucynta.
`
`
`The Division conducted extensive internal discussion regarding the CSS conclusions and
`recommendations from the two reviews, and had concerns regarding the following issues:
`1. Dr. Lerner expressed concern that the to-be-marketed formulation of tapentadol
`had more abuse-related adverse events than other formulations studied, and the
`Applicant should provide linkage for the PK/PD data for all formulations
`studied.
`
`The Division determined that since bioequivalence studies submitted with the
`Complete Response demonstrated a pharmacokinetic link between the previous
`formulations and the to-be-marketed formulations, this no longer represents a
`safety concern.
`
`2. The Applicant should provide a rationale for marketing the 250mg dose because
`there was an increased incidence of euphoria seen in patients receiving 250mg.
`
`
`
`The Division noted that the above conclusion was based on results of Phase 1
`studies, where healthy study subjects are given doses of tapentadol ER without
`titration. It is expected that higher doses would result in more abuse and opioid-
`related adverse events.1 It is therefore not necessary that the Applicant provide
`an explanation for this finding.
`
`
`1 Abuse potential assessments often consider responses from healthy subjects at supratherapeutic doses.
`NDA 200533
`Nucynta ER
`Division Director’s Review and Summary Basis for Approval
`August 25, 2011
`
`11
`
`Reference ID: 3006373
`
`

`

`
`3. Co-administration of tapentadol TRF with meals and alcohol resulted in
`increases in Cmax and AUC’s
`
`
`
`Dr. Lerner implied in her review that there is a significant food effect for
`tapentadol TRF, based on her review of a food effect study conducted in Japan,
`in contrast to the conclusion made by the clinical pharmacology team, that there
`is no food effect. This is discussed in detail in this review in Section 8, Safety,
`which explains why the Division agrees with the clinical pharmacology review
`team.
`
`
`Because of the conflicting conclusions made by the review division, the Clinical
`Pharmacology review team, and CSS, and in order to comply with the Equal Voice
`initiative, additional discussions were conducted among the Division Directors of the
`three groups. The result of these discussions was a memo dated August 3, 2011, by
`Michael Klein, Ph.D. of CSS that resolved the conflicting opinions of the different review
`teams.
`
`The following is taken from Dr. Klein’s memorandum:
`
`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:
`
`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 (R331333-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.
`
`1. Because the recent bioequivalence study resolved that the PK and AE profiles of
`different formulations are similar, Dr. Lerner’s first recommendation in the memo is
`withdrawn.
`
`NDA 200533
`Nucynta ER
`Division Director’s Review and Summary Basis for Approval
`August 25, 2011
`
`12
`
`Reference ID: 3006373
`
`

`

`2. Dr. Lerner’s second