CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`22-304
`
`CROSS DISCIPLINE TEAM LEADER REVIEW
`
`

`

`Cross Discipline Team Leader Review
`NDA 22-304, Tapentadol, immediate-release tables
`Robert B. Shibuya, M.D.
`
`Cross-Discipline Team Leader Review
`
`
`Date
`
`23 Se tember 2008
`
`_
`
`From
`Sub'ect
`NDA/BLA #
`Su lement#
`
`'
`
`Robert B. Shibu a, M.D., Clinical Team Leader
`Cross-DisciEline Team Leader Review
`NDAC
`
`
`
`Applicant
`
`Johnson & Johnson Pharmaceutical Research &
`Develo - ment
`22 Janu
`2008
`Date of Submission
`22 October 2008
`PDUFA Goal Date
`
`
`‘
`
`Proprietary Name /
`Established
`S .
`
`To be determined/Tapentadol HCl
`
`'
`
`Dosa_e forms / Stren_
`Pro . osed Indication
`Recommended:
`
`Tablet, 50, 75, 100 m;
`
`1. Relief of moderate to severe acute pain
`A roval
`
`0ND Action Packa e, includin_:
`
`Statistical
`
`Jonathan Norton, Ph.D.
`Dionne Price, Ph.D.
`Thomas Permutt, Ph.D_.
`
`
`
`
`Adam Wasserman, Ph.D.
`
`Ali Al-Hakim, PhD.
`
`
`
`
`
`
`
`Suresh Doddaaneni, PhD.
`Michelle Safarik, PA-C
`
`,
`
`Antoine El-Hage, Ph.D.
`Constance Lewin, M.D.
`
`Gita Akhavan-Toyserkani, PharmD
`Mary Dempsey
`Claudia Karwoski, PharmD
`
`DDMAC
`
`DSI
`
`OSE/DRISK
`
`‘
`
`1. Introduction
`
`
`
`
`
`
`
`
`
`Tapentadol is a New Molecular Entity (NME) with weak mu opioid agonist activity and
`norepinephrine uptake activity. It was developed under IND 61,345 for the management of
`acute moderate to severe pain. The chemical formula for tapentadol is C14H23NO*HCl and the
`chemical structure is shown on the next page.
`-
`
`_ Page 1 of 19
`
`l
`
`

`

`Cross Discipline Team Leader Review
`NDA 22-304, Tapentadol, immediate-release tables
`Robert B. Shibuya, MD.
`
`OH
`
`. HCl
`
`(R)
`
`(R)
`
`/
`
`For this immediate-release tablet, the applicant, Johnson & Johnson Pharmaceutical Research
`& Development, is seeking the indication of “the relief of moderate to severe acute pain.” At
`this time, the applicant has not provided an acceptable tradename. Therefore, the product will
`be referenced as “tapentadol” throughout this review. Proposed strengths are 50, 75, and 100
`mg.
`
`At various meetings, including a Pre-IND Meeting, the End-of-Phase 2 Meeting, and the Pre-
`NDA Meeting, the Division described what efficacy and safety data would support approval.
`The Division indicated that two multiple-dose studies of at least 2-5 days duration would be '
`required. The applicant felt that the pain in most acute pain scenarios is not of sufficient
`duration to demonstrate analgesia over 5 days. Therefore, the applicant proposed studying
`end-stage degenerative joint disease in one of the adequate and well-controlled studies. The
`Division agreed with this proposal.
`
`The issue of missing data was addressed on several occasions and the Division indicated that,
`due to the phenomenon of differential dropout, the applicant must use a conservative
`imputation scheme. The applicant decided to use Last Observation Carried Forward (LOCF),
`a non-conservative imputation scheme, as the primary method to account for missing data.
`The applicant included Baseline Observation Carried Forward (BOCF), a conservative
`imputation scheme, in the statistical analysis plan and agreed that the BOCF analysis must
`confirm any positive LOCF result. In the Agency review of this NDA, the efficacy studies
`were carefully assessed and reanalyzed to address this issue.
`
`Tapentadol is structurally related to tramadol (Ultram) and has similar pharmacological
`effects. Among typical opioid effects, tramadol, particularly in combination with monoamine
`oxidase inhibitors, is associated with seizures and serotonin syndrome. The safety assessment
`for tapentadol, in addition to the scrutiny afforded a NME, also assessed these specific areas of
`concern.
`
`Page 2 of 19
`
`2
`
`

`

`Cross Discipline Team Leader Review
`NDA 22-304, Tapentadol, immediate-release tables
`Robert B. Shibuya, M.D.
`
`In addition, as an opioid, given the issues of prescription drug abuse, we have given careful
`consideration to risk mitigation for tapentadol. While tapentadol is likely to be classified in
`Schedule II, because of tapentadol’s relative lack of potency and immediate-release
`formulation (such that an individual dosage unit is unlikely to cause significant harm to an
`individual), at this time, tapentadol immediate-release tablets will not be deemed to require a
`Risk Evaluation and Mitigation Strategy (REMS) and that routine pharmacovigilance and
`Schedule II controls should suffice to manage risks.
`
`2. Background
`
`Tapentadol is an immediate-release weak mu opioid agonist with analgesic activity for which
`the applicant is seeking an indication of the management of acute moderate to severe pain. As
`will be discussed in later sections of this review, the drug appears efficacious and the safety
`profile appears typical for an opioid. All review disciplines are recommending approval. The
`Office of Surveillance and Epidemiology felt that routine pharmacovigilance was appropriate
`and opined that the Applicant’s post-marketing safety surveillance was appropriate.
`
`3. CMC/Device
`
`-
`
`The CMC review was conducted by John Hill, Ph.D. Tapentadbl, immediate-release tablets
`are film—coated and undergo aC
`.
`7 Both
`the synthetic process and manufacturing process were felt to be robust by Dr. Hill. The
`product isfi
`’
`:7 Dr. Hill’s initial CMC review noted several
`deficiencies including contact information, limit of detection/quantitation for the dissolution
`method, method validation for the}; Jtest, and a letter of authorization to a DMF. The
`applicant’s response to an Information Request was adequate and Dr. Hill and Dr. Ali A1-
`Hakim, Chief, Branch 11, ONDQA, are recommending approval from the CMC perspective.
`The review of the Environmental Assessment was conducted by Ruth Ganunis who found the
`Applicant’s assessment acceptable.
`
`bill)
`
`4. Nonclinical Pharmacology/Toxicology
`
`The Pharmacology/Toxicology Review was conducted by Kathleen Young, Ph.D. with a
`secondary review by Adam Wasserman, Ph.D, Supervisory Pharmacologist.
`
`Tapentadol was subjected to the required battery of nonclinical testing for a NME. Key
`findings in the non—clinical program are summarized below.
`
`0 Tapentadol is a mu-opioid agonist with some sigma (82) activity and norephinephrine
`reuptake inhibitor activity. The molecule is structurally related to tramadol.
`0 Notable toxicities (beyond the expected, opioid-related CNS, GI, and respiratory
`effects) included:
`
`Page 3 of 19
`
`3
`
`

`

`Cross Discipline Team Leader Review
`NDA 22-304, Tapentadol, immediate-release tables
`Robert B. Shibuya, MD.
`
`0 Tapentadol caused convulsions in rats at very high IV doses (15 mg/kg). These‘
`effects in the rat were observed after the parent drug and metabolites had
`cleared. This finding was not further evaluated by the applicant. Convulsions ‘
`were noted in dogs, dosed subcutaneously and orally, at doses as low as 40
`mg/kg/day. Theconvulsions were observed across several studies of various
`chronicities. There was no evidence of tolerance to the convulsant effect
`"
`observed. Because of these nonclinical findings, humans at risk for seizure
`were excluded from participation in clinical trials with tapentadol.
`o Dose-related, reversible hepatotoxicity was observed, manifested by elevations
`in transaminases, alkaline phosphatase, and liver weights with hepatocellular
`hypertrophy and one instance of hepatic necrosis. Rats were more sensitive to
`tapentadol-associated hepatotoxicity than dogs. The hepatotoxicity was noted
`at fairly high doses in rats (150 mg/kg/day).
`o The other non-opioid-related target organ was the cardiovascular system.
`Tapentadol caused hERG channel inhibition at high concentrations
`(approximately 70-times the maximum Cmax of the maximum human dose)
`and it showed QT prolongation in 1'}: w'tro and 1'}: Viva dog pharmacology
`studies, again at high doses/concentrations. This activity has been associated
`with norepinephrine reuptake inhibition.
`0 Tapentadol was negative in the Ames and mouse micronucleus test. It was equivocal
`in the CHO assay. It is important to note that a 2-year'carcinogenicity study was
`negative.
`'
`0 With regard to reproductive toxicity, the only finding that exceeded historical control
`rates was ablepharia (absence of the eyelids) in Himalayan rabbits although the
`remainder of the studies were negative.
`
`'
`
`Drs. Young and Wasserman have recommended approval for this product from the
`Pharmacology/Toxicology perspective.
`
`5. Clinical PharmacologyIBiopharmaceutics
`
`The primary Clinical Pharmacology and Biopharmaceutics (CP/B) review was conducted by
`David Lee, Ph.D. with supervisory concurrenCe by Suresh Doddapaneni, Ph.D.
`
`The applicant is seeking the approval ofthree strengths, 50, 75, and 100 mg. The dosing
`regimen is to be every 4-6 hours. The applicant wishes to add a provision for patients to take
`one extra dose of tapentadol one hour following the first dose (“reload”).
`
`To support this dosing and administration scheme as well as address routine clinical
`pharmacology issues, the applicant conducted an extensive Clinical Pharmacology and
`Biopharmaceutics program. In total, the applicant conducted nine biopharrnaceutics studies
`providing information on absolute bioavailability, food effect, and dose linearity. Twenty-two
`clinical pharmacology studies were submitted providing data on metabolism, effects on the QT
`interval, special populations, drug-drug interactions, and pharrnacokinetic/pharmacodynamic
`correlation. With regard to studies directly related to dosing and administration, there were six
`Phase 2 studies (single- and multiple-dose) in patients following third-molar extraction,
`
`Page 4 of 19
`
`‘
`
`4
`
`

`

`Cross Discipline Team Leader Review -
`NDA 22—304, Tapentadol, immediate-release tables
`Robert B. Shibuya, MD.
`
`chronic non-cancer pain, and following bunionectomy that provided support for the dose
`range, dosing interval, and concept of “reloa .”
`
`Key findings from the CP/B program follow.
`
`0 The Agency agreed with the applicant that this product is BCS class I (highly soluble,
`highly permeable).
`o The capsule formulation used in Phase 1/2 was bioequivalent to the to-be-marketed
`film-coated tablet used in Phase 3.
`
`0 General clinical pharmacology information:
`0 Absolute oral bioavailability was 32% (fasted) and 42% (fed).
`Food caused a 16% increase in Cmax and a 25% increase in AUC.
`Tapentadol is dose—linear from 50 to 175 mg.
`The ill/2 is ~4.3 hours.
`
`The accumulation factor is 1.6 when dosed every 6 hours.
`0 The clearance is 1530 +/- 177 mL/min.
`0 Metabolic information:
`
`0000
`
`0 Approximately 97% is metabolized and excreted in urine and ~95% is excreted
`within 24 hours.
`-
`
`o The predominant metabolic pathway is Phase 2 conjugation of the parent drug
`(55% tapentadol-O-glucoronide and 15% tapentadol-O-sulfate).
`0 There is a lesser amount of Phase 1 metabolism (13% to N~desmethyl
`tapentadol via CYP2C9 and 2% to hydroxy tapentadol via CYP2D6).
`o The metabolites are not pharmacologically active.
`0 No clinically relevant inhibition of 1A2, 2C9, 2C19, 2D6, or 3A4 was
`observed.
`
`0 No clinically relevant induction of 1A2, 2C9, and 3A4 was observed.
`0 Tapentadol is neither a substrate or inhibitor of P-glycoprotein.
`o Drug-drug interactions
`_
`0 An 80 mg dose of tapentadol was tested in conjunction with metoclopramide,
`omeprazole, probenecid, naproxen, acetylsalicylic acid, and acetaminophen.
`No clinically relevant interactions were identified.
`0 As reported by Christine Gamett, Ph.D., a thorough QT study using 100 or 150 mg
`dosed every 6 hours (moxifloxacin control) showed no QT effect.
`0 Special populations information:
`o The PK parameters were similar in elderly and other healthy adults.
`0 There did not appear to be any difference in the PK of Japanese or non-
`Japanese subjects.
`.
`'
`0 With regard to gender, women in general had ~20% higher Cmax and'AUC
`values than men. After bodyweight normalization, this difference disappeared.
`
`o Hepatic impairment
`I The Cmax of tapentadol increased 1.4 and 25-fold in subjects with mild
`and moderate hepatic impairment, respectively.
`. The AUC of tapentadol increased 1.7 and 4.2-fold in subjects with mild
`and moderate hepatic impairment, respectively.
`
`Page 5 of 19
`
`5
`
`

`

`Cross Discipline Team Leader Review
`NDA 22—304, Tapentadol, immediate-release tables
`Robert B. Shibuya, MD.
`
`I The elimination half-life increased 1.4-fold in subjects with moderate
`hepatic impairment.
`I The applicant did not test the drug in subjects with severe hepatic
`impairment.
`0 Renal impairment
`I There were noeffects observed in the pharmacokinetics of the
`tapentadol moiety with perturbations in renal function.
`I However, Cmax and AUC for the tapentadol-O-glucoronide metabolite
`increased with increasing renal impairment (1.2- and 55-fold for Cmax
`and AUC in severe renal impairment).
`
`_
`
`Drs. Lee and Doddapaneni have recommended approval for this product from the Clinical
`Pharmacology perspective.
`
`6. Clinical Microbiology
`
`This section is not applicable since this is not an antimicrobial product.
`
`7. Clinical/Statistical- Efficacy
`
`The primarymedical review was conducted by Ellen W. Fields, M.D., MPH, Clinical Team
`Leader and the primary statistical review was conducted by Jonathan Norton, Ph.D. Please see
`Dr. Fields’ and Norton’s reviews for fiirther details regarding the clinical development
`program.
`
`During development, tapentadol, in both this immediate-release, acute pain formulation and an
`extended-release, chronic pain formulation was the subject of multiple meetings with the“
`Division. The original sponsor for this moiety, Grunenthal, is a German company and has
`been working closely with the European authorities to affect an approval in the EU.
`
`In these meetings, it became clear that Grunenthal/J&J were not going to be able to exactly
`meet the expectations of both the European authorities and FDA in that, according to the
`applicant, the EMEA wanted an i:
`._
`i:
`/
`
`3
`
`' hi4)
`
`:7
`
`'
`
`i
`
`_
`
`However, for this immediate-release, acute pain formulation, certain criteria for clinical trials
`were made clear by FDA. Over the course of the clinical development program,
`GrunenthaI/J&J agreed with the following:
`
`0 Efficacy must be demonstrated in at least two adequate and well-controlled, multiple-
`dose studies.
`
`0 A flexible dosing regimen of every 4-6 hours was acceptable if the clinical trial data
`contained sufficient detail in the dosing times to support this notion.
`0 Again, provided that the clinical trial data were of sufficient detail and supported the
`safety and efficacy of the “reload,” the Division would consider adding the “reload”
`concept into the Dosing and Administration section of the product labeling.
`
`Page 6 of19
`
`'
`
`6
`
`

`

`Cross Discipline Team Leader Review
`NDA 22-304, Tapentadol, immediate-release tables
`Robert B. Shibuya, MD.
`
`0 While the protocol may use LOCF as the primary imputation scheme, a conservative
`imputation scheme such as Baseline Observation Carried Forward (BOCF) must
`support the primary analysis in order for the study to be perceived as positive.
`0 Efficacy must be demonstrated over 3-5 days. Because many commonly used acute
`pain scenarios (bunionectomy, third-molar extraction) resolve by 5 days, alternative
`painful scenarios may be acceptable for study.
`0 The relevance of the positive control (oxycodone) will be .a review issue. C, j
`C
`7.
`
`7
`
`In the context of these agreements, the applicant has submitted two studies to support a finding
`of efficacy. Please see Dr. Field’s excellent review for further details regarding the pivotal
`efficacy studies.
`
`MM
`
`Study R331333PAI3003 (J&JRD )/KF5503/32 (Grunenthall will be referenced as “Study 32”
`in this review. Study 32 was a randomized, double-blind, active- and placebo—controlled,
`parallel-group study in patients with at least moderate pain following bunionectomy.
`
`Briefly, patients who had undergone an elective, unilateral first metatarsal bunionectomy and
`had pain of at least 4/10 following surgery and resolution of surgical anesthesia were eligible.
`In the context of the seizures observed in the nonclinical program, it is important to note that
`patients with a history of seizure disorder or those at risk of seizure (history of mild or
`moderate traumatic brain injury, stroke, TIA, or brain neoplasm within one year or history of
`severe brain injury, unconsciousness > 24 hours, posttraumatic amnesia > 24 hours 'within 15
`years) were consistently excluded from clinical trials with tapentadol.
`
`After screening and surgery, if sufficient pain was reported within 9 hours of surgery, patients
`were randomized and treated for a scheduled duration of 72 hours as inpatients. Patients were
`randomized to one of the following five treatments:
`0 Tapentadol, 50 mg Q 4-6 hours or
`o Tapentadol, 75 mg Q 4—6 hours or
`o Tapentadol, 100 mg Q 4-6 hours or
`o Oxycodone, 15 mg Q 4—6 hours or
`o Placebo
`
`No rescue was to be permitted although a “reload” of one additional dose, one hour following
`the first dose only was permitted. If rescue was used, patients were to be dropped from the
`study. Patients were followed with pain assessments (11-point NPRS for intensity, 5-point
`NRS for relief, patient global, and two-stopwatch) and adverse event monitoring. The
`duration of double-blind dosing was to be 72 hours and the protocol provided for a voluntary,
`9-day open-label extension.
`
`A total of 918 patients were screened and 603 were randomized. Subject disposition is
`summarized in Figure 1, from Dr. Fields’ review.
`
`Page 7 of19
`
`7
`
`

`

`Cross Discipline Team Leader Review
`NBA 22-304, Tapentadol, immediate-release tables
`Robert B. Shibuya, MD.
`Figure 1: Patient disposition, Study 32\.......J u..- .....,..
`Screened
`918
`
`. . .. -cr...“ u. Vuuv.--,
`
`
`
`Not el‘gible
`
`for randomization
`315
`
`[5 mg125
`
`Oxycodone I K
`
`qumtadol IR
`Twmladal IR
`‘I'apcntadol IR
`50 mg
`IIS
`
`75 mgno
`100mg
`I I9
`
`
`
`
`Witlulnwn
`Withdrawn
`28
`Wilhdmwn
`24
`Withdrawn
`
` l8
`I 3 Withdrawn
`
`
`
`Adm-53 Emu!
`
`Subject Choice
`Subject Choice
`Subject Chain:
`Subjecl Choice
`
`
`
`LackafEflFmLy
`(Sub/'21:! Wilma-aw Cans-em) I
`
`
`(Subject Willidlvw Comer”) l
`
`(Subject Widnb‘ew Content) I
`(Suhjecl Willuhew Come!!!) 3
`
`4
`Adverse Emm
`Adverse Ewnl
`6
`
`
`ilafi‘erse Emir
`
` 2
`
`Lackoijficlxy
`I2
`
`
`II7
`Lack 12fEflimcy
`23
`Lackaflzfi‘mg'
`l7
`Lacko/Efiimcy
`
` Olher
`
`
`
`
`
`
`Completed DoubbBIind
`Completed Double-Blind
`Compldtd Double-Blind
`Compleled DoubleBlind
`9!
`96
`IDS
`I07
`
`
`
`
`
`Entered Open-Label
`Entered Open-Label
`EnteredOpal-Label
`’
`s4
`85
`
`
`
`
`
`
`Completed Double-Blind
`60
`
`
`
`9 l
`
`Entered Open-Label
`[0!
`
`Entered Open-Label
`97
`
`hpcnlndol IR
`SDorIODmg
`423
`Dircamimmd(Tapenlmlollk 7.5 mg group)
`Comp/sled
`
`
`I
`427
`
`
`
`Predictably, given the fact that rescue was not permitted, the dropout rate was highest in the
`group randomized to placebo (~50%) and the dropouts almost universally dropped out due to
`lack of efficacy (59/60). The dropout rates ranged from 11-24% in the other arms and had
`much lower incidences of lack of efficacy (10-19%). Dr. Fields found that the demographic
`and baseline characteristics were reasonably balanced across study groups except the time
`from anesthesia stop to first dose of study drug which was shorter for the oxycodone group
`(mean 1.9 hrs) than the other groups (~25 hrs).
`
`The primary efficacy endpoint was the Summed Pain Intensity Difference over 48 hours
`(SPID48). The analysis was conducted on the Intention-To-Treat population, defined as all
`randomized patients who received at least one dose of study drug and had a baseline pain
`intensity score. Missing data were imputed using a LOCF scheme.
`
`The summary statistics for the primary endpoint are shown in this table from Dr. Fields’
`review below.
`
`Page 8 of 19
`
`

`

`Cross Discipline Team Leader Review
`NDA 22-304, Tapentadol, immediate«release tables
`Robert B. Shibuya, MD.
`
`Table 1: Primary efficacy analysis, Study 32
`
`Placebo
`Tapentadol IR
`Tapentadol IR
`Tapentadol IR nycodone HCl 1R
`50 mg
`75 mg
`100 mg
`15 mg
`(N=119)
`(N=120)
`(N=118)
`(N=125)
`
` -
`
`(N=120)
`
`0-48 Hours
`
`Mean (SD)
`Median
`(Range)
`
`LS Means ((lifi"
`fi‘om placebo)
`95% CI
`
`24.5 (120.93)
`43 .4
`(-278;274)
`
`119.1 (125.86)
`127.6
`(—1 851402)
`
`139.1 (118.93)
`131.3
`(4993162)
`
`167.2 (98.99)
`158.5
`(~94;408)
`
`172.3 (110.86)
`170.6
`(-l90;431)
`
`—
`
`——
`
`88.2
`
`113.5
`
`'
`
`141.4
`
`142.4
`
`60.71 to 115.59
`
`86.12 to 140.81‘
`
`113.98 to 168.90
`
`115.28 to 169.47
`
`<0.001
`<0.001
`<0.001
`--
`Adjusted p-value
`
`vs. placebo:1
`a Based on analysis of covariance model with factors of treatment, center, and baseline pain intensity as a
`covariate; Adjusted p-values using Hochberg procedure. Oxycodone group is not included.
`
`As Dr. Fields notes, the tapentadol-treated groups separatedfrom placebo and there was
`reasonable dose response observed between the tapentadol-treated patients.
`
`Using alternative imputation schemes [BOCF and Worst Observation Carried Forward
`(WOCF)] as well as various mathematical permutations of the pain scores (responder status,
`SPID over 12, 24, and 72 hours, etc.) all analyses supported the primary efficacy analysis.
`
`Secondary endpoints for Study 32 included time to first dose of rescue, responder status, and
`two—stopwatch data. The secondary endpoints also supported the finding of efficacy for
`tapentadol and tended to show a dose response between the tapentadol doses investigated. An
`example of one of the secondary endpoints is the continuous responder analysis from Dr.
`Fields’ review (Figure 2).
`‘
`
`Figure 2: Continuous responder analysis, Study 32
`Im-
`
`\ 50mg uni-o us
`1:.
`. 73"»; an... m
`—- -— - casso: loom; umnu
`l)xyuoduno IS n...
`‘ -- - ._ -'
`
`
`
`llO'
`
`70‘
`
`60'
`
`so
`
`40
`
`Jo -
`
`zo-
`
`
`
`Cumulative%ol'Subj.w/rcspons:
`
`Io
`
`
`>—U
`
`”GK,
`>--IU
`>~20
`% rcduccion in pain intensity From buselinc at 48 hours
`
`Page 9 ofl9
`
`9
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`

`

`,
`Cross Discipline Team Leader Review
`NDA 22-304, Tapentadol, immediate-release tables
`Robert B. Shibuya, M.D.
`
`With regard to the applicant’s concept of “reload,” a one-time-only second dose of study drug,
`one hour afier the first dose, I refer the reader to Dr. Norton’s review (page 34). Dr. Norton
`notes that, predictably, the “reloaders” had worse pain outcomes since the patients who
`reloaded were still eXperiencing significant pain following the first dose. However, Dr.
`Norton concludes that the data following the “reload’ dose suggest that the reload provided
`benefit.
`-
`
`The applicant’s statistical analysis, including the reanalysis using conservative imputation
`schemes, was confirmed by Dr. Norton.
`'
`
`Study R331333PAI3002 §J&JRD )/KF55 03/33 (Grunenthal) will be referenced as “Study 33”
`in this review. Study 33 was a randomized, double-blind, active- and placebo-controlled,
`parallel-group study in patients with pain in the setting of end-stage degenerative joint disease
`of the hip or knee. This patient population was selected because the applicant did not feel that
`the usual pain scenarios employed in clinical trials would be painful for an adequate duration
`to meet the Division’s requirement of at least 3-5 days.
`
`Briefly, eligible patients carried a clinical diagnosis of osteoarthritis of the hip or knee that
`were candidates for replacement of the affected joint and were currently at Step 2 or higher in
`the WHO pain ladder (combination opioid/non-opioid analgesic or opioid analgesic). Again,
`patients at risk for seizure were specifically excluded.
`
`Eligible patients were randomized to one of four groups:
`0 Tapentadol, 50 mg Q 4-6 hours or
`o Tapentadol, 75 mg Q 4—6 hours (uptitrated from 50 mg for the first 2 days) or
`o Oxycodone, 10 mg Q 4—6 hours or
`o Placebo
`
`Again, no rescue was to be permitted and if rescue was used, patients were to be dropped from
`the study. No reload was permitted in this study. Patients were followed with pain
`assessments (11-point NPRS for intensity, 5-point NRS for relief, patient global) and adverse
`event monitoring. The duration of double-blind dosing was to be 10 days.
`
`A total of 1,101 patients were screened and 674 were randomized. Subject disposition is
`summarized in Figure 3, from Dr. Fields’ review.
`
`APPEARS THIS WAY
`0N ORlGlNAL
`
`Page 10 ofl9
`
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`

`Cross Discipline Team Leader Review
`NDA 22—304, Tapentadol, immediate-release tables
`Robert B. Shibuya, M.D.
`
`Figure 3: Patient disposition, Study 33
`
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`Interestingly, the placebo grouphad the highest percentage of study completers (90%) .
`compared to 65-82% in the other groups. The most common reason for early discontinuation
`was adverse event in the active arms. Dr. Fields found that the demographic and baseline
`characteristics were reasonably balanced between treatment groups.
`
`The primary efficacy endpoint was the SPID—S days using a LOCF imputation scheme and an
`ITT population definition identical to that used in Study 32. The summary statistics for the
`SPID-S days is summarized in Table 2, from Dr. Fields’ review.
`
`Table 2: Summary Statistics, SPID-S days, Study 33
`Tapentadol IR Tapentadol 1R
`50 mg
`75 mg
`(N=153)
`(N='l66)
`n (96)
`n (94:)
`
`Placebo
`(N=169)
`[1 (9'6)
`
`Oxycodone
`HCl IR 10 mg
`(N=17l)
`n (9/8)
`
`Day 1-5
`N
`Mean (SD)
`Median
`(Range)
`
`-
`
`169
`130.6 (182.77)
`86.6
`(-358;695)
`
`166
`153
`229.2 (228.92) 223.8 (217.76)
`164.1
`210.2
`(-480;881)
`(—308z823)
`
`171
`236.5 (222.82)
`206.7
`(-268:884)
`
`LS Means (diff from placebo)
`95% CI
`Raw p-valne
`Adjusted p-value using
`Hochberg
`
`111.9
`97.5
`101.2
`--
`66.49 to 157.38
`54.58 to 147.89 51.81 to 143.26
`--
`<0.001
`<0.001
`<0.001
`--
`--
`<0.001
`<0.001
`--
`
`
`There was a statistically significant difference between the treatment groups and placebo. The
`data were also analyzed using BOCF and found to be rugged. However, it is interesting to
`note that no dose-response between the 50 and 75 mg doses of tapentadol was observed. Dr.
`Norton confirmed the analyses for Study 33.
`
`Pagellofl9
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`11
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`

`Cross Discipline Team Leader Review
`NDA 22-304, Tapentadol, immediate-release tables
`Robert B. Shibuya, MD.
`
`The secondary efficacy analyses also supported the primary. Again, fi‘om Dr. Fields’ review,
`Table 3 summarizes the secondary efficacy endpoints for Study 33.
`
`Table 3: Secondary efficacy endpoints, Study 33
`’
`Tapentadol IR
`Tapentadol
`Oxycodone HCl
`50mg
`IR 75mg
`IR 10mg
`
`(N=153)
`(N=166)
`(N=l7 1)
`5-day SPID (LOCF)
`LS Means diff. from placebo
`(95% CI)
`Adjusted p-value vs. placebo"’ b
`Unadjusted p—value vs. placeboa
`5-day SPID (r—aocrf‘“c
`5_day SPID (WOCDa
`Two-part model on ‘34: change NRS and drop-curd
`Pain assessment 230% improved at Day 5e
`Pain assessment 250% improved at Day 5e
`Distribution of responders at Day 5,
`Gehan test
`Distribution of responders at Day 5.
`Log—rank test
`Distribution of responders at Day 5,
`Van Der Waerden test
`
`-
`97.5
`(51.81, 143.26)
`41001
`"
`<0.001
`<0.001
`(0001
`0-033
`0-002
`0.107
`
`111.9
`(66.49, 157.38)
`-
`<0-001
`—
`<0.001
`<0.001
`(1091
`0-007
`0.626
`
`_
`
`101.2
`(54.58, 147.89)
`41001
`“
`<0-001
`<0.00l
`0-003
`09-7-8
`0-003
`0.011
`
`<0.001
`
`0.005
`
`0.003
`
`0.070
`
`.
`
`0.016
`
`0.503
`
`.
`
`0-142
`0-535
`0—626
`Time to first rescue medication c‘f
`<0.001
`<0.001
`<0.001
`2-day 5pm (LOCI-)3
`<0.001
`<0.001
`<0.001
`10ml, 3pm (LOCI—if
`<0.001
`<0.001
`<0.001
`5-day TOTPAR (LOCF) a
`<0.001
`<0.001
`<0.001
`5-day SPRID (LQCF)3
`Patient Global Impression of Changeg 0°05 (0901 <0-001
`
`
`
`3 Based on analysis ofcovariance model with factors of treatment, pooled center, and baseline pain
`intensity as a covariate.
`P-values adjusted for multiplicity using Hochberg procedure.
`P—values for tapentadol groups are adjusted for multiplicity using Hochberg procedure. P-value for
`oxycodone group is not adjusted for multiplicity. ANCOVA model includes all treatment groups.
`For percent change NRS on Day 5 (observed case): ANCOVA model includes treatment, pooled
`center as factors and baseline pain score as a covariate. For discontinuation: Logistic regression
`model includes treatment as a factor and baseline pain score as a covariate.
`P-value based on Generalized Cochran-Mantel—I-Iaenszel test for general association controlling for
`pooled center.
`Log rank test stratified with pooled center.
`P-value based on Generalized Cochran-Mantel-I—Iaenszel test for row mean scores differ controlling
`for pooled center.
`Higher value in SPID indicates greater pain relief.
`Higher value in TOTPAR, SPRID indicates greater pain relief
`
`”9"a
`
`' EFFICACY CONCLUSIONS
`
`The applicant has submitted two adequate and well-controlled studies that showed that
`tapentadol, dosed at strengths of 50 to 100 mg every 4-6 hours, provided analgesia compared
`to placebo. The post-bunionectomy study is undoubtedly pertinent to the proposed indication.
`In conjunction with the six Phase 2 studies in other conventional acute and chronic pain
`
`Page 12 of 19
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`Cross Discipline Team Leader Review
`NBA 22-304, Tapentadol, immediate-release tables
`Robert B. Shibuya, M.D.
`populations and the study done in patients with GA, it is clear that tapentadol is an effective
`analgesic. “Reload” appeared to provide benefit to patients who experienced inadequate
`analgesia following the first dose of tapentadol.
`
`8. Safety
`
`This is a high-level summary of the detailed review conducted by Dr. Fields for this New
`Molecular Entity. This section focuses on adverse events that were observed in the nonclinical
`program and those predicted because of the structural'and pharmacological similarity of
`tapentadol to tramadol. Please see Dr. Fields’ review for details.
`
`The applicant submitted a safety database consisting of 3,515 subjects and patients who were
`dosed with one or more doses of tapentadol. The exposed populations have included healthy
`volunteers, post-operative orthopedic and dental pain, and chronic, non-malignant pain. The
`safety database size exceeds the ICH El recommendations for a NME.
`
`Table 4, following, summarizes the numbers of subjects and patients treated by duration of
`treatment.
`
`
`
`-
`
`, Phase 2/3
`
`
`
`
`
`
`
`
`
`
`
`
`
`Table 4: Duration of thera with ta-entadol, dacebo, and ox codone
`Placebo
`Duration of treatmen n %
`Taentadol
`2178
`619
`48122
`191 31
`586 27
`199 32
`228 37
`m_ 534 25
`123 6
`1 <1
`454 21
`
`
`Source: 188, 4 Month Safety Update, page 96 (reformatted) -
`
`Table 4 shows that the vast majority of the patients were treated for 10 days or less although
`there is a substantial proportion (21%) who were treated for more than 45 days.
`
`Dr. Fields reviewed each death, non-fatal serious adverse event, and adverse event leading to
`discontinuation in detail. While some of these events could be reasonably attributed to
`treatment with tapentadol such as ileus, lethargy, etc., none ofthe deaths, serious adverse
`events, or adverse events leading to discontinuation were unexpected for an opioid agonist
`used in an acute setting.
`
`With regard to the common AEs, generally, the safety profile is consistent of thatof an opioid
`agonist with the most common AEs being nausea, dizziness, vomiting, somnolence,
`constipation, and pruritis. The common adverse events are summarized in Table 5 from Dr.
`Fields’ review.
`'
`
`Page 13 of 19
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`

`Cross Discipline Team Leader Review
`NDA 22-304, Tapentadol, immediate-release tables
`Robert B. Shibuya, MD.
`
`Table 5: TEAEs in at least 3% of patients in the Phase 2/3 multiple—dose, double-blind data
`set
`
`System organ class
`Preferred term
`Total no. subjects With TEAEs
`
`Placebo
`“A11" 'l'apentadol IR
`“All” Oxycodone IR
`(n=6 19) '
`(n=21 78)
`(n=6 75)
`
`u (%)
`11(%)
`n (%)
`11(2)
`243(11)
`113(17)
`
`Nervous system disorders
`Dizziness
`Sonmolence
`Headache
`Lethargy
`
`Gastrolntestlnal disorders
`Nausea
`Vomiting
`Constipation]
`Diarrhoea
`Dry mouth
`Abdominal pain
`
`Psychiatric disorders
`Confusional state
`Insomnia
`Euphoric mood
`Depressive symptom
`Anxiety
`Hallucination, visual
`
`General disorders and
`administration site conditions
`Fatigue
`hritability
`Chest discomfort
`
`Skin and subcutaneous tissue
`disorders
`Pnnitus
`Hyperhidrosis
`Pnnirus generalised
`
`Musculoskeletal and connective
`tissue disorders
`Muscle spasms
`
`Respiratory, thoracic and
`mediastinal disorders
`' noea
`
`5(1)
`3(<l)
`1(<1)
`”<1)
`0
`
`5( 1)
`4( 1)
`1(<l)
`0
`0
`o
`o
`
`3(<1)
`0
`1(<1)
`0
`0
`0
`1(<l)
`
`1(<1)
`1(<l)
`0
`0
`
`0
`0
`O
`0
`
`l(<1)
`0
`
`0
`0
`
`105( 5)
`57( 3)
`28(1)
`19(1)
`7(<1)
`
`95( 4)
`51(2)
`30( 1)
`13( 1)
`10 ( <1)
`7 ( <1)
`4 (<1)
`
`48(2)
`10 (<1)
`8(<1)
`6 ( <1)
`5 ( <1)
`5(<l)
`4(<1)
`
`37(2)
`14(1)
`7 ( <1)
`4(<I)
`
`2S( 1)
`8 ( <1)
`5 ( <1)
`5 ( <1)
`
`12( 1)
`4(<1)
`
`8 ( <1)
`4 ( <1)
`
`53( 8)
`27( 4)
`15(2)
`8(1)
`0
`
`82(1).)
`46( 7)
`35(5)
`18( 3)
`0
`0
`3(<1)
`
`11(2)
`1 (<1)
`2(<l)
`1 (<1)
`0
`0
`2(<i)
`
`12(2)
`5(1)
`2 (<l)
`0
`
`17( 3)
`11 ( 2)
`5( I)
`1 (<1)
`
`2( <1)
`0
`
`0
`0
`
`Dr. Fields found that there appeared to be dose-response for the severity of adverse e