CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`200533Orig1s000
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`PHARMACOLOGY REVIEW(S)
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`Supervisory Pharmacologist Memorandum
`
`NDA NUMBER:
`SERIAL NUMBER:
`DATE RECEIVED BY CENTER:
`PRODUCT:
`
`(Proposed) Trade Name:
`
`Established Name:
`
`INDICATION:
`
`200-533
`000
`12/1/2009
`
`Nucynta ER
`Tapentadol extended release oral tablets
`
`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
`
`
`SPONSOR:
`REVIEW DIVISION:
`
`PHARM/TOX REVIEWER:
`PHARM/TOX SUPERVISOR:
`DIVISION DIRECTOR:
`PROJECT MANAGER:
`
`
`
`
`Ortho-McNeil-Janssen-Pharmaceuticals, Inc.
`Division of Anesthesia and Analgesia
`Products (HFD-170)
`Armaghan Emami, Ph.D.
`Adam Wasserman, Ph.D.
`Bob Rappaport, M.D.
`Dominic Chiapperino, Ph.D.
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`I.
`
`
`EXECUTIVE SUMMARY
`
`BACKGROUND
`Regulatory Summary (Pharmacology/Toxicology)
`A.
`The present NDA is an extended release (ER) version of Nucynta® (tapentadol),
`a product approved by the Agency in 2008 for treatment of moderate to severe
`acute pain. The intended target population for Nucynta ER is moderate to severe
`chronic pain in adults who need continuous opioid management of their pain.
`The approved immediate release (IR) tablet is supplied in 50, 75, and 100 mg
`strengths to be taken six times per day (seven on first day) while the ER tablet is
`formulated in 50, 100, 150, 200, and 250 mg strengths to be administered BID.
`Pharmacokinetic studies in humans indicate AUC systemic exposure is within the
`approved IR product though Cmax is approximately 30% higher, likely due to the
`greater strength of the ER tablet (250 mg vs. 100 mg).
`
`The Division agreed with the Applicant as part of the Pre-NDA meeting of
`January 23, 2009 that no additional nonclinical studies would be necessary and
`that cross-referencing the NDA 22-304 for the IR tablet for nonclinical support
`would be sufficient for the present application.
`
`The original nonclinical review of NDA 22-304 recommending approval was
`conducted by Dr. Kathleen Young and a concurring Supervisory memo, as well
`as several memo addenda, was written by me.
`
`MAJOR NONCLINICAL ISSUES IDENTIFIED IN PRIMARY REVIEW
`II.
`Dr. Emami has noted in her review that the Nucynta ER formulation and drug
`substance/drug product specifications are acceptable. Upon review of all prior
`materials, however, she has re-evaluated the nonclinical toxicology package
`submitted in support of the original N22-304 and finds the IR tablet as well as the
`ER tablet is not fully supported by the nonclinical data (see Dr. Emami’s table in
`her Executive Summary). The original primary review contained a calculation
`error as described in my Supervisory Memo Addendum #3 of November 2008.
`Dr. Emami notes the NOAELs in the chronic toxicology studies in both rat and
`dog do not support the clinical systemic exposure (measured as area under the
`curve, AUC0-24 hr) at the maximum recommended human dose (MRHD). The
`highest dose tested in the rat barely reached the MRHD exposure and the dog
`exposure was far below (0.15X) human. The type of toxicity observed in
`nonclinical studies was principally CNS-related (as will be detailed in the next
`section). This typically correlates better with plasma levels (i.e. Cmax or Css).
`Clinical Cmax was covered by the rat though in the dog Cmax values were below
`the human except for the highest dose tested (1.4X). The majority of the parent
`drug is directly glucuronidated, rendering it inactive in analgesic assays. This
`metabolite forms the major human metabolite which circulates at levels >40X
`higher than tapentadol based on Cmax and AUC. This pattern holds in nonclinical
`models as well, though metabolism is even more extensive. Although the
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`NOAEL dose in the dog study does not provide support for the exposure to the
`glucuronidated metabolite, the highest dose used does cover this exposure and I
`note the rat NOAEL is 1.6X the exposure at the MRHD. Dr. Emami further
`correctly calculates that the NOAELs in the reproductive toxicology program as
`well as carcinogenicity bioassays do not cover the human clinical exposure to
`tapentadol at the MRHD either.
`
`Nonclinical in vivo toxicology studies (general, reproductive, and carcinogenicity)
`were carried out at or in excess of the maximum tolerated doses. The principal
`target organ identified was the CNS, and effects were dose-limiting in all studies.
`Observations mostly fall under the category of “clinical signs” and included in the
`rat lateral recumbency, irregular respiration, straub tail, cyanosis, irritability,
`hyperactivity, tremor and convulsions. In dogs decreased activity, labored
`breathing, tachypnea, rhinorrhea, salivation, tremors, and convulsions were
`seen. Other possible target organs included the liver in the rat, though this
`appears to be more likely centrilobular hepatocellular hypertrophy as an adaptive
`upregulation of metabolism. In the dog cardiac effects including QTc
`prolongation was noted. These findings, including convulsions, are commonly
`seen with opioids and/or NE reuptake inhibitors in nonclinical studies.
`
`The Applicant previously noted focal gliosis and perivascular mononuclear cell
`infiltration in the pons and medulla of mid-dose and high-dose animals in the 12-
`month dog toxicology studies and both the study pathologist as well as the
`external reviewing pathologist believed these were incidental due to the low
`incidence, severity, lack of dose-relatedness. The Applicant also stated they
`additionally did not believe these were therefore related to convulsions as they
`did not occur in the same animals. As part of her review of NDA 22-304 Dr.
`Young agreed with the Applicant that these findings did not represent a
`treatment-related effect. I did not remark on these observations in my original
`concurring Supervisory memo or addenda. Dr. Emami has pointed this
`observation out for further evaluation. I note one mid-dose animal with
`perivascular infiltration and gliosis in the pons and medulla was also an animal
`with convulsion noted. Although it would be most useful to have historical control
`data from this laboratory to rule out a treatment-related effect, several aspects
`temper concern the most critical of which was that it was not clearly dose-related.
`Although not observed in control or low-dose animals, there were 3 animals (2
`males, one female) in MD while there was only 1 animal (female) in HD with
`these findings despite a significantly higher exposure in the HD group animals.
`Findings after 52-weeks of exposure were graded as minimal to slight in severity.
`Gliosis of the CNS is considered an age-related phenomenon in dogs (Shimanda
`et al., 1992) and while the dogs on the study are not considered aged, there is a
`continuum of development of this pathology over the lifetime with moderate to
`severe levels of gliosis achieved in elderly dogs. Against this argument is the
`recent understanding that various opioids can activate glia through enhancement
`of microglial migration through P2X4 (purinergic) receptor activation (Horvath and
`DeLeo 2009) as well as through a non-stereoselective activation of toll-like
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`receptor 4 (TLR4) which has been posited to underlie the development of
`tolerance, dependence, reward, and respiratory depression. Spinal activation of
`glia as measured by glial fibrillary acidic protein (GFAP) has been reported with
`short-term administration of morphine (Tawfik et al., 2005) An inflammatory
`response with gliosis has been described with chronic spinal morphine, which
`can be blocked by naltrexone (Mattioli et al., 2010) and a similar but widespread
`CNS activation of glia has been shown with morphine administered systemically
`over shorter time-scales as well (Song et al., 2001). A recent review summarizes
`the relationship between opioids, glia and pro-inflammatory response (Watkins et
`al., 2009). Though these argue that the findings described in the tapentadol
`study in dog could be treatment-related, it does not appear that this minimal
`response to maximal treatment presents an unusual risk relative to the mainstays
`of pain treatment.
`
`In regards to exposures in the reproductive and carcinogenicity studies not being
`supportive of the clinical exposure at the MRHD due to reaching the maximum
`tolerated dose, this is not ideal but we cannot ask more of the Applicant. I note
`that there was no evidence of teratogenicity in reproductive toxicology studies
`conducted even up to exposures that met or exceeded the human exposure. In
`regards to the carcinogenicity study the Applicant was operating under a SPA
`agreement with the Agency and the studies were appropriately accepted for
`review.
`
`Putting the animal data into a broader context we have by this time accumulated
`a fairly significant clinical database which has largely showed classic opioid-
`related safety issues. Dr. Emami notes that there have been some post-
`marketing reports of serious adverse events including seizure, serotonin
`syndrome, and death. These are currently being assessed along with all
`tapentadol-related AE reports as part of a post-marketing safety evaluation
`conducted by the Office of Surveillance and Epidemiology (FDAAA provision:
`Section 915). Although not completed, informal communication with OSE
`appears to indicate these reports are not at a higher rate than would be
`expected. It is also worth noting that the approved Nucynta (immediate release)
`label relays concerns of seizure and serotonin syndrome as part of the Warnings
`and Precautions section.
`
`
`III.
`
`RECOMMENDATIONS
`
`A. Recommendation on approvability
`Although I recognize Dr. Emami’s evaluation that the nonclinical data is
`not technically supportive of the systemic exposure at the Maximum
`Recommended Human Dose (MRHD) for the ER tablet, the toxicities
`observed are largely confined to the CNS and are common to opioid
`and/or NE reuptake inhibitors. Also reassuring, a significant body of
`clinical safety data is available which has not to this point revealed
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`unusual toxicity for this drug relative to its class. I also note the systemic
`exposures with the ER tablet are similar to the IR tablet, though the
`increased ER product Cmax (130% relative to IR tablet) may result in
`increased incidence of CNS adverse effects. Taken together, I believe the
`NDA for Nucynta ER tablets may be approved.
`
`B. Recommendation for nonclinical studies
`None.
`
`C. Recommendations on labeling
`I concur with Dr. Emami’s labeling recommendations. The approved
`immediate-release Nucynta label only needs updating with appropriate
`safety margins based on the slightly different exposures noted with the ER
`tablet.
`
`
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`
`
`References
`Horvath RJ, DeLeo JA. Morphine enhances microglial migration through
`modulation of P2X4 receptor signaling. J Neurosci 2009 29(4):998-1005.
`
`Mattioli TA, Milne B, Cahill CM. Ultra-low dose naltrexone attenuates chronic
`morphine-induced gliosis in rats. Mol Pain 2010 16(6) 22
`
`Shimada A, Kuwamura M, Awakura T, Umemura T, Itakura C. An
`immunohistochemical and ultrastructural study on age-related astrocytic gliosis in
`the central nervous system of dogs. J Vet Med Sci. 1992 Feb;54(1):29-36.
`
`Song P, Zhao ZQ. The involvement of glial cells in the development of morphine
`tolerance. Neurosci Res. 2001 Mar;39(3):281-6.
`
`Tawfik VL, LaCroix-Fralish ML, Nutile-McMenemy N, Deleo JA. Transcriptional
`and translational regulation of glial activation by morphine in a rodent model of
`neuropathic pain JPharmacol Exp Ther 2005 313(3):1239-1247.
`
`Watkins LR, Hutchinson MR, Rice KC, Maier SF. The “Toll” of Opioid-Induced
`Glial Activation: Improving the clinical Efficacy of Opioids by Targeting Glia.
`Trends in Pharmacological Sciences 2009 30(11):581-591.
`
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`Application
`Type/Number
`--------------------
`NDA-200533
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`ORTHO MCNEIL
`JANSSEN
`PHARMACEUTICA
`LS INC
`
`------------------------------------------
`TAPENTADOL
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ADAM M WASSERMAN
`08/09/2010
`
`

`

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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`Indication:
`Applicant:
`
`200533
`000
`November 30, 2009
`December 1, 2009
`Nucynta (Tapentadol) ER Tablets
`Management of moderate to severe chronic pain
`Johnson & Johnson Pharmaceutical Research &
`Development, L.L.C. (J&JPRD)
`Division of Anesthesia and Analgesia Products
`Review Division:
`Armaghan Emami, Ph.D.
`Reviewer:
`Adam Wasserman, Ph.D.
`Supervisor/Team Leader:
`Bob Rappaport, M.D.
`Division Director:
`Dominic Chiapperino, Ph.D.
`Project Manager:
`Template Version: December 7, 2009
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 200-533 are owned by J&JPRD or are data for which
`J&JPRD has obtained a written right of reference.
`Any information or data necessary for approval of NDA 200-533 that J&JPRD does not
`own or have a written right to reference constitutes one of the following: (1) published
`literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug, as
`described in the drug’s approved labeling. Any data or information described or
`referenced below from a previously approved application that J&JPRD does not own (or
`from FDA reviews or summaries of a previously approved application) is for descriptive
`purposes only and is not relied upon for approval of NDA 200-533.
`
`1
`
`

`

`NDA # 200533 Reviewer: Armaghan Emami, PhD
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 3
`1.1 RECOMMENDATIONS............................................................................................ 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 5
`2 DRUG INFORMATION ............................................................................................ 8
`
`3 STUDIES SUBMITTED.......................................................................................... 12
`
`4 PHARMACOLOGY................................................................................................ 14
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 14
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 14
`SAFETY PHARMACOLOGY................................................................................... 14
`4.3
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 15
`
`6 GENERAL TOXICOLOGY..................................................................................... 16
`
`7 GENETIC TOXICOLOGY ...................................................................................... 20
`
`8 CARCINOGENICITY ............................................................................................. 20
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 20
`
`SPECIAL TOXICOLOGY STUDIES................................................................... 20
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 21
`
`APPENDIX/ATTACHMENTS............................................................................. 21
`
`10
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`11
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`12
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`2
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`NDA # 200533 Reviewer: Armaghan Emami, PhD
`
`1
`
`Executive Summary
`
`1.1 Recommendations
`1.1.1 Approvability: The information contained in the cross-referenced NDA 22-304
`submission (Tapentadol IR) indicates that the non-clinical studies of tapentadol, relied
`upon for this application, are not sufficient to support the maximum human exposure to
`tapentadol in Tapentadol Extended-Release (ER) for the clinical indication as proposed
`under NDA 200533.
`Therefore based solely on the pharmacology and toxicology data provided Tapentadol
`ER should not be approved under NDA 200533.
`
`1.1.2 Additional Non Clinical Recommendations: Due to intolerance of using higher
`doses in non-clinical studies, additional non clinical studies will not be informative.
`
`1.1.3 Labeling
`8.1 Pregnancy
`Pregnancy Category C.
`Tapentadol HCl was evaluated for teratogenic effects in pregnant rats and rabbits
`following intravenous and subcutaneous exposure during the period of embryofetal
`organogenesis. When tapentadol was administered twice daily by the subcutaneous
`route in rats at dose levels of 10, 20, or 40 mg/kg/day [producing up to 1.36 times the
`plasma exposure at the maximum recommended human dose (MRHD) of 500 mg/day
`for NUCYNTA™ ER based on an area under the time-curve (AUC) comparison], no
`teratogenic effects were observed. Evidence of embryofetal toxicity included transient
`delays in skeletal maturation (i.e., reduced ossification) at the 40 mg/kg/day dose which
`was associated with significant maternal toxicity. Administration of tapentadol HCl in
`rabbits at doses of 4, 10, or 24 mg/kg/day by subcutaneous injection [producing 0.3,
`0.8, and 2.5
` times the plasma exposure at the MRHD based on an AUC
`comparison] revealed embryofetal toxicity at doses ≥10 mg/kg/day. Findings included
`reduced fetal viability, skeletal delays and other variations. In addition, there were
`multiple malformations including gastroschisis/thoracogastroschisis, amelia/phocomelia,
`and cleft palate at doses ≥10 mg/kg/day and above, and ablepharia, encephalopathy,
`and spina bifida at the high dose of 24 mg/kg/day. Embryofetal toxicity, including
`malformations, may be secondary to the significant maternal toxicity observed in the
`study.
`In a study of pre- and postnatal development in rats, oral administration of tapentadol at
`doses of 20, 50, 150, or 300 mg/kg/day to pregnant and lactating rats during the late
`gestation and early postnatal period [resulting in up to 2.28 times the plasma exposure
`at the MRHD on an AUC basis] did not influence physical or reflex development, the
`outcome of neurobehavioral tests or reproductive parameters. Treatment-related
`developmental delay was observed, including incomplete ossification, and significant
`reductions in pup body weights and body weight gains at doses associated with
`maternal toxicity (150 mg/kg/day and above). At maternal tapentadol doses ≥150
`mg/kg/day, a dose-related increase in pup mortality was observed to postnatal Day 4.
`
`3
`
`(b) (4)
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`

`

`NDA # 200533 Reviewer: Armaghan Emami, PhD
`
`
`
`There are no adequate and well controlled studies of NUCYNTA™ ER in pregnant
`women. NUCYNTA™ ER should be used during pregnancy only if the potential benefit
`justifies the potential risk to the fetus.
`
`8.2 Labor and Delivery
`The effect of tapentadol on labor and delivery in humans is unknown. NUCYNTA™ ER
`is not recommended for use in women during and immediately prior to labor and
`delivery. Due to the mu-opioid receptor agonist activity of NUCYNTA™ ER, neonates
`whose mothers have been taking NUCYNTA™ ER should be monitored for respiratory
`depression. A specific opioid antagonist, such as naloxone, should be available for
`reversal of opioid induced respiratory depression in the neonate.
`
`8.3 Nursing Mothers
`There is insufficient/limited information on the excretion of tapentadol in human or
`animal breast milk. Physicochemical and available pharmacodynamic/toxicological data
`on tapentadol point to excretion in breast milk and risk to the suckling child cannot be
`excluded. NUCYNTA™ ER should not be used during breast-feeding.
`
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`Carcinogenesis
`Tapentadol was administered to rats (diet) and mice (oral gavage)
` for two years.
`In mice, tapentadol HCl was administered by oral gavage at dosages of 50, 100 and
`200 mg/kg/day for 2 years (up to
` 0.34 times in the male mice and 0.25 times
`in the female mice the plasma exposure at the maximum recommended human dose
`[MRHD] on an area under the time-curve [AUC] basis). No increase in tumor incidence
`was observed at any dose level.
`In rats, tapentadol HCl was administered in diet at dosages of 10, 50, 125 and 250
`mg/kg/day for two years (up to 0.20 times in the male rats and 0.75 times in the female
`rats the MRHD on an AUC basis). No increase in tumor incidence was observed at any
`dose level.
`
`Mutagenesis
`Tapentadol did not induce gene mutations in bacteria, but was clastogenic with
`metabolic activation in a chromosomal aberration test in V79 cells. The test was
`repeated and was negative in the presence and absence of metabolic activation. The
`one positive result for tapentadol was not confirmed in vivo in rats, using the two
`endpoints of chromosomal aberration and unscheduled DNA synthesis, when tested up
`to the maximum tolerated dose.
`
`Impairment of Fertility
`Tapentadol HCl was administered intravenously to male or female rats at dosages of 3,
`6, or 12 mg/kg/day (representing exposures of up to approximately 0.56 times in the
`male rats and 0.50 times in the female rats the exposure at the MRHD on an AUC
`basis, based on extrapolation from toxicokinetic analyses in a separate 4-week
`intravenous study in rats). Tapentadol did not alter fertility at any dose level. Maternal
`
`
`
`4
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA # 200533 Reviewer: Armaghan Emami, PhD
`
`toxicity and adverse effects on embryonic development, including decreased number of
`implantations, decreased numbers of live conceptuses, and increased pre- and post-
`implantation losses occurred at dosages ≥6 mg/kg/day.
`
`13.2 Animal Toxicology and/or Pharmacology
`In toxicological studies with tapentadol, the most common systemic effects of tapentadol
`were related to the mu-opioid receptor agonist and norepinephrine reuptake inhibition
`pharmacodynamic properties of the compound. Transient, dose-dependent and
`predominantly CNS-related findings were observed, including impaired respiratory
`function and convulsions, the latter occurring in the dog at plasma levels (Cmax), which
`are in the range associated with the maximum recommended human dose (MRHD).
`
`1.2 Brief Discussion of Nonclinical Findings
`Nucynta® (Tapentadol) is an analgesic compound that is being developed in an
`Extended-Release (ER) tablet formulation for the management of moderate to severe
`chronic pain in patients 18 years of age or older. Tapentadol pharmacology suggests a
`dual mechanism of action, involving both mu-opioid agonism and norepinephrine
`reuptake inhibition. Tapentadol is a centrally active stereoisomer; no metabolites with
`analgesic activity are known.
`A tapentadol immediate release (IR) tablet formulation received FDA approval for the
`relief of moderate to severe acute pain in patients 18 years of age or older (NDA 22-
`304, approved 20 November 2008). The Sponsor (J&JPRD on behalf of Ortho-McNeil-
`Janssen-Pharmaceuticals, Inc.) is cross-referencing to the IND 61,345, 105,766 and
`NDA 22-304 for nonclinical support of the safety of Tapentadol ER formulation. No new
`nonclinical studies for tapentadol were submitted with this NDA.
`Tapentadol IR is administered up to 100 mg 6 times per day (700 mg on the first day
`and 600 mg/day thereafter) while the proposed ER formulation is up to 250 mg twice a
`day. While ER AUC0-24 is approximately 40% lower than IR AUC0-24, the ER Cmax is
`approximately 30% greater than the IR Cmax at the MHRD.
`Tapentadol has been evaluated in a comprehensive preclinical program including
`pharmacological characterization, preclinical safety (safety pharmacology and
`toxicology), pharmacokinetics, and ADME. Non-clinical studies were reviewed by Dr.
`Kathy Young under NDA 22-304.
`The major toxicity findings of tapentadol were consistent with its mu-opioid receptor
`agonist activity (ie, effects on the gastrointestinal, central nervous, respiratory, and
`cardiovascular systems). At high doses of tapentadol, transient, dose dependent and
`predominantly CNS-related findings, e.g. fearfulness, sedation or excited behavior,
`recumbency and hunched posture, impaired respiratory function, rarely convulsions,
`were observed. In dogs, salivation, vomiting and retching were additionally observed.
`Tapentadol was shown to have pro-convulsant activity in rats, and induced convulsions
`in rats, mice, and dogs at high doses. The tapentadol-O-glucuronide metabolite may
`contribute to this effect. Changes of the liver and cardiovascular system (e.g. QT
`prolongation) were seen in rats and dogs respectively. Of note, toxicities observed in
`
`5
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`

`

`NDA # 200533
`
`Reviewer: Armaghan Emami, PhD
`
`non-clinical (rats and dogs) studies were associated with exposure levels that do not
`support human exposures.
`
`Overall, this reviewer believes that the non-clinical studies of Tapentadol are not
`sufficient to support the maximum human exposure to tapentadol in either the
`Tapentadol ER or IR product. In addition to the lack of supportive NOAEL exposures,
`the highest dose used in the chronic toxicology study in the dog was unable to reach the
`human exposure associated with the MRHD for the ER product, and neither chronic
`toxicology study reached AUC levels that support the MRHD exposure for the IR
`product. See the safety margin tables below for IR and ER formulations. The Safety
`margins for tapentadol IR are revised to utilize AUC 024 hr.
`
`SM for ta . entadol IR
`
`Dose
`("'9’
`kgld)
`
`HED
`("'9’
`kgld)‘
`
`Cmax
`
`(ngImL)
`
`AUC 024
`(ng.hrlmL)
`
`Human SM
`Based on Cmax
`
`Human SM
`Based on AUC
`
`Human
`IR
`MRHD
`
`100 mg]
`6 times a
`da
`
`paren
`t
`
`etabolit
`03
`
`parent metabolite
`
`parent metabolite
`
`parent
`
`metabolit
`
`~101
`c
`
`~4206
`
`aw652 ~120000
`c
`
`~
`C-
`
`28091 0.—‘Nco><><
`
`----
`
`wk
`
`NOAEL
`
`386
`479
`N
`_- 1181
`my 52 Iwk
`
`NOAEL [E- 5.5
`_\ O) N
`_- -
`_|§E-
`
`183
`
`~24227
`~3o419
`
`624
`1260
`
`~156905
`~2950 5
`
`3.8X
`4.7x
`
`5.8x
`7.2x
`
`~45066
`
`2537
`
`~491457
`
`11.7X 10.7X
`
`7563
`
`26003
`47424
`
`20
`
`355
`
`86308
`227917
`
`1.8X
`
`11.3x
`
`HED: Human Equivalent Dose (Assume 60 kg human) Approximate Cmax and AUC values (of
`metabolite) are from 13 weeks rat toxicity study. 0 This is a rough estimate across different studies (see
`appendix 3) ‘0 Based on Dr. David Lee‘s calculation (see Appendix 3)
`
`

`

`NDA # 200533
`
`Reviewer: Armaghan Emami, PhD
`
`SM for ta . entadol ER
`
`AUC (L24
`(ng.hr/mL)
`
`Human SM
`Based on Cmax
`
`Human SM
`Based on AUC
`
`metabolite
`
`metabolite
`
`rent metabolit
`
`B
`
`2288 C
`
`96492 C
`
`(1144x2)
`
`(48246x2)
`
`_lEfil- ~30419
`_-IIEII ~4soss
`
`1260
`2537
`
`”56905
`
`~295075
`~4914s7
`
`42X
`
`5.3x
`7.9x
`
`°°9
`
`wk
`
`5" ------
`
`NOAEL m- 7563
`_-IIE- 26003
`_EE-- 47424
`
`28091 MEI—WEE:-
`86308 EEK—mm
`227917 -__EIEZI
`
`HED: Human Equivalent Dose (Assume 60 kg human) Approximate Cmax and AUC values (of
`metabolite) are from 13-week rat toxicity study. c) See Appendix 2
`
`SM for tapentadol ER for reproductive and carcinogenicity studies (NOAELs taken
`from Dr. Kathleen Youn ’5 review of NBA 22-304
`
`Study
`
`Dose
`mglkgld
`
`NOAEL
`mglkgld
`
`AUC 0.24
`ng.hlmL
`
`Segment ||
`SC
`
`10,20,40
`
`Maternal
`toxicity: 10
`E b
`ftal
`m eryo e
`toxicity: 20
`
`814 (407x2)
`
`1764 (88m)
`
`Human SM
`based on
`AUC
`
`0 3X
`‘
`
`Rat
`
`Segment |l|
`
`(300 mglkgld)
`F0: 2546
`For 50,150,300
`
`(1273X 2)
`
`F1: 25,50,100
`
`F1: 263-513
`
`0.1X—0.2X
`
`Rat
`(TP2834)
`
`Segment |||
`gavage
`
`20.50.150.300
`
`Maternal
`toxici
`:50
`
`152°
`
`F1: 300 —_
`
`U1(.0(D
`pup develo . ment: 20
`
`
`
`. ava . e
`
`200
`
`458 (M)
`Carci
`Rat
`
`Dietary
`1705 (F)
`1o, 50, 125, 250
`250
`0.2x—o.7x
`
`

`

`NDA # 200533 Reviewer: Armaghan Emami, PhD
`
`Note:
`1. The systemic exposures (AUC) to the parent drug for almost all doses including
`the NOAEL in 26-week rats and 52-week dog repeat dose studies are below the
`clinical exposure associated with the MRHD for both IR and ER formulations.
`2. The peak plasma tapentadol concentration (Cmax) at LD and MD taken from the
`52-week dog study are below the clinical exposure associated with the MRHD for
`both IR and ER formulations, though the Cmax from the high dose (HD) in the 52-
`week dog study and from the 26-week rat study (all doses) represent greater
`than 1-fold the Cmax at the MRHD for both IR and ER formulation. Convulsions
`were seen in 2/8 HD dogs and the Cmax exposure margin associated with this
`dose level for the ER and IR formulation is 1.8 and 1.4 times greater than the
`clinical Cmax at the MRHD.
`3. The systemic exposures (AUC) to the metabolite at LD and MD in the 52-week
`dog study are below the clinical exposure associated with the MRHD for both IR
`and ER formulations.
`4. The systemic exposures (AUC) to the parent drug for the NOAEL taken from
`reproductive and carcinogenicity studies are below the clinical exposure
`associated with the MRHD.
`It is noted that significant CNS findings (hallucination, convulsion and serotonin
`syndrome) have been reported in postmarketing experience with Tapentadol IR
`(Nucynta®) tablets and are being evaluated by the Office of Surveillance and
`Epidemiology. Also a similar drug, Tramadol (with mu-opioid and NET inhibitory
`activities) showed seizures in post-marketing reporting and is described in the label.
`Notably, both Seizures and Serotonin Syndrome Risk are described in the approved
`Nucynta label.
`
` 2
`
`Drug Information
`
`2.1 Drug:
`Nucynta®
`2.1.1 CAS Registry Number (Optional)
`175591-09-0
`2.1.2 Generic Name
`Tapentadol HCL
`2.1.3 Code Name
`CG5503 and R331333
`2.1.4 Chemical Name
`3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2-methylpropyl]phenol
`
`8
`
`

`

`NDA # 200533 Reviewer: Armaghan Emami, PhD
`
`2.1.5 Molecular Formula/Molecular Weight
`C14H23NO.HCl / 257.80
`2.1.6 Structure
`
`
`2.1.7 Pharmacologic class
`Mu-Opioid receptor (MOR) agonist/norepinephrine (NE) re-uptake inhibitor
`
`2.2 Relevant IND/s, NDA/s, and DMF/s
`
`Submission Status/date Sponsor
`IND
`Active/
`J&JPRD
` 61,345
`12/04/2000
`
`Drug
`Tapentadol IR
`tablets
`
`IND
`105,766
`
`Active/
`7/19/2009
`
`J&JPRD
`
`
`
`Tapentadol ER
`tablets
`
`Indication
`Moderate to
`severe acute
`pain
`Chronic diabetic
`peripheral
`neuropathy
`
`Division
`DAAP
`
`DAAP
`
`NDA
`22-304
`
`approved
`11/20/2008
`
`This NDA
`200-533
`
`Under
`Review
`12/01/2009
`
`Ortho-
`McNeil-
`Janssen
`Ortho-
`McNeil-
`Janssen
`
`Tapentadol IR
`tablets (50, 75
`and 100 mg)
`Tapentadol ER
`tablets (50, 100,
`150, 200 and 250
`mg)
`
`Moderate to
`severe acute
`pain
`Moderate to
`severe chronic
`pain
`
`DAAP
`
`DAAP
`
`2.3 Clinical Formulation
`
`Tapentadol Tamper Resistant Extended-Release tablets in strengths of 50, 100, 150,
`200, and 250 mg (free base)
`2.3.1 Drug Formulation
`The compositional formulation of the Tamper Resistant Extended-Release tablets, 50-,
`100-, 150-, 200-, and 250-mg proposed for commercial manufacture are presented in
`Table 1 and Table 2 by the Sponsor.
`
`9
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA # 200533
`
`Reviewer: Armaghan Emami, PhD
`
`Cottponent
`
`Table I:
`
`T
`
`
`sition - Cort:
`ntadol Extended-Release Tablets Co
`
`Quality
`Dose Strength (Free Base of Tapentadol)
`Reference
`Function
`
`
` Tapcntadol HCI Non-
`Active
`
`
`(11331333)
`compendial
`'-
`-
`-_
`'
`;
`Polyethylene
`NF
`
`Oxide
`
`Hiromellose
`
`USP
`
`
`
`Polycth lene
`NF
`
`Gliol
`Vitamin E
`USP
`
`Polycth lene NF
`
`Glycol
`
`Total Core Tablet Weight
`
`
`
`-- = Not applicable
`
`Table 2:
`
`T:
`
`ntadol Extended-Release Tablets Co
`