CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`
`203794Orig1s000
`
`PHARMACOLOGY REVIEW(S)
`
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`

`

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`
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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:
`Review Division:
`
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`203-794
`001
`December 15, 2011
`December 15, 2011
`Tapentadol (Nucynta®) oral solution
`Moderate to severe acute pain in patients 18
`years of age or older
`
`Janssen Pharmaceuticals, Inc.
`Division of Anesthesia, Analgesia and Addiction
`Products
`
`Armaghan Emami, Ph.D.
`Adam Wasserman, Ph.D.
`Bob Rappaport, M.D.
`Dominic Chiapperino
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203-794 are owned by Janssen Pharmaceuticals, Inc. or
`are data for which Janssen Pharmaceuticals, Inc. has obtained a written right of
`reference. Any information or data necessary for approval of NDA 203-794 that Janssen
`Pharmaceuticals, Inc. 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 reflected in the drug’s approved labeling. Any data or
`information described or referenced below from reviews or publicly available summaries
`of a previously approved application is for descriptive purposes only and is not relied
`upon for approval of NDA 203-794.
`
`Reference ID: 3174624
`
`1
`
`

`

`NDA # 203-794, Nucynta oral solution
`
`
`
`
`Reviewer: Armaghan Emami, PhD
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 3
`1.1
`INTRODUCTION.................................................................................................... 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`1.3 RECOMMENDATIONS............................................................................................ 4
`2 DRUG INFORMATION ............................................................................................ 4
`2.1 DRUG................................................................................................................. 4
`2.2 RELEVANT INDS, NDAS, AND DMFS .................................................................... 5
`2.3 DRUG FORMULATION ........................................................................................... 5
`2.4 COMMENTS ON NOVEL EXCIPIENTS....................................................................... 6
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 6
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 7
`2.7 REGULATORY BACKGROUND ................................................................................ 7
`3 STUDIES SUBMITTED............................................................................................ 7
`
`4 PHARMACOLOGY.................................................................................................. 8
`
`5 PHARMACOKINETICS/ADME/TOXICOKINETICS ................................................ 8
`
`6 GENERAL TOXICOLOGY....................................................................................... 8
`
`7 GENETIC TOXICOLOGY ........................................................................................ 8
`
`8 CARCINOGENICITY ............................................................................................... 8
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY .................................. 8
`
`SPECIAL TOXICOLOGY STUDIES..................................................................... 8
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................... 8
`
`10
`
`11
`
`
`Reference ID: 3174624
`
`2
`
`

`

`NDA # 203-794, Nucynta oral solution
`
`
`
`
`Reviewer: Armaghan Emami, PhD
`
`1
`
`Executive Summary
`
`1.1
`
`Introduction
`
`Janssen Research & Development, LLC (JRD) is submitting a New Drug Application for
`Nucynta® (tapentadol) oral solution. The indication for this NDA is for the management
`of moderate to severe acute pain in patients age 18 or older, as in the approved NDA
`022-304 (November 2008) for Nucynta immediate-release tablets. Also, a tapentadol
`extend release tablet formulation received FDA approval for the management of
`moderate to severe chronic pain (NDA 200-533, approved 25 August 2011).
`
`This application cross-references NDA 022-304 for clinical, nonclinical toxicology and
`pharmacology information. No nonclinical or clinical studies are provided with this
`application. A biowaiver for clinical studies was granted by the FDA on 29 June 2011.
`This NDA only consists of CMC data to support Nucynta oral solution, labeling and
`packaging components.
`
`1.2 Brief Discussion of Nonclinical Findings
`
`Tapentadol is an opioid agent with a dual mode of analgesic action, the inhibition of
`norepinephrine combined with moderate opioid agonist activity. Tapentadol has been
`evaluated in a comprehensive preclinical program including pharmacological
`characterization, preclinical safety (safety pharmacology and toxicology),
`pharmacokinetics, and ADME. Nonclinical studies were reviewed by Dr. Kathy Young
`under NDA 022-304.
`
`The major toxicity findings of tapentadol were consistent with its mu-opioid receptor
`agonist activity (i.e., effects on 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 and rarely convulsions
`were observed in nonclinical models. 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 (increases of
`liver enzymes and liver weights, and histopathology findings of hepatocellular
`hypertrophy), and cardiovascular system (e.g. QT prolongation) were seen in rats and
`dogs respectively. Of note, toxicities observed in nonclinical (rats and dogs) studies
`were associated with exposure levels below human exposures at maximum
`recommended human dose (MRHD).
`
`It is noted that significant CNS findings (hallucination, convulsion and serotonin
`syndrome) have been reported in postmarketing experience with Nucynta IR tablets.
`Both seizures and serotonin syndrome risk are described in the approved Nucynta
`label.
`
`Reference ID: 3174624
`
`3
`
`

`

`
`
`Reviewer: Armaghan Emami, PhD
`
`NDA # 203-794, Nucynta oral solution
`
`There are no novel excipients in the proposed drug product formulation. The excipients
`are within the limits allowed in previously approved product as listed in the FDA’s
`Inactive Ingredient Database (IIG) except for the artificial raspberry flavor that has not
`been used in any approved drug product. However, based on CMC review of DMF
`(30-Jan-2012) by Dr. Craig Bertha, all of the components of this flavor are GRAS and
`can be added to foods. The total daily intake of all inactive ingredients together would
`be 10 mg at most and does not represent an issue of toxicologic concern. Moreover,
`drug substance and drug product specifications for impurities/degradants are below the
`ICH Q3A & Q3B levels for qualification.
`1.3 Recommendations
`1.3.1 Approvability: From the nonclinical pharmacology toxicology perspective, this
`NDA may be approved. The indication, patient population and dosage of Nucynta oral
`solution are the same as approved IR product and the formulation is acceptable.
`
`1.3.2 Additional Non Clinical Recommendations: None
`
`
`
`1.3.3 Labeling: Dosage is the same as approved IR product; therefore no changes to
`the nonclinical sections of the label are recommended.
`
`2 Drug Information
`
`2.1 Drug
`
`CAS Registry Number: 175591-09-0
`
`Generic Name: Tapentadol
`
`Chemical Name:
`
`3-[(1R,2R)-3-(dimethylamino)-1-ethyl-2- methylpropyl]phenol monohydrochloride
`Molecular Formula: C14H23NO·HCl
`Molecular Weight: 257.81 g/mol; Free base: 221.35 g/mol
`
`Structure or Biochemical Description:
`
`
`
`4
`
`Reference ID: 3174624
`
`(b) (4)
`
`

`

`NDA # 203-794, Nucynta oral solution
`
`Reviewer: Armaghan Emami, PhD
`
`Pharmacologic Class: mu-opioid receptor agonist and NE reuptake inhibitor
`
`2.2 Relevant INDs, NDAs, and DMFs
`
`W Status/date WERE—WW
`IND
`Active/
`JRD
`Tapentadol IR
`61 ,345
`12/04/2000
`
`severe acute
`
`tablets Moderate to
`
`IND
`1 05,766
`
`Active/
`7/19/2009
`
`oain
`
`Tapentadol ER
`tablets
`
`Chronic diabetic DAAAP
`peripheral
`neuro ath
`
`IND
`
`Active/
`
`1 08,134
`
`3/22/201 1
`
`Tapentadol OS
`
`Pediatric acute
`
`DAAAP
`
`pain
`
`(5)“)
`
`NDA
`22-304
`
`approved
`1 1/20/2008
`
`Ortho-
`McNeil—
`Janssen
`
`Tapentadol IR
`tablets (50, 75
`and 100 m
`
`Moderate to
`
`DAAAP
`
`severe acute
`
`o ain
`
`NDA
`
`200-533
`
`approved
`8/25/201 1
`
`pain
`
`Ortho-
`
`McNeil-
`
`Janssen
`
`Tapentadol ER
`tablets (50, 100,
`150, 200 and
`
`Moderate to
`
`severe chronic
`
`2.3 Drug Formulation
`
`The drug product is an aqueous solution of tapentadol HCI. The drug product packages
`of 100 and 200 mL of formulation have a concentration of 20 mg/mL.
`
`Composition of Tapentadol ZO-mg/mL Oral Solution
`C ponent
`Quality Standard3
`Function
`
`Quantity
`(mg/ml)
`
`Tapentadol HCl
`Citric acid monohydrate
`Sucralose
`
`Comp any specification
`USP/P11. Em.
`NF/‘Ph. Eur.
`
`Raspberry flavor
`
`Comp any specification
`
`Sodium hydroxide
`
`NF/‘Ph. Eur.
`
`Purified water
`
`USP/Pb. Eur.
`
`Active ingredient
`
`23.3
`
`"’""
`
`1 “There multiple compendia are listed. the compendium applied during testing is specific
`to the applicable region for commercial distribution.
`
`Reference
`
`ID: 3174624
`
`

`

`NDA # 203-794, Nucynta oral solution
`
`Reviewer: Armaghan Emami, PhD
`
`2.4 Comments on Novel Excipients
`
`All the excipients are within the "6 levels established for oral administration, except for
`artificial raspberry flavor. However, according to Dr. Craig Bertha (CMC reviewer), the
`level of this raspberry flavor is acceptable since all of the components of the flavor are
`GRAS and can be added to foods (see Dr. Bertha’s review, DMF M", 30-Jan-2012).
`
`2.5 Comments on Impurities/Degradants of Concern
`
`o The maximum dose according to the proposed labeling is 600 mg of tapentadol
`daily, thus the qualification thresholds for degradants in the drug substance and the
`drug product are
`"m respectively. Thus the current limits of NMT
`“m for any individual impurity in the drug substance and NMT
`9‘" for any
`unspecified individual degradant in the drug product are acceptable.
`
`Copied from the NDA submission
`
`SEificat'nns for Drug Substance
`Test Methods
`Test Parameter
`Acfl Criteria
`1. Appearance
`W'Irilc lu off-while powder Visual examination
`2.
`Identification ofR331333I
`3. HPLC
`
`Similar retention time for
`
`AD-TM-R331333-DS-HPLC-04
`
`b.
`
`Infrared Absorption
`
`sample and reference
`mhrtion peak
`
`Exhibits absorption bands
`at the samewavelengths as
`those of a similar
`
`preparation ofthe
`tapentadol hydrochloride
`standard
`
`Current USP“ 197“
`
`1:. Chloride
`
`3. Assay of R331333
`ll . Chromatographic Flu-it}.F (HPLC)
`a. Any individual rmprnity
`b. Total'
`“d6
`
`5. Enantiomeric Purity (Chiral
`NW {3'
`6. WaterContent
`
`7. Heavy Metals'
`8 Residue on Ignition‘
`9 Residual Solvents:I
`
`Couplies
`
`98.040105;
`
`Not morethan
`Notmor'ethan
`
`Not less than
`
`Not more tlar
`
`Not more liar
`Not more thar
`
`Cmrent USP " 191‘
`
`AD-‘IM-R331333-DS-HPLC-04
`
`"9‘
`(5K
`
`AD-‘lM-R331333-DS-HPLC-04
`AD-TM—R331333-DSHPLC-04
`
`AD-TM-R331333-DS—HPLC—02
`
`Current USP < 921" '> Method I
`
`Current USP 231‘- - Method 11
`Crnrent USP -- 281 '
`
`(5X4)
`
`‘ This test is conducted for release only.
`
`Reference ID: 31 74624
`
`

`

`NDA # 203-794, Nucynta oral solution
`
`Reviewer: Armaghan Emami, PhD
`
`Copied from the NDA submission
`
`Specifications for Tanentadol Oral Solution. 20-m2“mL
`
`00(4)
`
`0 This formulation is aqueous based for oral administration and does not contain
`co-solvents, and the drug is for treatment of acute pain therefore no additional
`extractable/Ieachable information would be necessary (Guidance for Industry:
`Container Closure Systems for Packaging Human Drugs and Biologics, Chemistry,
`Manufacturing, and Controls Documentation, May 1999).
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`The drug product is to be indicated for the relief of moderate to severe acute pain in
`patients 18 years of age or older, as in the approved IR drug product. The drug product
`formulation has a concentration of 20 mg/mL corresponding to the labeled doses of 50-
`100 mg to be taken every 4-6 hours. Daily doses of more than 700 mg the first day and
`more than 600 mg on subsequent days are not recommended by the applicant in the
`label.
`
`2.7 Regulatory Background
`
`This 505 (b1) application cross-referenced NDA 022-304 for clinical, nonclinical and
`pharmacology information.
`
`3
`
`Studies Submitted
`
`This NDA only consists of CMC data to support Nucynta oral solution, labeling and
`packaging components.
`
`Reference ID: 3174624
`
`

`

`NDA # 203-794, Nucynta oral solution
`
`
`
`
`Reviewer: Armaghan Emami, PhD
`
`Pharmacology
`
` 4
`
`
`N/A
`5
`N/A
`6 General Toxicology
`N/A
`7 Genetic Toxicology
`N/A
`8 Carcinogenicity
`N/A
`9 Reproductive and Developmental Toxicology
`N/A
`10 Special Toxicology Studies
`N/A
`
`Integrated Summary and Safety Evaluation
`11
`JRD is submitting a 505 (b1) application for Nucynta® (tapentadol) oral solution. The
`indication for this NDA is for the management of moderate to severe acute pain in
`patients age 18 or older, as in the approved NDA 022-304 (Nucynta IR tablets). JRD
`cross-referenced NDA 022-304 for clinical, nonclinical toxicology and pharmacology
`information. No nonclinical or clinical studies are provided with this application. This
`NDA consists of CMC information to support Nucynta oral solution, labeling and
`packaging components.
`The indication, patient population and dosage of Nucynta oral solution are the same as
`approved IR product. Moreover, there is no concern about excipients and
`impurities/degradants in the drug product, therefore from the nonclinical perspective,
`this NDA may be approved.
`
`
`Pharmacokinetics/ADME/Toxicokinetics
`
`Reference ID: 3174624
`
`8
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ARMAGHAN EMAMI
`08/15/2012
`
`ADAM M WASSERMAN
`08/15/2012
`I concur the NDA may be approved from the nonclinical perspective.
`
`Reference ID: 3174624
`
`

`

`PHARMACOLOGY/TOXICOLOGY NDA FILEABILITY CHECKLIST
`
`__
`NDA N“mb°" 20“”
`
`Applicant: Janssen Research & Stamp Date: December 15,
`Development, LLC
`
`201 1 Drug Name: Nucynta
`
`ta n entadol Oral Solution
`
`NDA Type: 505(b)
`
`DAAAP/OND/CDER/FDA
`
`
`On initial overview of the NDA application for Refuse to File (RTF):
`
`All non-clinical studies cross-referenced to NDA 22304
`
`__
`On its face, is the pharmacology section
`of the NDA/BLA organized (in accord
`with 21 CFR 314 and current guidelines +
`for format and content) in a manner to
`allow substantive review to begin?
`
`ISthepharmaCOIogY/tOXiCOIogyseetion '-of the NDA/BLA indexed and paginated
`
`in a manner allowing substantive review +
`to begin?
`
`studies, safety pharmacology, etc)?
`
`On its face, is the
`.harmacology/toxicology section of the
`I A/BLA legible so that substantive
`review can begin?
`
`Are all required (*) and requested
`BBIND studies (in accord with 505(bl)
`and (b2) including referenced literature)
`completed and submitted in this
`D A/BLA
`
`(carcinogenicity*, mutagenicity*,
`teratogenicity*, effects on fertility*,
`'uvenile studies, acute and repeat dose
`adult animal studies*, maximum
`tolerated dose determination, dermal
`irritancy, ocular irritancy, photo co-
`carcinogenicity, animal pharmacokinetic
`
`+
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`Reference ID: 3119154
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`Page 1 of 3
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`If the formulation to be marketed is
`different from the formulation used in
`the toxicology studies, have studies
`been conducted with the appropriate
`formulation?
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`Is (are) the excipient(s) appropriately
`qualified (including interaction between
`the excipients if applicable)?
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`7 On its face, does the route of
`administration used in the animal
`studies appear to be the same as the
`intended human exposure route? If not,
`has the sponsor submitted a rationale to
`justify the alternative route?
`8 Has the sponsor submitted a
`statement(s) that all of the pivotal
`pharm/tox studies have been performed
`in accordance with the GLP regulations
`(21 CFR 58) or an explanation for any
`significant deviations?
`
`9 Has the sponsor submitted all special
`studies/ data requested by the Division
`during pre-submission discussions with
`the sponsor?
`
`10 Are the proposed labeling sections
`relative to pharmacology, reproductive
`toxicology, and carcinogenicity
`appropriate (including human dose
`multiples expressed in either mg/m2 or
`comparative serum/plasma levels) and
`in accordance with 201.57?
`
`11 Has the sponsor submitted any toxicity
`data to address impurities, new
`excipients, leachables, etc. issues.
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`Reference ID: 3119154
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`Page 2 of 3
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` The Sponsor addressed abuse potential in
` NDA 22304
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`12 Has the sponsor addressed any abuse
`potential issues in the submission?
`13 If this NDA/BLA is to support a Rx to
`OTC switch, have all relevant studies
`been submitted?
`14 From a pharmacology/ toxicology
`perspective, is the NDA/BLA fileable?
`If ``no`` please state below why it is not.
`IS THE PHARMACOLOGY/TOXICOLOGY SECTION OF THE APPLICATION
`FILEABLE? Yes
`
`Please identify and list any potential review issues to be forwarded to the Applicant for the
`74-day letter.
`
`Comments to Sponsor: None
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`+
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`Reference ID: 3119154
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`Page 3 of 3
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`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ARMAGHAN EMAMI
`04/19/2012
`
`ADAM M WASSERMAN
`04/19/2012
`
`Reference ID: 3119154
`
`