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

`

`Sponsor:
`Relevant NDA(s)
`Relevant IND(s):
`Formulation; Strength(s):
`Proposed Indication:
`
`Proposed Dosage
` Regimen:
`
`•
`
`CLINICAL PHARMACOLOGY REVIEW MEMO
`NDA: 203794
`Submission Date:
`12/15/11
`Submission Type
`1S
`Brand/Code Name:
`Nucynta™ Oral Solution
`Generic Name:
`Tapentadol oral solution
`Primary Reviewer:
`David Lee, Ph.D.
`Team Leader:
`Yun Xi, Ph.D.
`OCP Division:
`DCP 2
`Division of Anesthesia, Analgesia and Addiction
`OND Division:
`Products
`Janssen Pharmaceuticals, Inc.
`22-304
`61,345
`20 mg/mL
`• For the management of moderate to severe acute
`pain in patients 18 years of age or older
`Individualize dosing according to the severity of
`pain being treated; 50 mg, 75 mg, or 100 mg Q4 - 6
`h depending upon pain intensity. On the first day of
`dosing, the second dose may be administered as
`soon as one hour after the first dose, if adequate pain
`relief is not attained with the first dose. Subsequent
`dosing is 50 mg, 75 mg, or 100 mg Q 4 - 6 h and
`should be adjusted to maintain adequate analgesia
`with acceptable tolerability. Daily doses greater than
`700 mg on the first day of therapy and 600 mg on
`subsequent days have not been studied and are,
`therefore, not recommended.
`
`
`Table of Contents
`
`1 EXECUTIVE SUMMARY........................................................................................ 2
`
`1.1
`1.2
`1.3
`
`Recommendations............................................................................................................................. 2
`Phase IV Commitments.................................................................................................................... 2
`Summary of Clinical Pharmacology Findings ............................................................................... 2
`
`2 DETAILED LABELING RECOMMENDATIONS............................................... 3
`
`
`
`Reference ID: 3177272
`
`1
`
`

`

`3 APPENDICES ............................................................................................................ 3
`
`Proposed Package Insert - Not applicable..................................................................................... 3
`3.1
`Individual study review – Not applicable ....................................................................................... 3
`3.2
`Consult Review (including Pharmacometric Reviews) – Not applicable..................................... 3
`3.3
`Cover Sheet and OCPB Filing/Review Form ................................................................................. 3
`3.4
`________________________________________________________________________
`
` Executive Summary
`
` 1
`
`1.1 Recommendations
`
`The Office of Clinical Pharmacology / Division of Clinical Pharmacology II (OCP/DCP-
`II) has reviewed the information submitted in the current application and found the
`submission acceptable from clinical pharmacology perspective. There are no Labeling
`related comments to be conveyed to the Applicant at this time.
`
`
`1.2 Phase IV Commitments
`
`Not applicable.
`
`1.3 Summary of Clinical Pharmacology Findings
`
`Janssen Research & Development, LLC, submitted a New Drug Application (NDA) for
`Nucynta® (tapentadol) Oral Solution, on behalf of Janssen Pharmaceuticals, Inc., in
`accordance with Section 505(b) of the Federal Food, Drugs, and Cosmetic Act. The
`indication for this NDA is for the management of moderate to severe acute pain, as in the
`approved NDA 22304 for Nucynta® (tapentadol) immediate-release tablets (Janssen
`Research). A reference is made to NDA 22304 for Clinical, Nonclinical, Toxicology,
`and Pharmacology information.
`
`No clinical studies were provided with this Application, due to the fact that a biowaiver
`was requested and granted by the Agency on 6/29/09. In the memo dated February 24,
`2012 by Dr. Christine Moore, Acting Office Director of Office of New Drug Quality
`Assessment (ONDQA), the suitability of a biowaiver for NDA 203794 Nucynta Oral
`Solution relative to the immediate release tablet was further discussed. It is stated that
`“Based on the information reviewed, I deem that the biowaiver granted by ONDQA for
`IND 61,345 on 6/29/09 is valid for NDA 203794”.
`
`In spite of the fact that biowaiver being granted, the Applicant has submitted Study
`HP5503/59, titled, “A relative bioavailability trial to compare a new tapentadol oral
`solution 100 mg with the tapentadol immediate release 100 mg tablet,” on 2/7/12.
`According to the Applicant, Study 5503/59 utilized the same tapentadol solution
`formulation that is the subject to this NDA approval. The tapentadol immediate release
`
`
`
`Reference ID: 3177272
`
`2
`
`

`

`tablet used in study contains the equivalent formulation as the current FDA-approved
`NUCYNTA (tapentadol) formulation, only with the exception of the colorant used in the
`film-coating.
`
`Since the Agency granted the biowaiver of the proposed tapentadol solution, this
`application may be approved based on the biowaiver without additional clinical or
`clinical pharmacology studies. From a clinical pharmacology perspective, the submitted
`study report HP5503/59 will be considered as non-pivotal information and will not be
`reviewed. No OSI inspection will be requested for this study.
`
`
` 2
`
` Detailed Labeling Recommendations
`
`
`There are no changes to the Label regarding Clinical Pharmacology.
`
` Appendices
`
` 3
`
`3.1 Proposed Package Insert - Not applicable
`
`3.2
`
`Individual study review – Not applicable
`
`3.3 Consult Review (including Pharmacometric Reviews) – Not applicable
`
`3.4 Cover Sheet and OCPB Filing/Review Form
`
`
`Office of Clinical Pharmacology
`New Drug Application Filing and Review Form
`General Information About the Submission
`
`
`NDA/BLA Number
`OCP Division (I, II, III, IV, V)
`Medical Division
`OCP Reviewer
`
`Information
`
`203794
`II
`DAAAP
`David Lee, Ph.D.
`
`
`
`Brand Name
`Generic Name
`Drug Class
`Indication(s)
`
`Information
`Nucynta Oral Solution
`Tapentadol Oral Solution
`Pain
`For the management of
`moderate to severe acute
`pain in patients 18 years
`of age or older
`
`Solution 20 mg/mL
`
`OCP Team Leader
`
`Yun Xu, Ph.D.
`
`Dosage Form
`
`
`
`Reference ID: 3177272
`
`3
`
`

`

`Pharmacometrics Reviewer
`
`-
`
`Dosing Regimen
`
`Date of Submission
`Estimated Due Date of OCP Review
`Medical Division Due Date
`PDUFA Due Date
`
`Dec 15, 2011
`Sept 15, 2012
`Sept 15, 2012
`Oct 15, 2012
`
`Route of Administration
`Sponsor
`Priority Classification
`
`
`50 mg, 75 mg, or 100 mg
`Q4 - 6 h depending upon
`pain intensity. On the first
`day of dosing, the second
`dose may be administered
`as soon as one hour after
`the first dose, if adequate
`pain relief is not attained
`with the first dose.
`Subsequent dosing is 50
`mg, 75 mg, or 100 mg Q 4
`- 6 h and should be
`adjusted to maintain
`adequate analgesia with
`acceptable tolerability.
`Daily doses greater than
`700 mg on the first day of
`therapy and 600 mg on
`subsequent days have not
`been studied and are,
`therefore, not
`recommended.
`Oral
`Janssen
`Standard
`
`
`
`Clin. Pharm. and Biopharm. Information
`Number of
`“X” if included
`Number of
`studies
`at filing
`studies
`reviewed
`submitted
`
`
`
`
`
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`
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`Critical Comments If any
`
`
`
`
`
`
`STUDY TYPE
`Table of Contents present and sufficient to
`locate reports, tables, data, etc.
`Tabular Listing of All Human Studies
`HPK Summary
`Labeling
`Reference Bioanalytical and Analytical
`Methods
`I. Clinical Pharmacology
` Mass balance:
` Isozyme characterization:
` Blood/plasma ratio:
` Plasma protein binding:
` Pharmacokinetics (e.g., Phase I) -
`Healthy Volunteers-
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`4
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` Dose proportionality -
`fasting / non-fasting single dose:
`fasting / non-fasting multiple dose:
` Drug-drug interaction studies -
`In-vivo effects on primary drug:
`In-vivo effects of primary drug:
`In-vitro:
`
`single dose:
`multiple dose:
`
`single dose:
`multiple dose:
`
`ethnicity:
`gender:
`pediatrics:
`geriatrics:
`renal impairment:
`hepatic impairment:
`
`Patients-
`
` Subpopulation studies -
`
`
`
`Reference ID: 3177272
`
`

`

` PD -
`
` PK/PD -
`
` Population Analyses -
`
`Phase 1 and/or 2, proof of concept:
`Phase 3 clinical trial:
`
`Phase 2:
`Phase 3:
`
`Data rich:
`Data sparse:
`
`II. Biopharmaceutics
` Absolute bioavailability
` Relative bioavailability -
`
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`solution as reference:
`alternate formulation as reference:
` Bioequivalence studies -
`traditional design; single / multi dose:
`replicate design; single / multi dose:
` Food-drug interaction studies
` Bio-waiver request based on BCS
` BCS class
` Dissolution study to evaluate alcohol induced
` dose-dumping
`III. Other CPB Studies
` Genotype/phenotype studies
` Chronopharmacokinetics
` Pediatric development plan
` Literature References
`Total Number of Studies
`
`
`
`On initial review of the NDA/BLA application for filing:
`
`
`Content Parameter
`
`Criteria for Refusal to File (RTF)
`1 Has the applicant submitted bioequivalence
`data comparing to-be-marketed product(s)
`and those used in the pivotal clinical trials?
`2 Has the applicant provided metabolism and
`drug-drug interaction information?
`3 Has the sponsor submitted bioavailability
`data satisfying the CFR requirements?
`4 Did the sponsor submit data to allow the
`evaluation of the validity of the analytical
`assay?
`5 Has a rationale for dose selection been
`submitted?
`Is the clinical pharmacology and
`biopharmaceutics section of the NDA
`organized, indexed and paginated in a
`manner to allow substantive review to
`begin?
`Is the clinical pharmacology and
`biopharmaceutics section of the NDA
`legible so that a substantive review can
`begin?
`Is the electronic submission searchable,
`does it have appropriate hyperlinks and do
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`6
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`Yes No N/A
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`Comment
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`Biowaiver is granted for this product.
`
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`Reference ID: 3177272
`
`5
`
`

`

`the hyperlinks work?
`
`10
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`14
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`17
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`
`Criteria for Assessing Quality of an NDA (Preliminary Assessment of Quality)
` Data
`
`9 Are the data sets, as requested during pre-
`
`submission discussions, submitted in the
`appropriate format (e.g., CDISC)?
`If applicable, are the pharmacogenomic data
`sets submitted in the appropriate format?
` Studies and Analyses
`11
`Is the appropriate pharmacokinetic
`information submitted?
`12 Has the applicant made an appropriate
`attempt to determine reasonable dose
`individualization strategies for this product
`(i.e., appropriately designed and analyzed
`dose-ranging or pivotal studies)?
`13 Are the appropriate exposure-response (for
`desired and undesired effects) analyses
`conducted and submitted as described in the
`Exposure-Response guidance?
`Is there an adequate attempt by the applicant
`to use exposure-response relationships in
`order to assess the need for dose
`adjustments for intrinsic/extrinsic factors
`that might affect the pharmacokinetic or
`pharmacodynamics?
`15 Are the pediatric exclusivity studies
`adequately designed to demonstrate
`effectiveness, if the drug is indeed
`effective?
`16 Did the applicant submit all the pediatric
`exclusivity data, as described in the WR?
`Is there adequate information on the
`pharmacokinetics and exposure-response in
`the clinical pharmacology section of the
`label?
` General
`18 Are the clinical pharmacology and
`biopharmaceutics studies of appropriate
`design and breadth of investigation to meet
`basic requirements for approvability of this
`product?
`19 Was the translation (of study reports or
`other study information) from another
`language needed and provided in this
`submission?
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`IS THE CLINICAL PHARMACOLOGY SECTION OF THE APPLICATION
`FILEABLE? _____yes___
`
`
`
`Reference ID: 3177272
`
`6
`
`

`

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`Date
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`Date
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`
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`If the NDA/BLA is not fileable from the clinical pharmacology perspective, state the reasons and
`provide comments to be sent to the Applicant.
`
`
`
`Please identify and list any potential review issues to be forwarded to the Applicant for the 74-
`day letter.
`
`Reviewing Clinical Pharmacologist
`
`
`Team Leader/Supervisor
`
`
`
`
`Janssen Research & Development, LLC, submitted a New Drug Application (NDA) for
`Nucynta® (tapentadol) Oral Solution, on behalf of Janssen Pharmaceuticals, Inc., in
`accordance with Section 505(b) of the Federal Food, Drugs, and Cosmetic Act. The
`indication for this NDA is for the management of moderate to severe acute pain, as in the
`approved NDA 22304 for Nucynta® (tapentadol) immediate-release tablets by the same
`Sponsor. A reference is made to NDA 22304 for Clinical, Nonclinical, Toxicology, and
`Pharmacology information.
`
`No clinical studies were provided with this Application, due to the fact that a biowaiver was
`requested and granted by the Agency on 6/29/09. In spite of the fact that biowaiver being
`granted the Applicant has submitted Study HP5503/59, titled, “A relative bioavailability trial
`to compare a new tapentadol oral solution 100 mg with the tapentadol immediate release 100
`mg tablet,” on 2/7/12. According to the Applicant, Study 5503/59 utilized the same
`tapentadol solution formulation that is the subject to this NDA approval.
`
`In the memo dated February 24, 2012 by Dr. Christine Moore, Acting Office Director of
`ONDQA, the suitability of a biowaiver for NDA 203794 Nucynta Oral Solution relative to
`the immediate release tablet is discussed. It is stated that “Based on the information reviewed,
`I deem that the biowaiver granted by ONDQA for IND 61,345 on 6/29/09 is valid for NDA
`203794”. Since the Agency granted the biowaiver of the proposed tapentadol solution and it
`is deemed valid, this application may be approved based on the biowaiver grant without
`additional clinical or clinical pharmacology studies. Therefore, the submitted study report
`HP5503/59 will be considered as non-pivotal information and no OSI inspection will be
`requested for this study.
`
`From a clinical pharmacology perspective, the application is recommended for filing.
`We will request the Sponsor to submit the following information for completeness of the
`submission:
`
`1. Regarding study HP5503/59, confirm that:
`
`
`
`
`Reference ID: 3177272
`
`7
`
`

`

`a. Tapentadol oral solution used in the study is the to-be-marketed formulation; and
`
`b. FDA-approved Nucynta (tapentadol) immediate-release tablet was the immediate-
`release tablet formulation used as reference.
`
`2. In addition to submitted Bioanalytical Analyses Study SBA_S_09040 (i.e., study
`PK1210A), and in order to have complete information concerning bioanalytical analyses,
`submit the following reports:
`
`a. PK1134, “Complete Validation of an LC-MS/MS method for the determination of
`R331333 and R403347 in human serum,” December 2007, including also Amendment 1
`to study report PK1134, January 2009, containing long-term (24 months) stability data at
`-25°C
`
`
`b. PK1070 (SBA_S_07093), “Partial validation of a method for the determination of
`CG5503 free base and its metabolite CG5503 glucuronide (GRTE1472) in human serum
`by LC-MS/MS,” including also Amendment 1 to report SBA_S_07093, 2008, containing
`freeze/thaw stability data (-25°C/room temperature) and short-term (72 hours) stability
`data at room temperature
` respectively);
`and,
`
`
`c. PK711 (SBA_S_04004), “Stability of CG5503, CG5503 glucuronide (GRTE1472),
`and CG5503 sulfate (GRT3793H) in human blood and human serum - investigation by
`LC-MS/MS,” October 2007, containing post-preparative stability data, 192 hours at 8°C
`(conditions during autosampling)
`
`
`
`
`
`
`Reference ID: 3177272
`
`8
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`DAVID J LEE
`08/21/2012
`
`YUN XU
`08/21/2012
`
`Reference ID: 3177272
`
`

`

`Application No.:
`Submission Date:
`
`Division:
`
`Sponsor:
`
`Trade Name:
`Generic Name:
`
`Indication:
`
`BIOPHARMACEUTICS FILING REVIEW
`Office of New Drug Quality Assessment
`
`NDA 203-794
`Reviewer: Kareen Riviere, Ph.D.
`December 15, 2011
`Anesthesia, Analgesia, and
`Addiction Products
`Janssen Research & Development,
`LLC
`NUCYNTA®
`Tapentadol
`
`Acting Biopharmaceutics Supervisory Lead:
`Angelica Dorantes, Ph.D.
`Secondary Signature: Sandra Suarez-Sharp,
`Ph.D.
`Date Assigned: December 21, 2011
`Date of Review: February 24, 2012
`Type of Submission: 505(b)(2) New Drug
`Application
`
`The management of moderate to
`severe acute pain.
`
`Solution/ 20 mg per mL
`Oral
`
`Formulation/strengths:
`Route of
`Administration:
`
`SUBMISSION:
`This is a 505(b)(2) New Drug Application for 20 mg/mL tapentadol oral solution. The indication is for the
`management of moderate to severe acute pain.
`
`BIOPHARMACEUTIC INFORMATION:
`Tapentadol is currently approved as NUCYNTA® (tapentadol) immediate-release tablets 50 mg, 75 mg, and 100mg
`strengths (NDA 22-304). This NDA provides for an oral solution formulation to be used for the same indication as the
`approved indication for the immediate release tablets.
`
`This submission includes a BA/BE waiver request. A biowaiver for the CFR BA/BE requirements was granted for
`this product by the FDA on June 29, 2009 on the basis that tapentadol is a BCS Class 1 compound. Tapentadol was
`granted BCS 1 classification by the Agency, despite its low oral absolute bioavailability
`.
`
`However, the proposed drug product does not qualify for a BA/BE waiver for the following reasons:
`
`
`1. According to the BCS guidance for industry, demonstration of in vivo BA or BE may not be necessary for
`pharmaceutically equivalent drug products containing Class 1 drug substances, as long as the inactive
`ingredients used in the dosage form do not significantly affect absorption of the active ingredients.
`
`
`2. The proposed product and the reference product do not meet the definition of pharmaceutical equivalents
`established in 21CFR 320.1 (c):
`Pharmaceutical equivalents means drug products in identical dosage forms that contain
`identical amounts of the identical active drug ingredient, i.e., the same salt or ester of the
`same therapeutic moiety, or, in the case of modified release dosage forms that require a
`reservoir or overage or such forms as prefilled syringes where residual volume may vary, that
`deliver identical amounts of the active drug ingredient over the identical dosing period; do
`not necessarily contain the same inactive ingredients; and meet the identical compendial or
`other applicable standard of identity, strength, quality, and purity, including potency and,
`where applicable, content uniformity, disintegration times, and/or dissolution rates.
`
`3. The proposed product contains sucralose as an inactive ingredient. Published scientific literature indicates,
`although not totally conclusive, that sucralose may potentially affect the absorption and bioavailability of
`drugs (Abou-Donia et al. 2008,
`).
`
`
`
`Reference ID: 3092176
`
`
`
`1
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`During the January 31, 2012 filing meeting for this NDA, ONDQA-Biopharmaceutics communicated to the
`reviewing team their concerns regarding the potential effect that the presence of sucralose could have on the
`bioavailability of tapentadol oral solution. Biopharmaceutics suggested that data from an acceptable in vivo
`bioequivalence study may be needed to support the approval of the proposed product under this NDA application and
`mentioned that the lack of this information may potentially preclude the filing of this NDA from a Biopharmaceutics
`perspective.
`
`Subsequently, it was determined that the Applicant had already submitted, under IND 108,134, the synopsis for study
`No. HP5503/59, which objective was to evaluate the BA/BE of the proposed oral product (5 mL of 20 mg/mL) vs. the
`IR oral tablet (100 mg).
`
`In response to the FDA’s request made during the February 2, 2012 teleconference, the Applicant submitted on
`February 7th, an amendment to the NDA including the complete final report for BA/BE study HP5503/59. The
`following was stated in the Applicant’s cover letter dated February 7, 2012:
`
`
`Reference is made to New Drug Application (NDA) 203794 for NUCYNTA® (tapentadol) Oral
`Solution, submitted 15 December 2011. Reference is also made to a teleconference with FDA on
`02 February 2012. FDA noted that during their 45 day review, they learned that the Division of
`Biopharmaceutics no longer issues biowaiver requests for products that contain sucralose, due to
`concerns about bioavailability. A biowaiver had been granted for the NUCYNTA® oral solution in
`2009, but FDA said that they would now require a bioavailability study. FDA noted that a
`synopsis for study HP5503/59;R331333PAI1044, “A relative bioavailability trial to compare a
`new tapentadol oral solution 100 mg with the tapentadol immediate release 100 mg tablet”, was
`previously submitted to the Oral Solution IND 108134. FDA agreed that if the formulation is the
`same in both the study and the NDA, they would consider this study to support the Oral Solution
`NDA and they requested that the full clinical study report be submitted to the NDA. We confirmed
`to the division via email that the formulation is the same, and noted additionally that the batch
`analysis for the batch used in the study was included in the initial submission for NDA 203794. On
`behalf of Janssen Pharmaceuticals Inc., Janssen Research & Development LLC (JRD) is
`submitting the aforementioned study report.
`
`
`The acceptability of the BA/BE study submitted to support the approval of the proposed product is a review issue.
`The provided BA/BE study No. HP5503/59 will be reviewed by the Clinical Pharmacology Team from OCP.
`Therefore, the acceptability of the waiver request is no longer a review issue for evaluation by the Biopharmaceutics
`Team.
`
`RECOMMENDATION:
`The ONDQA-Biopharmaceutics Team has reviewed the information provided in NDA 203-794 for filing purposes.
`From a Biopharmaceutics perspective, NDA 203-794 for NUCYNTA® (tapentadol) Oral Solution is fileable.
`
`
` Kareen Riviere, Ph.D. Sandra Suarez-Sharp, Ph.D.
` Biopharmaceutics Reviewer Senior Biopharmaceutics Reviewer
` Office of New Drug Quality Assessment Office of New Drug Quality Assessment
`
` cc: Christine M.V. Moore, Ph.D.
`
`
`Reference ID: 3092176
`
`
`
`2
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`KAREEN RIVIERE
`02/24/2012
`
`ANGELICA DORANTES
`02/24/2012
`
`Reference ID: 3092176
`
`