CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`204592Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`
`CLINICAL REVIEW
`
`Application Type NDA
`Application Number(s) 204592
`Priority or Standard Standard
`
`Submit Date(s) December 20, 2012
`Received Date(s) December 20, 2012
`PDUFA Goal Date October 20, 2013
`Division / Office DAAAP/ODE II
`
`Reviewer Name(s) Steven Galati M.D.
`Review Completion Date September 17, 2013
`
`Established Name Diclofenac
`(Proposed) Trade Name Zorvolex
`Therapeutic Class NSAID
`Applicant
`Iroko Pharmaceuticals
`
`Formulation(s) Capsule
`Dosing Regimen 18-35mg taken TID
`Indication(s) Treatment of acute mild to
`moderate pain
`Intended Population(s) Patients with mild to moderate
`acute pain
`
`
`Reference ID: 3375013
`
`1
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`
`2
`
`
`
`Table o Contents
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT ......................................... 6
`1.1 Recommendation on Regulatory Action ............................................................. 6
`1.2 Risk Benefit Assessment .................................................................................... 6
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 7
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 7
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 7
`2.1 Product Information ............................................................................................ 7
`2.2 Tables of Currently Available Treatments for Proposed Indications ................... 7
`2.3 Availability of Proposed Active Ingredient in the United States .......................... 8
`2.4
`Important Safety Issues With Consideration to Related Drugs ........................... 8
`2.5 Summary of Presubmission Regulatory Activity Related to Submission ............ 9
`2.6 Other Relevant Background Information .......................................................... 11
`3 ETHICS AND GOOD CLINICAL PRACTICES ....................................................... 11
`3.1 Submission Quality and Integrity ...................................................................... 11
`3.2 Compliance with Good Clinical Practices ......................................................... 11
`3.3 Financial Disclosures ........................................................................................ 13
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 13
`4.4 Clinical Pharmacology ...................................................................................... 13
`5 SOURCES OF CLINICAL DATA............................................................................ 14
`5.1 Tables of Studies/Clinical Trials ....................................................................... 14
`5.2 Review Strategy ............................................................................................... 15
`5.3 Discussion of Individual Studies/Clinical Trials ................................................. 15
`6 REVIEW OF EFFICACY ......................................................................................... 48
`Efficacy Summary ...................................................................................................... 48
`6.1
`Indication .......................................................................................................... 49
`6.1.1 Methods ..................................................................................................... 49
`6.1.2 Demographics ............................................................................................ 49
`6.1.3 Subject Disposition .................................................................................... 49
`6.1.4 Analysis of Primary Endpoint(s) ................................................................. 49
`6.1.5 Analysis of Secondary Endpoints(s)........................................................... 53
`6.1.7 Subpopulations .......................................................................................... 54
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 55
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects ................. 55
`6.1.10 Additional Efficacy Issues/Analyses ........................................................... 55
`
`Reference ID: 3375013
`
`2
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`7 REVIEW OF SAFETY ............................................................................................. 55
`Safety Summary ........................................................................................................ 55
`7.1 Methods ............................................................................................................ 56
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 56
`7.1.2 Categorization of Adverse Events .............................................................. 56
`7.2 Adequacy of Safety Assessments .................................................................... 57
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations ..................................................................................... 57
`7.2.2 Explorations for Dose Response ................................................................ 57
`7.2.4 Routine Clinical Testing ............................................................................. 57
`7.3 Major Safety Results ........................................................................................ 57
`7.3.1 Deaths ........................................................................................................ 57
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 58
`7.3.3 Dropouts and/or Discontinuations .............................................................. 58
`7.3.4 Significant Adverse Events ........................................................................ 58
`7.4 Supportive Safety Results ................................................................................ 59
`7.4.1 Common Adverse Events .......................................................................... 59
`7.4.3 Vital Signs .................................................................................................. 60
`7.4.5 Special Safety Studies/Clinical Trials ......................................................... 61
`7.5 Other Safety Explorations ................................................................................. 61
`7.5.1 Dose Dependency for Adverse Events ...................................................... 61
`7.5.2 Time Dependency for Adverse Events ....................................................... 61
`7.5.3 Drug-Demographic Interactions ................................................................. 61
`7.6 Additional Safety Evaluations ........................................................................... 63
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 63
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound ...................... 65
`7.7 Additional Submissions / Safety Issues ............................................................ 66
`8 POSTMARKET EXPERIENCE ............................................................................... 67
`9 APPENDICES ........................................................................................................ 68
`9.1 Literature Review/References .......................................................................... 68
`9.2 Labeling Recommendations ............................................................................. 68
`9.3 Advisory Committee Meeting ............................................................................ 70
`APPENDIX ................................................................................................................ 71
`
`
`
`Reference ID: 3375013
`
`3
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`
`Table of Tables
`Table 1: Brand Name Diclofenac Products and Indications ........................................... 8
`Table 2: Key Presubmission Regulatory Activity ........................................................... 9
`Table 3: OSI Inspected Clinical Sites ............................................................................ 12
`Table 4: Results of the OSI Review by Site ................................................................... 13
`Table 5: Clinical Trials Submitted in Support of this Application .................................... 14
`Table 6: Dosing of Treatment Groups DIC3-08-04 ....................................................... 17
`Table 7: Schedule of Events ....................................................................................... 22
`Table 8: Demographic Characteristics – Safety Population ......................................... 28
`Table 9: Summary of Baseline Characteristics – Safety Population .............................. 29
`Table 10: Summary of Major Protocol Violations .......................................................... 30
`Table 11: Applicants Statistical Analysis (ANCOVA) of ITT Population......................... 32
`Table 12: Model 2: Gender as Covariate ....................................................................... 34
`Table 13: Analysis of the Visual Analogue Scale Summed Pain Intensity Difference
`Over 0 to 4 Hours, 0 to 8 Hours, and 0 to 24 Hours—Intent-to-Treat Population .......... 36
`Table 14: Analysis of Total Pain Relief Over 0 to 4 Hours, 0 to 8 Hours, 0 to 24 Hours,
`and Over 0 to 48 Hours — Intent-to Treat Population ................................................... 37
`Table 15: Time to Onset of Analgesia (Measured as Time to Perceptible Pain Relief
`Confirmed by Meaningful Pain Relief) — Intent-to-Treat Population ............................. 39
`Table 16: Summary of Peak Pain Relief — Intent-to-Treat Population ......................... 41
`Table 17: Time to Meaningful Pain Relief – ITT Population ......................................... 42
`Table 18: Time to First Use of Rescue Medication — Intent-to-Treat Population .......... 43
`Table 19: Patient’s Global Evaluation of Trial Drug — ITT Population ......................... 44
`Table 20: Study Schedule ............................................................................................. 46
`Table 21 – Rescue in DIC3-08-04 ................................................................................. 50
`Table 22 – Sensitivity Analysis of SPID48 Using Observed Pain Scores Regardless of
`Rescue .......................................................................................................................... 50
`Table 23: Additional Efficacy Analysis for VASSPID48 – Pre-rescue Score Carried Forward
`for Six hours ................................................................................................................... 53
`Table 24: Subgroup Analysis on the Primary Endpoint ....................................................... 54
`Table 25: Summary of Severe Treatment-Emergent Adverse Events by Preferred Term
` ...................................................................................................................................... 58
`Table 26: Summary of Most Frequent Treatment-Emergent Adverse Events (5% or
`More of Subjects in Any Treatment Group) by Preferred Term — Safety Population ... 60
`Table 27: Subgroup Analysis by Age – Safety Population ............................................ 62
`Table 28: Summary of Most Frequent Treatment Emergent Adverse Events (5% or
`More of Subjects in Any Diclofenac Treatment Group) by Preferred Term — Study
`DIC3-08-04 - Safety Population with Overall Population and Subgroups by Gender .... 62
`Table 29: Proposed Timeline for Pediatric Studies ...................................................... 65
`Table 30: Additional Requested Clinical Submissions to NDA 204592 ......................... 66
`
`
`Reference ID: 3375013
`
`4
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`
`Table of Figures
`Figure 1: Subject Disposition for Controlled Trial DIC3-08-04 ....................................... 27
`Figure 2: VASSPID-48 Results in the ITT population with Baseline Pain as Only
`Covariate ....................................................................................................................... 33
`Figure 3: Time to Onset of Analgesia – ITT Population ................................................ 40
`Figure 4: Average Pain Over Time – BOCF After Rescue ............................................ 51
`Figure 5: Average Pain Over Time Using Observed Pain Scores (No Imputation) ....... 52
`Figure 6: Percentage of Subjects with Different Frequency of Rescue Medications ..... 53
`
`
`
`Reference ID: 3375013
`
`5
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`Approval with revisions to the proposed label.
`
`1.2 Risk Benefit Assessment
`The Applicant submitted the results of a pivotal Phase 3 trial using the to-be-marketed
`formulation, in conjunction with the Agency’s previous findings of safety and efficacy for
`the reference drug Cataflam (NDA 020142), for the treatment of acute mild to moderate
`pain. I have determined that this trial was designed and conducted in a reasonably
`adequate and well-controlled fashion that is sufficient to rely upon for a determination of
`efficacy and safety. The data reviewed, in the pivotal controlled clinical trial, in patients
`with acute pain after bunionectomy, support the effectiveness of diclofenac acid
`capsules for the treatment of acute pain in this population as evidenced by the statistical
`significance of the primary endpoint compared to placebo and the clinically meaningful
`benefit of this finding. The safety data did not demonstrate any new safety signal
`beyond what is already known for diclofenac. The safety profile for the intended patient
`population is acceptable.
`
`Benefits:
`• Evidence of effectiveness was established in a single, pivotal, placebo-controlled
`trial using the primary endpoint, VAS summed pain intensity difference
`(VASSPID) over 0 to 48 hours and was further confirmed in a sensitivity analysis
`on this endpoint using observed pain scores (see Section 6 for more details).
`• The primary efficacy analysis is further supported by results in favor of diclofenac
`on various secondary endpoints.
`• Diclofenac is a well-established analgesic and this dosage form offers an
`additional treatment option for patients with mild to moderate acute pain.
`
`
`Risks:
`• No new safety signal was identified in review of this application.
`• The most commonly reported adverse events were postprocedural edema and
`nausea. Review of the safety data does not suggest a relationship between
`these events and diclofenac. Edema was likely related to the bunionectomy, and
`it occurred at approximately the same frequency across all groups. Nausea was
`most common in the placebo group, likely due to the increase in opioid rescue in
`that group.
`
`
`Overall, the risk-benefit profile of diclofenac acid capsules in this population is favorable.
`
`Reference ID: 3375013
`
`6
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation
`Strategies
`I have identified no further safety issues in the review of this application that warrant
`additional postmarket risk evaluation and mitigation strategies.
`1.4 Recommendations for Postmarket Requirements and Commitments
`The following pediatric studies are required:
`
`
`• Study 1: An open-label pharmacokinetic and safety study or studies of an age-
`appropriate formulation of diclofenac in pediatric patients 6 to < 17 years of age
`with acute pain.
`• Study 2: An open-label pharmacokinetic and safety study or studies of an age-
`appropriate formulation of diclofenac in pediatric patients 2 to < 6 years of age
`with acute pain.
`• Study 3: A pharmacokinetic, safety, and efficacy study or studies of an age-
`appropriate formulation of diclofenac in pediatric patients 1 to < 2 years of age
`with acute pain.
`
` 2
`
` Introduction and Regulatory Background
`
`
`2.1 Product Information
`Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-
`inflammatory, analgesic, and antipyretic activities. Diclofenac is a potent inhibitor of
`both COX-1 and COX-2. The efficacy of diclofenac is associated with the inhibition of
`COX-2 while the adverse effects of diclofenac are probably related to inhibition of COX-
`1, which causes a decrease in prostaglandin synthesis. The Applicant developed a
`new formulation (as an acid form called Zorvolex) of diclofenac capsules in 18mg and
`35mg doses to be taken three times per day. This new formulation was studied in a
`single, pivotal trial in patients with acute pain after bunionectomy.
`
`Zorvolex (diclofenac acid capsules) are immediate release capsules with the proposed
`indication for the treatment of mild to moderate pain in adults. The Applicant’s rationale
`for developing Zorvolex is that they purport their technology significantly reduces
`particle size promoting the dissolution and absorption of diclofenac. The Applicant
`believes the improved dissolution properties of Zorvolex are associated with rapid
`absorption resulting in comparable pain relief to Cataflam 50 mg tablets at a 20% lower
`dose of diclofenac than Cataflam 50 mg tablets. They also purport that the lower dose
`may have the potential for an improved safety profile compared with Cataflam 50 mg
`tablets.
`2.2 Tables of Currently Available Treatments for Proposed Indications
`Alternative treatment options include other prescription strength NSAIDs and
`acetaminophen.
`
`Reference ID: 3375013
`
`7
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`2.3 Availability of Proposed Active Ingredient in the United States
`Multiple approved drug products containing the active ingredient diclofenac are
`available and marketed in the United States as a treatment for multiple indications
`(Table 1).
`
`Table 1: Brand Name Diclofenac Products and Indications
`Drug Product
`NDA
`Approval
`Dose
`Name
`Date
`Form
`Zipsor
`06/16/2009 Capsule
`Pennsaid
`11/04/2009 Lotion
`
`22202
`20947
`
`Indication
`
`Relief of mild to moderate pain
`Treatment of signs and
`symptoms of osteoarthritis
`Treatment of pain in minor sports
`injuries
`Treatment of osteoarthritis of
`joints amenable to superficial
`treatment such as the hands and
`knees
`Relief of the signs and symptoms
`of osteoarthritis and rheumatoid
`arthritis
`Acute or long-term use in the
`relief of signs and symptoms of
`ankylosing spondylitis
`Treatment of primary
`dysmenorrhea
`Relief of mild to moderate pain;
`signs and symptoms of
`osteoarthritis and rheumatoid
`arthritis
`
`Treatment of rheumatoid arthritis
`and osteoarthritis
`
`Diclofenac
`Patch
`Voltaren Gel
`
`21234
`
`01/31/2007 Patch
`
`22122
`
`10/17/2007 Gel
`
`Voltaren
`
`19201
`
`07/28/1988 Tablet
`
`Cataflam
`
`20142
`
`11/24/1993 Tablet
`
`Voltaren XR
`
`20254
`
`03/8/1996 Tablet
`
`
`
`Important Safety Issues With Consideration to Related Drugs
`2.4
`NSAIDs may cause an increased risk of serious cardiovascular thrombotic events,
`myocardial infarction, and stroke, which can be fatal. This risk may increase with
`duration of use. Patient’s with cardiovascular disease or risk factors for cardiovascular
`disease may be at greater risk. NSAIDs are contraindicated for treatment of peri-
`operative pain in the setting of coronary artery bypass graft (CABG) surgery. NSAID’s
`cause an increased risk of serious gastrointestinal adverse events including bleeding,
`ulceration, and perforation of the stomach or intestines, which can be fatal.
`
`Reference ID: 3375013
`
`8
`
`

`

`Clinical Review
`
`Steven Galati M.D.
`
`NDA 204592
`
`Zorvolex/Diclofenac acid capsules
`
`Summary of Presubmission Regulatory Activity Related to
`2.5
`Submission
`
`Multiple products containing the active ingredient diclofenac have previously been
`approved in the United States for a number of indications, as listed above (Table 1).
`The application for Zorvolex (diclofenac acid) Capsules was submitted and filed as a
`505(b)(2) NDA relying upon the Agency’s previous findings of safety and efficacy for
`Cataflam (020142). During the clinical development, the Applicant referred to their drug
`as Zorvolex "
`“"0.” However during the End of Phase 2 meeting held on
`November 9, 2010, the Division informed the Applicant that
`“"0 must be
`“M". Therefore, the drug product does not meet the Agency definition of a
`"m Upon submission of the NDA, the Applicant referred to Zorvolex as
`"m instead 01
`"m.
`
`(b) (4)
`
`The drug development program was conducted under IND 103880. Key regulatory
`activity related to this NDA is noted in Table 2 that follows.
`
`Table 2: Key Presubmission Regulatory Activity
`m Meeting! Submission Type _mm_
`
`
`
`to o ivotal, acute oain stud
`
`o The overall design of Protocol
`DIC3-08-04, a randomized,
`double-blind, multiple-dose,
`parallel-group, active- and
`placebo-controlled trial of
`diclofenac
`“"9
`
`capsules for the treatment of
`acute post-operative pain
`after bunionectomy, is
`acceptable to support an
`efficacy claim for the
`treatment of mild to moderate
`
`acute pain
`Agreement on design,
`primary endpoint (VAS
`SPID48), and imputation
`methods
`
`Comparative claims would
`require replicated
`demonstration of su . eriorit
`
`505(b)(2) pathway
`appropriate
`Pediatric requirements:
`efficac , safe , and PK usin.
`
`1/29/2010
`
`Special Protocol Assessment:
`Agreement for Protocol DIC3-08-04
`
`11/9/2010
`
`Type B End of Phase 2 Meeting
`
`Reference ID: 3375013
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`
`Date
`
`Meeting/ Submission Type
`
`3/16/2012
`
`Proprietary Name (Zorvolex)
`
`6/7/2012
`
`Pre-NDA Meeting
`
`Reference ID: 3375013
`
`10
`
`Comments
`an age-appropriate
`formulation in patients 1 to < 2
`years with acute pain; safety
`and PK using an age-
`appropriate formulation in
`patients to < 17 years with
`acute pain; may be possible
`to waive the pediatric study
`requirements for ages birth to
`1 year because there is
`evidence strongly suggesting
`that the drug product would
`be ineffective or unsafe in this
`age group
`• Reliance on prior findings of
`efficacy for another diclofenac
`product for acute pain and the
`proposed Phase 3 study
`(DIC3-08-04) for the
`treatment of acute post-
`operative pain after
`bunionectomy may be
`adequate to support an
`efficacy claim for this
`indication
`• Should Iroko choose to
`conduct the efficacy study
`without food intake
`restrictions, this would not be
`sufficient to demonstrate the
`lack of a clinical food effect
`• Safety data on at least 350
`patients
`• Conditional acceptance of
`proposed proprietary name
`• Reference drug is Cataflam
`• Waivers will be determined by
`the Pediatric Research
`Committee, however, it
`appears reasonable to
`consider a waiver of studies
`for pediatric patients up to
`one year of age
`
`(b)
`(4)
`
`

`

`Clinical Review
`
`Steven Galati M.D.
`
`NDA 204592
`
`Zorvolex/Diclofenac acid capsules
`
`m Meetin SubmissionT re —m_
`
` 0 Applicant should consider
`
`studying food effect on
`analgesic efficacy to avoid
`labeling instructions about
`taking your product on an
`
`2.6 Other Relevant Background Information
`
`(5) (4)
`
`3 Ethics and Good Clinical Practices
`
`Submission Quality and Integrity
`3.1
`All data and documents in this application were electronically submitted following the
`guidances for electronic submission. The documents were organized in electronic
`Common Technical Document (eCTD) format. The datasets were not in Study Data
`Tabulation Model (SDTM) format. The overall quality of the submission was adequate.
`The organization and the ability to navigate the NDA were acceptable. A number of
`information requests were sent to the Applicant for additional information, and the
`responses were timely and adequate (see Section 7.7, Table 29).
`
`3.2 Compliance with Good Clinical Practices
`The Applicant stated that all studies were conducted in accordance with Guidelines for
`Good Clinical Practice and the Declaration of Helsinki and in compliance with the United
`States Food and Drug Administration regulations for informed consent and protection of
`patient rights as described in 21 Code of Federal Regulations Parts 50, 56, and 312.
`The Applicant also states that the studies were approved by Institutional Review
`Boards/Independent Ethics Committees and that all studies underwent regular
`monitoring by the Applicant or an appointed Contract Research Organization.
`
`The Office of Scientific Investigations (OSI) conducted routine inspection of two clinical
`investigator sites in support of this NDA (see Table 3). The sites were selected based
`on the number of enrolled subjects.
`
`Reference ID: 3375013
`
`1 1
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`Table 3: OSI Inspected Clinical Sites
`
`
`
`
`Source: Adapted from Clinical Study Report (CSR), Appendix 16.1.4.1
`
`
`Site 001 received a classification of Voluntary Action Indicated (VAI). The OSI
`reviewer, Dr. Cynthia Kleppinger, determined the violations had no significant impact on
`the safety or efficacy data. In general, the inspectional findings support validity of data
`as reported by the Applicant under this NDA. Below is a summary from Dr. Kleppinger’s
`Clinical Inspection Summary(Table 4).
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3375013
`
`12
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`Table 4: Results of the OSI Review by Site
`
`
`
`Key:
`NAI = No deviation from regulations
`VAI = Deviation(s) from regulations
`
`Source: Dr. Cynthia Kleppinger’s OSI Clinical Inspection Summary, page 2
`
`3.3 Financial Disclosures
`
`The Applicant submitted Form FDA 3454 “Certification: Financial Interests and
`Arrangements of Clinical Investigator”, attached with a list of 44 of the 45 investigators
`listed in the study reports, certifying that they had no financial interests or arrangements
`to disclose (see Appendix for Clinical Investigator Financial Disclosure).
`
`One sub-investigator at site 001 was referenced as being out of the office and would be
`sent a copy of the financial interests form to sign at a later date. Given only one sub-
`investigator failed to fill out the financial interests form and none of the remaining
`investigators had financial interests or arrangements to disclose, the possibility of bias
`in the results based on financial interests is unlikely.
`
` 4
`
` Significant Efficacy/Safety Issues Related to Other Review
`Disciplines
`
`No clinically relevant data was submitted to or reviewed by the chemistry manufacturing
`and controls, clinical microbiology, preclinical and pharmacology/toxicology review
`disciplines.
`
`4.4 Clinical Pharmacology
`
`The study DIC1-12-07, conducted with commercial scale, serves as the pivotal clinical
`pharmacology study for this application (n=35). This study evaluated the relative
`bioavailability (BA) of 35mg of diclofenac acid capsules compared to Cataflam 50mg
`tablets, as well as dose-proportionality and food effect. The design compared a 20%
`lower dose of diclofenac acid compared to the reference drug Cataflam. Under fasted
`
`Reference ID: 3375013
`
`13
`
`

`

`Clinical Review
`Steven Galati M.D.
`NDA 204592
`Zorvolex/Diclofenac acid capsules
`
`conditions, the study showed a 26% lower (geometric mean) peak concentrations
`(Cmax) and 23% lower (geometric mean) AUC (AUC0-t and AUC0-∞) when comparing
`diclofenac acid to Cataflam. There was no difference in time to reach peak
`concentrations (Tmax) between diclofenac acid capsules and Cataflam tablets (~1 hour
`for both). Under fed conditions, diclofenac acid capsules compared to Cataflam
`showed a 48% lower Cmax and 26% and 23% lower (geometric mean) AUC0-t and
`AUC0-∞ values, respectively. The Tmax for diclofenac acid was delayed by ~1 hour
`compared to Cataflam (Cataflam-2.33 hr vs. diclofenac acid -3.32 hr) under fed
`conditions. There were no differences in elimination half-life (T1/2) between diclofenac
`acid and Cataflam under fasted or fed conditions.
`
`The smaller particle size of diclofenac acid capsules has provided no additional
`advantage in either rate (Cmax and Tmax) or the extent of absorption (AUC) compared
`to Cataflam when taken under fasted conditions. In contrast, when taken under fed
`conditions, diclofenac acid capsules has delayed rate of absorption compared to the
`Cataflam (decreased Cmax and delayed Tmax).
`
`The 18 and 35 mg diclofenac capsules show dose proportional pharmacokinetics for
`Cmax and AUC under fasted conditions. When taken under fed conditions, diclofenac
`capsules shows 60%, 14% and 11% lower Cmax , AUC0-t, and AUC0-∞, respectively
`compared to fasted conditions. Taking diclofenac with food delayed the Tmax by 2.32
`hours (1.0 hour fasted vs 3.32 hours fed). Please see the full clinical pharmacology
`review by Dr. Suresh Naraharisetti for further details.
`
` 5
`
` Sources of Clinical Data
`5.1 Tables of Studies/Clinical Trials
`The clinical trials conducted in support of this supplemental NDA for Diclofenac
` capsules are listed in below (Table 5).
`
`
`Table 5: Clinical Trials Submitted in Support of this Application
`
`
`
`DIC3-08-04
`
`Bunionectomy
`
`Relevance
`Population Number of Subjects
`Clinical Trial
`Clinical Trials Contributing to Efficacy Review (Controlled Trials)
`Zorvolex = 216
`Contains efficacy data in pain
`Placebo = 101
`population
`Celexcoxib = 105
`Clinical Trials Contributing to Safety Review
`Zorvolex = 216
`Contains safety data in the pain
`Placebo = 101
`population
`Celexcoxib = 105
`Contains safety and PK data in
`Healthy
`N =38
`DIC1-12-07
`volunteers
`the pain population
`Source: Derived from Applicant’s submission, NDA 204592
`
`DIC3-08-04
`
`Bunionectomy
`
`Reference ID: 3375013
`
`14
`
`(b) (4)
`
`

`

`Clinical Review
`
`Steven Galati M.D.
`
`NDA 204592
`
`Zorvolex/Diclofenac acid capsules
`
`Review Strategy
`5.2
`DIC3—O8—04 (controlled trial) is the pivotal trial reviewed for efficacy and safety. The
`primary analyses of both safety and efficacy will rely only on DIC3—08-04, along with the
`Agency’s previous findings of safety and effectivenesss for diclofenac [505(b)(2)]. The
`Applicant submitted other studies that will provide support for the pivotal trial. DICZ-08-
`03 is a Phase 2, proof-of-concept (POC) study using the POC formulation and not the
`commercial formulation. DIC2-08—03 was reviewed to support efficacy and safety of the
`pivotal trial, but not as a primary source of data. The design and results from the
`individual controlled trials submitted in support of efficacy in the indicated population are
`reviewed in Section 5.3, Discussion of Individual Studies/Clinical Trials. The primary
`efficacy analyses of trial DIC3—08-04 were confirmed by Dr. Feng Li, statistical reviewer.
`
`In addition to the studies in Table 1, the Applicant submitted additional safety
`information
`
`"M"
`
`and an additional pharmacokinetic (PK) study using the POC formulation in
`DIC1-08-01. The "’""trials are ongoing and the Applicant submitted interim analyses
`without the raw datasets, so they will not be included in the formal safety analysis.
`However, these trials were briefly reviewed to detect potential safety signals (see
`relevant sections in Section 7 of this review).
`
`5.3 Discussion of Individual Studies/Clinical Trials
`
`Trial DIC3-08-04
`
`“A Phase 3, Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Active- and
`Placebo-Controlled Study of Diclofenac
`“’mformulation Capsules for the Treatment of
`Acute Postoperative Pain After Bunionectomy"
`
`Conducted from 10/26/2011 to 2/21/2012
`
`Four sites, all located in the United States
`
`Protocol
`
`Objective/Rationale
`The primary objective is to evaluate the analgesic efficacy of diclofenac
`capsules compared with placebo in subjects with acute postoperative
`pain after bunionectomy
`
`The secon