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

`

`
`
`
`
`
`
`
`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:
`
`204-592
`000/Original submission
`12/20/2012
`12/20/2012
`Zorvolex® (diclofenac acid)
` Treatment of mild to moderate acute pain
`Iroko Pharmaceuticals, LLC, Philadelphia, PA
`Division of Anesthesia, Analgesia, and Addiction
`Products (HFD-170)
`Z. Alex Xu, PhD, DABT
`Adam Wasserman, PhD
` Bob Rappaport, MD
`Swati Patwardhan
`
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 204-592 are owned by Iroko Pharmaceuticals, LLC or
`are data for which Iroko Pharmaceuticals, LLC has obtained a written right of reference.
`Any information or data necessary for approval of NDA 204-592 that Iroko
`Pharmaceuticals, LLC 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 204-592.
`
`Reference ID: 3374368
`
`1
`
`

`

`NDA 204-592
`
`
`
`
`Reviewer: Z. Alex Xu
`
`TABLE OF CONTENTS
`
` 1
`
` EXECUTIVE SUMMARY ......................................................................................... 3
`1.1
`INTRODUCTION.................................................................................................... 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`1.3 RECOMMENDATIONS............................................................................................ 5
`2 DRUG INFORMATION ............................................................................................ 6
`2.1 DRUG................................................................................................................. 6
`2.2 RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 6
`2.3 DRUG FORMULATION ........................................................................................... 7
`2.4 COMMENTS ON NOVEL EXCIPIENTS....................................................................... 7
`2.5 COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ......................................... 7
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 8
`2.7 REGULATORY BACKGROUND ................................................................................ 8
`3 STUDIES SUBMITTED............................................................................................ 9
`3.1
`STUDIES REVIEWED............................................................................................. 9
`3.2
`STUDIES NOT REVIEWED ..................................................................................... 9
`3.3
`PREVIOUS REVIEWS REFERENCED........................................................................ 9
`4 PHARMACOKINETICS/ADME/TOXICOKINETICS ................................................ 9
`
`5 SPECIAL TOXICOLOGY STUDIES ...................................................................... 11
`
`6 LITERATURE SUBMISSION................................................................................. 14
`
`7 APPENDIX/ATTACHMENTS................................................................................. 14
`
`
`Reference ID: 3374368
`
`2
`
`

`

`NDA 204-592
`
`
`1
`
`Executive Summary
`
`
`
`Reviewer: Z. Alex Xu
`
`Introduction
`1.1
`Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) which has been approved
`by the Agency with various salt formula and different formulations including Cataflam®
`(NDA 20-142; Novartis Pharmaceuticals Corporation), a diclofenac potassium oral
`tablet, for treatment of primary dysmenorrhea, relief of mild to moderate pain, and relief
`of the signs and symptoms of OA and RA in adults. This submission is a 505(b)(2)
`application referencing Cataflam which seeks approval of Zorvolex (diclofenac acid
`) for treatment of mild to moderate acute pain.
`
`
`The application relies on prior findings of safety and efficacy of the reference drug,
`Cataflam along with results of 4 clinical trials conducted by the Applicant. There is
`limited nonclinical information submitted to support the approval of Zorvolex. Zorvolex
`capsule is a reformulation of diclofenac with a reduced particle size which was
`hypothesized to improve bioavailability after oral administration. Of note, reduction of
`particle size does not appear to impose additional risk of toxicity since the particles will
`be dissolved in gastric fluid after administration. The Applicant proposed that with
`improved bioavailability, a 20% reduction in the diclofenac dose of Zorvolex could
`provide comparable pain relief to Cataflam 50 mg tablets, while offering the potential to
`improve the safety profile of this NSAID compound. However, clinical studies did not
`prove this hypothesis. Dose-normalized systemic exposure of diclofenac of Zorvolex
`was actually slightly lower than that of Cataflam in human at equivalent dose. The
`recommended maximum dosage is 35 mg TID which is covered by the recommended
`maximum dosage in Cataflam label (50 mg TID) based on systemic exposure. In
`addition, the treatment duration for Zorvolex does not appear to be longer than that of
`Cataflam as suggested by the indication. Therefore, nonclinical toxicity studies are not
`needed for Zorvolex NDA submission. The excipients in the drug formulation are not
`novel and the amounts of these excipients in the drug product do not exceed those of
`prior approved products by the Agency. All impurities in the drug substance and
`product are below the qualification level as required by the ICH Q3A and Q3B guidance.
`For impurities with structure alert for genotoxicity, computational toxicity analysis which
`is also known as quantitative structure-relationship analysis (QSAR) were conducted to
`investigate the potential for genotoxicity, which is consistent with the Agency’s current
`thinking.
`
`1.2 Brief Discussion of Nonclinical Findings
`Three known diclofenac acid related impurities were identified in the drug substances
`and drug product (impurity A, B, and C). According to the specifications of drug
`substance, the level of these known impurities is no more than (NMT)
`% of the drug
`substance, which is lower than the qualification threshold level as required by ICH
`guidance Q3A: impurities in new drug substances. In addition, the levels of these
`impurities in the drug product are NMT
`% and % in the 18 mg and 35 mg
`strength capsule, respectively, according to the release and shelf-life specifications of
`
`Reference ID: 3374368
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 204-592
`
`Reviewer: Z. Alex Xu
`
`the drug product. These specifications are less than the qualification threshold levels
`required by the ICH guidance Q3B: impurities in new drug products, when the daily
`intake of drug product is 10-100 mg and 100 mg -2 g, respectively. Therefore, additional
`toxicity studies for impurity qualification as required by ICH Q3 guidance are not needed
`for the Zorvolex NDA. For impurities that are less than the qualification threshold but
`with a structure alert for genotoxicity, a computational genotoxicity assessment is
`required for qualification. According to Dr. Ying Wang, the CMC reviewer for this
`product, impurity B and C have structure alerts. The Applicant conducted a
`computational toxicity evaluation to assess the potential genotoxicity of impurity A, B,
`and C using the MC4PC system. MC4PC is a knowledge—based system using statistical
`correlation which is designed to evaluate/predict the associations between the structure
`of the chemicals and their potential activities in a specific biological assay such as Ames
`assay, in vitro chromosomal assay, and in vivo micronucleus assay, etc. MC4PC
`performs analysis using modules developed by the Informatics and Computational
`Safety Analysis Staff (ICSAS) group of the us FDA
`“9‘". The results of
`the analysis predicted that all 3 impurities are negative in Ames assay, in vitro gene
`mutation assay, in vitro chromosomal assay, in vivo micronucleus assay, and in vivo
`gene mutation assay, suggesting these are non-genotoxic. Based on the current
`thinking of the Agency, only the Ames assay is considered for computational toxicology
`analysis because of the large variability and unreliability in the data of other assays. If
`the computational analysis for Ames assay is negative, there is no need to further
`investigate the genotoxicity potential of an impurity. Notably, the Applicant’s evaluation
`did not incorporate an evaluation in an expert rule-based QSAR model. Evaluation in
`models with both statistical correlation and expert rules are considered necessary by
`the Agency. Therefore, the structures of these compounds were sent to CDER
`computational toxicity group (CTG) for analysis of the association of the structures with
`the potential activity in Ames assay using MC4PC system and another knowledge-
`based system, Leadscope Model Appliers (LMA). Both MC4PC and LMA systems use
`statistical correlations to make predictions.
`In addition, a Derek analysis system which
`uses human expert rules for prediction was also used in the analysis conducted by
`CTG. The results of the analysis predicted that all 3 known impurities of the Zorvolex
`are negative in Ames assay thus not considered to be mutagenic. Overall, the known
`impurities of Zorvolex were sufficiently qualified.
`
`A pharmacokinetic study was included in this submission to compare the bioavailability
`between the diclofenac acid
`“m capsule formulation and Voltaren® immediate—
`release tablet (diclofenac potassium) in beagle dogs. In this study, 6 dogs/group were
`administered Voltaren 25 mg tablet, diclofenac acid
`0"" capsule 18 mg and
`diclofenac acid
`“m capsule 35 mg. The diclofenac
`“m capsule 18 mg
`produced higher Cmax (30% T) and AUCo—4hr (16% T) as compared to Voltaren 25 mg
`after dose normalization. However, this effect was not seen with administration of
`"'"" capsule 35 mg. The dose normalized Cmax (l 4%) and AUG (18%) at
`"M" 35 mg were generally similar to those of Voltaren 25 mg tablet. In addition,
`there was no significant difference in Tmax between the Voltaren 25 mg group and
`W" 18 mg group while Tmax of
`“M 35 mg group was 45% higher than that
`of Voltaren 25 mg group. Overall, this study did not provide convincing evidence to
`
`Reference ID: 3374368
`
`

`

`
`
`Reviewer: Z. Alex Xu
`
`NDA 204-592
`
`demonstrate that the reduction of particle size of diclofenac significantly improves
`absorption and systemic exposure. This study is not required for NDA approval since
`human PK data of Zorvolex are available.
`
`In addition, the Applicant conducted nonclinical literature search using National Library
`of Medicine (NLM, PUBMED) as the search engine with publication period from 1978 –
`2012, attempting to support the efficacy and safety of diclofenac . The publications
`which were found by literature search are listed in Appendix 1. Since the safety of
`Zorvolex is covered in dosage and duration by the referenced FDA approved drug
`product, Cataflam, information from these publications will not be included in the label of
`Zorvolex. These publications were not evaluated.
`
`In summary, Zorvolex NDA referenced Cataflam to support the safety of dosage and
`duration; therefore, nonclinical toxicity studies are not needed. There are no safety
`issues for excipients. In addition, the impurities of Zorvolex drug substance and drug
`products were appropriately qualified.
`1.3 Recommendations
`
`1.3.1 Approvability
`Zorvolex may be approved for the proposed indication from the nonclinical perspective
`
`1.3.2 Additional Non Clinical Recommendations
`None
`
`1.3.3 Labeling
`Labeling of Zorvolex is still ongoing. Topics that will be addressed from nonclinical
`perspective include: 1) Converting the pregnancy (8.1), Labor and Delivery (8.2), and
`Nursing mother (8.3) section into PLLR format; 2) Revision of Nonclinical Toxicology
`section (13) if necessary.
`
`The current Cataflam label does not contain the Nonclinical toxicology section (13). In
`2005, when revisions to all NSAID labeling was initiated, the Agency incorrectly
`informed sponsors to leave out the pregnancy or carcinogenicity data if toxic effects
`were not seen in their studies. In this submission, the Applicant cited Zipsor® (NDA 22-
`202, diclofenac potassium) for the Nonclinical toxicology section in the Zorvolex label.
`Of note, Zipsor was approved in 2009 as a 505 (b)(2) application which also referenced
`Cataflam. The language of Nonclinical Toxicology section in the original Cataflam label
`will be retrieved and compared with the proposed language of this section in Zorvolex
`label. Revision will be made if necessary
`
`Reference ID: 3374368
`
`5
`
`

`

`NDA 204-592
`
`2 Drug Information
`
`
`
`Reviewer: Z. Alex Xu
`
`2.1 Drug
`CAS Registry Number (Optional)
`
`Generic Name
`
`Code Name
`
`Chemical Name: 2-(2-(2,6-dichlorophenylamino)phenyl) acetic acid
`
`Molecular Formula/Molecular Weight
`
`Diclofenac
`
`Diclofenac acid
`
`
`C14H11Cl2NO2; MW = 296.15
`
`
`Structure or Biochemical Description
`
`
`
`Pharmacologic Class: Nonsteroidal Anti-inflammatory Drug
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
`Zorvolex was developed under IND 103,880. Diclofenac has been approved by the
`Agency with various salt formula and formulations as shown in the below table.
`
`List of Approved diclofenac drug products
`NDA No. Drug name Active
`Date of
`ingredient
`approval
`Diclofenac Na +
`12/1997
`misoprostol
`Diclofenac K+
`Diclofenac Na+
`
`Formulation
`
`Indication
`
`Oral tablet
`
`Oral solution
`
`Ophthalmic
`solution
`Patch
`
`Topical
`solution
`Topical gel
`(3%)
`
`Treatment of the signs and symptoms of OA or RA in
`patients at high risk of developing NSAID-induced gastric
`and duodenal ulcers and their complications
`Acute treatment of migraine attacks with or without aura
`
`Postoperative inflammation in cataract extraction
`
`Treatment of acute pain due to minor strains, sprains, and
`contusions
`
`Treatment of signs and symptoms of osteoarthritis
`
`Treatment of actinic keratoses
`
`20-607
`
`Arthrotec
`
`22-165
`
`20-809
`
`21-234
`
`Cambia
`
`Diclofenac
`Sodium
`Flector
`
`20-947
`
`Pennsaid
`
`06/2009
`
`05/1998
`
`Diclofenac
`epolamine
`Diclofenac Na+
`
`01/2007
`
`11/2009
`
`21-005
`
`Solaraze
`
`Diclofenac Na+
`
`11/2000
`
`Reference ID: 3374368
`
`6
`
`

`

`NDA 204-592
`
`Reviewer: 2. Alex Xu
`
`
`
`22—202
`
`Zipsor
`
`Diclofenac K+
`
`06/2009
`
`Oral capsule
`
`11¢]in Ofmild ‘0 mate acute Pain in adults
`
`modaatcpaimthc signsandsympmmsofOAandRA 19-201
`
`Voltaren
`
`Diclofenac Na+
`
`07/1 988
`
`Enteric-coated
`tablets
`
`Relief 9”“? signs a_n_dW of 0% RA and
`mlosmg Mum
`
`2.3 Drug Formulation
`
`The composition of the drug product is shown below as extracted from the submission
`Table 2.3.P.1-1
`Composition of Zorvolex Capsules 18 mg
`
`Amount per Capsule
`.
`
`(tngi‘rapsnle ““2””
`Component
`Active pltzu'inncentical
`
`Diclofenac acid [8.0
`ingredient
`
`.
`
`Inctose monollyrhate
`lVlicTocrystalline cellulme
`Croscarmellose sodium
`
`Sodilun lauryl sulfate
`
`0’) (0
`
`
`
`Sodnun stezuyl funizuate
`Total capsule fill weight
`Size 2 capsule with a blue
`body witlt "IF-303"
`unprinted in white ink
`and a light green cap with
`“l 8 mg“ printed m white
`ink
`
`Capsule shell
`
`1 capsule
`
`
`Table 2.3.P.1-2 Composition of Zorvolex Capsules 35 mg
` Amount per Capsule
`Function
`(mgrcapsule weight) Component
`
`
`Active pharmaceutical
`Diclofenac acid
`35.0
`
`
`
`
`
`
`
`ingredient
`
`
`
`Lactose monohydrate
`(b) (9
`lxlicrocrystalline cellulose
`
`
`Croscarmellose sodium
`
`Sodium lautyl sulfate
`
`Soduun stemyl tunizunte
`
`Total capsule fill weight
`
`Size 1 capsule consisting
`
`
`of a blue body with “IP-
`
`204“ imprinted 111 “lute
` 1 capsule
`ink and a green cap with
`“35 mg" printed in white
`
`ink
`Abbreviations: NF=Nanonal Formulary
`
`
`
`Capsule shell
`
`
`
`2.4 Comments on Novel Excipients
`
`There are no novel excipients in the drug product. The amounts of the excipients used
`in the drug product are below those in approved oral products by the Agency as shown
`in the Inactive Ingredients for FDA Approved Drugs database.
`
`2.5 Comments on Impurities/Degradants of Concern
`
`For the drug substance, the acceptance criterion for each diclofenac acid known related
`substance A, B and C (impurity A, B, and C), was set at not more than (NMT)
`(“""%
`
`Reference ID: 3374368
`
`

`

`
`
`Reviewer: Z. Alex Xu
`
`
`
`NDA 204-592
`
`based on the ICH qualification threshold. Based on the ICH Q3A guidance, if the drug
`substance is administered ≤ 2 g/day, the qualification threshold of a drug substance
`impurity is 0.15% of the drug substance or 1 mg per day intake of the impurity,
`whichever is lower. In this case, the total intake per day of an impurity is
` which is significantly lower than the qualification
`threshold based on mg amount. The unknown impurities are NMT
`% which is less
`than the identification threshold required by the ICHQ3A guidance.
`For the drug product, the reported impurity levels (NMT) are shown in tables of release
`specifications and shelf-life specifications of the drug product with same acceptance
`criteria, as in the table below.
`
`
`Known (%)
`
`Unknown (%)
`
`Total (%)
`
`Impurity A
`
`Impurity B
`
`Impurity C
`
`Impurity levels
`(NMT) in Zorvolex
`product
`18 mg capsule
`35 mg capsule
`
`
`The impurities in the drug product (also known as degradants) are regulated according
`to ICH Q3B: Impurities in New Drug Products. The impurity levels in Zorvolex are below
`the required threshold for identification and qualification as required by ICH Q3B.
`
`Of note, if an impurity possesses a structure alert for genotoxicity, qualification is
`needed even the level of this impurity is below the ICH Q3 qualification threshold.
`Based the Agency’s current policy, computational toxicity assessments are needed to
`investigate the potential of genotoxicity. For computational toxicology analysis, only
`Ames is considered because of the large variability and unreliability in the data of other
`assays. If QSAR for Ames assay is negative, there is no need to further investigate the
`genotoxicity potential of an impurity (if ≤ ICH Q3 qualification threshold). The Applicant
`submitted computational genotoxicity studies (QSAR analysis) of the 3 known impurities
`and the results indicated that the all 3 impurities are not genotoxic. Analysis from the
`CDER Computational Toxicology Consultation Service for a QSAR analysis of genetic
`toxicity confirmed that these compounds are not mutagenic. Overall, the impurities in
`the drug substance and drug product of Zorvolex area considered to be qualified. There
`are no impurity issues for Zorvolex.
`
`2.6 Proposed Clinical Population and Dosing Regimen
`ZORVOLEX is indicated for acute treatment of mild to moderate pain in adults
`2.7 Regulatory Background
`The sponsor submitted the IND (IND 103,880) for the development of diclofenac
` capsules in March, 2009. In an advice letter sent to the Sponsor in response
`to the questions included in the IND submission, the Division stated that “additional
`nonclinical safety studies are not required to support the safety of diclofenac for an NDA
`provided clinical exposure to diclofenac is within the approved limits of the RLD”.
`However, the Division indicated that the safety of any novel excipient, as well as any
`
`Reference ID: 3374368
`
`8
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 204-592
`
`Reviewer: 2. Alex Xu
`
`impurities which exceed ICH thresholds must be adequately qualified for safety. Similar
`information was conveyed to the Sponsor in the EOP2 and pre-NDA meeting.
`
`3
`
`Studies Submitted
`
`3.1
`
`Studies Reviewed
`
`Diclofenac: A comparative bioavailability study in non-naive
`
`1609-002
`
`eC'ID
`
`bea . le do - s Computational assessment and evaluation of potential
`
`genotoxicity of 3 diclofenac degradation products using
`MC4PC
`
`11455-21237
`
`eCTD
`
`3.2
`
`Studies Not Reviewed
`
`None
`
`3.3
`
`Previous Reviews Referenced
`
`None
`
`4
`
`PharmacokineticslADMEIToxicokinetics
`
`Study Title: Diclofenac: A comparative bioavailability study in non-naive beagle
`dogs
`
`Study no.:
`Study report location:
`Conducting laboratory and location:
`09/2008
`Date of study initiation:
`GLP compliance: Yes
`QA statement: Yes
`
`1609-002
`eCTD
`
`(5) (4)
`
`Non-naive female beagle dogs at 9 months to 3 years of age were used in the study.
`The experiment design is shown below as extracted from the study report. Voltaren®
`tablet 25 mg (diclofenac potassium salt tablet which is similar to Catflam), and capsules
`of 35 mg (diclofenac
`W" or 18 mg (diclofenac
`W" diclofenac acid
`"M
`particles were administered orally once on day 1 during the study.
`
`Reference ID: 3374368
`
`

`

`NDA 204-592
`
`Reviewer: 2. Alex Xu
`
`Group Assignments
`
`Group
`Number
`
`’l‘est Article
`
`Number of Female
`Animals
`
`
`
`Voltaren" Rapid 25 mg
`(Diclofenac potassium salt)
`
`
`Diclofenac
`"M"
`35 mg (acid)
`
`
`
`3
`Diclofenac
`
`18 mg (acid)
`
`(I!) (4)
`
`Animals were observed for mortality and clinical signs. The body weight was recorded
`on the day of dosing. Blood samples were collected prior to dosing, and post-dosing at
`10, 20, 30, and 45 minutes, and 1, 1,5, 2, 4, 6,8, 12, 24, 30, 36, and 48 hours. PK
`
`parameters were calculated.
`
`Results:
`
`The dose normalized Cmax and AUC are shown in the table below. At 18 mg, the
`diclofenac acid
`"“0 particles appeared to produce higher than Voltaren 25 mg in
`Cmax (30% T) and AUCMhr(16% T). However, this was not seen at 35 mg diclofenac
`acid
`M" group. This may be because of the ratio of available area for absorption
`versus the amount of drug substance. Nevertheless, these data did not suggest that
`absorption may be increased by reduction of particle size of the drug substance.
`
`Com arison of C"lax and AUC with dosin . correction
`
`Voltaren 25 mg
`
`Diclofenac acid
`M“) 35 mg
`
`Diclofenac acid
`“"0 18 mg
`
`PK parameters
`normalized by
`dose
`
`Cm/mg Wm»
`
`AUCMh/mg
`(ng0hr/ml)
`
`AUCamn/mg
`(ng-hr/ml)
`
`
`
`692
`
`753
`
`1262
`
`1205
`
`In addition, there was no significant difference in Tmax between the Voltaren 25 mg
`(I!) (4)
`(5) (4)
`group and
`group while Tmax of
`group was 45% higher than that of
`Voltaren 25 mg group as shown in the table below (extracted from the study report).
`Overall, reduction of particle size may not play an important role in diclofenac drug
`substance absorption and systemic exposure.
`
`Reference ID: 3374368
`
`1 0
`
`

`

`NDA 204-592
`
`Reviewer: Z. Alex Xu
`
`Table 2. Summary Statistics for Plum-Minute Parameter: for Dtclolenac In Dogs
`
`secv
`
`3.57 - 10.0
`
`14.000
`14.200
`
`10,900
`101%
`
`0.625
`1.00
`
`4.920 - 15.500
`8.020 - 24.100
`
`8,080 - 16.900
`
`0.167 - 1.50
`0.333 - 2.00
`0.333 - 1.00
`
`13,4133 - 2|.686
`22,373 . 32,814
`12,494 - 18,367
`
`21.764 - 44.800
`36.410 -67.384
`18.935 - 27.255
`
`23.867 - 49.925'
`
`39,517 ~69,999‘
`19.005 40.132
`
`7.02 - 21.7'
`
`5.35 -6.70‘
`
`27.660
`40.584
`20.524
`147%
`7496
`33.233'
`
`42,368‘
`22.461
`129%
`68%
`8.78'
`
`6.10°
`6.77
`
`11,793 i 4.631
`15.920 * 6.293
`
`11,107 : 3,127
`135%
`
`0.708 f 0.488
`1.03 t 0.65
`
`17.296 i 3,239
`26,356 i 4.104
`14,423 i 2,223
`
`29.107 1 8.342
`44,186 1: 11.560
`21,703 i 3.213
`152%
`75%
`35,030 i 9.999'
`
`48,813 1 14.220”
`23.086 3 4.116
`139%
`66%
`10.9 t 6.1‘
`
`6.06 +. 0.70"
`6.78 1 2.32
`
`39%
`40%
`
`28%
`
`69%
`64%
`
`29%
`26%
`15%
`
`29%
`
`29%
`18%
`
`56%
`
`12%
`42%
`
`’
`
`-
`
`“WM!
`0')an
`VR
`
`0‘0
`0(4)
`”(ova
`0')an
`
`n — 6.:xceplasnoled.
`' nLS
`" n14
`
`5
`
`Special Toxicology Studies
`
`Study title: Computational assessment and evaluation of potential genotoxicity of 3
`diclofenac degradation products using MC4PC
`
`Study no.:
`Study report location:
`Conducting laboratory and location:
`GLP compliance:
`
`11455-21237
`eCTD
`
`No
`
`(1’)“)
`
`The purpose of this study was to perform a hazard assessment of the potential
`genotoxicity of three known impurities identified in diclofenac drug substance and drug
`
`Reference ID: 3374368
`
`1 1
`
`

`

`NDA 204-592
`
`Reviewer: Z. Alex Xu
`
`product. These included
`“m
`impurity A),
`m“)
`impurity B), and
`impurity C). The structures of these compounds are as
`
`(m4)
`
`follow.
`
`(5) (4)
`
`The assessment was performed with a computer-based expert system consisting of the
`MC4PC software and 4 sets of carefully designed expert modules, i.e., two sets for
`rodent carcinogenicity (public domain and proprietary), one set for cardiotoxicity, and
`one regulatory relevant set for genotoxic potential. The modules were developed by the
`ICSAS group of the us FDA
`"m. MC4PC is a knowledge-based system
`designed to evaluate the associations between the structure of the chemicals and their
`potential activities in a specific biological assay. Its main goal is to find the structural
`entities that discriminate active molecules from inactive ones and its success is
`
`dependent on the validity of the working hypothesis that a relationship exists between
`chemical structure and activity. The results of the assessment were summarized in the
`following tables as extracted from the study report. The RCA (Research Cooperative
`Agreement with ICSAS FDA) method expert analysis is a protocol currently used by
`FDA/CDER ICSAS to perform human expert prediction of toxicity for test chemicals by
`processing MC4PC output data and identify structural alerts across multiple
`toxicologically related endpoints. The process typically involves combining data
`obtained from a module set consisting of modules representing 3—6 (as many as 20)
`closely related endpoints. Based on the RCA analysis, all 3 compounds were predicted
`to be negative in Ames assay, in vitro gene mutation assay (MA in vitro),
`in vitro
`chromosomal assay (CA in vitro), in vivo micronucleus assay (MN in vivo), and in vivo
`gene mutation assay (MA in vivo) except “inclusive” for
`"MB in MA in vitro and CA in
`vitro.
`In addition, although it was predicted to be negative in Ames for
`“MA and in MA
`in vivo for
`“MB, there were possible structure coverage problems as shown below.
`However, the final conclusion represented the conclusion from the review expert in
`0"" taking into account all the available evidence, including the
`W"
`available experimental results.
`
`and
`
`Reference ID: 3374368
`
`1 2
`
`

`

`NDA 204-592
`
`Reviewer: 2. Alex Xu
`
`Table 3. Summary of results and overall conclusions for the genotoxicity tests
`FINAL
`CA In WWO
`
`
` CONCLUSION
`
`
`
`RCA
`
`
`“HM“
`Review
`
`[mm
`( al
`Expon
`
`
`
`
`
`AMES = bacterial ullutauou assay. MA = mammahm CA : chmunsouml alienation. MN : mouse lulcrouucleus
`' positive: l 'l porennally positive. - negative: l-l potentially negative —mconclml\'e " possible smlcnutll coverage problems
`
`Based on these results, it was concluded in the study report that, overall, the 3
`compounds
`"MA,
`“MB, and
`“’mC) did not demonstrate convincing evidence of
`activity in genotoxicity test assessments.
`
`Based on the current thinking of the Agency, only Ames is considered right now for
`computational toxicology analysis because of the large variability and unreliability in the
`data of other assays. If the computational analysis for Ames assay is negative, there is
`no need to further investigate the genotoxicity potential of an impurity. The structures of
`these compounds were also sent to the CDER Computational Toxicology Group (CTG)
`for evaluation of Ames assay in order to confirm the results from the Applicant. All 3
`compounds were determined to be no structure alerts using Derek Nexus software, an
`analysis system based on human expert rules for toxicity prediction. However,
`“""B
`and
`“MC were identified to contain structure alerts by Dr. Ying Wang, the CMC
`reviewer of the drug product. Using MC4PC as well as LMA (Leadscope Model
`Appliers) system, all 3 compounds were predicted to be non-mutagenic as shown below
`(extracted from CTG report). Predictions were made using statistical correlations in
`MC4PC and LMA systems.
`
`Table 1. Results of CDER in silico anal sisl
`
` Substance A
`
`Derek Nexus
`Leadscope
`
`Substance B
`
`Substance C
`
`‘
`
`Salmonella
`Muta-enicit
`
`Derek Nexus
`
`Leadsoope
`
`MC4PC
`
`Derek Nexus
`Leadscope
`
`
`
`Reference ID: 3374368
`
`1 3
`
`

`

`NDA 204-592
`
`
`
`
`Reviewer: Z. Alex Xu
`
`
`
`
`Of note, the analysis from the CTG group was conducted based on only dataset of
`salmonella bacterial strains. E. coli strain models were not included. According to Dr.
`Mark Powley, an expert of computational toxicity assessment in CDER, the currently
`available E.coli models are based on small training sets and are not very useful. He also
`indicated that very few bacterial mutagens were only positive in E. coli and the inclusion
`of E. Coli strains is not critical.
`6
`Literature submission
`The Applicant conducted nonclinical literature search using National Library of Medicine
`(NLM, PUBMED) as the search engine with publication period from 1978 - 2012. Since
`the safety of Zorvolex is covered by the referenced FDA approved drug product,
`Cataflam, and the information from these publications will not be included in the label of
`Zorvolex. These publications were not fully reviewed and evaluated by this reviewer.
`
`
` 7
`
` Appendix/Attachments
`
`
`Appendix 1 list of nonclinical publications included in this submission
`
`1. Ahmad M, Iqbal M, Murtaza G. Comparison of bioavailability and pharmacokinetics of diclofenac sodium and
`diclofenac potassium in normal and alloxan-diabetic rabbits. Pak J Pharm Sci. 2012; 25(2):301-306.
`
`2. Brambilla G, Mattioli F, Robbiano L, Martilli A. Update of carcinogenicity studies in animals and humans of 535
`marketed pharmaceuticals. Mutation Research 2012; 750:1-51.
`
`3. Buvanendran A, Reuben SS. Nonsteroidal anti-inflammatory drugs, Acetaminophen, and COX-2 inhibitors. In
`Raj's Practical Management of Pain, Edition 2008; Chapter 35; 671-692.
`
`4. Cataflam [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2011.
`
`5. Chan LY, Chiu PY, Sui SSN, Lau TK. A study of diclofenac-induced teratogenicity during organogenesis using a
`whole rat embryo culture model. Human Repro 2001; 16(11):2390-2393.
`
`6. Chan LY, Chiu PY, Siu SSN, Wang CC, Lau TK. Diclofenac-induced embryotoxicity is associated with increased
`embryonic 8-isoprostaglandin F2α level in rat whole embryo culture. Reprod Tox 2002; 16:841-844.
`
`7. ChemIDPlus Advanced [Internet]. Bethesda (MD): United States National Library of Medicine’s Chem SIS
`System; [cited 2012 April 05]. Diclofenac. CAS Registry Number 15307-86-5 [about 4 p]. Available from:
`http://chem.sis nlm nih.gov/chemidplus
`
`8. ChemIDPlus Advanced [Internet]. Bethesda (MD): United States National Library of Medicine’s Chem SIS
`System; [cited 2012 April 05]. Diclofenac Sodium. CAS Registry Number 15307-79-6 [about 5 p]. Available from:
`http://chem.sis nlm nih.gov/chemidplus
`
`
`Reference ID: 3374368
`
`14
`
`

`

`
`
`Reviewer: Z. Alex Xu
`
`NDA 204-592
`
`9. ChemIDPlus Advanced [Internet]. Bethesda (MD): United States National Library of Medicine’s Chem SIS
`System; [cited 2012 April 05]. Diclofenac Related Compound A. CAS Registry Number 15362-40-0 [about 2 p].
`Available from: http://chem.sis nlm nih.gov/chemidplus
`
`10. Chung MC, Leandro dos Santos J, Oliveira EV, Blau L, Menegon RF, Peccinini RG. Synthesis, ex vivo and in
`vitro hydrolysis study of an indoline derivative designed as an anti-inflammatory with reduced gastric ulceration
`properties. Molecules. 2009; 14:3187-3197.
`
`11. Evanson NK [Internet]. Diclofenac. xPharm: The Comprehensive Pharmacology Reference. Elsevier Inc. 2007;
`1-7. Available from: http://dx.doi.org/10.1016/B978- 008055232-3.61588-0
`
`12. European Pharmacopoeia fifth Edition. European Directorate for Medicines and Healthcare, Strausbourg,
`France. Diclofenac potassium and diclofenac sodium. 2005; 1419-1422.
`
`13. Gan TJ. Diclofenac: an update on its mechanism of action and safety profile. Current Medical Research and
`Opinion. 2010; 26(7):1715-1731.
`
`14. GENETOX [Internet]. Bethesda (MD): United States National Library of Medicine; [cited 2012 May 05]
`Diclofenac, Genetox 15307-86-5 [about 1 p]. Available from:http://toxnet nlm nih.gov
`
`15. Gökçimen A, Rağbetli MC, Baş O, Tunc AT, Aslan H, Yazici AC, Kaplan S. Effect of prenatal exposure to an
`anti-inflammatory drug on neuron n