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

`

`BIOPHARMACEUTICS REVIEW
`Office of New Drug Quality Assessment
`Application No.: NDA 204-592
`Division of Anesthesia,
`Analgesia and Addiction
`Products
`Iroko Pharmaceuticals
`
`Division:
`
`Reviewer: Banu S. Zolnik, Ph.D.
`
`Applicant:
`
`Biopharmaceutics Secondary Signature:
`Sandra Suarez-Sharp, Ph.D.
`Biopharmaceutics Supervisory Lead
`(Acting): Richard Lostritto, Ph.D.
`
`February 5, 2013
`Generic Name: Diclofenac Acid
`Date Assigned:
`For the treatment of acute
`
`pain of mild to moderate
`Date of Review:
` in adults.
`Route of
`Oral
`Capsules, 18 mg and 35 mg
`Administration
`SUBMISSIONS REVIEWED IN THIS DOCUMENT
`Primary Review due
`Date of informal/Formal Consult
`in DARRTS
`September 17, 2013
`
`Trade Name:
`
`Zorvolex
`
`Indication
`
`Formulation/
`Strength
`
`Submission Dates
`
`December 20, 2012
`May 01, 2013
`Type of Submission:
`
`Review Key Points:
`
`September 12, 2013
`
`NA
`
`Original 505 (b)(2) Standard Review
`
`
` Dissolution method and acceptance criterion
`
`
`
`
`SUMMARY OF BIOPHARMACEUTICS FINDINGS:
`In NDA 204-592, Iroko Pharmaceuticals seeks approval to market Diclofenac Acid Capsules for
`the treatment of mild to moderate acute pain in adults. The proposed commercial strengths of
`diclofenac acid are 18 mg and 35 mg. Diclofenac capsules
`
`. The applicant conducted BE studies on both
`
`strengths.
`
`The development program supporting this submission consisted of two phase 1 PK studies
`(DIC1-08001 and DIC1-12-07), one phase 2 (DIC 2-08-03), and one phase 3 (DIC 3-08-04)
`efficacy study. The Phase 1 study DIC1-12-07 and the pivotal phase 3 efficacy studies were
`conducted using the commercial formulation of Zorvolex capsules 18 mg, and 35 mg. All the PK
`studies are being reviewed by Office of Clinical Pharmacology (OCP).
`
`This review evaluates and makes recommendations on the acceptability of the dissolution method
`and acceptance criterion.
`
`DISSOLUTION METHOD AND ACCEPTANCE CRITERION
`The following dissolution method and acceptance criterion for diclofenac acid capsules, 18 mg
`and 35 mg originally proposed by the Applicant are deemed acceptable:
`
`
`
`
`
`Reference ID: 3372775
`
`1
`
`(b) (4)
`
`(b) (4)
`
`

`

`USP Type
`I (basket)
`
`100
`rpm
`
`37°C in 05°C 900 mL
`
`Q= 8% in 20
`10 mM citric acid
`buffer (pH 5.5) with minutes
`0.05 % SLS
`
`Discriminating ability of the dissolution method was assessed during development. It was shown
`that the dissolution method discriminates for batches manufactured using
`(0(4)
`
`
`
`The results of the bioavailability studies comparing the proposed product to the reference
`drug product showed that changes in particle size did not result in improved bioavailability.
`suggesting that particle size may not be a critical material attribute in this case. However. the
`outcome of these results should be interpreted with caution since there may be potential
`confounding formulation effects.
`
`The dissolution acceptance criterion was based on the results of the performance of biobatches,
`clinical. commercial, and stability batches.
`
`RECOMMENDATION:
`
`The ONDQA/Biopharmaceutics team has reviewed NDA 204-592 and its amendments submitted
`on May 1. 2013. The above mentioned dissolution method and dissolution acceptance criterion
`for Diclofenac Acid Capsules. 18 mg and 35 mg have been accepted by the 0NDQA—
`Biopharmaceutics team.
`
`From the Biopharmaceutics perspective. NDA 204-592 for Diclofenac Acid Capsules, 18 mg and
`35 mg is recommended for APPROVAL.
`
`Banu S. Zolnik, Ph. D.
`Biopharmaceutics Reviewer
`Office of New Drug Quality Assessment
`
`Sandra Suarez—Sharp, Ph. D.
`Biopharmaceutics Secondary Signature
`Office of New Drug Quality Assessment
`
`cc: R LostIitto
`
`Reference ID: 3372775
`
`

`

`BIOPHARMACEUTICS ASSESSMENT
`
`1. BACKGROUND
`
`Submission: Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID). The
`Applicant
`is seeking approval
`to market Zorvolex capsules, 18 mg and 35 mg
`administered orally three times a day for the treatment of mild to moderate acute pain in
`adults.
`
`The Applicant submitted this 505 (b) (2) Application to rely on the Agency’s findings of
`the safety and effectiveness of the previously approved drug product, Cataflam® 50 mg
`(diclofenac potassium immediate release tablets, NDA 20-142). Diclofenac capsules 18
`mg and 35 mg are
`(low
`composition. The applicant conducted BE studies on both strengths.
`
`The development program supporting this submission consisted of two phase 1 PK
`studies (DICl—08001 and DICl—12-07), one phase 2 (DIC 2-08—03), and one phase 3
`(DIC 3—08-04) efficacy study. The Phase 1 study DICl-12-07 and the pivotal phase 3
`eflicacy studies were conducted using the commercial formulation of Zorvolex capsules
`18 mg, and 35 mg. All the PK studies are being reviewed by CCP.
`
`Review: The Biopharmaceutics review is focused on the acceptability of the dissolution
`method and acceptance criterion.
`
`Drug Substance
`Drug substance solubility increases with the increase in pH. Solubility of diclofenac is
`0.08060 mg/mL in pH 5.75 Citrate Buffer with 0.05% SLS. For 18 mg, and 35 mg
`strength capsules, the concentration of diclofenac in 900 mL media is 0.019 mg/mL and
`0.037 mg/mL, respectively. Therefore, solubility of diclofenac in the proposed media is
`approximately 4.5 times the 18 mg dose, and 2.3 times the 35 mg dose. It is estimated
`that sink conditions are achieved for both strenghts.
`
`Drug Product
`Zorvolex capsules are a reformulation of diclofenac, in the acid form. The manufacturm'
`process involves
`(m
`
`7
`
`are microcrystalline
`cellulose, croscarmellose sodium, sodium stearyl fumarate and sodium lauryl sulfate.
`Below tables summarize the formulation of Zorvolex Capsules, 18 mg and 35 mg.
`
`Reference ID: 3372775
`
`

`

`Overview of the Components of Zorvolex Capsules 18 mg
`Table 2.3.P.2-1
`Used in Clinical Studies
`
`mm
`mum-m-
`Diclofenac
`
`Lactose monohydrate, NF
`
`Mcrocrystalline cellulose, NF
`
`Cmscannellose sodium, NF
`
`Sodium lauryl sulfate, NF
`
`Sodium stearyl fumarat , NF
`
`Purified water, USP'
`
`Total (mg/capsule
`Abbreviations: NF=National Formullry; USP = United States Pharmac
`'
`
`eia' %w/w = °/owei htlwei
`
`I
`
`Tablou.P.2-2 Owaothanpomnuotmmfim
`Usedlncnnlcalsmaa
`
`Used in POC Formulation for Initial Phase 1 and Phase 2
`' UthOCmeWPh-u 1 “M2
`
`Mflm' 1‘?an Family. USP 8 United Slates Maven; 8w." :- Gauguin-n
`
`Reviewer ’s Comments
`
`18 mg and 35 mg strengths used in commercial studies areH.
`
`As noted above, the phaimacokinetic and pivotal clinical stu es were con ucte usmg
`the 18 mg and 35 mg capsule strengths.
`
`Reference ID: 3372775
`
`

`

`2. DISSOLUTION METHOD
`
`Dissolution testing is performed at release and on stability. The dissolution method being
`proposed for Zorvolex capsules, 18 mg and 35 mg is summarized below:
`
`A aratus
`
`(basket)
`
`S - eed USP Type I
`
`100 rpm 37°C a: 05°C 900 mL
`
`10 mM citric acid buffer
`(pH 5.5) with 0.05 %
`SLS
`
`Reviewer ’s Comments:
`The A licant conducted dissolution studies at different basket rotation speeds of I
`100, flrpm and showed that dissolution rate
`basket 5 eed of
`“11. Additionally, the Applicant varied SLS concentrations 0
`
`1n the medla and showed all dissolution profiles were s1m11ar.
`
`
`
`The discriminatin abili of the dissolution method was evaluated b v
`
`
`
`to the Applicant regarding the impact of particle size on dissolution.
`
`
`
`Table1: Particle Size DishibutionDissolutionMethod
`
`C aractenzation Me 0 page 12
`
`Reference ID: 3372775
`
`

`

`3. DISSOLUTION ACCEPTANCE CRITERION
`
`Applicant’s Originally Proposed Dissolution Acceptance Criterion
`The proposed dissolution acceptance criterion for 18 mg and 35 mg is as follows:
`
`
`
`Q='% in 20 minutes
`
`120
`
`Zorvolex Capsules 18 mg
`
`
`
`80
`
`96Released 40
`
`100
`
`80
`
`20
`
`5
`
`10
`
`20
`Till. (minutes)
`
`30
`
`45
`
`Figure 4: Comparative mean dissolution profiles plotted by the reviewer of three
`commercial stability batches of18 mg strength
`
`Reference ID: 3372775
`
`10
`
`

`

`
`
`Zorvolex Capsules 35 m9
`
`120
`
`'5Released
`
`
`
`100
`
`80
`
`20
`
`60
`
`40
`
`5
`
`1o
`
`20
`Tune (minutes)
`
`so
`
`45
`
`Figure 5: Comparative mean dissolution profiles plotted by the reviewer of three
`commerch stability batches of35 mg strength
`
`Reviewa' ’s Comments:
`
`Based on the figures above, the acceptance criterion proposed by the Applicant is found
`acceptable. It should be noted that for 18 mg (commercial batches [0309359, 10306589,
`10306925, and L0306926) and 35 mg strength (commercial batches 10306590,
`10306927 and 1.0306928) were used for the PK, the clinical and the stability studies.
`
`Reference ID: 3372775
`
`1 1
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BANU S ZOLNIK
`09/12/2013
`
`SANDRA SUAREZ
`09/16/2013
`
`Reference ID: 3372775
`
`

`

`CLINICAL PHARMACOLOGY REVIEW
`
`Formulation; Strength(s):
`
`Immediate—release capsules; 18 and 35 mg
`
`Clinical Pharmacology Reviewer:
`
`Suresh B Naraharisetti, Ph.D.
`
`OCP Division:
`
`0ND Division:
`
`Sponsor:
`
`Division of Clinical Pharmacology II
`
`Division of Anesthesia and Analgesia Products
`
`Iroko Pharmaceuticals, LLC
`
`18 mg or 35 mg orally three times a day
`
`Proposed Indication:
`
`Treatment of mild to moderate acute pain in adults
`
`Proposed Dosage Regimen:
`
`TABLE OF CONTENTS
`
`1.0 EXECUTIVE SUMIVIARY ................................................................................................................... 2
`
`1.1 RECOMMENDATION............................................................................................................................. 2
`1.2 PHASE 4 Com...................................................................................................................... 2
`1.3. SLMMARYOF CLINICAL PmmcozochlNDnvcs........................................................................... 2
`
`2.0 QUESTION BASED REVIEW ............................................................................................................ 4
`
`2.1 GENERAL Armmvms OF THE DRUG................................................................................................... 4
`2.2 GLNERAL CLINICAL PHARMACOLOGY .................................................................................................. 7
`2.3. INIRLvszc FACTORS ........................................................................................................................... 11
`2.4. GENERAL Blopmnmcumcs ......................................................................................................... 12
`2. 5. ANALYTICAL SECHON........................................................................................................................ 19
`
`3. DETAILED LABELING RECOMMENDATIONS ............................................................................ 20
`
`4.0 APPENDICES ...................................................................................................................................... 22
`
`4.1 SPONSOR ’3 PROPOSED LABEL............................................................................................................ 22
`4.2 [ADIVEUAL SanSHvorsrs:........................................................................................................... 48
`4.2.1 STwYDEsIGNs: .............................................................................................................................. 48
`4.2.2 STLDYSHVOPSES ............................................................................................................................. 48
`4.3 Com SHEETAAD OCPB ch/REWEWFORM............................................................................. 59
`
`Reference ID: 3374276
`
`

`

`1.0 Executive Summary
`
`1.1 Recommendation
`
`From the Clinical Pharmacology perspective, NDA 204592 submitted on
`03/12/2012 is acceptable provided an agreement can be reached between the sponsor and
`the Agency regarding the language in the package insert.
`
`1.2
`
`Phase 4 Commitments
`
`None
`
`1.3. Summary of Clinical Pharmacology Findings
`
`Iroko Pharmaceuticals, LLC submitted a 505 (b) (2) application for Zorvolex capsules, an
`immediate-release (1R) formulation of Diclofenac for the treatment of mild to moderate
`acute pain in adults. The application is relying on the prior findings of safety and
`efficacy of the reference drug, Cataflam® (NDA 020142). The proposed dose strengths
`are 18 and 35 mg,
`(h)«)_ The sponsor proposed dosage
`regimen is 18 mg or 35 mg orally three times a day
`(m4)
`
`Diclofenac is approved and marketed in the United States as immediate release, modified
`release (both delayed and extended release) and topical formulations for the treatment for
`multiple pain indications. The proposed Zorvolex capsules are a reformulation of
`diclofenac (in acid form) with reduced particle size. Zorvolex capsules are 20% lower in
`‘molar’ diclofenac dose compared to Cataflam tablets (diclofenac potassium salt). The
`calculation of 20% lower molar dose is described in the section 2.1.1. The two 20% lower
`
`strengths of Zorvolex capsules are 18 mg and 35 mg compared to 25 mg and 50 mg
`strengths of Cataflam. The 25 mg strength of Cataflam is however discontinued and the
`Federal Register determination is that the product was not discontinued or withdrawn for
`safety or efficacy reasons.
`
`Sponsor’s rationale for reduced particle size of the proposed formulation is to increase
`the surface area to-mass ratio and thereby facilitate the rapid absorption in the GI tract.
`However, the label for Cataflam indicates that diclofenac is completely absorbed (100%)
`following oral administration, with mean peak concentrations (Tmax) appearing within 1
`hour. Therefore, there may be little room for a new formulation to improve on the
`absorption of the drug.
`
`For this NDA, the safety, the end of Phase 2, the pre—NDA meetings were held on
`04/01/2009, 11/ 09/2010 and 06/7/2012, respectively under IND 103880. The clinical
`development program includes two clinical pharmacology studies and two clinical
`studies.
`
`Clinical Pharmacology Studies:
`Two clinical pharmacology studies, DIC 1-08-01 and DIC 1-12-07 are conducted for this
`application. Out of these two studies, DIC 1—08—01 was conducted with initial proof of
`concept formulation and hence not reviewed expect for the food effect data of Cataflam.
`
`2
`
`Reference ID: 3374276
`
`

`

`
`
`The study DIC1-12-07 was conducted with commercial scale formulation and serves for
`assessing clinical pharmacology information for this product.
` DIC1-12-07 (Phase 1): Relative bioavailability (BA), dose-proportionality and
`food effect study. This study was conducted with commercial scale formulation
`and fulfills the clinical pharmacology information of the proposed product from
`regulatory requirement perspective.
`
`
`Clinical Studies:
`Sponsor conducted one Phase 2 and one Phase 3 clinical studies. The Phase 2 study,
`DIC2-08-03 was conducted with initial proof of concept formulation. The Phase 3 study,
`DIC3-08-04 conducted commercial scale formulation serves as pivotal clinical safety and
`efficacy study for this product.
` DIC2-08-03 (Phase 2 study): Single dose study conducted in patients following
`surgical removal of impacted third molars. This study was conducted with a POC
`formulation and hence only serves as support to efficacy and safety of the pivotal
`trial DIC3-08-04, but not as a primary source of data.
` DIC3-08-04 (Phase 3 study): Multiple dose, pivotal safety and efficacy study in
`patients with acute postoperative pain following bunionectomy. This study was
`conducted with a commercial scale formulation.
`
`
`Relative bioavailability of Zorvolex compared to reference drug Cataflam:
`The relative bioavailability of Zorvolex 35 mg capsules was compared to Cataflam 50 mg
`tablets under fasting and fed conditions in 35 healthy subjects.
` When taken under fasted conditions, 20% lower dose of Zorvolex capsules (35
`mg) compared to reference Cataflam tablets (50 mg) results in 26% lower
`(geometric mean) peak concentrations (Cmax) and 23% lower (geometric mean)
`AUC (AUC0-t and AUC0-∞). There was no difference in time to reach peak
`concentrations (Tmax) between Zorvolex capsules and Cataflam tablets and it was
`~1 hr for both.
` When taken under fed conditions, the 20% lower dose of Zorvolex capsules (35
`mg) compared to the Cataflam tablets (50 mg) results in a 48% lower (geometric
`mean) Cmax and 26% and 23% lower (geometric mean) AUC0-t and AUC0-∞,
`respectively. The Tmax for Zorvolex was delayed by ~1 hr compared to Cataflam
`(Cataflam-2.33 hr vs. Zorvolex-3.32 hr) under fed conditions.
` There were no differences in elimination half-life (T1/2) between Zorvolex and
`Cataflam under fasted or fed conditions.
`
`
`Reviewer comments on formulation:
`The smaller particle size of Zorvolex capsules, as claimed by the sponsor 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, Zorvolex capsules has delayed rate (decreased Cmax and
`delayed Tmax) of absorption compared to the Cataflam
`
`
`
`
`
`
`
`3
`
`Reference ID: 3374276
`
`

`

`
`
`Dose Proportionality between 18 and 35 Zorvolex capsules:
`
` The two strengths Zorvolex capsules,18 and 35 mg
` pharmacokinetics for Cmax and
`
`AUC under fasted conditions
`
`
`Food Effect on Zorvolex capsules:
`The food effect was assessed for Zorvolex 35 mg capsules as well as reference drug
`Cataflam 50 mg tablets under fasting and fed conditions in 35 healthy subjects.
` When taken under fed conditions, Zorvolex capsules results in significant food
`effect in terms of reduced Cmax. Under fed conditions, Zorvolex capsules results
`in 60%, 14% and 11% lower Cmax, AUC0-t and AUC0-∞, respectively compared to
`fasted conditions. Taking Zorvolex with food delayed the Tmax by 2.32 hr (~139
`minutes) (1.0 hr fasted vs 3.32 hr fed).
` The reference drug Cataflam results in 43% and 28% lower Cmax under fed
`conditions without change in AUC, respectively in the studies DIC1-08-01 and
`DIC1-12-07. For food effect, the Cataflam label indicates 30% lower Cmax
`without change in AUC and can be dosed without regards to meals.
` The observed 60% lower Cmax for Zorvolex capsules in the food effect PK study
`is considered significant. Based on the single-oral-dose PK profile of Zorvolex
`capsules, the diclofenac is almost completely eliminated from the body by 8 hours
`(no accumulation). Since Zorvolex is administered TID (every 8 hr) and no
`accumulation from the previous dose, even after multiple dosing every-dose of
`Zorvolex capsules will have similar food effect as observed for a single dose.
`Hence, Zorvolex capsules are to be labeled as ‘Taking Zorvolex with food may
`cause a reduction in effectiveness compared to taking Zorvolex on an empty
`stomach.
`Overall, adequate information has been provided characterizing the clinical
`pharmacology aspects of Zorvolex tablets.
`
`2.0 Question Based Review
`
`2.1 General Attributes of the Drug
`
`2.1.1 What are the highlights of the chemistry and physical-chemical properties of
`the drug substance, and the formulation of the drug product?
`
`
`
`
`
`Reference ID: 3374276
`
`4
`
`(b) (4)
`
`

`

` Table 2.1.1: Physical-Chemical Properties of Diclofenac Acid
`
`I
`; Name
`Diclofenac Acid
`
`2—[2-(2,6-dichlorophenylamino)phenyl]acetic acid
`
`
`
`
`CI
`
`
`
`
`Chemical Name
`
`
`NH
`
`
`
`
`
`
`
`
`white to sli- -t ellowish
`
`
`Cl
`
`OH
`
`0
`
`Molecular Fornulla
`
`Cl4Hl 1C12N02
`
`Molecular Weight
`
`.
`
`Formulation:
`
`Zorvolex capsules are a reformulation of diclofenac with reduced particle size. Zorvolex
`capsules are 20% lower in diclofenac dose compared to Cataflam tablets (potassium salt).
`The two strengths of Zorvolex ca
`es are 18
`and 35
`to the 25
`and
`
`
`
`2.1.2. What is the regulatory history of diclofenac products?
`
`Diclofenac is an approved drug that is already available and marketed in the United
`States as a treatment for multiple indications as shown in Table 2.1.2.
`
`Reference ID: 3374276
`
`

`

`
`
`Flector
`
`21234
`
`01/31/2007
`
`Patch
`
`Voltaren Gel
`
`22122
`
`10/17/2007
`
`Gel
`
`Voltaren
`
`19201
`
`07/28/1988
`
`Tablet
`
`Cataflam
`
`20142
`
`11/24/1993
`
`Tablet
`
`20254
`
`03/8/1996
`
`Table 2.1.2: Brand name diclofenac products and indications:
`Drug Product NDA
`Approval Date Dose Form
`Indication
`Zipsor
`22202
`06/16/2009
`Capsule
`Relief of mild to moderate pain
`Pennsaid
`20947
`11/04/2009
`Lotion
`Treatment of signs and symptoms of
`osteoarthritis (OA)
`Topical treatment of acute pain due
`to minor strains, sprains, and
`contusions.
`Treatment of OA of joints amenable
`to superficial treatment such as the
`hands and knees
`Relief of the signs and symptoms of
`OA and rheumatoid arthritis
`(RA),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 OA and RA
`ER Tablet Treatment of RA and OA
`
`Voltaren XR
`
`2.1.3 What is the composition of the to-be-marketed formulation of Zorvolex
`capsules?
`The proposed commercial dosage forms of Zorvolex capsules include 18 mg and
`35 mg strengths of diclofenac acid. Table 2.1.3 provides the quantitative composition for
`both tablet strengths and the function of each component.
`
`Table 2.1.3: Composition of Zorvolex capsules (18 and 35 mg)
`Strength
`18
`Amount per
`Capsule
`(mg/capsule
`weight)
`18
`
`NF
`NF
`
`Lactose monohydrate
`Microcrystalline
`cellulose
`NF
`Croscarmellose sodium
`NF
`Sodium lauryl sulfate
`Sodium stearyl fumarate NF
`Total capsule fill weight
`-
`
`
`NF - National Formulary
`# Size 2 capsule with a blue body with “IP-203” imprinted in white ink and a light green cap with “18 mg”
`printed in white ink.
`$ Size 1 capsule with a blue body with “IP- 204” imprinted in white ink and a green cap with “35 mg”
`printed in white ink
`
`
`
`
`1 capsule #
`
`1 capsule $
`
`
`
`6
`
`Reference ID: 3374276
`
`Component
`Diclofenac acid
`
`35
`Amount per
`Capsule
`(mg/capsule
`weight)
`35.0
`
`Quality
`Standard Function
`
`Active
`pharmaceutical
`ingredient
`
`(b) (4)
`
`

`

`
`
`
`2.1.4 What are the proposed mechanism(s) of action and therapeutic indication(s)?
`Diclofenac is a nonsteroidal anti-inflammatory drug (NSAID) that exhibits anti-
`inflammatory, analgesic, and antipyretic activities in animal models. The mechanism of
`action of diclofenac, like that of other NSAIDs, is not completely understood but may be
`related to regulation of prostaglandin synthesis via prostaglandin synthetase. The
`mechanism involves an inhibition of cyclooxygenase (COX-1 and COX-2) pathways.
`The proposed indication for Zorvolex capsules is for treatment of mild to moderate acute
`pain in adults.
`
`2.1.5 What are the proposed dosage and route of administration?
`Zorvolex capsules are intended for oral administration. The proposed dosage is 18 mg or
`
`35 mg orally three times a day.
`
`2.1.6 What are the core studies submitted in this NDA?
`The clinical development program includes one pivotal clinical pharmacology study and
`one clinical safety and efficacy study.
` DIC1-12-07 (Phase 1 study using commercial scale formulation): Relative BA, dose
`proportionality and food effect study. This study is a randomized, single-dose, five-
`way crossover, relative bioavailability study of Zorvolex capsules 18 mg and 35 mg
`and Cataflam® 50 mg tablets, in healthy subjects under fed and fasting conditions.
`This study fulfills the clinical pharmacology requirements of the proposed product.
` DIC3-08-04 (Phase 3 study using commercial scale formulation): A Phase 3,
`randomized, double-blind, multiple-dose, parallel-group, active- and placebo-
`controlled study of Zorvolex capsules for the treatment of acute postoperative pain
`after bunionectomy. This is the pivotal safety and efficacy study for this product.
`
`2.2 General Clinical Pharmacology
`
`2.2.1 What are the design features of the clinical pharmacology and clinical studies
`used to support dosing or claims?
`
`The clinical efficacy study, DIC3-08-04 for treatment of acute postoperative pain after
`bunionectomy and the clinical pharmacology study characterizing the formulation form
`the basis to support the dosing for this NDA
`
`For final assessment of the safety and efficacy findings, see Clinical review by Dr. Steven
`Galati (reviewing Medical Officer). Following is a brief summary of the Clinical
`Efficacy assessment provided by Dr. Dr. Steven Galati:
`
`Design: Phase 3, multicenter, randomized, double-blind, multiple-dose, parallel-group,
`active- and placebo-controlled study to evaluate the safety and efficacy of 2 dosing
`regimens of Zorvolex Capsules (35 mg 3 times daily [TID] or 18 mg TID) in subjects
`with acute postoperative pain after bunionectomy. On Day 1 of the study, when subjects
`requested pain medication, a Visual Analog Scale (VAS) assessment was to be
`performed. Subjects with a pain intensity rating ≥ 40 mm on a 100-mm VAS within 9
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`hours of discontinuation of regional anesthesia were to be eligible. Pain intensity (VAS)
`and pain relief (5-point categorical scale) assessments were to be performed during the 48
`hour period after Time 0. Safety was to be assessed by the incidence of treatment-
`emergent AEs (TEAEs) and changes in vital sign measurements. TEAEs were to be
`recorded during the inpatient portion of the study as well as 1 week after discharge. The
`TEAEs after discharge were to be reported to the investigator at a 1 week follow-up visit.
`
`Treatment
`Once the pain intensity entry criteria were to be met, subjects were to be randomly
`assigned to 1 of 4 treatment groups (Table 2.2.1): Zorvolex Capsules 35 mg TID (n=107)
`or 18 mg TID (n=109); placebo (n=106); or celecoxib capsules 200 mg BID (n=106).
`Study drug was to be administered in a QID regimen for 48 hours after the first dose,
`with a maximum of 4 doses (active and/or dummy) in a 24-hour period. One tablet of
`hydrocodone/acetaminophen 10 mg/325 mg was to be allowed every 4 to 6 hours as
`needed for rescue.
`
`Table 2.2.1: Dosing of Treatment Groups DIC3-08-04
`
`
`
`Source: Applicant’s Protocol p. 39
`
`Efficacy
`The primary efficacy analysis was based on the primary endpoint VAS summed pain
`intensity difference (VASSPID) over 0 to 48 hours (VASSPID0-48) in the ITT
`population. Baseline pain on to the VAS pain scale was a mean (SD) value of 75.4
`(16.27) mm and was evenly balanced across treatment groups. The primary efficacy
`analysis was performed using an analysis of covariance (ANCOVA) model, which
`included treatment effect as the factor and baseline pain intensity as the covariate (Model
`1). For Model 1, the LS mean (standard error [SE]) was used in the primary analysis. In
`comparison with the placebo group, the largest difference in squares mean (SE) was seen
`for the 35-mg diclofenac treatment group (446.946 [122.2935]) indicating a statistically
`significant difference (P < 0.001). Differences in the 18-mg diclofenac group 316.145
`(121.5971) (P < 0.010) and the celecoxib treatment group 313.119 (122.5676) (P <
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`0.011) compared with the placebo group were of a lesser magnitude than the 35mg
`diclofenac.
`
`Safety
`Deaths: No subjects died during the trial.
`
`Serious Adverse Events (SAEs): One subject experienced a serious AE during the
`
`trial. The subject was in the Celecoxib group.
`Discontinuations Due to Adverse Events: No subject discontinued due to an AE
`during the trial.
`Common Adverse Events: 77 (72%) and 84 (77.1%) subjects experienced at least
`1 TEAE in the 35mg and 18mg diclofenac groups, respectively. 86 (81.1%) and
`83 (78.3%) subjects experienced at least 1 TEAE in the Celecoxib and placebo
`groups, respectively. The most frequent AEs were nausea (23.4%, 31.2%),
`headache (10.3%, 15.6%) and dizziness (4.7%, 15/6%) in 35mg and 18mg
`diclofenac groups, respectively.
`
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`Conclusion
`Diclofenac was evaluated at a dose of 18-35 mg, given three times per day, in one
`adequate and well-controlled trial. Both the 18mg and 35mg groups showed statistical
`significance in the primary analysis when compared to placebo. In general, there were
`supportive findings in both treatment groups through the secondary analyses as well.
`There is a trend towards improved efficacy and time to onset among the diclofenac 35mg
`subjects compared to the 18mg group. However, no clear dose response can be
`determined from the design and analyses performed.
`
`
`
`2.2.2 What efficacy and safety information (e.g., biomarkers, surrogate endpoints,
`and clinical endpoints) contribute to the assessment of clinical pharmacology study
`data? How was it measured?
`No biological biomarker was assessed in this NDA. In the randomized, double-blind,
`multiple-dose, parallel-group, active- and placebo-controlled study (DIC3-08-04), the
`primary efficacy end point was the s VAS summed pain intensity difference (VASSPID)
`over 0 to 48 hours (VASSPID0-48).
`
`2.2.3. What are the general PK characteristics of the drug?
`The absorption, distribution, metabolism, and excretion of diclofenac as a molecular
`entity are described in the label for the reference listed drug (Cataflam Label, 2005).
`
`2.2.4 Were the active moieties in the plasma (or other biological fluid) appropriately
`identified and measured to assess pharmacokinetic parameters and exposure
`response relationships?
`Diclofenac analgesic activity is primarily due to the parent compound diclofenac; only
`the parent compound was measured to assess the PK parameters.
`
`2.2.5. What are the characteristics of drug absorption? Are Zorvolex parameters
`dose proportional?
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`From the Cataflam package insert, it is known that diclofenac is 100% absorbed
`after oral administration compared to IV administration as measured by urine recovery.
`However, due to first-pass metabolism, only about 50% of the absorbed dose is
`systemically available. Hence its absolute bioavailability is 55%.
`
`Dose proportionality of Zorvolex tablets:
`The dose proportionality between two strengths, 18 and 35 mg Zorvolex capsules was
`assessed as part of study DIC1-12-07 under fasting conditions. Note that the two
`strengths Zorvolex, 18 and 35 mg
`.
`
`Treatments:
` Zorvolex capsules
` Zorvolex capsules
`
`18 mg Fasted (lot #L0309359)
`35 mg Fasted (lot #L0309360)
`
`
`The mean ± SD concentration-time profiles and PK parameters for 18 and 35 mg
`Zorvolex capsules are shown in the Figures 2.2.5 and Table 2.2.5a, respectively. The
`dose proportionality for dose normalized diclofenac plasma PK parameters (35 mg vs. 18
`mg) is shown in the Table 2.2.5b. The dose normalized PK parameters show that 18 and 35
`mg Zorvolex capsules results in dose proportional pharmacokinetics for Cmax and AUC
`under fasted conditions
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`2.3. Intrinsic factors
`
`2.3.1. What is the pediatric plan?
`Zorvolex is a capsule formulation and this application triggers PREA because it is a new
`dosage form. For pediatric studies, Sponsor requested for a waiver from birth to
`and deferral for of pediatric studies for
` 17 years, however not acceptable to the
`Division.
`
`Below is the pediatric studies requirement for this application, based on the discussion
`with Pediatric Review Committee (PeRC), on September 4, 2013.
`Partial waiver in pediatric patients aged birth to < one year
`•
`– Product does not represent a meaningful therapeutic benefit over existing
`therapies for pediatric patients of this age and is not likely to be used in a
`substantial number of pediatric patients in this age group.
`• Deferral for pediatric patients aged 1 to < 18 years. Required pediatric studies as
`below:
`– Study 1: An open-label pharmacokinetic and safety study or studies of an
`age appropriate formulation of diclofenac in pediatric patients 6 to < 18
`years of age with acute pain.
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`— 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