CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`204592Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`Summary Review for Regulatory Action
`
`electronic stamp)
`haron Hertz, M.D.
`From
`
`Subject
`Deputy Division Director Summary Review
`NDA #
`204592/000
`
`Iroko Pharmaceuticals
`A licant Name
`
`Date of Submission
`December 20, 2012
`PDUFA Goal Date
`October 20. 2013
`
`Zorvolex /Diclofenac
`Proprietary Name /
`
`Established (USAN) Name
`DosaUeForms/Stren h
`Pro nosed Indication s
`
`Casules, 18m and 35 m
`For the treatment of mild to moderate acute ain
`
`Action/Recommended Action:
`
`Material Reviewed/Consulted
`
`0ND Action Packa n e, includin :
`
`Medical Officer Review
`
`Steven Galati, M.D.
`
`Pharmacology Toxicology Review
`CMC Review
`
`Alex Xu, Ph.D., Adam Wasserman, PhD.
`Yin Wan , Ph.D., Prasad Peri, Ph.D.
`
`OBP Review
`
`Banu S. Zolnik, Ph.D, Sandra Suarez, Ph.D.
`
`Fen Li, Ph.D., Janice Derr, PhD.
`
`Clinical Pharmacology Review
`OSI
`
`Suresh Naraharisetti, Ph.D., Yun X11, Ph.D.
`Cynthia F. Kleppinger, M.D., Janice Pohlman, M.D.,
`M.P.H.
`
`
`
`CDTL Review
`
`OSE/DIVIEPA
`
`OPDP/DCDP
`
`OMP/DMPP
`
`Joshua Llo d, M.D.
`
`Vicky Borders-Hemphill, Pharm.D., Jamie Wilkins-
`Parker, PharmD.
`
`Elmice Chung—Davies, Pharm.D., L. Shenee’ Toombs,
`PharmD.
`
`LaShawn Griffiths, MSHS-PH, BSN, RN, Barbara
`Fuller, RN, MSN, CWOCN
`
`Stephen P. Donald, M.S.
`
`CMC Microbiology
`0ND=Ofice ofNew Drugs
`0513: Otfice of Surveillance and Epidemiology
`DMEPA=Division of Medication EnorsPrevention
`DSI=Division of Scientific Investigations
`CD'I'IFCross-Discipline Team leader
`0PDP=0flice of Prescription Drug Promotion
`DCDP=Division ofConsumer Drug Promotion
`0MP=0flice ofMedical Policy Initiatives
`DMPP=Division ofMedical Policy Programs
`
`NDA 204-592 Dep Dir Memo Zorvolexdoc
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`Page 1 of 8
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`Reference ID: 3392832
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`

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`Signatory Authority Review Template
`
`1. Introduction
`
`This is a 505(b)(2) new drug application for Zorvolex, a new immediate-release capsule
`formulation of diclofenac acid. The referenced product is NDA 020142, Cataflam Tablet, an
`immediate—release formulation of diclofenac potassium. The key issues that will be discussed
`in this review are the Applicant’s theory about the effect of a smaller particle size of diclofenac
`in this formulation and the food effect.
`
`2. Background
`
`The Applicant conducted the clinical development program under IND 103,880 and proposes
`to market Zorvolex in two capsule strengths, 18 mg and 35 mg to be dosed three times daily.
`The application is supported by a relative bioavailability and food effect study, a Phase 2
`single-dose study and a Phase 3 efficacy study that was the subject of a special protocol
`agreement, along with relying, in part, on the Agency’s prior finding of efficacy and safety of
`Cataflam. The Applicant developed Zorvolex as a new formulation of diclofenac with reduced
`particle size, intended to promote the dissolution and absorption of diclofenac. However, the
`absorption of diclofenac from Cataflam is nearly 100% following oral administration. The
`Applicant claimed that the improved dissolution properties of Zorvolex would be associated
`with rapid absorption resulting in comparable pain relief to Cataflam at an approximately 20%
`lower dose, although they did not conduct any studies with Cataflam as an active comparator.
`For further details about the development program, refer to reviews by Drs. Lloyd and Galati.
`
`3. CMC/Device
`
`(m4), held by
`DMF
`acceptable. As noted by Dr. Wang:
`
`(but), supports the drug substance and was found to be
`
`The Zorvolex Capsules commercial manufacturing process involves
`
`(m4)
`
`NDA 204-592 Dep Dir Memo Zorvolex.doc
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`Page 2 of 8
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`Reference ID: 3392832
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`

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`The proposed dissolution method and dissolution acceptance criteria were found to be
`acceptable. The Applicant’s request for elimination of bioburden and specified microorganism
`testing for product release and approval of the stability protocol was found acceptable.
`
` concur with the conclusions reached by the chemistry reviewer regarding the acceptability of
`the manufacturing of the drug product and drug substance, and with the categorization of the
`particle size
`. Manufacturing site inspections were
`acceptable. The Applicant’s request for a categorical exclusion (21CFR25.31(a)) is supported
`by the their argument that approval of Zorvolex will "not increase overall use" of diclofenac as
`Zorvolex will compete with existing approved applications. The Applicant also postulated that
`Zorvolex may reduce environmental introductions due to lower dosage levels, but this is
`speculative and without data to support that the lower dosage levels will provide comparable
`efficacy. Stability testing supports an expiry of 24 months. There are no outstanding issues.
`
`
`
`4. Nonclinical Pharmacology/Toxicology
`
`As noted by Dr. Xu, while three diclofenac-related impurities are below qualification
`threshold, two have structural alerts for genotoxicity. A computational toxicity evaluation of
`all three impurities predict that they are not mutagenic. I concur with the conclusions reached
`by the pharmacology/toxicology reviewer that there are no outstanding pharm/tox issues that
`preclude approval.
`
`
` I
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`As noted by Dr. Naraharisetti:
`
`
`
`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.
`
`
`
`
`NDA 204-592 Dep Dir Memo Zorvolex.doc
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`Page 3 of 8
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`Reference ID: 3392832
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`(b) (4)
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`Dose Proportionality between 18 and 35 Zorvolex capsules:
`
`• The two strengths Zorvolex capsules,18 and 35 mg are
` results in dose proportional 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.
`
`
`Dr. Naraharisetti concludes:
`
`
`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.
`
`
`The Applicant developed Zorvolex to have a greater extent of absorption than Cataflam and
`has failed to demonstrate this to be the case. The relative bioavailability study demonstrated
`bioequivalence when adjusted for dose, so that Zorvolex represents a smaller dose of
`diclofenac than is available with Cataflam, although the difference in weight of the salt vs. the
`free acid makes comparing the strengths confusing. I concur with the conclusions reached by
`the clinical pharmacology/biopharmaceutics reviewer that there are no outstanding clinical
`pharmacology issues that preclude approval.
`
`
`
`
`NDA 204-592 Dep Dir Memo Zorvolex.doc
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`Page 4 of 8
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`Reference ID: 3392832
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`(b) (4)
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`

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`6. Clinical Microbiology
`
`
`N/A
`
`
`
`7. Clinical/Statistical-Efficacy
`
`
`Efficacy is supported by one Phase 3 study. A single-dose Phase 2 study was conducted with
`an early formulation and will not be considered further. The Phase 3 study was a randomized,
`double-blind, multicenter, parallel, active and placebo-controlled study evaluating the efficacy
`and safety of two dosing regimens of Zorvolex capsules in subjects with acute postoperative
`pain after bunionectomy. Details of the study design can be found in Dr. Galati’s review.
`Efficacy was demonstrated in this study based on the primary efficacy analysis of the summed
`pain intensity difference (SPID) over 48 hours. The Applicant’s method of handling the effect
`of the use of rescue medication was unusual in that all efficacy results following the use of
`rescue were imputed using the baseline score, rather than the more common method of
`imputing the pre-rescue pain score for the period of time the rescue was expected to be active.
`As more than 80% of the study population used rescue medication, this masked much of the
`effect of Zorvolex. Dr. Li conducted several sensitivity analyses including an analysis of pain
`intensity over time without imputation and an analysis in which pain scores within a time
`window after taking rescue medication were replaced with the pre-rescue pain score. Both of
`these analyses demonstrated efficacy for both doses of Zorvolex as compared to placebo, as
`well as efficacy of an active comparator, celecoxib. No comparative claims with celecoxib are
`supported by this single efficacy study.
`
`As shown in the analysis of data without imputation by Dr. Li, depicted in Figure 2 (page 11)
`from his review, Zorvolex had a statistically significant difference from placebo, indicating
`that in combination with the rescue medication, Zorvolex produced an analgesic effect
`superior to placebo in combination with the rescue medication. The high use of rescue also
`indicates that Zorvolex alone is not sufficient to manage the pain following bunionectomy,
`particularly in the first few hours following surgery, and is consistent with the indication for
`mild to moderate pain,
`. As the purpose of the study was to
`confirm that the lower doses of Zorvolex were effective, and as studies of mild pain can be
`methodologically challenging, the use of the post-bunionectomy surgery study population is
`acceptable.
`
`
`
`
`
`
`
`
`
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`NDA 204-592 Dep Dir Memo Zorvolex.doc
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`Page 5 of 8
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`Reference ID: 3392832
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`(b) (4)
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`
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`Figure 2: Average Pain Over Time – No Imputation After Rescue
`
`
`
`Although an active comparator arm of Cataflam would have enabled the Applicant to evaluate
`whether their initial hypothesis of greater absorption leading to greater efficacy with a lower
`dose had merit, as well as providing early evidence of any differences in safety due to the
`different doses, the Applicant chose not to include a head-to-head comparison with Cataflam.
`Therefore, no comparative claims against Cataflam may be made in labeling or in promotional
`materials.
`
`
`
`
`8. Safety
`
`
`The assessment of safety is based primarily on data from the Phase 3 efficacy study. The
`overall exposure to Zorvolex was 216 subjects who received at least one dose of diclofenac
`(35mg and 18mg groups). As noted by Dr. Galati, no new significant safety concerns were
`identified. There were no deaths or serious adverse events in patients treated with Zorvolex.
`
`It is difficult to assess the adverse events specific to Zorvolex in this population as more than
`80% of subjects received rescue doses of an opioid during the study. Therefore, the reporting
`of adverse reactions in the package insert includes some events that were more frequent in
`placebo patients who relied on opioids for analgesia in the postoperative periods in order to
`provide some information about the frequency of adverse events with Zorvolex. The most
`frequent treatment emergent adverse events occurring in at least 5% of patients in a Zorvolex
`or placebo treatment group were edema, nausea, headache, dizziness vomiting, hematoma,
`constipation, and pruritus.
`
`NDA 204-592 Dep Dir Memo Zorvolex.doc
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`Page 6 of 8
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`Reference ID: 3392832
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`
`Zorvolex will have the class language in the package insert including all of the same warnings
`as Cataflam and will have the NSAID class medication guide.
`
`
`9. Advisory Committee Meeting
`No advisory committee was convened for this application.
`
`
`10.
`
`Pediatrics
`
` A
`
`
`
` deferral for pediatric studies was granted and the Applicant will perform following studies
`according to the requirements under the Pediatric Research Equity Act. Studies under the age
`of 1 year have been waived for diclofenac products due to immaturity of relevant metabolic
`pathways.
`
`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
`
`11.
`
`Other Relevant Regulatory Issues
`
`
`Inspection of two clinical sites were conducted. Inclusion of a patient with a history of gastric
`ulcer and missed pain assessments were noted at one site that enrolled 143 subjects resulting in
`issuance of a Form FDA 483 and Voluntary Actions Indicated, the response by the investigator
`were adequate, and a conclusion, based on review of the full Establishment Inspection Report
`(EIR) was that the data from this site appear acceptable and the deviations noted do not
`indicate serious deviations/findings that would impact the validity or reliability of the
`submitted data.
`
`There are no other unresolved relevant regulatory issues.
`
`
`
`NDA 204-592 Dep Dir Memo Zorvolex.doc
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`Page 7 of 8
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`Reference ID: 3392832
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`

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`12.
`
`Labeling
`
`
`The proprietary name of Zorvolex was found acceptable. Reviews of the package insert,
`medication guide, and carton and container labels were conducted, as appropriate by OSE’s
`Division of Medication Error Prevention and Analysis, OMP’s Division of Medical Policy
`Programs, and OPDP’s Division of Consumer Drug Promotion and comments were conveyed
`to the Applicant for inclusion in labeling.
`
`
`
`13.
`
`Decision/Action/Risk Benefit Assessment
`• Regulatory Action - Approval
`
`
`
`• Risk Benefit Assessment
`Zorvolex is a novel formulation of diclofenac, in this case the free acid, intended
`for the management of mild to moderate pain. There is evidence of efficacy from
`one adequate and well-controlled trial. There is evidence of safety from the same
`clinical trial as well as through reliance on the Agency’s prior findings of efficacy
`and safety for Cataflam. The primary differences between Zorvolex and Cataflam
`is that the former uses the free acid form of diclofenac, while the latter uses the
`potassium salt of diclofenac, and when corrected for differences related to the
`weights of the free acid and salt, the 18 mg and 35 mg strengths of Zorvolex are
`20% lower than the 25 mg and 50 mg strengths of Cataflam.
`
`• Recommendation for Postmarketing Risk Management Activities
`None
`
`• Recommendation for other Postmarketing Study Commitments
`The only post marketing requirements are those required under the Pediatric
`Research Equity Act:
`
`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
`
`
`
`
`
`
`
`
`
`NDA 204-592 Dep Dir Memo Zorvolex.doc
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`Page 8 of 8
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`Reference ID: 3392832
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`

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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`SHARON H HERTZ
`10/18/2013
`
`Reference ID: 3392832
`
`