CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203168Orig1s000
`
`
`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
`
`203168
`Application number:
`000
`Supporting document/s:
`6/5/2012
`Applicant’s letter date:
`6/7/2012
`CDER stamp date:
`Product: ProlensaTM: bromfenac ophthalmic solution, 0.07%
`Indication:
`Treatment of inflammation and pain associated
`with cataract extraction
`ISTA Pharmaceuticals, Inc
`CDER/OAP/Division of Transplant and
`Ophthalmology Products
`Robeena Aziz, MPH, PhD
`Lori Kotch, PhD, DABT
`Renata Albrecht, MD
`Michael Puglisi
`
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`
`Applicant:
`Review Division:
`
`Disclaimer
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 203168 are owned by ISTA Pharmaceuticals, Inc or are
`data for which ISTA Pharmaceuticals, Inc has obtained a written right of reference. Any
`information or data necessary for approval of NDA 203168 that ISTA Pharmaceuticals
`Inc. 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
`203168.
`
`Reference ID: 3271050
`
`1
`
`

`

`NDA 203 168
`
`
`
`Robeena M. Aziz, MPH, PhD
`
`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY ......................................................................................... 4
`1.1
`INTRODUCTION.................................................................................................... 4
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 5
`1.3
`RECOMMENDATIONS............................................................................................ 6
`DRUG INFORMATION ............................................................................................ 8
`2.1
`DRUG: BROMFENAC SODIUM, 0.07%..................................................................... 8
`2.2
`RELEVANT INDS AND NDAS................................................................................. 9
`2.3
`DRUG FORMULATION ........................................................................................... 9
`2.4
`COMMENTS ON NOVEL EXCIPIENTS..................................................................... 10
`2.5
`COMMENTS ON IMPURITIES/DEGRADANTS OF CONCERN ....................................... 11
`2.6
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN .................................... 11
`2.7
`REGULATORY BACKGROUND .............................................................................. 11
`STUDIES SUBMITTED.......................................................................................... 11
`3.1
`STUDIES REVIEWED........................................................................................... 11
`3.2
`STUDIES NOT REVIEWED ................................................................................... 12
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 12
`PHARMACOLOGY................................................................................................ 12
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 12
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 12
`4.3
`SAFETY PHARMACOLOGY................................................................................... 12
`PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 13
`5.1
`PK/ADME........................................................................................................ 13
`6 GENERAL TOXICOLOGY..................................................................................... 17
`6.1
`SINGLE-DOSE TOXICITY..................................................................................... 17
`6.2
`REPEAT-DOSE TOXICITY.................................................................................... 18
`7 GENETIC TOXICOLOGY ...................................................................................... 20
`7.4
`OTHER GENETIC TOXICITY STUDIES.................................................................... 20
`CARCINOGENICITY ............................................................................................. 20
`
` 1
`
`2
`
`3
`
`4
`
`5
`
`8
`
`9
`
`10
`
`11
`
`12
`
`REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 20
`
`SPECIAL TOXICOLOGY STUDIES................................................................... 20
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 21
`
`APPENDIX/ATTACHMENTS............................................................................. 22
`
`Reference ID: 3271050
`
`2
`
`

`

`NDA 203 168
`
`
`
`Robeena M. Aziz, MPH, PhD
`
`Table of Tables
`
`Table 1: List of nonclinical studies conducted supporting bromfenac ophthalmic solution,
`0.07%.............................................................................................................................. 5
`Table 2: Qualitative and quantitative composition of bromfenac ophthalmic solution,
`0.07%............................................................................................................................ 10
`Table 3: Comparison Table of proposed, approved and nonclinical toxicology
`study formulation........................................................................................................ 10
`Table 4: List of impurities present in bromfenac ophthalmic solution, 0.07%...... 11
`Table 5: Mean ppm of bromfenac in aqueous humor at indicated time after
`instillation (mean of 2 rabbits at each time-point).................................................... 13
`Table 6: Mean ppm of bromfenac in aqueous humor at indicated time after
`instillation (mean of 2 rabbits at each time-point).................................................... 15
`Table 7: Mean ppm of bromfenac in aqueous humor at indicated time after
`instillation (mean of 3 rabbits at each time-point).................................................... 17
`Table 8: Study protocol ............................................................................................. 19
`
`
`Reference ID: 3271050
`
`3
`
`

`

`NDA 203 168
`
`Robeena M. Aziz, MPH, PhD
`
`1
`
`Executive Summary
`
`1 .1
`
`Introduction
`
`The sponsor (ISTA Pharmaceuticals, Inc) is submitting this NDA application for
`bromfenac ophthalmic solution, 0.07% (also referred to bromfenac sodium, or
`bromfenac in this review). Bromfenac ophthalmic solution 0.07% is a topical,
`nonsteroidal anti-inflammatory drug (NSAID) indicated for the treatment of inflammation
`and pain associated with cataract extraction. Patients will apply one drop to affected
`eye(s) once daily beginning one day prior to cataract surgery, on the day of surgery,
`and through 14 days post surgery.
`
`The indication is the same as the currently marketed product, BromdayTM (bromfenac
`ophthalmic solution) 0.09%, administered once daily (sNDA 021664 for BromdayTM FDA
`approval on 10/2010) and XibromTM administered twice daily (NDA 21644 FDA approval
`3/2005). The bromfenac ophthalmic solution 0.07% formulation in the current
`submission differs from the currently marketed bromfenac 0.09% product in the
`amounts of bromfenac sodium and its target pH.
`m"
`
`The same manufacturer, Regis
`Technologies, will continue to supply the bromfenac sodium solution.
`
`The oral formulation of bromfenac (Duract capsules) was developed by Wyeth-Ayerst
`and was approved for marketing under NDA 20 535 in 1997. However, due to clinical
`findings of hepatotoxicity after marketing, Duract was withdrawn from the market in
`June 1998.
`
`Bromfenac sodium was licensed to Senju Pharmaceutical Co., Ltd, Osaka, Japan for
`development as an ophthalmic solution in Japan (Bronuck®; bromfenac sodium
`ophthalmic solution, 0.1% dosed BID). The Japanese formulation is identical to the US
`product, with the concentration of the active shown as the salt form (0.1% bromfenac
`sodium) rather than the free acid (0.09% bromfenac), respectively. Bronuck was
`approved in Japan in July 2000, and is indicated for the treatment of blepharitis,
`conjunctivitis, scleritis (including episcleritis) and post-operative inflammation.
`
`Senju conducted non-clinical and clinical studies for bromfenac ophthalmic solution and
`obtained approval for marketing in Japan in 2000. Senju recently sublicensed
`bromfenac for ophthalmic use in the United States to ISTA Pharmaceuticals, Inc. The
`non—clinical studies submitted in this NDA were conducted by Wyeth-Ayerst and Senju
`Pharmaceuticals. The nonclinical studies to support this NDA application are referenced
`to the approved products mentioned above.
`
`This indication in the current submission is supported by two clinical trials (Studies Nos.
`SOO124-ER and SOO124-WR) to evaluate the efficacy and safety of bromfenac
`ophthalmic solution 0.07% vs. placebo for the treatment of ocular inflammation and pain
`associated with cataract surgery.
`
`Reference ID: 3271 050
`
`

`

`NDA 203 168
`
`Robeena M. Aziz, MPH, PhD
`
`1.2
`
`Brief Discussion of Nonclinical Findings
`
`The sponsor referred to the nonclinical information submitted to NDAs 21 644
`(bromfenac solution, 0.09%) and 20 535 (bromfenac sodium capsules) for nonclinical
`support for the current NDA application. NDA 21 644 was reviewed by Dr. Conrad H.
`Chen, PhD.
`
`No additional nonclinical studies were required for this current NDA. However, in a pre—
`NDA meeting held on 8/29/2011, FDA requested a comparison of the excipients in the
`new formulation and the previously approved 0.09% formulation. This comparison
`consists of three pharmacokinetic distribution studies, as well as a toxicology study
`conducted with a higher concentration of bromfenac (0.18%) at the same pH and with
`similar excipients as the proposed formulation. All studies were conducted in rabbits.
`Table 1 outlines the studies.
`
`Table 1: List of nonclinical studies conducted supporting bromfenac ophthalmic
`solution, 0.07%
`
`Esmtizigtration
`Description of study
`Type of study
`Pharmacokinetics——
`12-hour aqueous humor
`pharmacokinetics with
`Xibrom — 0.09% and
`0.08% Bromfenac
`
`topical ocular
`instillation
`
`NP050905
`
`Distribution 1
`
`(rabbits)
`
`12-hour aqueous humor
`pharmacokinetics with
`Xibrom QD — 0.18% and
`0.20% Bromfenac
`
`12-hour aqueous humor
`pharmacokinetics with
`Xibrom QD — 0.18%,
`Bromfenac,
`“m
`Tyloxapol, ""“"Sodium
`Sulfite and (Xibrom QD -
`0.18% Bromfenac, m"
`Tyloxapol,
`“m Sodium
`
`topical ocular
`instillation
`
`NP051001
`
`topical ocular
`.
`.
`.
`Instillatlon
`
`NP060702
`
`P0800004
`
`—1'"-——
`Toxicity of different
`formulations of bromfenac
`
`Topical instillation
`studies2
`
`(rabbits)
`
`ophthalmic solutions
`when administered at
`
`topical ocular
`instillation
`
`varying frequencies daily
`for 28 da 3
`
`The distribution studies were not GLP compliant.
`
`Reference ID: 3271 050
`
`

`

`NDA 203 168
`
`
`
`Robeena M. Aziz, MPH, PhD
`
`2The toxicology study was GLP compliant.
`
`Summary of pharmacokinetics distribution studies:
`The sponsor submitted three individual distribution studies using multiple formulations
`and concentrations of bromfenac ophthalmic solutions containing 14C-labeled
`bromfenac (See Table 1 for Study Nos.). The solutions were administered by ocular
`instillation to rabbits, and the aqueous humor levels of radioactivity were measured at 1,
`2, 4, 8, and 12 hours following instillation. The results of these studies showed that
`after 8 and 12 hours, the 0.18% bromfenac ophthalmic solution achieved twice the
`aqueous humor bromfenac concentration of the currently approved 0.09% formulation
`(see specific study reviews for details). The increased aqueous humor levels was
`attributed to the increased concentration of active ingredient, and the lower pH of the
`formula [pH=7.8 (in 0.18% formulation) vs. pH=8.3 (in 0.09% formulation)].
`
`Summary of toxicology studies (topical instillation study):
`In the toxicology study, two formulations of bromfenac ophthalmic solution (0.18% and
`0.08%) were administered at varying frequencies for 28 days by ocular administration to
`rabbits (See Table 1 for Study No.). The 0.08% formulation differed from the 0.18%
`formulation in that it contained
` sodium sulfite, and was formulated at a pH
`of 8.3 ( as compared to pH 7.8 in 0.18% formulation). Sodium sulfite has been used in
`the approved 0.09% formulation at a
` and the same amount will be used in
`the current 0.07% formulation. For each formulation, there were 3 study groups of
`rabbits (N=4/sex/dose) with instillation frequencies of 1, 2 and 4 times per day,
`respectively, for the three 0.18% bromfenac study groups; and instillation frequencies of
`2, 4 and 8 times per day, respectively, for the three 0.08% bromfenac study groups. At
`each instillation, a 50 (cid:541)L drop of test article were administered into the right eye, and 50
`(cid:541)L of saline solution was administered into the left eye.
`
`There was no mortality during the study. Clinical abnormalities included a slight ocular
`discharge on 2 occasions during the study at 2 instillation time points (once following a
`test article instillation, and once following a saline control instillation). These
`observations, however, were not considered to be drug related. There were no ocular
`abnormalities in any of the rabbits during ophthalmic examinations. All animals
`exceeded their initial body weight at study termination (Day 29). Furthermore, there
`were no remarkable changes and/or findings in gross necropsy or histopathological
`examination at study termination (Day 29). Therefore, the bromfenac ophthalmic
`solutions were considered to be non-toxic and nonirritating to the rabbit eye when
`administered for 28 consecutive days at a concentration of 0.08% (8 times per day at
`approximate 1-hour intervals) or at a concentration of 0.18% (4 times per day at
`approximate 2-hour intervals).
`1.3 Recommendations
`
`1.3.1 Approvability
`From a pharmacology/toxicology perspective, approval is recommended.
`
`
`Reference ID: 3271050
`
`6
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 203 168
`
`Robeena M- AZiZ, MPH, PhD
`
`1.3.2 Additional Non Clinical Recommendations
`
`Labeling changes:
`
`For all nonclinical sections of the label (i.e. 8.1, 8.3, 12.1 and 13.1) the proposed
`labeling is similar to that of Bromdayoand XibromTM 0.09% (NDA 21 664). The
`recommended reviewers changes to the sponsor-proposed label were made to adjust
`for mglm2 scaling"In systemic studies, ensure correct use of terminology (teratogen-),
`and to include effects that were omitted in the sponsor’s proposed label (i.e. dystocia
`and delayed parturition).
`
`Italics and blue = additions
`
`Strikethrough and red = deletions
`
`Treatment of rats at oral doses u to 0.9 m k /da
`
`treatment-related malformations in reproduction studies. However, embryo-fetal
`lethality and maternal toxicity were produced in rats and rabbits at 0. 9 mg/kg/day
`and 7.5 mg/kg/day, respective! .
`In rats, bromfenac treatment caused delayed
`
`parturition at0.3mg/kg/daym anddystocia, increasedneonatal
`
`mortality and reduced postna a gro
`
`a
`
`. mg/kg/day.
`
`There are no adequate and well-controlled studies in pregnant women. Because
`animal reproduction studies are not always predictive of human response, this drug
`should be used during pregnancy only if file potential benefit justifies the potential
`risk to the fetus.
`
`Because of the known effects of prostaglandin biosynthesis-inhibiting drugs on the
`fetal cardiovascular system (closure of ductus arteriosus), the use of Prolensa
`ophthalmic solution during late pregnancy should be avoided.
`
`8.3 Nursing Mothers
`
`Caution should be exercised when Prolensa ophflIaImic solution is administered to a
`nursing woman
`
`Reference ID: 3271050
`
`

`

`NDA 203 168
`
`Robeena M. Aziz, MPH, PhD
`
`12.1 Mechanism of Action
`
`Bromfenac is a nonsteroidal anti-inflammatory drug (NSAID) that has anti-
`inflammatory activity. The mechanism of its action is thought to be due to its ability to
`block prostaglandin synthesis by inhibiting cyclooxygenase 1 and 2. Prostaglandins
`have been shown in many animal models to be mediators of certain kinds of
`intraocular inflammation. In studies performed in animal eyes, prostaglandins have
`been shown to produce disruption of the blood-aqueous humor barrier, vasodilation,
`increased vascular permeability, leukocytosis, and increased intraocular pressure.
`
`13 NONCLINICAL TOXICOLOGY
`
`13. 1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Long-term carcinogenicity studies in rats and mice given oral doses of bromfenac up
`to 0.6 mglkg/day
`m4)
`
`and 5 mglkg/day
`significant increases in tumor incidence.
`Bromfenac did not show mutagenic potential in various mutagenicity studies,
`including the reverse mutation, chromosomal aberration, and micronucleus tests.
`
`respectively, revealed no
`
`"m
`
`Bromfenac did not impair fertility when administered orally to male and female rats at
`doses up to 0.9 mg/kg/day and 0.3 mglkg/day, respectively
`mu)
`
`2
`
`Drug Information
`
`2.1
`
`Drug: Bromfenac sodium, 0.07%
`
`CAS Registry Number (Optional): 120638—55—3
`
`Generic Name: bromfenac sodium, bromfenac
`
`Code Name: AH R-1 02828, WAX-121 165A
`
`Chemical Name: sodium [2-amino-3-(4-bromobenzoyl) phenyl] acetate sesquihydrate or
`benzeneacetic acid, 2—amino—3-(4—brombobenzoyl)—, monosodium salt, sesquihydrate
`
`Molecular Formula/Molecular Weight: C15H11BrNNa03l383 glmole
`
`Structure or Biochemical Description
`
`0
`
`Hz"
`
`cnacozua - 11/2 H20
`
`Reference ID: 3271 050
`
`

`

`NBA 203 168
`
`Robeena M. Aziz, MPH, PhD
`
`Pharmacologic Class: non-steroidal anti-inflammatory drug
`
`Relevant INDs and NDAs
`
`Approval date if
`Description of
`IND/NDA
`ao . licable
`submission
`number
`
`
`Bromfenac sodium
`
`hydrate ophthalmic
`solution
`
`sNDA 21 664 —
`BromdayTM 0.09%
`
`GB dosing
`
`bromfenac sodium
`
`hydrate ophthalmic
`solution drops
`
`NBA 21 664 —
`XibromTM 0.09%
`
`BID dosing
`
`bromfenac sodium
`
`hydrate ophthalmic
`solution drops
`
`NBA 20 535 —
`
`Duract®
`(Letter of
`Authorization
`- rovided - Pfizer
`
`bromfenac sodium
`
`capsules
`
`Withdrawn in 6/1998
`
`Treatment of post-
`operative ocular
`inflammation in patients
`who have undergone
`cataract extraction with
`
`posterior chamber
`intraocular lens
`
`Treatment of
`
`postoperative
`inflammation in patients
`who have undergone
`cataract extraction
`
`beginning 1 day prior to
`cataract surgery,
`continue on the day of
`surgery, and for 14 days
`after cataract suro e
`Treatment of
`
`postoperative
`inflammation in patients
`who have undergone
`cataract extraction
`
`beginning 1 day prior to
`cataract surgery,
`continue on the day of
`surgery, and for 14 days
`after cataract suro e
`
`short-tenn management
`of acute and chronic
`
`pain
`
`10/2010
`
`03/2005
`
`2.3
`
`Drug Formulation
`
`The drug substance, bromfenac sodium, formulated as an ophthalmic solution was
`approved March 2005. Regis Technologies will continue to supply bromfenac sodium
`manufactured according to Senju Pharmaceutical's DMF 16414. The DMF was updated
`in August 2011. Table 2 lists the qualitative and quantitative composition of the 0.07%
`formulation.
`
`Reference ID: 3271 050
`
`

`

`NBA 203 168
`
`Robeena M. AZiZ, MPH, PhD
`
`Table 2: Qualitative and quantitative composition of bromfenac ophthalmic
`solution, 0.07%
`
`Component
`
`Function
`
`Bromf
`
`.07%
`
`
`
`...m...W.
`
`Boric acid
`
`Sodium botate
`
`Sodium sulfite
`
`Edetate disodium (EDTA)
`
`Tyloxapol
`
`Bmzalkonium chloride
`
` Equivalent to 0.07 bromfenac fi'ee acid
`2
`if
`to
`'
`H to 7.8
`
`2.4
`
`Comments on Novel Excipients
`
`All excipients meet current USP/NF criteria and are within the limits of the previously
`previous approved ophthalmic product, bromfenac ophthalmic solution, 0.09% (NDA
`21664— XibromTM 0.09%), with the following exceptions (see Table 3):
`o
`
`the 0.07% formulation differs in the drug (API) concentration
`
` . differs in pH
`
`0
`differs in use of tyloxapol, raflter man—
`
`Sodium sulfite (at proposed“as not included in the 0.18% nonclinical batch
`
`used for nonclinical toxicology s u y, ut was included in the 0.08% batch (Study No.
`P0800004 — a topical ocular instillation study). Additionally, the current 0.07%
`formulation will contain the same concentration of sodium sulfite as that contained in the
`currently approved bromfenac 0.09% formulation (NDA 21644- XibromTM 0.09%), No
`serious adverse events attributed tom have been reported to date. As such,
`
`this amount of sodium sulfite to be a
`
`o e .07% formulation is considered
`
`qualified by existing clinical data, as well as provided nonclinical data.
`
`Table 3: Comparison Table of proposed, approved and nonclinical toxicology
`study formulation
`
`Reference ID: 3271050
`
`1 0
`
`

`

`NDA 203 168
`
`Robeena M. AZiZ, MPH, PhD
`
`0.0796 Break-ac
`SSW/v
`
`"Ida-”Mm. 0.09%
`“IN
`
`0.18% Formula
`With
`
`
`
`Boric_Acid
`
`SodhlnBonte (decahydnte)
`
`0.0805
`
`odhlnsnlfite
`
`A
`
`MWthDMfimmflzfimmbefmmdhothum-dophflnlmkdmgmu
`
`2.5
`
`Comments on Impurities/Degradants of Concern
`
`There are no pharmacology/toxicology concerns regarding impurities. Table 4 lists the
`impurities presented in the 0.07% formulation. The acceptance criteria for the specified
`impurities are set at or lower than- which is the identification threshold according
`ICH Q33.
`
`Table 4: List of impurities present in bromfenac ophthalmic solution, 0.07%
`Compound Identification
`
`Chemical Name
`
`2.6
`
`Proposed Clinical Population and Dosing Regimen
`
`- Proposed clinical population: patients who have undergone cataract extraction
`- Dosing regimen: Apply one drop to affected eye(s) once daily beginning one day
`prior to cataract surgery, on the day of surgery, and through 14 days post
`surgery.
`
`2.7
`
`Regulatory Background
`
`- A Type B meeting (pre—NDA) was held with FDA on 8/29/11
`
`3
`
`Studies Submitted
`
`3.1
`
`Studies Reviewed
`
`Three pharmacokinetic distribution studies and one toxicology study was reviewed in
`the current submission (see below). All other studies were reviewed under previous
`NDAs listed in Section 2.2 — Relevant INDs and NDAs.
`
`Pharrnacokinetics - Distribution
`
`Reference ID: 3271050
`
`1 1
`
`

`

`NDA 203 168
`
`
`
`Robeena M. Aziz, MPH, PhD
`
`Study No.
`NP050905
`
`Module
`4.2.2.3
`
`NP051001
`
`4.2.2.3
`
`NP050905
`
`4.2.2.3
`
`Study No.
`POS00004
`
`Module
`4.2.2.2
`
`Study Title
`12-hour evaluation of the aqueous humor pharmacokinetics of
`two formulations of 14C labeled bromfenac following topical
`instillation into the eyes of New Zealand White Rabbits
`12-hour evaluation of the aqueous humor pharmacokinetics of
`two formulations of 14C labeled bromfenac following topical
`instillation into the eyes of New Zealand White Rabbits
`12-hour evaluation of the aqueous humor pharmacokinetics of
`two formulations of 14C labeled bromfenac following topical
`instillation into the eyes of New Zealand White Rabbits
`
`Toxicology
`Study Title
`A 28-day toxicity study of bromfenac ophthalmic solutions
`administered by the ocular route to rabbits
`
`Studies Not Reviewed
`3.2
`All were reviewed under the relevant INDs and NDAs.
`3.3
`Previous Reviews Referenced
`Please see Section 2.2 - Relevant INDs and NDAs above
`4
`Pharmacology
`
`Primary Pharmacology
`4.1
`No additional studies were needed to support the current submission. Secondary
`pharmacology studies using bromfenac sodium was evaluated by Wyeth-Ayerst under
`NDA 20 535. The completed primary and secondary pharmacology studies were
`intended to provide proof of-concept for the drug.
`4.2
`Secondary Pharmacology
`No additional studies were needed to support the current submission. Secondary
`pharmacology studies using bromfenac sodium was evaluated by Wyeth-Ayerst under
`NDA 20 535.
`.
`Safety Pharmacology
`4.3
`No additional studies were needed to support the current submission. A battery of
`safety pharmacology studies following oral and IV dosing in several species using
`bromfenac sodium was evaluated by Wyeth-Ayerst under NDA 20 535.
`
`Reference ID: 3271050
`
`12
`
`

`

`NDA 203 168
`
`Robeena M. Aziz, MPH, PhD
`
`5
`
`PharmacokineticsIADMEIToxicokinetics
`
`5.1
`
`PKIADME
`
`Early studies conducted by Wyeth-Ayerst (NDA 20 535) established the bioavailability,
`general pharmacokinetics, excretion routes and rates, protein binding, and metabolic
`pathway of bromfenac sodium when given both oral and IV routes. Senju
`Pharmaceuticals conducted studies examining the distribution and metabolism of radio-
`labeled bromfenac sodium in ocular tissues following topical ocular instillation of an
`ophthalmic solution in rabbits. For the current submission, three additional studies were
`conducted by the Sponsor to measure bromfenac levels of various formulations in the
`aqueous humor of rabbits. All pharmacokinetic studies are listed in Table 1 and are
`reviewed below.
`
`NP050905: 12-hour evaluation of the aqueous humor pharmacokinetics of two
`formulations of 1“C labeled bromfenac following topical instillation into the eyes
`of New Zealand White Rabbits
`
`Key Study Findings:
`- The currently approved 0.09% formulation achieved peak levels of 0.064 ppm
`bromfenac in the aqueous humor at two hours, with levels decreasing to 0.009
`ppm at 12 hours.
`- The new 0.08% formulation achieved peak levels of 0.093 ppm bromfenac in the
`aqueous humor at two hours, with levels decreasing to 0.005 ppm at 12 hours.
`- Thus the 0.08% formulation showed a somewhat higher level of mean bromfenac
`concentration in the aqueous humor. The clinical formulation in the current
`submission is similar in composition to the new 0.08% formulation.
`- Summary of findings are listed in Table 5.
`
`Table 5: Mean ppm of bromfenac in aqueous humor at indicated time after
`instillation (mean of 2 rabbits at each time-point)
`.
`mum“
`—___M-
`—m
`
`mmNaOH Water: (1.5. both fornmlations
`
`
`
`Report #:
`Study report location:
`Conducting Laboratory and Location:
`
`NP050905
`Module 4.2.3.3
`
`“N"
`
`Date of Study Initiation
`GLP Compliance
`
`9/28/2005
`No
`
`Reference ID: 3271 050
`
`1 3
`
`

`

`NDA 203 168
`
`Robeena M. Aziz, MPH, PhD
`
`No
`14C bromfenac sodium; CP-2301
`-
`- Formula 1 - Xibrom 0.09%
`
`vehicle; Lot No. 0250-45-2
`- Formula 2 - New Xibrom 0.08%
`
`vehicle; Lot No. 0250-44-2
`
`Single dose on Day 1(50 pL or 0.046 mg) using a calibrated pipette,
`into the right eye of each animal
`Rabbits / New Zealand White
`
`20 females assigned to 10 study groups (2 females/dose)
`
`.5
`
`Text Article
`'
`t
`
`Route
`
`Dose
`Volume
`
`Necropsy
`imc Post-Dose
`
`1 hour :t 5 niirmtcs
`50 pl
`Topical ocular instillation
`Formula 1 (Xibrom - 0.09%)
`2 hours :t 15mm
`50 uL
`Topical ocular instillation
`Formula 1 (Xibrom — 0.09%)
`50 uL Home 1 15 mm
`Topical ocular instillation
`Fommla l (Xibrom— 0.09%)
`50 uL
`8 hours i 15 11an
`Topical ocular instillation
`Formula 1 (Xibrom- 0.09%)
`SOuL
`thourst ”minim-s
`Topicalocularinsullation
`Formula 1 (KM—0.09%)
`SOuL
`lhouriSmimitcs
`Topicalocularinsttllation
`Fomflacherhmm—ODM)
`50 uL
`2 hours i 15 mimics
`Topical ocular instillation
`Formula 2 (New Xibrom - 0.08%)
`50 pl,
`4 hours i 15 mimitee
`Topical ocular instillation
`Formrla 2 (New Xibrom - 0.08%)
`Topical ocular instillatim sour.
`8hmi15mimtcs
`Formula2 (New Xibrom-0.08%)
`Topical ocular instillation
`50 pl.
`12 hours i 15 minutes
`Formula 2 (New Xibrom - 0.08%)
`
`
`-——=r:c:-n:nc10w:>
`
`NNNNNNNNNN
`
`Topical ocular instillation into the coniunctival sac
`'
`m4)
`-
`-
`
`'
`
`'
`
`QA Report
`Drug and lot #
`
`Doses:
`
`Species/str
`ain:
`
`Number/sex
`
`[group
`time point:
`
`or
`
`Route
`
`Vehicle
`
`Formulation
`
`Age:
`Weight:
`Parameters
`
`measured:
`
`OphthalmicSolution
`
`[09'3 Formulation Concentration
`
`
`
`currently approvedde
`I DA 021664)
`
`[089". Formulation Concentration
`
`developmental formulation)
`
`
`Bromfenrc Boriceeid
`
`009°.
`
`
`
`horate
`
`Sodium
`
`
`
`sulfite
`
`50d"!!!
`
`
`
`0.08%
`
`edetate
`
`chloride
`
`
`
`
`Disodium Tyloxrpol Bennlkonmm Pon'donei
`
`"” ’
`
`12 weeks
`
`2.5 to 3 kg
`Body weights
`Mortality/morbidity
`Aqueous humor sample was collected from the dosed eye of each
`animal at necropsy
`Radioactivity for 1 C bromfenac present in the aqueous humor
`samples was determined by LSC.
`Sampling time 1 to 12 hours
`
`Reference ID: 3271 050
`
`14
`
`

`

`NDA 203 168
`
`Robeena M. Aziz, MPH, PhD
`
`NP051001: 12-hour evaluation of the aqueous humor pharmacokinetics of two
`formulations of 1"C labeled bromfenac following topical instillation into the eyes
`of New Zealand White Rabbits
`
`Key Study Findings:
`- The new 0.18% formulation achieved peak levels of 0.567 ppm bromfenac in the
`aqueous humor at two hours, with levels decreasing to 0.017 ppm at 12 hours.
`- The new 0.20% formulation achieved peak levels of 0.265 ppm bromfenac in the
`aqueous humor at two hours, with levels decreasing to 0.012 ppm at 12 hours.
`- Thus, compared to Study No. NP050905, the bromfenac concentration for the
`0.18% formulation was approximately twice that for the 0.09% formulation.
`- Summary of findings are listed in Table 6.
`
`Table 6: Mean ppm of bromfenac in aqueous humor at indicated time after
`instillation (mean of 2 rabbits at each time-point)
`
`“Ii-“mum
`
`«NOE. Water: (1.5. boih formulations
`
`Report #:
`Study report location:
`Conducting Laboratory and Location:
`
`NP051001
`Module 4.2.3.3
`
`M"
`
`Date of Study Initiation
`GLP Compliance
`QA Report
`Drug and lot #
`
`9/28/2005
`No
`No
`14C bromfenac sodium; CP-2301
`-
`- Formula 1 — New Xibrom 0.18%; Lot
`No. lSTA—R—05-0252-12-A
`
`- Formula 2 - New Xibrom 0.20% Lot No.
`
`lSTA-R—05-0252-12-B
`
`Doses
`
`Species]
`strain
`NUMBER/
`SEX/
`GROUP 0R
`TIMEPOINT
`
`Route
`
`Single dose on Day 1 (0.060 - 0.090 mglanimal for 0.18% formula;
`and 0.055 — 0.099 mglanimal for the 0.20% formula) using a calibrated
`pipette into the right eye of each animal
`Rabbits/ New Zealand White
`
`20 females assigned to 10 study groups (2 females/dose)
`
`Topical ocular instillation into the conjunctival sac
`
`Reference ID: 3271 050
`
`15
`
`

`

`NDA 203 168
`
`Robeena M. Aziz, MPH, PhD
`
`Sodium
`
`Disodioin
`
`Beualkonium
`
`rhloiidi
`
`Tylompol
`
`
`Sodium
`bonri
`
`Bmmiemc Boric acid
`
`Ophthalmic Solution
`
`veh'c'e .
`:ormu'atlo
`
`Age
`Weight
`
`Parameter
`measured
`
`
`0.18°.iFormlancoConcmnaiiou
`
`i‘dei'elopmeotalz'mnmlation)
`
`023‘? I leaticn Concentration
`
`
`
`developmental famolation)
`11 weeks
`1.71 -2.55 kg
`- Body weights
`- Mortality/morbidity
`- Aqueous humor sample was collected from the dosed eye of each
`.
`ammal at_ 99””?!-
`.
`- RadioactIVIty for C bromfenac present In the aqueous humor
`samples was determined by LSC.
`- Sampling time 1 to 12 hours
`
`NP060702: 12-hour evaluation of the aqueous humor pharmacokinetics of two
`formulations of 1"C labeled bromfenac following topical instillation into the eyes
`of New Zealand White Rabbits
`
`Report #:
`Study report location:
`Conducting Laboratory and Location:
`
`NP060702
`Module 4.2.3.3
`
`M"
`
`Date of Study Initiation
`GLP Compliance
`QA Report
`Drug and lot #
`
`9/18/06
`No
`Yes 0, No (x)
`14C bromfenac sodium; CP-2301
`Formula 1 and 2 — New Xibrom 0.18%; Lot
`No. CP-2301
`
`Key Study Findings:
`- This study compared two different 0.18% formulations; one with
`“M" sodium sulfite (Formula 1) and one with m" tyloxapol, M“)
`(Formula 2).
`- Note the clinical formulation contains tyloxapol at
`
`“M and sodium sulfite at
`
`“M" tyloxapol,
`sodium sulfite
`
`Reference ID: 3271 050
`
`1 6
`
`

`

`NDA 203 168
`
`M (4)
`
`Robeena M. Aziz, MPH, PhD
`
`- Formula 1 achieved peak levels of 0.225 ppm bromfenac in the aqueous humor
`at two hours, with levels decreasing to 0.016 ppm at 12 hours.
`- Formula 2 achieved peak levels of 0.1 11 ppm bromfenac in the aqueous humor
`at two hours, with levels decreasing to 0.008 ppm at 12 hours.
`- Thus at 2 hours, an increase in the concentration of tyloxapol and sodium sulfite
`(Formula 2) resulted in approximately half of mean bromfenac in the aqueous
`humor when compared to Formula 1 where the levels of tyloxapol and sodium
`sulfite were lower.
`
`- Summary of findings are listed in Table 7.
`
`Table 7. Mean ppm of bromfenac in aqueous humor at indicated time after
`\“.0. v.- "0....-
`~u on“ I"“u,
`instillation (mean of 3 rabbits at each time-foint)
`ommsm “n—“m om ———
`
`
`
`(b) “’MOH. Water: (1.5. both formulanons
`
`Doses:
`
`Species/strain:
`Number/sex/
`Group:
`Route:
`vehIC'e .
`Formulation
`
`Age:
`Weight:
`Parameters
`measured:
`
`Single dose on Day 1, 0.58 - 0.9 mg/eye using a calibrated pipette into
`the light eye of each animal
`Rabbits / New Zealand White
`30 females assigned to 10 study groups (3 females/dose)
`
`Topical ocular instillation into the coniunbct‘lyal sac
`0.13% Ophthalmicsolution
`Bromfemc Both-acid
`111:?
`8:33;? Tm? Tyloxapol ”Tami“ Pon‘done
`a»
`
`
`
`14-18 weeks
`2.1 1-2.73 kg
`- Body weights
`- Mortality/morbidity
`- Aqueous humor sample was collected from the dosed eye of each
`animal at necropsy
`- Radioactivity