CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`22-228
`
`
`
`APPLICA TI0N NUMBER:
`
`CROSS DISCIPLINE TEAM
`
`LEADER REVIEW
`
`
`
`
`
`22-228
`
`CROSS DISCIPLINE TEAM
`LEADER REVIEW
`
`

`

`
`Date
`From
`Subject
`NDA #
`Applicant
`Date of Submission
`PDUFA Goal Date
`Type of Application
`Name
`Dosage forms / Strength
`Proposed Indication(s)
`
`Recommended:
`
`
`Cross-Discipline Team Leader Review
`
`August 25, 2009
`William M. Boyd, M.D.
`Cross-Discipline Team Leader Review
`22-288
`ISTA Pharmaceuticals, Inc.
`November 12, 2008
`September 12, 2009
`505(b)(1)
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`Topical ophthalmic solution
`Indicated for the treatment of itching associated with
`allergic conjunctivitis
`Recommended for Approval
`
`1. Introduction
`
`
`Chemical Structure of Bepotastine Besilate
`
`
`
`
`Bepotastine besilate (+)-(S)-4-{4-[(4-Chlorophenyl)(2-pyridyl)methoxy] piperidino} butyric acid
`monobenzenesulfonate was originally developed in Japan by Ube Industries, Ltd. and Tanabe Seiyaku
`Co., Ltd. as a treatment for allergic rhinitis. Bepotastine besilate is a histamine H1 receptor antagonist
`and has an inhibitory action on eosinophilic infiltration to inflammatory sites.
`
`The support of clinical safety and efficacy for bepotastine besilate ophthalmic solution included 3
`clinical studies conducted in the United States under IND 66,864. One safety study (CL-SAF-
`0405071-P) and two efficacy studies (ISTA-BEPO-CS01 and CL-S&E-0409071-P) were performed.
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`
`2. Background
`
`
`An oral preparation of bepotastine besilate [Talion tablets, Mitsubishi Tanabe Pharma Corporation
`(formerly Tanabe Seiyaku Company, Ltd.)] was approved in Japan in July 2000 as a treatment for
`allergic rhinitis (10mg p.o. bid for up to 4 weeks). In January 2002, the additional indication of
`pruritus/itching accompanying urticaria and other skin diseases was approved in Japan. Bepotastine is
`a new molecular entity in the United States.
`
`Studies CL-S&E-0409071 and CL-SAF-0405071 (7/23/07 SPA response) were performed after
`submission of a Special Protocol Assessment (SPA). There was an EOP 2 Meeting held on 8/15/07, a
`SPA Meeting held on 9/17/08, and a pre-NDA Meeting on 8/4/08.
`
`The efficacy endpoints chosen for the phase 3 studies have been widely used in clinical studies of
`ophthalmic solutions and are recognized as reliable, accurate, and relevant for evaluation of the
`efficacy and safety of investigational products. For an indication for the treatment of allergic
`conjunctivitis, a demonstration of efficacy is recommeded to include evidence of statistical
`significance and clinical relevance in the resolution of both ocular itching and redness. In the case of
`antigen challenge studies or controlled environmental studies, the difference between groups is
`recommended to be at least one unit on a scale from zero to four.
`
`
`
`Table of Currently Available Treatments for Proposed Indication of Itching Associated with
`Allergic Conjunctivitis
`
`Name of Drug
`Nedocromil
`Ketorolac
`Azelastine
`Pemirolast
`Olopatanol
`Epinastine
`
`NDA
`21-009
`19-700
`21-127
`21-079
`21-545
`21-565
`
`
`Brand Name
`Alocril
`Acular
`Optivar
`Alamast
`Pataday
`Elestat
`
`Adverse events for this class of drugs (topical H1 antagonists) are well known. Common side effects
`seen with this class include: headache, asthenia, blurry vision, eye burning/stinging upon instillation,
`eye pain, cold/flu symptoms, cough, fatigue, dry eye, foreign body sensation, lid edema, keratitis,
`hyperemia, nausea, phayrngitis, pruritis, rhinitis, sinusitis, sore throat, and taste perversion/bitter taste.
`
`
`
`
`
`
`
`2
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`3. CMC
`
`
`From the two CMC Reviews finalized 7/27/09 and 8/9/09:
`
`Bepotastine besilate is manufactured by Ube Industries and the information for the NDA is submitted
`through DMF #19966. Bepotastine besilate is a white crystalline powder with
`.
`It is very soluble in
` but sparingly soluble in
`. It is stable when exposed to
`light, and optically active. The S-isomer is the active drug and
`is controlled as an impurity
`through synthesis. The distribution coefficient in 1-octanol is higher than in aqueous buffer in the pH
`5-9 range. There are 10 potential impurities but only one impurity is above 0.1%. Two potential
`
`genotoxic impurities
` are controlled below
` is controlled below
`. Residual
`. Bepotastine besilate is stable under long term storage
`conditions for (25ºC/60% RH) over 5 years.
`
`Bepotastine besilate was originally developed as an oral tablet dosage form and received approval in
`Japan in 2000 for allergic rhinitis. Bepotastine besilate ophthalmic solution 1.5% is an aqueous
`solution to be administered as drops at or near physiological pH range of tears. The formulation
`contains sodium chloride, monobasic sodium phosphate as dihydrate, benzalkonium chloride, sodium
`hydroxide and purified water; typically these components are used for adjusting tonicity, preservative
`action, pH adjustment, buffering capacity and a vehicle for administration. It was demonstrated during
`the formulation development that sodium chloride, in addition to its use to
`
` All excipients are of USP/NF grade. It is manufactured as a
`
` solution.
`
`
`DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT:
`
`
`
`
`
`
`
`
`
`Table of Composition of Bepotastine Besilate Ophthalmic Solution
`
`
`
`
`
`3
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b
`)
`(4
`)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`PROPOSED REGULATORY SPECIFICATIONS:
`
`
`
`
`
`
`
`4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`
`From the CMC Review finalized 7/27/09:
`
`FACILITIES INSPECTIONS:
`The overall recommendation from the Office of Compliance is “Acceptable” in EES.
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`From the original Pharmacology/Toxicology Review finalized 7/21/09:
`
`The pharmacology/toxicology reviewer has no objection to the approval of this NDA.
`
`Bepotastine besilate in the Bepreve formulation did not cause ocular inflammation or histopathologic
`changes in rabbits or dogs. There are some data that suggest that Bepreve may have an affinity for
`melanin binding based on the observation of presence in the iris in an ocular toxicity study and to
`pigmented tissues in a radiolabeled study. This association with melanin appears to be reversible,
`reaching levels below limit of detection when given enough time for clearance after dosing (e.g. 30
`days after single dose of radiolabeled compound, bepotastine besilate was no longer detected in
`pigmented tissues).
`
`The pivotal study for the proposed indication was a 26 week study in dogs using 4 and 8X per day
`dosing with the 1.5% TAU-284 solution. The 4X/day dosing paradigm was determined to be the
`NOAEL based on decreases in A and B wave amplitude in electroretinograms (ERG) in the 8X/day
`dose group. When considering systemic exposures seen in this study, the identified NOAEL for ERG
`endpoints provides a 15X safety factor over that of anticipated systemic exposures seen with topical
`ocular use in humans. Several short term ocular toxicity studies demonstrated that bepotastine besilate
`solutions up to 2% in concentration were well tolerated in various animal species. Bepreve also did not
`demonstrate strong hypersensitivity reactions with repeated use.
`
`Although bepotastine besilate appears to be a substrate for Cyp450 metabolism in rodents, it does not
`appear to be a target/inhibitor of human CYP450 enzymes. In both rats and dogs, test article is
`primarily excreted in feces and urine. Additional information may be found in the clinical
`pharmacology review.
`
`The exec-CAC concluded that bepotastine besilate did not significantly induce neoplasms in 2 year
`dietary carcinogenicity studies in mice (at margin of exposure relative to human after ophthalmic use
`of 353) or in rats (at a margin of exposure relative to human of 200) .
`
`Pregnancy category C is recommended for this product due to the observation of a rare skeletal
`malformation seen in the fertility/early embryo development study in rats at the 1000 mg/kg dose. The
`approximate margin of exposure for the 200 mg/kg/day NOAEL identified in this study was 3,300X
`that of anticipated human systemic exposure with topical ocular use. In rats given oral doses of 100
`mg/kg/day, an increased incidence of stillborns was observed (~200X human systemic exposure for
`
`
`
`
`
`
`5
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`ocular use). At the 1000 mg/kg/day dose level in this same study, an increase in stillborns, decreased
`survival and decreased rate of development were observed in pups. There were no effects observed in
`rats treated with 10 mg/kg/day (representing a maximal systemic concentration approximately 18 times
`that anticipated for topical ocular use in humans).
`
`From a radiolabeled study in pregnant rats, it is recognized that bepotastine besilate can rapidly
`distribute to the yolk sac/placenta and to the fetus. Bepotastine besilate was transferred to the yolk
`sac/placenta at levels nearly equivalent to maternal maximal plasma concentration; ~33-55% of
`bepotastine besilate was transferred to the developing fetus. At 24 hours following a single oral
`administration of 3 mg/kg, ~ 5.9% and 3.1% of maximal plasma TAU-284 concentrations were
`detected in the brain and liver of the fetus at 24 hours postdose. Bepotastine besilate was also noted to
`be transferred to milk in lactating rats, with milk concentrations being 1.5 to 2 times maximal plasma
`concentrations by 1 hour postdose and reaching levels below the limit of detection by 48 hours
`postdose.
`
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`
`From the original Clinical Pharmacology Review finalized 5/22/09:
`
`The clinical pharmacology information provided by the Applicant is acceptable.
`
`The applicant submitted clinical pharmacology data for bepotastine from the Japanese development
`programs, including a Phase 1 pharmacokinetic (PK) study examining systemic exposure following
`bepotastine besilate ophthalmic solutions 1.0% and 1.5% instilled as repeated doses (QID) over a 7 day
`period (Study SNJ-TO-02), as well as data from multiple Phase 1 studies from the oral development
`program. The clinical pharmacology information provided by the Applicant is acceptable.
`
`
`
`6. Sterility Assurance
`
`
`From the original Product Quality Microbiology Review finalized 6/17/09:
`
`There are no microbiology deficiencies identified.
`
`
`
`
`
`6
`
`(b) (4)
`
`1 Page(s) has been Withheld in Full following this page as B4 (CCI/TS)
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`
`7. Clinical/Statistical - Efficacy
`
`
`From the original Medical Officer Review dated 8/13/2009:
`
`Analyses of Endpoints
`
`Primary Efficacy Variables for Studies ISTA-BEPO-CSO1 and CL-S&E-0409071-P
`
`The primary efficacy variables were:
`• Ocular itching evaluated by the subject at 3, 5, and 7 minutes post challenge (0-4 unit [nine step]
`scale, allowing half unit [one step] increments)
`• Conjunctival redness evaluated by the investigator at 7, 15, and 20 minutes post challenge (0-4
`unit [9 step] scale, allowing half unit [one step] increments).
`
`
`To demonstrate clinical significance in a CAC study, the difference between groups should be at least
`one unit on a scale from 0-4 at a majority of the time points evaluated. This endpoint was duplicated
`in two trials only at the 8 hours post-dosing CAC with both concentrations of drug (bepotastine 1%
`and 1.5%). Bepotastine besilate ophthalmic solution 1.5% produced greater clinical response than
`bepotastine besilate ophthalmic solution 1% in reducing ocular itching at both 8-hour and 16- hour
`duration-of-action time points versus vehicle. The data support bepotastine 1.5% with bid dosing for
`the treatment of itching associated with allergic conjunctivitis.
`
`
`
`
`
`
`8
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`ITCHING
`
`Study ISTA-BEPO-CSO1: Ocular Itching (ITT Population with LOCF)
`
`Bepotastine 1.5%
`N=35
`
`2.57
`2.81
`2.82
`
`
`1.16
`1.34
`1.31
`
`
`0.73
`0.80
`0.82
`
`
`0.49
`0.71
`0.67
`
`
`Visit
`
`Visit 2
`3 Minutes Post-Challenge
`5 Minutes Post-Challenge
`7 Minutes Post-Challenge
`
`Visit 3b – 16 Hour
`3 Minutes Post-Challenge
`5 Minutes Post-Challenge
`7 Minutes Post-Challenge
`
`Visit 4 – 8 Hour
`3 Minutes Post-Challenge
`5 Minutes Post-Challenge
`7 Minutes Post-Challenge
`
`Visit 5 – 15 minutes
`3 Minutes Post-Challenge
`5 Minutes Post-Challenge
`7 Minutes Post-Challenge
`
`Visit
`
`
`Bepotastine 1%
`N=36
`
`2.52
`2.73
`2.75
`
`
`1.44
`1.58
`1.44
`
`
`1.15
`1.29
`1.27
`
`
`0.56
`0.72
`0.70
`
`Vehicle
`N=36
`
`2.35
`2.76
`2.81
`
`
`2.10
`2.37
`2.27
`
`
`2.06
`2.33
`2.23
`
`
`1.87
`2.07
`1.95
`
`Bepotastine 1.5%
`Difference in
`Mean Itching
`Grades (Vehicle
`– Active)
`
`
`0.9
`1.0
`1.0
`
`
`
`1.3
`1.5
`1.4
`
`
`
`1.4
`1.4
`1.3
`
`p-value
`
`
`
`<0.001
`<0.001
`<0.001
`
`
`
`<0.001
`<0.001
`<0.001
`
`
`
`<0.001
`<0.001
`<0.001
`
`p-value
`
`
`
`0.002
`<0.001
`<0.001
`
`
`
`<0.001
`<0.001
`<0.001
`
`
`
`<0.001
`<0.001
`<0.001
`
`Bepotastine 1%
`Difference in
`Mean Itching
`Grades (Vehicle
`– Active)
`
`
`Visit 3B (Day 1)-CAC at 16 hours
`post dosing
`3 min post-CAC
`5 min post-CAC
`7 min post-CAC
`
`Visit 4 (Day 14)-CAC at 8 hours
`post-dosing
`3 min post-CAC
`5 min post-CAC
`7 min post-CAC
`
`Visit 5 (Day 28)-CAC at 15 minutes
`post-dosing
`3 min post-CAC
`5 min post-CAC
`7 min post-CAC
`
`
`0.7
`0.8
`0.8
`
`
`
`0.9
`1.0
`1.0
`
`
`
`1.3
`1.4
`1.3
`
`
`
`
`
`
`9
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`Study CL-S&E-0409071-P: Ocular Itching (ITT Population with LOCF)
`
`Bepotastine 1.5%
`N=43
`0
`3.22
`
`
`2.51
`2.99
`3.07
`
`
`1.23
`1.44
`1.23
`
`
`0.89
`0.95
`0.87
`
`
`0.4
`0.46
`0.51
`
`
`Visit
`
`Visit 1-Baseline
`10 Minutes post-challenge
`
`Visit 2
`3 Minutes Post-Challenge
`5 Minutes Post-Challenge
`7 Minutes Post-Challenge
`
`Visit 3b – 16 Hours
`3 Minutes Post-Challenge
`5 Minutes Post-Challenge
`7 Minutes Post-Challenge
`
`Visit 4 – 8 Hours
`3 Minutes Post-Challenge
`5 Minutes Post-Challenge
`7 Minutes Post-Challenge
`
`Visit 5 – 15 Minutes
`3 Minutes Post-Challenge
`5 Minutes Post-Challenge
`7 Minutes Post-Challenge
`
`Visit
`
`
`Bepotastine 1%
`N=44
`0
`3.3
`
`
`2.57
`2.99
`3.05
`
`
`1.27
`1.42
`1.19
`
`
`0.96
`1.01
`0.94
`
`
`0.42
`0.6
`0.64
`
`Vehicle
`N=43
`0
`3.23
`
`
`2.63
`2.9
`3.05
`
`
`1.83
`2.15
`2.02
`
`
`2.18
`2.27
`2.1
`
`
`1.85
`2.07
`1.93
`
`Bepotastine 1.5%
`Difference in
`Mean Itching
`Grades (Vehicle
`– Active)
`
`
`0.6
`0.7
`0.8
`
`
`
`1.3
`1.3
`1.2
`
`
`
`1.5
`1.6
`1.4
`
`P value
`
`
`
`0.0051
`0.0021
`0.0003
`
`
`
`<0.001
`<0.001
`<0.001
`
`
`
`<0.001
`<0.001
`<0.001
`
`P value
`
`
`
`0.0055
`0.0006
`0.0001
`
`
`
`<0.001
`<0.001
`<0.001
`
`
`
`<0.001
`<0.001
`<0.001
`
`
`
`10
`
`Bepotastine 1%
`Difference in
`Mean Itching
`Grades (Vehicle
`– Active)
`
`
`Visit 3B (Day 1)-CAC at 16 hours
`post-dosing
`3 min post-CAC
`5 min post-CAC
`7 min post-CAC
`
`Visit 4 (Day 14)-CAC at 8 hours
`post-dosing
`3 min post-CAC
`5 min post-CAC
`7 min post-CAC
`
`Visit 5 (Day 28)-CAC at 15 minutes
`post-dosing
`3 min post-CAC
`5 min post-CAC
`7 min post-CAC
`
`
`
`
`
`
`0.6
`0.7
`0.8
`
`
`
`1.2
`1.3
`1.2
`
`
`
`1.4
`1.5
`1.3
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`REDNESS
`
`
`Visit
`
`Bepotastine 1%
`N=44
`
`Visit 2
`2.01
`7 Minutes Post-Challenge
`2.21
`15 Minute Post-Challenge
`20 Minutes Post-Challenge 2.19
`
`
`Visit 3b
`
`7 Minutes Post-Challenge
`1.42
`15 Minutes Post-Challenge 1.53
`20 Minutes Post-Challenge 1.47
`
`
`Visit 4
`
`7 Minutes Post-Challenge
`1.26
`15 Minutes Post-Challenge 1.56
`20 Minutes Post-Challenge 1.55
`
`
`Visit 5
`
`7 Minutes Post-Challenge
`1.11
`15 Minute Post-Challenge
`1.45
`20 Minutes Post-Challenge 1.44
`
`Vehicle
`N=43
`
`2.10
`2.25
`2.25
`
`
`1.79
`1.81
`1.70
`
`
`1.67
`1.84
`1.84
`
`
`1.91
`2.05
`1.95
`
`Study ISTA-BEPO-CSO1: Clinical Assessment of Conjunctival Redness (ITT Population with LOCF)
`
`Bepotastine 1.5%
`N=43
`
`2.03
`2.29
`2.28
`
`
`1.63
`1.81
`1.78
`
`
`1.30
`1.47
`1.52
`
`
`1.37
`1.65
`1.62
`
`
`Time of Post-CAC Observation
`
`
`Visit 3B
`7 min post-CAC
`15 min post-CAC
`20 min post-CAC
`
`Visit 4
`7 min post-CAC
`15 min post-CAC
`20 min post-CAC
`
`Visit 5
`7 min post-CAC
`15 min post-CAC
`20 min post-CAC
`
`
`
`
`
`
`
`
`Bepotastine 1%
`Difference in
`Mean Redness
`Grades (Vehicle
`– Active)
`
`0.4
`0.3
`0.2
`
`
`0.4
`0.3
`0.3
`
`
`0.8
`0.6
`0.5
`
`P value
`
`
`0.012
`0.048
`0.102
`
`
`0.014
`0.071
`0.083
`
`
`<0.001
`<0.001
`<0.001
`
`Bepotastine 1.5%
`Difference in
`Mean Redness
`Grades (Vehicle
`– Active)
`
`0.2
`0.0
`-0.1
`
`
`0.4
`0.4
`0.3
`
`
`0.6
`0.4
`0.3
`
`P value
`
`
`0.208
`0.755
`0.711
`
`
`0.029
`0.062
`0.137
`
`
`0.004
`0.039
`0.151
`
`
`
`11
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`Study CL-S&E-049071-P: Clinical Assessment of Conjunctival Redness (ITT Population with LOCF)
`
`Visit
`
`Bepotastine 1.5%
`N=43
`0.63
`2.68
`
`
`0.67
`2.46
`2.59
`2.60
`
`0.63
`
`
`1.80
`1.85
`1.87
`
`
`0.69
`1.59
`1.76
`1.77
`
`
`0.60
`1.42
`1.59
`1.67
`
`Vehicle
`N=43
`0.58
`2.60
`
`
`0.63
`2.40
`2.53
`2.50
`
`0.6
`
`
`1.89
`1.99
`1.98
`
`
`0.63
`1.8
`1.88
`1.84
`
`
`0.56
`1.85
`1.97
`1.87
`
`Bepotastine 1%
`N=44
`0.52
`Visit 1-Baseline
`2.6
`10 minutes post-challenge
`
`
`
`Visit 2
`0.65
`Pre-CAC
`2.41
`7 Minutes Post-Challenge
`2.49
`15 Minute Post-Challenge
`20 Minutes Post-Challenge 2.52
`
`
`Visit 3a Pre-CAC
`0.61
`
`
`Visit 3b
`
`7 Minutes Post-Challenge
`1.46
`15 Minutes Post-Challenge 1.6
`20 Minutes Post-Challenge 1.62
`
`
`Visit 4
`
`Pre-CAC
`0.6
`7 Minutes Post-Challenge
`1.35
`15 Minutes Post-Challenge 1.57
`20 Minutes Post-Challenge 1.59
`
`
`Visit 5
`
`Pre-CAC
`0.49
`7 Minutes Post-Challenge
`1.28
`15 Minute Post-Challenge
`1.51
`20 Minutes Post-Challenge 1.64
`
`Time of Post-CAC Observation
`
`
`Bepotastine 1%
`Difference in
`Mean Redness
`Grades (Vehicle
`– Active)
`
`0.4
`0.4
`0.4
`
`
`0.5
`0.3
`0.3
`
`
`0.6
`0.5
`0.2
`
`P value
`
`
`0.005
`0.017
`0.041
`
`
`0.001
`0.036
`0.103
`
`
`0.001
`0.002
`0.148
`
`Bepotastine 1.5%
`Difference in
`Mean Redness
`Grades (Vehicle
`– Active)
`
`0.1
`0.1
`0.1
`
`
`0.2
`0.1
`0.1
`
`
`0.4
`0.4
`0.2
`
`P value
`
`
`0.547
`0.388
`0.500
`
`
`0.107
`0.360
`0.591
`
`
`0.003
`0.011
`0.225
`
`
`
`12
`
`Visit 3B
`7 min post-CAC
`15 min post-CAC
`20 min post-CAC
`
`Visit 4
`7 min post-CAC
`15 min post-CAC
`20 min post-CAC
`
`Visit 5
`7 min post-CAC
`15 min post-CAC
`20 min post-CAC
`
`
`
`
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`Neither concentration of bepotastine provides a clinically significant reduction in redness compared to
`vehicle at any study visit during the treatment period.
`
`Secondary Efficacy Variables for Studies ISTA-BEPO-CSO1 and CL-S&E-0409071-P
`
`Ocular symptom scores:
`• Ciliary and episcleral redness evaluated by the investigator at 7, 15, and 20 minutes post
`challenge (0-4 unit (nine step) scale, with half unit (one step) increments allowed)
`• Chemosis evaluated by the investigator at 7, 15, and 20 minutes post challenge (0-4 unit (one
`step) scale, with half unit (one step) increments allowed)
`• Lid swelling evaluated by the subject at 7, 15, and 20 minutes post challenge (0-3 unit scale,
`whole unit increments only)
`• Tearing evaluated by the subject at 7, 15, and 20 minutes post challenge (graded absent or
`present)
`• Ocular mucous discharge evaluated by the investigator at 7, 15, and 20 minutes post challenge
`(graded absent or present)
`
`
`Non-ocular symptom scores:
`• Rhinorrhea, ear or palate pruritus, nasal pruritus, and nasal congestion evaluated by the subject at
`7, 15, and 20 minutes post challenge (0-4 unit scale, whole unit increments only)
`• A composite score of rhinorrhea, ear or palate pruritus, nasal pruritus, and nasal congestion
`evaluated by the subject at 7, 15, and 20 minutes (0-16 unit scale)
`
`
`None of the secondary endpoints achieved clinical success (i.e., both statistical and clinical
`significance) as defined in the trial protocol in either study.
`
`Efficacy Summary Statement
`
`There is substantial evidence of effectiveness consisting of adequate and well controlled studies which
`demonstrate that patients receiving Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`experienced a statistically and clinically significant response in the reduction of ocular itching. The
`data support Bepreve (bepotastine besilate ophthalmic solution) 1.5% administered twice a day for the
`treatment of itching associated with allergic conjunctivitis.
`
`There is not substantial evidence that patients receiving Bepreve (bepotastine besilate ophthalmic
`solution) 1.5% experienced a statistically and clinically significant response in the reduction of ocular
`redness. The data does not support Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`administered twice a day for the treatment of redness associated with allergic conjunctivitis.
`
`
`
`
`
`
`
`
`
`
`
`13
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`8. Safety
`
`
`From the original Medical Officer Review dated 8/13/2009:
`
`Three studies are used to support the safety and efficacy of bepotastine. The main support for the
`safety of bepotastine besilate 1.5% comes from Study CL-SAF-0405071. The patient exposure and
`safety assessments were adequate.
`
`
`Treatment Duration (Safety Population) for Study CL-SAF-0405071
`
`Mean Treatment Duration (Days, +/- sd)
`Treatment Group
`40.4 (6.7)
`Bepotastine besilate 1.5% (N=572)
`42.0 (0.4)
` Age 3-9 (N=47)
`41.2 (5.6)
` Age 10-17 (N=40)
`40.1 (7.1)
` Age >=18 (N=485)
`
`
`40.6 (6.5)
`Vehicle (N=286)
`42.0 (0.4)
` Age 3-9 (N=25)
`42.1 (0.3)
` Age 10-17 (N=15)
`40.3 (6.9)
` Age >= 18 (N=246)
`*Treatment duration was defined as the number of days between the first and last instillation of masked investigational
`product.
`
`No patient or subject deaths occurred during the conduct of the two Phase 3 clinical studies and the
`additional safety study that form the basis of this application.
`
`
`
`
`Bepotastine 1%
`
`Study ISTA-BEPO-CSO1: Patient Disposition
`
`Bepotastine besilate 1.5%
`
`35
`35
`35
`32
`
`36
`36
`36
`35
`
`Vehicle
`
`36
`36
`36
`34
`
`Randomized
`Safety Population
`ITT Population with LOCF
`PP Population
`
`
`Subject No.
`1026-025
`1045-040
`1064-052
`1140-063
`
`
`
`
`
`
`
`
`
`Study ISTA-BEPO-CSO1: Patient Withdrawals
`
`Treatment Group Reason For Withdrawal
`Vehicle
`Subject decision/non-compliance-missed Visit 3B and Visit 4
`Bepotastine 1.5%
`Subject decision/non-compliance-missed Visit 3B and Visit 4
`Bepotastine 1.5%
`Unacceptable baseline itching and redness at Visit 5
`Bepotastine 1.5%
`Subject decision/non-compliance-missed Visit 3B and Visit 4
`
`
`
`14
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`Study CL-S&E-0409071: Patient Disposition
`
`Bepotastine 1% Bepotastine besilate 1.5%
`
`43
`43
`43
`38
`
`44
`44
`44
`43
`
`Vehicle
`
`43
`43
`43
`36
`
`
`
`Randomized
`Safety Population
`ITT Population with LOCF
`PP Population
`
`
`Study CL-S&E-0409071: Patient Withdrawals
`
`
`Reason For Withdrawal
`Treatment Group
`Subject No.
`Subject decision/non-compliance
`Vehicle
`1003-050
`Subject decision/non-compliance
`Vehicle
`2001-066
`Subject decision/non-compliance
`Vehicle
`3016-010
`Subject decision/non-compliance
`Bepotastine 1.5%
`3028-027
`Exclusion criteria*
`Bepotastine 1.5%
`3057-002
`Subject decision/non-compliance
`Bepotastine 1.5%
`4007-125
`Subject decision/non-compliance
`Vehicle
`4045-128
`Subject decision/non-compliance
`Vehicle
`5003-110
`Subject decision/non-compliance
`Bepotastine 1.5%
`5005-111
`Exclusion criteria*
`Bepotastine 1.5%
`5012-099
`Subject decision/non-compliance
`Vehicle
`5016-098
`Subject decision/non-compliance
`Bepotastine 1%
`5031 -097
`Subject decision/non-compliance
`Vehicle
`5034-101
`*Subjects manifested signs or symptoms of clinically active allergic conjunctivitis (defined as any ocular itching or an
`ocular redness score >1, for any vessel bed) at the start of the study visit.
`
`
`Study CL-SAF-0405071: Subject Disposition
`
`Bepotastine besilate 1.5%
`
`575
`Number of Randomized subjects
`575
`Number of Subjects in Safety Population *
`87
`Number of Pediatric Subjects in Safety Population
`133
`Patients that Underwent ECC-Baseline
`125
`Patients that Underwent ECC- Day 84
`532 (92.5%)
`Number of Subjects Completed Study**
`
`Reason For Withdrawal
`6
` AE
`3
` Protocol Violation
`32
` Subject Decision/Non-Compliance
`2
` Other
`*Safety population defined as subjects who received at least 1 dose of investigational product.
`**A completed subject is defined as one who has completed all study visits and received at least 75% of scheduled doses.
`
`Twelve subjects withdrew from the study early with an AE being listed as the reason for study
`discontinuation (six in bepotastine group and six in the vehicle group).
`
`
`
`
`Vehicle
`286
`286
`40
`69
`68
`269 (94.1%)
`
`6
`0
`10
`1
`
`
`
`
`
`
`15
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`Subject Number
`3010-541
`3018-549
`3076-604
`3079-607
`
`Treatment Group
`Bepotastine
`Vehicle
`Vehicle
`Bepotastine
`
`Study CL-SAF-0405071: Patient Withdrawals Due to Adverse Events
`
`AE Leading to Discontinuation
`Intermittent headaches associated with study drops
`Sinusitis and ear infection
`Neck and shoulder pain subsequent to car accident
`Intermittent HTN worsening over 20 days of dosing and non-ocular
`allergies
`Pneumonia
`Intermittent headache and earache
`Sinusitis
`Eyelid pain and eyelid margin crusting
`Bronchitis and ocular stinging and photophobia
`Eye irritation, redness, blurred vision, and burning upon instillation
`Three styes
`Eye irritation
`
`Bepotastine
`Bepotastine
`Vehicle
`Vehicle
`Bepotastine
`Vehicle
`Vehicle
`Bepotastine
`
`3098-625
`3102-629
`5084-842
`6059-053
`6110-093
`6241-209
`6300-259
`6318-274
`
`
`Study CL-SAF-0405071: Treatment Emergent Ocular Adverse Events (Safety Population)
`
`
`
`Eye disorders
`Eye irritation
`Dry eye
`Ocular hyperemia
`Asthenopia
`Eye pain
`Eye puritis
`Lacrimation increased
`Photophobia
`Conjunctival cyst
`Conjunctival hemorrhage
`Eyelid margin crusting
`Eyelid pain
`FBS
`Punctate keratitis
`Abnormal sensation in eye
`Eye discharge
`Eye swelling
`Eye edema
`Eyelid pruritis
`Glare
`Keratitis
`Vision blurred
`Vitreous floaters
`
`Vascular Disorders
`Hyperemia
`
`General disorders
`
`
`
`
`Bepotastine besilate 1.5%
`N=575
`
`27
`6
`2
`1
`2
`3
`3
`2
`1
`0
`1
`1
`2
`1
`0
`0
`1
`1
`1
`1
`1
`0
`1
`
`
`2
`
`
`
`Vehicle
`N=286
`
`6
`5
`4
`3
`2
`1
`0
`1
`1
`2
`1
`1
`0
`1
`1
`1
`0
`0
`0
`0
`0
`1
`0
`
`
`0
`
`
`
`
`
`16
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`
`Sensation of pressure
`
`Infections
`Hordeolum
`
`Injury
`Contusion
`
`Skin disorders
`Photosenstivity reaction
`
`Nervous system disorders
`Taste perversion
`Bad taste
`Headache
`After taste
`Nerve compression
`Parosmia
`Taste abnormality
`Taste bitter
`Taste metallic
`
`Infections
`Nasophayngitis
`Influenza
`Sinusitis
`Bronchitis
`UTI
`Ear infection
`Folliculitis
`Herpes zoster
`Pharyngitis
`Pneumonia
`Tooth abscess
`Vaginal infection
`Viral pharyngitis
`
`Respiratory disorders
`Nasal congestion
`Rhinorrhea
`Cough
`Post-nasal drip
`Pharngolaryngeal pain
`Sneezing
`Wheezing
`Asthma
`Sinus congestion
`
`Musculoskeletal
`Back pain
`
`
`
`
`Bepotastine besilate 1.5%
`N=575
`0
`
`
`0
`
`
`0
`
`
`1
`
`
`84
`45
`20
`14
`0
`1
`1
`1
`1
`
`
`12
`3
`1
`2
`1
`0
`1
`1
`0
`1
`0
`1
`0
`
`
`5
`3
`2
`4
`1
`2
`2
`1
`1
`
`
`1
`
`Vehicle
`N=286
`1
`
`
`1
`
`
`1
`
`
`0
`
`
`4
`1
`7
`2
`1
`0
`0
`0
`0
`
`
`5
`0
`2
`0
`1
`1
`0
`0
`1
`0
`1
`0
`1
`
`
`0
`2
`2
`0
`1
`0
`0
`0
`0
`
`
`1
`
`
`
`17
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`
`Plantar fasciitis
`Tendonitis
`Arthralgia
`Musculoskeletal pain
`Neck pain
`Osteoarthritis
`Pain in extremity
`
`GI disorders
`GERD
`Tooth impacted
`Abdominal pain
`Dry mouth
`Nausea
`Paresthesia oral
`Vomiting
`
`Injury and poisoning
`Contusion
`Accident
`Animal bite
`Fall
`Joint sprain
`Limb injury
`Procedural pain
`Road traffic accident
`Tendon rupture
`
`Skin disorders
`Drug eruption
`Eczema
`Rash
`Urticaria
`
`Ear disorders
`Ear pain
`Eustachian tube obstruction
`Tinnitus
`
`Cardiac disorders
`Extrasystole
`
`General disorders
`Chest pain
`
`Immune system disorders
`Hypersensitivity
`
`Metabolism disorder
`Hypercholesterolemia
`
`
`
`
`Bepotastine besilate 1.5%
`N=575
`1
`1
`1
`0
`0
`1
`1
`
`
`2
`1
`0
`1
`1
`0
`0
`
`
`1
`1
`0
`1
`1
`0
`1
`1
`0
`
`
`1
`0
`1
`0
`
`
`1
`1
`1
`
`
`1
`
`
`1
`
`
`1
`
`
`0
`
`Vehicle
`N=286
`1
`1
`0
`1
`1
`0
`0
`
`
`0
`1
`1
`0
`0
`1
`1
`
`
`1
`0
`1
`0
`0
`1
`0
`0
`1
`
`
`0
`1
`0
`1
`
`
`0
`0
`0
`
`
`0
`
`
`0
`
`
`0
`
`
`1
`
`
`
`18
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`
`Vehicle
`Bepotastine besilate 1.5%
`N=286
`N=575
`
`
`
`
`
`Vascular disorders
`0
`1
`HTN
`*Treatment-emergent adverse events were defined as those occurring during the 6-week dosing period.
`
`The most commonly reported non-ocular AEs were in the taste-related category. The taste-related
`category includes specific AEs described by the subjects as taste perversion, bad taste, aftertaste, taste
`abnormality, bitter taste, or metallic taste. In the bepotastine 1.5% group, 25% of subjects reported at
`least 1 taste-related AE. This incidence had a statistical significance greater than the 2.4% incidence
`reported in the vehicle treatment group (P <0.0001).
`
`Safety Summary Statement
`
`There is substantial evidence of safety consisting of adequate and well controlled studies which
`demonstrate that Bepreve, dosed twice a day, is safe for the treatment of itching associated with
`allergic conjunctivitis.
`
`The most common adverse reaction occurring in approximately 25% of patients was a taste perversion
`following instillation. Other adverse reactions which occurred in 2-5% of subjects were eye irritation,
`headache, and nasopharyngitis.
`
`
`9. Advisory Committee Meeting
`
`
`The Dermatologic and Ophthalmic Drugs Advisory Committee of the Food and Drug Administration
`met on June 26, 2009 at the Hilton Hotel Washington/Silver Spring, 8727 Colesville Road, Silver
`Spring, Maryland. Michael X. Repka, M.D., chaired the meeting.
`
`Attendance:
`Dermatologic and Ophthalmic Drugs Advisory Committee Members present (voting):
`Michael X. Repka, M.D. (Acting Chair), Allan R. Rutzen, M.D.
`Temporary Voting Members:
`Michael W. Belin, M.D.; Lynn K. Gordon, M.D., Ph.D.; Susan M. MacDonald, M.D.; Philip Lavin,
`Ph.D.; Paula Cofer (Patient Representative)
`Industry Representative (non-voting):
`Ellen Strahlman, M.D., M.H.Sc
`FDA Participants (non-voting):
`Edward M. Cox, M.D., MPH; Wiley Chambers, M.D.; Rhea Lloyd, M.D.; Sonal Wadhwa, M.D.,; Yan
`Wang, Ph.D.
`Open Public Hearing Speaker:
`None
`
`The following questions were posed to the Committee:
`
`
`
`
`
`
`19
`
`

`

`CDTL Review
`William M. Boyd, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`1. Do you think adequate safety and efficacy for bepotastine ophthalmic solution has been
`demonstrated for the treatment of itching due to allergic conjunctivitis?
`
`
`
`
`
`
`
`The committee voted 7-Yes and 0-No.
`
`2. If yes, on which study(ies) are you basing your decision?
`
`All committee members stated they based their decision on Studies ISTA-BEPO-CS01
`CL-S&E-0409071, and CL-SAF-0405071.
`
`3. If no, what additional study(ies) should be performed? Do you have any suggestions regarding
`trial design?
`
`
`Not applicable.
`
`4. Do you have an