`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`22-228
`
`
`APPLICA TI0N NUMBER:
`
`SUMMARY REVIEW
`
`SUMMARY REVIEW
`
`
`
`
`
`22-228
`
`
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`
`
`Page: 1
`
`
`Date
`From
`NDA #
`Applicant
`Date of Submission
`Type of Application
`Name
`Dosage forms / Strength
`Proposed Indication(s)
`
`Recommended:
`
`
`Division Director Review
`
`August 19, 2009
`Wiley A. Chambers, M.D.
`NDA 22-288
`ISTA Pharmaceuticals, Inc.
`November 12, 2008
`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.
`
`The support of clinical safety and efficacy for bepotastine besilate ophthalmic solution consisted of 3
`clinical studies conducted in the United States under IND 66,864 (CL-SAF-0405071-P, ISTA-BEPO-
`CS01 and CL-S&E-0409071-P).
`
`
`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
`besilate (in any dosage form) has not previously been approved in the United States for any indication.
`
`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
`
`
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`Page: 2
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`studies, the difference between groups is recommended to be at least one unit on a scale from zero to
`four.
`
`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.
`
`
`Table of Currently Available Treatments for Proposed Indication of Itching Associated with
`Allergic Conjunctivitis
`
`
`Brand Name
`Alocril
`Acular
`Optivar
`Alamast
`Pataday
`Elestat
`
`
`3. CMC
`
`Name of Drug
`nedocromil
`ketorolac
`azelastine
`pemirolast
`olopatanol
`epinastine
`
`NDA
`21-009
`19-700
`21-127
`21-079
`21-545
`21-565
`
`
`The CMC Reviewer recommends approval in his review dated 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 no odor and a bitter
`taste. 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
` is controlled below
`below
` Residual
`. Bepotastine besilate is stable under long term
`storage conditions for (25ºC/60% RH) over 5 years.
`
`Bepotastine besilate ophthalmic solution 1.5% is an aqueous solution. The formulation contains
`sodium chloride, monobasic sodium phosphate as dihydrate, benzalkonium chloride, sodium hydroxide
`and purified water. It was demonstrated during the formulation development that sodium chloride, in
`addition to its use to
` also helps in
` All
`excipients are of USP/NF grade. It is manufactured as a
`
`DESCRIPTION AND COMPOSITION OF THE DRUG PRODUCT:
`Bepotastine besilate
`
`
`
`Active
`
`Sodium chloride
`
`
`
`Monobasic Sodium Phosphate, Dihydrate
`Benzalkonium chloride
`
`
`Sodium hydroxide
`
`
`
`
`Preservative
`pH adjuster
`
`
`
`qs to pH 6.8
`
`
`
` solution.
`
`
`
`
`
`
`
`(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)
`
`
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`Water for Injection
`
`PROPOSED REGULATORY SPECIFICATIONS:
`
`
`
`
`
`
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`
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`Page: 3
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`
`
`qs to 1 mL
`
`FACILITIES INSPECTIONS:
`The overall recommendation from the Office of Compliance is “Acceptable” in EES.
`
`4. Nonclinical Pharmacology/Toxicology
`
`
`The pharmacology/toxicology reviewer has no objection to the approval of this NDA as noted in the
`review dated 7/21/09.
`
`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 radio-labeled 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 radio-labeled compound, bepotastine besilate was no longer detected in
`pigmented tissues).
`
` 26 week study in dogs using 4 and 8X per day dosing with the 1.5% 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
`
` A
`
`
`
`
`
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`
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`
`
`
`
`(b) (4)
`
`
`
`Page: 4
`
`
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`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.
`
`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
`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 radio-labeled 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 bepotastine 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
`
`
`The clinical pharmacology information provided by the Applicant is acceptable in a review dated
`5/22/09.
`
`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.
`
`
`
`
`
`
`
`
`
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`
`
`
`6. Sterility Assurance
`
`Page: 5
`
`
`The application was recommended for approval from a Product Quality Microbiology prospective in
`the Review dated 6/17/09.
`
`
`7. Clinical/Statistical - Efficacy
`
`
`Medical Officer Review dated 8/13/2009 recommends approval of the application.
`
`Primary Efficacy Variables for Studies ISTA-BEPO-CSO1 and CL-S&E-0409071-P
`
`
`• 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).
`
`
`
`
`
`
`
`
`
`(b) (4)
`
`
`
`Division Director Memo
`Wiley A. Chambers, 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
`
`
`
`
`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
`
`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%
`Difference in
`Mean Itching
`Grades (Vehicle
`– Active)
`
`
`0.7
`0.8
`0.8
`
`
`
`0.9
`1.0
`1.0
`
`
`
`1.3
`1.4
`1.3
`
`p-value
`
`
`
`0.002
`<0.001
`<0.001
`
`
`
`<0.001
`<0.001
`<0.001
`
`
`
`<0.001
`<0.001
`<0.001
`
`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
`
`
`Study CL-S&E-0409071-P: Ocular Itching (ITT Population with LOCF)
`
`Page: 6
`
`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
`
`
`
`
`
`
`
`
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`
`
`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
`
`Bepotastine 1%
`Difference in
`Mean Itching
`Grades (Vehicle
`– Active)
`
`
`0.6
`0.7
`0.8
`
`
`
`1.2
`1.3
`1.2
`
`
`
`1.4
`1.5
`1.3
`
`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
`
`
`
`
`Page: 7
`
`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
`
`
`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
`
`
`P value
`
`
`
`0.0055
`0.0006
`0.0001
`
`
`
`<0.001
`<0.001
`<0.001
`
`
`
`<0.001
`<0.001
`<0.001
`
`
`
`
`
`
`
`
`
`Division Director Memo
`Wiley A. Chambers, 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
`
`Page: 8
`
`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
`
`
`
`
`
`
`
`Division Director Memo
`Wiley A. Chambers, 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
`
`
`
`Page: 9
`
`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
`
`
`
`
`
`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
`
`
`
`
`
`
`Page: 10
`
`
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`Efficacy Summary Statement
`Relief of ocular itching was demonstrated in replicated trials at the initial and 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%. The data
`support bepotastine 1.5% with bid dosing for the treatment of itching associated with allergic
`conjunctivitis.
`
`Neither concentration of bepotastine provides a clinically significant reduction in redness compared to
`vehicle at any study visit during the treatment period.
`
`
`
`8. Safety
`
`
`Treatment Duration (Safety Population) for Study CL-SAF-0405071
`
`All Patients
`Vehicle
`Bepotastine besilate 1.5%
`
`286
`575
`Number of Randomized subjects
`286
`575
`Number of Subjects in Safety Population
`40
`87
`Number of Pediatric Subjects in Safety Population
`69
`133
`Patients that Underwent ECC-Baseline
`68
`125
`Patients that Underwent ECC- Day 84
`269 (94.1%)
`532 (92.5%)
`Number of Subjects Completed Study**
`
`
`Reason For Withdrawal
`6
`6
` AE
`0
`3
` Protocol Violation
`10
`32
` Subject Decision/Non- Compliance
`1
`2
` Other
`**A completed subject is defined as one who has completed all study visits and received at least 75% of scheduled doses.
`
`Pediatrics
`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.
`
`
`
`
`
`
`
`
`
`
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`Patient Withdrawals – All studies
`
`Page: 11
`
`
`Treatment Group Reason For Withdrawal
`
`Study
`
`CL-S&E-040901
`CL-SAF-0405071
`CL-S&E-040901
`CL-S&E-040901
`CL-SAF-0405071
`CL-SAF-0405071
`CL-SAF-0405071
`CL-SAF-0405071
`
`CL-SAF-0405071
`CL-S&E-040901
`CL-S&E-040901
`CL-S&E-040901
`ISTA-BEOP-CS01
`ISTA-BEOP-CS01
`ISTA-BEOP-CS01
`CL-SAF-0405071
`
`CL-SAF-0405071
`CL-SAF-0405071
`CL-SAF-0405071
`CL-SAF-0405071
`CL-S&E-040901
`CL-S&E-040901
`CL-S&E-040901
`CL-S&E-040901
`CL-S&E-040901
`CL-S&E-040901
`CL-S&E-040901
`ISTA-BEOP-CS01
`CL-SAF-0405071
`
`
`Subject
`No.
`5031 -097 Bepotastine 1%
`6110-093 Bepotastine 1.5%
`3057-002 Bepotastine 1.5%
`5012-099 Bepotastine 1.5%
`6318-274 Bepotastine 1.5%
`3102-629 Bepotastine 1.5%
`3010-541 Bepotastine 1.5%
`3079-607 Bepotastine 1.5%
`
`3098-625 Bepotastine 1.5%
`3028-027 Bepotastine 1.5%
`4007-125 Bepotastine 1.5%
`5005-111 Bepotastine 1.5%
`1045-040 Bepotastine 1.5%
`1140-063 Bepotastine 1.5%
`1064-052 Bepotastine 1.5%
`6241-209 Vehicle
`
`6059-053 Vehicle
`3076-604 Vehicle
`5084-842 Vehicle
`3018-549 Vehicle
`1003-050 Vehicle
`2001-066 Vehicle
`3016-010 Vehicle
`4045-128 Vehicle
`5003-110 Vehicle
`5016-098 Vehicle
`5034-101 Vehicle
`1026-025 Vehicle
`6300-259 Vehicle
`
`Subject decision/non-compliance
`Bronchitis and ocular stinging and photophobia
`Exclusion criteria – Ocular redness or itching prior to challenge
`Exclusion criteria – Ocular redness or itching prior to challenge
`Eye irritation
`Intermittent headache and earache
`Intermittent headaches associated with study drops
`Intermittent HTN worsening over 20 days of dosing and non-
`ocular allergies
`Pneumonia
`Subject decision/non-compliance
`Subject decision/non-compliance
`Subject decision/non-compliance
`Subject decision/non-compliance-missed Visit 3B and Visit 4
`Subject decision/non-compliance-missed Visit 3B and Visit 4
`Unacceptable baseline itching and redness at Visit 5
`Eye irritation, redness, blurred vision, and burning upon
`instillation
`Eyelid pain and eyelid margin crusting
`Neck and shoulder pain subsequent to car accident
`Sinusitis
`Sinusitis and ear infection
`Subject decision/non-compliance
`Subject decision/non-compliance
`Subject decision/non-compliance
`Subject decision/non-compliance
`Subject decision/non-compliance
`Subject decision/non-compliance
`Subject decision/non-compliance
`Subject decision/non-compliance-missed Visit 3B and Visit 4
`Three styes
`
`
`
`
`
`
`
`
`
`
`
`Page: 12
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`Study CL-SAF-0405071:
`Treatment Emergent Ocular Adverse Events reported in greater than 1 patient
`
`
`
`Bepotastine besilate 1.5%
`N=575
`84
`45
`27
`20
`14
`12
`6
`5
`4
`3
`3
`3
`3
`2
`2
`2
`2
`2
`2
`2
`2
`2
`2
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`
`Taste perversion
`Bad taste
`Eye irritation
`Headache
`After taste
`Nasophayngitis
`Dry eye
`Nasal congestion
`Post-nasal drip
`Rhinorrhea
`Eye puritis
`Lacrimation increased
`Influenza
`Ocular hyperemia
`Eye pain
`Cough
`Photophobia
`FBS
`Hyperemia
`Bronchitis
`Sneezing
`Wheezing
`GERD
`Asthenopia
`Sinusitis
`Conjunctival cyst
`Eyelid margin crusting
`Eyelid pain
`Punctate keratitis
`UTI
`Pharngolaryngeal pain
`Back pain
`Plantar fasciitis
`Tendonitis
`Tooth impacted
`Contusion
`
`
`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).
`
`Vehicle
`N=286
`4
`1
`6
`7
`2
`5
`5
`0
`0
`2
`1
`0
`0
`4
`2
`2
`1
`0
`0
`0
`0
`0
`0
`3
`2
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`1
`
`
`
`
`
`
`
`
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`Safety Summary Statement
`
`
`
`Page: 13
`
`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.
`
`The committee unanimously concluded that adequate safety and efficacy for bepotastine ophthalmic
`solution had been demonstrated for the treatment of itching due to allergic conjunctivitis. All
`committee members stated they based their decision on Studies ISTA-BEPO-CS01, CL-S&E-0409071,
`and CL-SAF-0405071.
`10.
`Pediatrics
`
`
`This drug was tested in a pediatric population. Safety and efficacy of Bepreve (bepotastine besilate
`ophthalmic solution) 1.5% have not been established in pediatric patients under 2 years of age because
`the disease is not considered to be reliably diagnoses below the age of 2 years. Efficacy in pediatric
`patients under 10 years of age was extrapolated from clinical trials conducted in pediatric patients
`greater than 10 years of age and from adults. Although there is no recognized differences in the
`disease in pediatric patients below the age of 10 and adults, patients under 10 years of age are not
`considered reliable historians for reported ocular itching scores.
`
`
`11.
`
`Other Relevant Regulatory Issues
`
`
`DSI
`A Division of Scientific Investigations (DSI) audit was conducted as reported in the review dated
`6/29/09. Four domestic sites were selected for inspection. This was a re-inspection of Dr. Torkildsen
`who was previously inspected 10/05/2006 and received a final classification of NAI.
`
`The clinical investigator (CI) sites requested for inspections for CL-S&E-0409071-P were those with
`the highest enrollment numbers (approximately one half of subjects enrolled in the study). For CL-
`SAF-040571-P the CI site requested for inspection enrolled greater that one third of all subjects
`enrolled in the study. For ISTA-BEPO-CS01, the single CI site requested for inspection although it
`
`
`
`
`
`
`
`
`
`Page: 14
`
`
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`had previously been inspected by the FDA (Torkildsen; 10/05/2006; NAI), was responsible for all
`enrolled subjects in this study.
`
`In general, Protocols CL-S&E-0409071, ISTA-BEPO-CS01, and CL-SAF-0405071-P appear to have
`been conducted adequately and the data in support of the NDA appear reliable. The final classification
`of the inspection of ISTA Pharmaceuticals Inc. is NAI. The final classifications of the Clinical
`Investigator inspections of Dr. Torkildsen and Dr. Michaelson are Voluntary Action Indicated (VAI).
`While regulatory violations occurred at these sites, the safety and efficacy data from these sites are
`considered reliable. The preliminary classifications of the Clinical Investigator inspections of Dr.
`Bergmann and Dr. Macejko are NAI.
`
`
`FINANCIAL DISCLOSURE
`The applicant has examined its financial data regarding significant payments of other sorts made to all
`investigators in the studies and equity information as provided by the investigators, as defined in 21
`CFR 54.2. There is no evidence to suggest that the results of the study were impacted by any financial
`payments.
`
`DMEPA
`The Division of Medication Error Prevention and Analysis (DMEPA) Proprietary Name Risk
`Assessment considered the potential similarity of 39 names to the proposed name, Bepreve. However,
`DEMEPA concluded that these names would not render the proposed name, Bepreve, vulnerable to
`name confusion that could lead to medication errors. Thus, DMEPA had no objection to the use of the
`proprietary name Bepreve for this product. The Division of Anti-Infective & Ophthalmology
`Products concurred with this assessment.
`
`DMEPA also provided recommendations on the packaging configuration and the package insert
`labeling. These are incorporated into the Medical Officer’s labeling where appropriate.
`
`DDMAC
`DDMAC reviewed the proposed product labeling for Bepreve (bepotastine besilate ophthalmic
`solution) 1.5% submitted by the applicant on August 12, 2009, and their comments were considered as
`described in the CDTL review.
`
`
`BIOSTATISTICS
`The application is recommended for approval from the Biostatistics prospective as noted in the review
`dated 7/31/09. The studies demonstrated that: (1) Both Bepreve 1.5% and Bepreve 1.0% achieved the
`pre-defined clinical and statistical significance in the primary endpoint of ocular itching; (2) Bepreve
`1.5% had numerical advantage (in terms of the point estimate) over Bepreve 1.0% in the primary
`endpoint of ocular itching; (3) Both Bepreve 1.5% and Bepreve 1.0% failed in the primary endpoint of
`conjunctival redness.
`
`
`
`
`
`
`
`
`
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`12.
`
`Labeling
`
`
`
`Page: 15
`
`
`NDA 22-288, Bepreve (bepotastine besilate ophthalmic solution) 1.5% is recommended to be
`approved for the treatment of itching associated with allergic conjunctivitis with the labeling submitted
`on August 12 and 13, 2009 and found below.
`
`The following package insert submitted by ISTA, Inc. on 8/12/2009 and carton and container labeling
`submitted on 8/13/09 are acceptable:
`
`
`
`
`
`
`
`
`
`
`
`
`
`6 Page(s) of Draft Labeling have been Withheld in Full
`following this page as B4 (CCI/TS)
`
`(b) (4)
`
`
`
`Division Director Memo
`Wiley A. Chambers, M.D.
`NDA 22-288
`Bepreve (bepotastine besilate ophthalmic solution) 1.5%
`
`
`
`
`
`13.
`
`Recommendations/Risk Benefit Assessment
`
`Page: 22
`
`
`RECOMMENDED REGULATORY ACTION:
`NDA 22-288, Bepreve (bepotastine besilate ophthalmic solution) 1.5% is recommended to be
`approved for the treatment of itching associated with allergic conjunctivitis.
`
`There is substantial evidence of safety and 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.
`
`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.
`A subset of these events was observed with this product.
`
`Pharmacology/Toxicology, CMC, Biostatistics, Clinical, Clinical Pharmacology, and Product Quality
`Microbiology reviews concur with the recommendation to approve this application.
`
`RECOMMENDATION FOR POSTMARKETING RISK MANAGEMENT ACTIVITIES:
`There are no risk management activities recommended beyond the routine monitoring and reporting of
`all adverse events.
`
`There are no recommended Postmarketing Requirements or Phase 4 Commitments.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Wiley A. Chambers, MD
`Acting Director
`Division of Anti-Infective and Ophthalmology Products
`Office of Antimicrobial Products
`Office of New Drugs
`
`
`
`
`
`
`
`
`
`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`WILEY A CHAMBERS
`08/25/2009
`
`