CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`22-228
`
`
`APPLICA TI0N NUMBER:
`
`OFFICE DIRECTOR MEMO
`
`OFFICE DIRECTOR MEMO
`
`
`
`
`
`
`22-228
`
`

`

`NDA 22-288 Bepreve (bepotastine besilate ophthalmic solution)1.5%
`Deputy Office Director Decisional Memo
`
`Page 1 of 12
`
`Deputy Office Director Decisional Memo
`
`
`
`Date
`From
`Subject
`NDA #
`Applicant Name
`Date of Submission
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Dosage Forms / Strength
`Proposed Indication
`
`(electronic stamp)
`John Farley, M.D., M.P.H.
`Deputy Office Director Decisional Memo
`22-288
`ISTA Pharmaceuticals Inc.
`November 12, 2008
`September 12, 2009
`Bepreve /
`bepotastine besilate ophthalmic solution 1.5%
`Topical ophthalmic solution
`Indicated for the treatment of itching associated with
`allergic conjunctivitis
`Recommended for Approval
`
`Action:
`
`
`
`Material Reviewed/Consulted
`OND Action Package, including:
`Names of discipline reviewers
`Sonal D. Wadhwa, M.D.
`Medical Officer Review
`Mushfiqur Rashid, Ph.D.
`Statistical Review
`Pharmacology Toxicology Review Theresa Allio, Ph.D.
`CMC Review/OBP Review
`Shrikant Pagay/ Elaine Morefield, Ph.D.
`Microbiology Review
`John W. Metcalfe, Ph.D.
`Clinical Pharmacology Review
`Kimberly L. Bergman, Pharm.D.
`DDMAC
`Beth Carr, Pharm.D., Lynn Panholzer, Pharm.D.
`DSI
`Jean Mulinde, M.D.
`CDTL Review
`William M. Boyd, M.D.
`OSE/DEpi
`
`OSE/DMEPA
`Raichell S. Brown, Pharm.D., J.D.
`OSE/DRISK
`
`Other – Div. Director Review
`Wiley A. Chambers, M.D.
`OND=Office of New Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`DSI=Division of Scientific Investigations
`CDTL=Cross-Discipline Team Leader
`OSE= Office of Surveillance and Epidemiology
`DEPi= Division of Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DRISK=Division of Risk Management
`
`
`
`
`
`
`
`

`

`NDA 22-288 Bepreve (bepotastine besilate ophthalmic solution)1.5%
`Deputy Office Director Decisional Memo
`
`Page 2 of 12
`
`,
`
`1. Introduction
`
`Bepotastine besilate is a relatively selective H1 receptor antagonist and has an inhibitory
`action on eosinophilic infiltration to inflammatory sites.
`
`Bepotastine besilate ophthalmic solution 1.5% is a sterile ophthalmic solution of
`bepotastine besilate. The solution also contains sodium chloride
`monobasic sodium phosphate dehydrate
`, benzalkonium chloride as a
`preservative, sodium hydroxide for pH adjustment, and water for injection as a solvent.
`
`The proposed indication is treatment of ocular itching associated with allergic
`conjunctivitis in patients age 3 years and older.
`
`The proposed dosing regimen is instill one drop into the affected eye(s) twice a day.
`
`The proposed proprietary name is Bepreve.
`
`The support of clinical safety and efficacy for bepotastine besilate ophthalmic solution
`consisted of 3 clinical studies conducted in the US. One safety study (CL-SAF-0405071-
`P) and two efficacy studies (ISTA-BEPO-CS01 and CL-S&E-0409071-P) were
`performed.
`
`The review team has reviewed issues pertinent to their respective disciplines with regard
`to the safety and efficacy of bepotastine besilate ophthalmic solution 1.5% for the
`indication proposed. For a detailed discussion of NDA 22-288, the reader is referred to
`individual discipline specific reviews, the Cross-Discipline Team Leader Review, and the
`Division Director Review.
`
`2. Background/Regulatory
`
`Bepotastine besilate was originally developed in Japan as a treatment for allergic rhinitis.
`An oral preparation (Talion tablets, Mitsubishi Tanabe Pharma Corporation) was
`approved in Japan in July 2000 as a treatment for allergic rhinitis. In January 2002, the
`additional indication of pruritis/itching accompanying urticaria and other skin diseases
`was approved in Japan. Bepotastine is not an approved product in the U.S.
`
` A
`
` series of meetings were held between the applicant and the Agency regarding the
`development of Bepotastine besilate ophthalmic solution. Studies CL-S&E-0409071
`(7/23/07-SPA response and 12/3/07 SPA final response) and CLSAF-0405071 (7/23/07
`SPA response) were performed under SPA. There was an EOP 2 Meeting on 8/15/07,
`SPA Meeting on 9/17/08, and pre-NDA Meeting on 8/4/08.
`
`NDA 22-288 is submitted as a “stand alone” NDA.
`
`3. Chemistry Manufacturing and Controls / Product Quality Microbiology
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22-288 Bepreve (bepotastine besilate ophthalmic solution)1.5%
`Deputy Office Director Decisional Memo
`
`Page 3 of 12
`
`Reviewer Recommendations: From the chemistry, manufacturing, and controls
`standpoint, the reviewer recommended the NDA for approval.
`
` I
`
` concur that there are no outstanding CMC issues precluding approval.
`
`
`Drug substance impurities did not exceed acceptable concentrations. All excipients are
`of USP/NF grade. Release and stability testing included all standard tests for sterile
`ophthalmic solutions. The drug substance and drug product quality is reproducible based
`on the batch analysis data for release and stability. Manufacturing processes for the drug
`substance and drug product are well controlled. In the course of the review, queries were
`sent to the sponsor and all responses were deemed satisfactory by the reviewer.
`
`Four facilities involved in the manufacturing, testing, or packaging of the product were
`inspected and all evaluated as satisfactory.
`
`Stability testing supports an expiry of 12 months for the 1 mL fill and 18 months for the
`2.5 mL, 5mL, and 10mL fill when stored at 25 degrees C.
`
`4. Non-Clinical Pharmacology Toxicology
`
`Reviewer Recommendations: The reviewer had no objections to the approval of this NDA
`from a Pharmacology/Toxicology perspective. No additional non-clinical studies were
`recommended. Labeling as Pregnancy Category C is recommended. The Pharm/Tox
`Reviewer recommended that Bepreve should only be used during pregnancy and
`labor/delivery if the potential benefit justifies the potential risk to the fetus. The
`Pharm/Tox Reviewer recommended that caution should be exercised when Bepreve is
`administered to nursing women.
`
` I
`
` concur that there are no outstanding pharm tox issues that preclude approval.
`Appropriate information concerning use by pregnant and nursing women is included in
`Section 8 of the PI.
`
`Long-term dietary studies in mice and rats were conducted to evaluate the carcinogenic
`potential of bepotastine besilate. Bepotastine besilate did not significantly induce
`neoplasms in mice receiving systemic exposures approximating 350 times and rats
`receiving systemic exposures approximating 200 times that anticipated with human
`topical ocular use. There was no evidence of mutagenicity in in-vitro testing.
`
`Evidence of infertility and conceptus loss was seen in rats given oral bepotastine besilate
`1000 mg/kg/day. There was no evidence of infertility observed in rats given 200
`mg/kg/day (representing approximately 3330 times the maximal systemic concentration
`anticipated for topical ocular use in humans). A rare skeletal malformation was observed
`in the fertility/early embryo development study in rats at the 1000 mg/kg dose. An
`increased rate of stillborns and decreased rate of pup development was observed in rats at
`high doses of bepotastine besilate, but not at doses resulting in concentrations well-
`exceeding that anticipated for topical ocular use in humans. There are no adequate and
`
`
`
`

`

`NDA 22-288 Bepreve (bepotastine besilate ophthalmic solution)1.5%
`Deputy Office Director Decisional Memo
`
`Page 4 of 12
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`well-controlled studies of bepotastine besilate in pregnant women. Thus, Pregnancy
`Category C was recommended.
`
`In lactating rat studies, the milk concentration of bepotastine besilate was higher than the
`maternal blood plasma concentration. It is not known if the drug is excreted in human
`milk. Thus, the reviewer recommended a caution be included in the label.
`
`There was evidence in animal studies that the drug may have an affinity for melanin
`binding based on the observation of presence in the iris in an ocular toxicity study and in
`the pigmented tissues in a radio-labeled study. The association with melanin appears
`reversible, reaching below the limit of detection 30 days post a single dose.
`
` A
`
` 26 week study in dogs using the 4 and 8X per day dosing with the 1.5% solution. The
`4X per day dosing was determined to be the NOAEL based on decreases in A and B
`wave amplitude in electroretinograms in the 8X per day group. The NOAEL provides a
`15X safety factor over that of anticipated systemic exposures anticipated with topical use
`in humans.
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`Reviewer Recommendations: The reviewer stated that the clinical pharmacology
`information provided by the applicant is acceptable. The reviewer concluded that the
`proposed dosing regimen of one drop of the 1.5% solution into the affected eye(s) twice a
`day is supported by the data submitted.
`
` I
`
`
`
` concur that there are no outstanding clinical pharmacology issues that preclude
`approval.
`
`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. Additional data from
`multiple Phase 1 studies from the Japanese oral development program were also
`submitted in this application. The clinical pharmacology findings from these studies are
`summarized as follows:
`- Following ophthalmic administration of bepotastine besilate bilaterally four times daily
`for seven days in healthy male subjects, bepotastine plasma concentrations peaked at
`approximately one to two hours post-instillation. Maximum plasma concentrations were
`suggestive of a dose dependent increase in exposure; Cmax values for 1.0% and 1.5%
`bepotastine besilate were 5.138 ± 2.503 ng/mL and 7.335 ± 1.876 ng/mL, respectively.
`Plasma concentrations at 24 hours post-instillation were below the quantifiable limit
`(2 ng/mL) in 11/12 subjects in the two dose groups.
`- Following a single, oral 10 mg dose of bepotastine besilate in healthy subjects, the
`maximum plasma concentration of bepotastine was 101.3 ± 3.5 ng/mL. This is over
`10 times that of the Cmax attained following one drop of 1.5% bepotastine besilate
`
`

`

`NDA 22-288 Bepreve (bepotastine besilate ophthalmic solution)1.5%
`Deputy Office Director Decisional Memo
`
`Page 5 of 12
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`ophthalmic solution instilled to both eyes four times daily. Thus, the potential for adverse
`effects resulting from systemic exposure following administration of bepotastine besilate
`ophthalmic solution, 1.5% is low.
`- The plasma protein binding of bepotastine in humans was approximately 55% and
`independent of bepotastine concentration following oral administration.
`- In vitro metabolism studies with human liver microsomes demonstrated that bepotastine
`is minimally metabolized by CYP450 isozymes and bepotastine does not inhibit the
`activity of CYP3A4, CYP2C9, and CYP2C19. Thus, bepotastine besilate has a low
`potential for drug interactions via inhibition of CYP3A4, CYP2C9, and CYP2C19.
`- Following single oral doses ranging from 2.5 to 40 mg in healthy male volunteers,
`approximately 76 to 88% of the bepotastine besilate dose was excreted in urine by
`24 hours.
`
`The Reviewer also reviewed studies CL-SAF-0405071-P, ISTA-BEPO-CS01, and CL-
`S&E-0409071-P and concurred with findings regarding Efficacy and Safety detailed
`below in Sections 7 and 8 of this review. The Reviewer stated that the 1.5% solution is
`acceptable from a Clinical Pharmacology perspective.
`
`6. Clinical Microbiology
`
`Reviewer Recommendation: Approval
`
` I
`
` concur that there are no outstanding clinical microbiology or sterility issues that
`preclude approval.
`
`Manufacturing processes, container closure and package integrity, preservative
`effectiveness to maintain sterility were reviewed and deemed satisfactory. No
`microbiology deficiencies were identified.
`
`7. Clinical/Statistical Efficacy
`
`Clinical Reviewer Recommendations: Approval. The reviewer stated that the clinical
`studies contained in the submission support the use of bepotastine besilate ophthalmic
`solution 1.5% for the treatment of itching associated with allergic conjunctivitis.
`
`Statistical Reviewer Recommendations: Approval of Bepreve 1.5% for the treatment of
`ocular itching associated with allergic conjunctivitis.
`
` I
`
`
`
` concur that the efficacy of bepotastine besilate ophthalmic solution 1.5% for the
`treatment of ocular itching associated with allergic conjunctivitis has been demonstrated.
`
`The support of efficacy for bepotastine besilate ophthalmic solution consisted of 2
`clinical studies conducted in the U.S. (ISTA-BEPO-CS01 and CL-S&E-0409071-P).
`Both of these were conjunctival antigen challenge (CAC) studies. For the demonstration
`of efficacy in the treatment of allergic conjunctivitis, the Agency has recommended that
`evidence include demonstration of both statistical significance and clinical relevance in
`
`

`

`NDA 22-288 Bepreve (bepotastine besilate ophthalmic solution)1.5%
`Deputy Office Director Decisional Memo
`
`Page 6 of 12
`
`the resolution of ocular itching and redness. In the case of antigen challenge studies or
`controlled environmental studies, the point estimate of the difference between groups is
`recommended to be at least one unit on a scale from zero to four as demonstration of
`clinical relevance.
`
`Study ISTA-BEPO-CS01: A Single-Center, Double-Masked, Randomized, Vehicle-
`Controlled, Evaluation of the Onset and Duration of Action of Two Concentrations (1%
`and 1.5%) Bepotastine Besilate Ophthalmic Solution in the CAC Model of Acute
`Allergic Conjunctivitis
`
`The primary objective of this study was to establish the efficacy of bepotastine besilate
`ophthalmic solution 1% and 1.5% compared to vehicle in alleviating the signs and
`symptoms of CAC-induced allergic conjunctivitis at 15 minutes, 8 hours, and 16 hours
`following investigational product instillation. This was a single-center, double-masked,
`randomized, vehicle-controlled, CAC study planned for patients with a demonstrated
`history of allergic conjunctivitis who were ≥ 10 years of age. This study consisted of a
`total of 5 visits, conducted over approximately 7 weeks. The primary efficacy variables
`were subject-evaluated ocular itching at 3, 5, and 7 minutes post CAC and investigator-
`evaluated conjunctival redness at 7, 15, and 20 minutes post CAC. Itching and redness
`scales were based on a 5-unit (9 steps) grading scale with half unit (one step) increments
`allowed.
`
`Subjects were evaluated during screening for a consistent allergic response to a defined
`allergen as judged by grades of 2.0 units or greater for ocular itching and hyperemia in at
`least 2 out of the 3 vessel beds examined during two screening visits. At Visit 1, allergen
`instilled in each eye of subjects was titrated for the induction of an ocular allergic
`response to obtain the lowest concentration of allergen that produced an allergic
`response. Any subject who met the criteria for an allergic response continued to Visit 2 at
`which time the allergen of the same identity and dose used in the previous visit was
`instilled in each subject eye and an ocular allergic response was confirmed. Only subjects
`who met the study criteria for a positive CAC reaction at Visits 1 and 2 continued to Visit
`3A. At Visit 3A, a computer-generated randomization list was used to assign the subjects
`(in 1:1:1 proportions) to one of three treatment groups (bepotastine 1%, bepotastine
`1.5%, or vehicle). Subjects in each treatment group received 3 doses of investigational
`product during the course of participation in this study. At Visits 3A, 4 (14 +/- 3 days
`post Visit 3A), and 5 (28 +/- 3 days post Visit 3A), a trained technician instilled 1 drop of
`the assigned investigational product into both eyes of each subject. CAC was performed,
`using the previously validated allergen dose for each subject at: 16 hours (duration-of-
`action acceptable for drugs intended to be dosed QD), 8 hours (duration-of-action
`acceptable for drugs intended to be dosed BID), or 15 minutes (onset of action) post
`investigational product instillation during Visit 3A, 4, and 5, respectively. Signs and
`symptoms of allergic conjunctivitis were then graded over a 20-minute period following
`the CAC.
`
` A
`
`
`
` total of 107 subjects were randomized in study ISTA-BEPO-CS01. For ITT
`population, there was no difference among arms for age, gender, ethnicity, race, or eye
`
`

`

`NDA 22-288 Bepreve (bepotastine besilate ophthalmic solution)1.5%
`Deputy Office Director Decisional Memo
`
`Page 7 of 12
`
`color. Six patients were excluded from the PP population (one for I/E protocol violation,
`one for missed visit protocol violation, and four early discontinuations). Thus, the PP
`population consisted of 101 subjects. Note that this is a single site trial.
`
`Study C-S&E-0409071-P: A Multi-Center, Double-Masked, Randomized, Vehicle-
`Controlled, Evaluation of the Onset and Duration of Action of Two Concentrations of
`Bepotastine Besilate Ophthalmic Solution (1% and 1.5%) in the Conjunctival Allergen
`Challenge (CAC) Model of Acute Allergic Conjunctivitis
`
`The primary objective of this study was to establish the safety and efficacy of bepotastine
`besilate ophthalmic solution 1% and 1.5% compared to vehicle in alleviating the signs
`and symptoms of allergic conjunctivitis at 15 minutes, 8 hours, and 16 hours following
`investigational product instillation using the CAC model of allergic conjunctivitis in
`subjects with a history of allergic conjunctivitis. This was a multi-center, double-masked,
`randomized, vehicle-controlled, CAC study planned for approximately 130 subjects with
`a demonstrated history of allergic conjunctivitis who were ≥10 years of age. This study
`was conducted at 5 sites and consisted of 5 visits, completed over approximately 7 weeks.
`The primary efficacy measures, secondary efficacy measures, and study procedures were
`the same as for Study ISTA-BEPO-CS01. The only additional measure performed was
`patient ocular comfort scores.
`
` A
`
`
`
` total of 130 subjects were randomized in study C-S&E-0409071-P. For ITT
`population, there was no difference among arms for age, gender, ethnicity, race, or eye
`color. Thirteen patients were excluded from the PP population (all classified as
`discontinued/withdrawn, most no-shows based on CRF review). Thus, the PP population
`consisted of 117 subjects.
`
`Efficacy Analyses for Both Studies: The primary efficacy analyses in the two phase 3
`studies were based on the ITT population with LOCF method for imputing missing data.
`Sensitivity analyses using PP population and ITT population with observed data only
`were carried out and results consistent with those of the primary analyses. More
`conservative multiplicity adjustments were made by the Statistical Reviewer with no
`change in the conclusions of the analyses. The average score of each subject’s eyes was
`the unit used for comparison between bepotastine and vehicle for all analyses. Clinical
`significance required at least a 1 unit difference in the point estimate between arms for
`the majority of time points at a study visit during the treatment period. Clinical success at
`a study visit required achievement of both statistical and clinical significance for a
`majority of time points. Clinical efficacy for ocular itching and conjunctival redness was
`considered to have been achieved by showing clinical success at Visit 5 (CAC at 15 min
`post dosing) as well as at Visit 3B (CAC 16 hours post dosing) and/or Visit 4 (CAC 8
`hours post dosing).
`
`In both studies, a robust statistically significant difference in mean itching grades vs.
`vehicle was noted for both the 1% and 1.5% bepotastine solutions for Visits 3A, 4, and 5
`at 3, 5, and 7 minutes post CAC for both the ITT and PP populations. However, to
`demonstrate clinical significance, a difference between groups of at least one unit on the
`
`

`

`NDA 22-288 Bepreve (bepotastine besilate ophthalmic solution)1.5%
`Deputy Office Director Decisional Memo
`
`Page 8 of 12
`
`ocular itching scale of 0-4 at a majority of time points evaluated was required. This
`difference of at least one unit was duplicated in the two trials only at the 8 hours post
`dosing CAC (Visit 4) with both the 1% and 1.5% concentrations of the drug. The 1.5%
`solution produced a greater difference in point estimate for the mean itching grades vs.
`vehicle than the 1% solution at both the 8 hours post dosing (Visit 4) and 16 hours post
`dosing (Visit 3A) CAC visits. Thus, the Clinical, Statistical, and CDTL Reviewers felt
`that the data supports a preferred dosing using the 1.5% solution bid for the treatment of
`itching associated with allergic conjunctivitis. The percentage of eyes with no itching at
`various post-CAC times was evaluated in a post-hoc analysis using the ITT population
`with LOCF. This post-hoc analysis supported the conclusion that the 1.5% solution had a
`clinical response of greater magnitude than the 1% solution. With respect to conjunctival
`redness, neither concentration of bepotastine was found to produce a clinically significant
`reduction (difference of at least one unit in the point estimate for mean conjunctival
`hyperemia scores) compared to vehicle at any study visit in either study. The Clinical
`and Statistical reviewer concurred that both the 1.0% and 1.5% solutions failed in the
`primary endpoint of conjunctival redness. Long-term effectiveness was not evaluated in
`these studies as the duration of treatment for the subjects in these trials was three single
`doses at three separate visits.
`
`8. Safety
`
`Recommendations: The Clinical Reviewer and CDTL recommended that the benefits of
`using this drug outweigh the risks for the above indication. No proposed risk
`management action except standard post-marketing collection and reporting of adverse
`experiences and no Phase 4 clinical study commitments were recommended.
`
` I
`
`
`
` concur with these recommendations. The common adverse effects described in labeling
`include mild taste disturbance as well as eye irritation, headache, and nasopharyngitis.
`
`Study CL-SAF-0405071: The main support of safety for bepotastine 1.5% came from
`study CL-SAF-0405071 “A Multi-Center, Double-Masked, Randomized, Vehicle-
`Controlled, Parallel-Group Study Evaluating the Safety of Bepotastine Besilate
`Ophthalmic Solution 1.5% Used Twice Daily in Healthy, Normal Volunteers”. This trial
`was conducted at 6 sites in the U.S. The dosing regimen for all subjects was 1 drop
`administered bilaterally, twice daily, for 6 continuous weeks. The target study population
`was subjects 3 years of age and older with normal ocular health. Randomization was at a
`ratio of 2:1 (active: vehicle) and subjects were not stratified by age group. This study
`consisted of 4 visits conducted over approximately 43 days for all study participants
`except for a subset of subjects who underwent ocular endothelial cell counts (ECC). At 1
`of the 6 study sites, a sub-population of subjects ≥10 years of age who agreed to undergo
`specular microscopy at Visit 1 (baseline) and again at Visit 5 (Day 84 + 7) was identified.
`To be enrolled, a baseline ECC of ≥2200 cells/mm2 was necessary. All subjects who did
`not undergo endothelial cell counts at Visit 1 completed the clinical trial at Visit 4.
`
`575 subjects were randomized to bepotastine besilate 1.5% and 286 to vehicle. Of the 861
`total subjects enrolled, 127 were pediatric subjects. Of the pediatric subjects, 72 were 3-9
`
`

`

`NDA 22-288 Bepreve (bepotastine besilate ophthalmic solution)1.5%
`Deputy Office Director Decisional Memo
`
`Page 9 of 12
`
`years of age and 55 were 10-17 years of age. Studies to evaluate metabolism, clearance,
`and interaction were not performed due to the negligible systemic absorption of
`bepotastine given by the topical route of administration. No deaths occurred during study
`CL-SAF-0405071. No serious adverse events were reported during study CL-SAF-
`0405071. 801 subjects completed the study and this was proportionate between arms.
`Twelve subjects withdrew from the study early with an AE being listed as the reason for
`study discontinuation (6 in the bepotastine group and 6 in the vehicle group).
`
`Four adverse events occurred in ≥2% of subjects in the bepotastine besilate ophthalmic
`solution 1.5% treatment group: taste disturbance upon instillation, eye irritation,
`headache, and naso-pharyngitis. 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, 25.2% 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). There was a considerable variation
`in the frequency of taste-related issues reported as AEs between sites: the percentage of
`subjects in the bepotastine besilate ophthalmic solution 1.5% treatment group reporting a
`taste-related AE varied from 0% (investigative site 5) to 42% (investigative site 6). In
`addition, subjects receiving bepotastine 1.5% did not experience any clinically significant
`changes from baseline or compared to subjects receiving vehicle in any of the other
`safety measurements (visual acuity, intraocular pressure, dilated fundoscopy, slit-lamp
`biomicroscopy, ocular endothelial cell counts, and ocular comfort evaluations). The type
`and pattern of occurrence of treatment-emergent AEs related to the investigational
`product in the 2 pediatric age subgroups were similar to those observed in the overall
`safety population. There were no clinically significant differences in endothelial cell
`density between the bepotastine 1.5% and the vehicle arms. The data did not show
`evidence of a delayed toxicity or increased safety risks associated with duration of
`exposure.
`
`Studies ISTA-BEPO-CS01 and C-S&E-0409071-P: The safety population was defined
`as all subjects in these studies who received at least one dose of test agent. There were
`107 subjects in the safety population for ISTA-BEPO-CS01 and 130 subjects in the
`safety population for CL-S&E-0409071-P. In both studies, the following safety measures
`were evaluated: visual acuity, slit lamp biomicroscopy, IOP measurement, dilated
`fundoscopy, adverse event reporting. There were no SAEs or deaths reported. Adverse
`ocular events were infrequent and more common in the vehicle group. Non-ocular
`adverse events (none severe) occurred with greater frequency in the bepotastine arms in
`study ISTA-BEPO-CS01, and this was due to the greater incidence of dysgeusia in these
`groups. Ocular comfort was evaluated in study C-S&E-0409071-P on each occasion that
`subjects received investigational product. There were no differences in ocular comfort
`scores between the two concentrations of bepotastine and vehicle at any time point.
`
`Other: Electrocardiograms were not obtained in any of the reviewed studies. Drug-drug
`interaction studies were not performed. The drug has not been tested in pregnant women.
`
`
`
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`

`NDA 22-288 Bepreve (bepotastine besilate ophthalmic solution)1.5%
`Deputy Office Director Decisional Memo
`
`Page 10 of 12
`
`Post-Marketing Reporting: Post-marketing reporting in Japan of Talion tablets was
`summarized for approximately 6 years of marketing experience. The most common
`adverse events were drowsiness (1.32%) and upper abdominal pain (0.13%). In addition,
`long term use of Talion tablets was investigated as part of another post-marketing study
`conducted in Japan. The most common adverse events were drowsiness and dry mouth
`(0.26%), and upper abdominal pain, facial edema, and pharyngeal edema (each 0.09%).
`Adverse events in the geriatric population were not different than that in the general
`population. A retrospective analysis of the safety of Talion tablets in pediatric patients
`ages 5-14 years was completed in Japan. The incidence of side effects was not different
`than that in the adult reports.
`
`9. Advisory Committee Meeting
`
`Since this is a NME (new molecular entity) advisory committee was convened on June
`26, 2009.
`The following questions were presented to the committee:
`
`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 any suggestions concerning the proposed draft labeling of the product?
`There were no suggestions regarding the proposed draft labeling.
`
`10. Pediatrics
`
` partial waiver of the 0 months -2 years and 11 months age group was requested by the
`sponsor with the rationale that study of this age group was not feasible as there were too
`few children in this age group with the condition to study. This partial waiver was
`approved as the disease is not considered to be reliably diagnosed below the age of 2
`years.
`
`Children 10 years of age and above were included in the CAC efficacy studies. There are
`no recognized differences in the disease in pediatric patients below the age of 10 years
`and older children or adults. However, children under 10 years of age are not considered
`reliable historians for the reporting of ocular itching scores. Thus, 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 adults.
`
` A
`
`
`
`

`

`NDA 22-288 Bepreve (bepotastine besilate ophthalmic solution)1.5%
`Deputy Office Director Decisional Memo
`
`Page 11 of 12
`
`
`
`Bepreve was tested for 6 weeks in 87 subjects ranging in age between 3 and 17 years of
`age in ISTA safety study CL-SAF-0405071-P. The safety profile did not differ in this
`group from the patient population 18 years and older.
`
`The PeRC reviewed this NDA on 5/27/09.
`
`11. Other Relevant Regulatory Issues
`
`There are no unresolved relevant regulatory issues.
`
`DSI inspections of selected sites for studies ISTA-BEPO-CS01, CL-S&E-0409071, and
`L-SAF-0405071 were conducted. In addition, inspection of the sponsor, ISTA
`Pharmaceuticals, was conducted. DSI concluded that, in general, the protocols appear to
`have conducted adequately and the data in support of the NDA appear reliable. There
`were regulatory violations noted at two investigator sites, but the safety and efficacy data
`from these sites was considered reliable.
`
`Financial Disclosure: There were no investigators with proprietary interest or with any
`significant interest in the drug product in ISTA-BEPO-CS01, CL-S&E-0409071, or CL-
`SAF-0405071.
`
`12. Labeling
`
`DMEPA proprietary name risk assessment review was conducted and it was determined
`that the proposed name, Bepreve, would be unlikely to be vulnerable to name confusion
`that could lead to medication errors. DDMAC had no concerns regarding the proposed
`name from a promotional perspective.
`
`DMEPA also provided recommendations on the packaging configuration and the package
`insert. These were incorporated in the labeling where appropriate. The DMEPA
`reviewer subsequently reviewed the final packaging configuration and package insert and
`indicated concurrence.
`
`DDMAC recommended changes to the Warnings and Precautions section of the
`Highlights of Prescribing Information to add, “Lenses may be reinserted after 10 minutes
`following administration of Bepreve” to the sentence “Remove contact lenses prior to
`installation of Bepreve”. The CDTL disagreed with this recommendation due to concern
`that this may be misunderstood and promote the use of contact lenses when the eyes are
`red. I concur with the CDTL recommendation. More detailed informat