CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`
`APPLICATION NUMBER:
`22-228
`
`
`
`APPLICA TI0N NUMBER:
`
`CLINICAL PHARMACOLOGY AND
`
`CLINICAL PHARMACOLOGY AND
`BIOPHARMACEUTICS REVIEW(S)
`BIOPHARMACEUTICS REVIEW! S 2
`
`
`
`
`
`22-228
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`
`
`
`
`
`NDA:
`Submission Date(s):
`Brand Name
`Generic Name
`Primary Reviewer
`Team Leader
`OCP Division
`OND Division
`Applicant
`Relevant IND(s)
`Submission Type; Code
`Formulation; Strength(s)
`Indication
`
`22-288
`12NOV2008
`Bepreve™
`Bepotastine Besilate Ophthalmic Solution 1.5%
`Kimberly L. Bergman, Pharm.D.
`Charles Bonapace, Pharm.D.
`DCP4
`DAIOP
`ISTA Pharmaceuticals®, Inc.
`IND 66,864
`Original NDA; 505(b)(1) application; 1S (new molecular entity)
`Bepotastine Besilate Ophthalmic Solution 1.5%
`Treatment of ocular itching associated with allergic conjunctivitis
`in patients age 3 years or older
`
`
`
`
`TABLE OF CONTENTS
`
`1. EXECUTIVE SUMMARY .................................................................................................................. 2
`1.1. RECOMMENDATION....................................................................................................................... 2
`1.2. PHASE IV COMMITMENTS............................................................................................................. 2
`1.3.
`SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY FINDINGS............................................. 2
`2. QUESTION BASED REVIEW ........................................................................................................... 4
`2.1. GENERAL ATTRIBUTES OF THE DRUG .......................................................................................... 4
`2.2. GENERAL CLINICAL PHARMACOLOGY......................................................................................... 5
`2.3.
`INTRINSIC FACTORS .................................................................................................................... 14
`2.4. EXTRINSIC FACTORS ................................................................................................................... 14
`2.5. GENERAL BIOPHARMACEUTICS .................................................................................................. 14
`2.6. ANALYTICAL SECTION................................................................................................................. 14
`3. LABELING RECOMMENDATIONS ............................................................................................. 17
`4. APPENDICES .................................................................................................................................... 19
`4.1.
`INDIVIDUAL STUDY REVIEWS...................................................................................................... 19
`
`
`
`
`
`1
`
`

`

`
`1. EXECUTIVE SUMMARY
`
`Bepotastine besilate is a selective histamine H1-receptor antagonist. Bepreve™ (bepotastine
`besilate ophthalmic solution), 1.5% is a sterile ophthalmic solution of bepotastine besilate
`proposed for the treatment of itching associated with signs and symptoms of allergic
`conjunctivitis in patients aged 3 years or older. The proposed dosage and route of administration
`for Bepreve™ (bepotastine besilate ophthalmic solution), 1.5% is as follows: instill one drop into
`the affected eye(s) twice a day (BID). Bepotastine besilate (also known as TAU-284 and SNJ-
`1773) was originally developed in Japan by Ube Industries, Ltd. and Tanabe Seiyaku Co., Ltd. as
`a treatment for allergic rhinitis. An oral preparation of bepotastine besilate (Talion® tablets,
`Mitsubishi Tanabe Pharma Corporation [formerly Tanabe Seiyaku Company, Ltd.]) was
`approved in Japan in July 2000 and launched in October 2000. In January 2002, the additional
`indication of pruritus/itching accompanying urticaria and other skin diseases was approved in
`Japan.
`
`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. To support the safety and efficacy of Bepreve™
`(bepotastine besilate ophthalmic solution), 1.5%, the applicant conducted one Phase 2/3 (single
`site) and one Phase 3 (multisite), placebo-controlled, double-masked, randomized conjunctival
`allergen challenge (CAC) efficacy studies with bepotastine besilate ophthalmic solutions 1.0%
`and 1.5% in male and female subjects aged 10 years and older who have a positive history of
`allergic conjunctivitis (Studies ISTA-BEPO-CS01 and CL-S&E-0409071-P). Both pivotal trials
`evaluated the clinical efficacy of two bepotastine besilate ophthalmic solutions (1.0% and 1.5%)
`at each of two durations of action (8 hours, considered acceptable for a drug intended for dosing
`BID, and 16 hours, considered acceptable for a drug intended for dosing QD) by having 5 subject
`visits over approximately 7 weeks. In addition, a Phase 3 multisite, double-masked, randomized,
`placebo-controlled, parallel-group study (CL-SAF-0405071-P) evaluated the safety of bepotastine
`besilate ophthalmic solution 1.5% administered 2 times per day (BID) for 6 weeks in healthy,
`normal volunteers 3 years of age and older.
`
`
`1.1. Recommendation
`
`
`The clinical pharmacology information provided by the Applicant is acceptable.
`
`
`1.2. Phase IV Commitments
`
`
`No phase IV commitments are recommended.
`
`
`1.3. Summary of Important Clinical Pharmacology Findings
`
`
`Bepreve™ (bepotastine besilate ophthalmic solution), 1.5% is a sterile ophthalmic solution of
`bepotastine besilate proposed for the treatment of itching associated with signs and symptoms of
`allergic conjunctivitis in patients aged 3 years or older. The proposed dosage and route of
`administration for Bepreve™ (bepotastine besilate ophthalmic solution), 1.5% is as follows:
`instill one drop into the affected eye(s) twice a day (BID). The extent of systemic exposure to
`bepotastine following topical ophthalmic administration of bepotastine besilate 1.0% and 1.5%
`ophthalmic solution was evaluated in a multiple-dose pharmacokinetic (PK) study in 12 healthy
`
`
`
`2
`
`

`

`adults (Study SNJ-TO-02). 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 the below 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
`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.
`
`
`Based on the assessment of systemic exposure information for Bepreve™ (bepotastine besilate
`ophthalmic solution), 1.5%, the regulatory requirement for submission of in vivo bioavailability
`data has been adequately addressed.
`
`
`
`
`_______________________________________
`Kimberly L. Bergman, Pharm.D.
`Division of Clinical Pharmacology 4
`Office of Clinical Pharmacology
`
`
`_______________________________________
` Charles R. Bonapace, Pharm.D.
`Team Leader
`
`
`
`Concurrence:
`
`
`
`
`
`
`
`
`
`cc:
`Division File: NDA 22-288
`HFD-520 (CSO/Rodriguez)
`HFD-520 (MO/Wadhwa)
`HFD-520 (Chambers, Boyd)
`HFD-880 (Lazor, Reynolds, Bonapace)
`
`
`
`3
`
`

`

`
`2. QUESTION BASED REVIEW
`
`Since this submission is an NDA for a locally administered ophthalmic drug product, only
`relevant questions from the OCP question-based review (QBR) format are addressed below.
`
`2.1. General Attributes of the Drug
`
`2.1.1. What are the highlights of the chemistry and physical-chemical properties of the drug
`substance and the formulation of the drug product?
`
`
`Bepreve™ (bepotastine besilate ophthalmic solution), 1.5% is a sterile, clear colorless to pale
`yellow aqueous solution containing bepotastine besilate as the active ingredient. Bepreve™
`ophthalmic solution is supplied as a sterile, aqueous 1.5% solution, with a pH of 6.8 and an
`osmolality of approximately 290 mOsm/kg.
`
`Structural Formula: C21H25ClN2O3•C6H6O3S
`
`Chemical Structure:
`
`
`
`
`Chemical Name: (+)-(S)-4-{4-[(4-Chlorophenyl)(2-pyridyl)methoxy] piperidino} butyric acid
`monobenzenesulfonate
`
`Compendial Name: Bepotastine Besilate
`
`
`International Nonproprietary Name (INN): Bepotastine
`
`Company Laboratory Code: TAU-284, SNJ-1773
`
`Chemical Abstract Service (CAS) Registry Number: 190786-44-8
`
`Molecular Weight: 547.06
`
`The qualitative and quantitative composition of the proposed Bepreve™ (bepotastine besilate
`ophthalmic solution), 1.5% drug product is shown in Table 2.2-1.
`
`
`
`
`
`
`
`
`
`
`4
`
`

`

`Table 2.2-1
`
`
`
`
`Composition of Bepotastine Besilate Ophthalmic Solution, 1.5%
`
`Function
`Active ingredient
`
`%, w/w
`1.5%
`
`Component
`Bepotastine Besilate
`Sodium Chloride
`Monobasic Sodium Phosphate,
`Dihydrate
`Benzalkonium Chloride
`Sodium Hydroxide
`Water for Injection
`Source: Section 3.2.P.1
`
`Preservative
`pH adjustment
`Solvent
`
`0.005%
`Adjust pH to 6.8
`QS to 100 mL
`
`
`
`2.1.2. What is the proposed mechanism of drug action and therapeutic indication?
`
`Bepotastine is a selective histamine H1-receptor antagonist. Bepreve™ (bepotastine besilate
`ophthalmic solution), 1.5% is proposed for the treatment of itching associated with signs and
`symptoms of allergic conjunctivitis in patients aged 3 years or older.
`
`2.1.3. What is the proposed dosage and route of administration?
`
`The proposed dosage and route of administration for Bepreve™ (bepotastine besilate ophthalmic
`solution), 1.5% is as follows: instill one drop into the affected eye(s) twice a day (BID).
`
`2.2. General Clinical Pharmacology
`
`2.2.1. What are the design features of the clinical pharmacology and clinical studies used to
`support dosing claims?
`
`
`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. To support the safety and efficacy of Bepreve™
`(bepotastine besilate ophthalmic solution), 1.5%, the applicant conducted one Phase 2/3 (single
`site) and one Phase 3 (multisite), placebo-controlled, double-masked, randomized conjunctival
`allergen challenge (CAC) efficacy studies with bepotastine besilate ophthalmic solutions 1.0%
`and 1.5% in male and female subjects aged 10 years and older who have a positive history of
`allergic conjunctivitis (Studies ISTA-BEPO-CS01 and CL-S&E-0409071-P). Both pivotal trials
`evaluated the clinical efficacy of two bepotastine besilate ophthalmic solutions (1.0% and 1.5%)
`at each of two durations of action (8 hours, considered acceptable for a drug intended for dosing
`BID, and 16 hours, considered acceptable for a drug intended for dosing QD) by having 5 subject
`visits over approximately 7 weeks. In addition, a Phase 3 multisite, double-masked, randomized,
`placebo-controlled, parallel-group study (CL-SAF-0405071-P) evaluated the safety of bepotastine
`besilate ophthalmic solution 1.5% administered 2 times per day (BID) for 6 weeks in healthy,
`normal volunteers 3 years of age and older. Design features of the relevant studies conducted in
`the Bepreve™ (bepotastine besilate ophthalmic solution), 1.5% development program are
`summarized in Table 2.2.1-1.
`
`
`
`
`5
`
`(b) (4)
`
`

`

`Table 2.2.1-1 Summary of the Bepotastine Besilate Ophthalmic Solution, 1.5% Clinical Development Program
`
`
`Study
`
`ISTA-BEPO-
`CS01
`
`CL-S&E-
`0409071-P
`
`CL-SAF-
`0405071-P
`
`Study
`Design
`
`Study
`Objective
`
`Phase 2/3, single center,
`double-masked,
`randomized, placebo-
`controlled, CAC study
`
`Efficacy and safety of bepotastine besilate ophthalmic
`solution 1.0% and 1.5% compared to placebo in
`alleviating the signs and symptoms of CAC-induced
`allergic conjunctivitis at 15 minutes, 8 hours, and
`16 hours following medication instillation
`
`Phase 3, multi-center,
`double-masked,
`randomized, placebo-
`controlled, CAC study
`
`Phase 3, multi-center,
`randomized, double-
`masked, vehicle-
`controlled, parallel-
`group study
`
`Efficacy and safety of bepotastine besilate ophthalmic
`solution 1.0% and 1.5% compared to placebo in
`alleviating the signs and symptoms of CAC-induced
`allergic conjunctivitis at 15 minutes, at 8 hours, and at
`16 hours following investigational product instillation
`
`Evaluate the safety of bepotastine besilate ophthalmic
`solution 1.5% in healthy, normal volunteers
`
`SNJ-TO-02
`
`Phase 1, open-label
`study
`
`Investigate the safety and PK of 1.0% and 1.5%
`SNJ-1773 ophthalmic solutions
`
`TP, test product
`Source: Table 5.2 Tabular Listing of Clinical Studies
`
`Test Product(s);
`Dosage Regimen;
`Route of
`Administration;
`Treatment Duration
`TP: Bepotastine besilate
`ophthalmic solution 1.0%,
`1.5%, or Placebo; Dose: One
`drop at Visit 3A, Visit 4, and
`Visit 5; Route: ophthalmic;
`Duration: 7 weeks
`TP: Bepotastine besilate
`ophthalmic solution 1.0%,
`1.5%, or Placebo; Dose: One
`drop at Visit 3A, Visit 4, and
`Visit 5; Route: ophthalmic;
`Duration: 7 weeks
`TP: Bepotastine besilate
`ophthalmic solution 1.5% or
`Placebo; Dose: one drop
`BID; Route: ophthalmic;
`Duration: 6 weeks to 12
`weeks
`TP: SNJ-1773 1.0% or
`1.5%; Dose: one drop QID;
`Route: ophthalmic;
`Duration: 7 days
`
`Population
`
`# Subjects
`
`107
`
`130
`
`CAC-induced
`allergic
`conjunctivitis
`patients
`
`CAC-induced
`allergic
`conjunctivitis
`patients
`
`Healthy subjects
`
`861
`
`Healthy subjects
`(Japanese)
`
`12
`
`
`
`6
`
`

`

`
`2.2.2. What is the basis for selecting the response endpoints (i.e. clinical or surrogate
`endpoints) or biomarkers (collectively called pharmacodynamics (PD)) and how are they
`measured in clinical pharmacology and clinical studies?
`
`
`The primary efficacy variables for both efficacy CAC trials were ocular itching and conjunctival
`hyperemia (redness). The primary efficacy variable of ocular itching was evaluated by subjects at
`3, 5, and 7 minutes post-CAC, while conjunctival hyperemia was investigator-evaluated at 7, 15,
`and 20 minutes post-CAC. Severity scales for both measures were based on a 5-point (nine-step)
`scale with half unit (one step) increments allowed (e.g. grades 0 through 4). The average score of
`each subject’s eyes was used for comparison between bepotastine besilate ophthalmic solutions
`(1.0% and 1.5%) and the placebo ophthalmic solution.
`
`Clinical efficacy for both primary efficacy variables required demonstration of clinical and
`statistical significance at Visit 5 (the onset of action CAC test) and at Visit 3B (the 16 hour
`duration of action CAC test) or Visit 4 (the 8 hour duration of action CAC test). The studies
`consisted of six 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 (Day 0). At Visits 3A, 4, and 5, investigational product was instilled, and conjunctival
`allergen challenge (CAC) was performed, using the previously validated allergen dose for each
`subject, at: 16 hours (assessed at Visit 3B or Day 1; 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.
`
`Secondary efficacy variables included rhinorrhea, nasal congestion, tearing, ciliary and episcleral
`hyperemia, chemosis, ocular mucous discharge, eyelid swelling, nasal pruritus, and ear or palate
`pruritus, and a total non-ocular (principally nasal) composite symptom scores.
`
`2.2.3. Are the active moieties in the biological fluid appropriately identified and measured to
`assess pharmacokinetic parameters?
`
`
`The active moiety bepotastine was appropriately identified and measured in plasma and urine for
`purposes of assessment of systemic exposure following ocular and oral administration by a
`validated high performance liquid chromatographic (HPLC) method with UV-detection.
`
`2.2.4. Exposure-Response
`
`
`2.2.4.1. What are the characteristics of the exposure-response relationships (dose-
`response, concentration-response) for efficacy?
`
`
`Summaries of treatment differences for ocular itching and conjunctival hyperemia (both eyes
`averaged) for both pivotal studies combined are presented in Tables 2.2.4.1-1 and 2.2.4.1-2.
`Based on the applicant’s analyses of Studies ISTA-BEPO-CS01 and CL-S&E-0409071-P, both
`bepotastine besilate ophthalmic solutions (1.0% and 1.5%) were efficacious for reduction of
`ocular itching, but not conjunctival hyperemia, in the CAC model compared to placebo with a
`
`
`
`7
`
`

`

`duration of action of at least 8 hours. In addition, clinical benefit was seen with bepotastine
`besilate ophthalmic solution 1.5% for reduction of CAC-induced ocular itching compared to
`placebo for a duration of action of at least 16 hours. Neither concentration of bepotastine besilate
`ophthalmic solution (1.0% or 1.5%) demonstrated clinical efficacy compared with placebo in
`reducing conjunctival hyperemia at any visit.
`
`Results of a 2-sample t-test comparing the differences in reduction of ocular itching response
`between the two bepotastine besilate ophthalmic solution strengths (1.0% and 1.5%) indicated
`that there was no statistically significant difference between the two active formulations in
`reducing ocular itching compared with placebo, although the 1.5% strength approached statistical
`superiority to 1.0% (P ≤ 0.05) at Visit 4.
`
`
`
`8
`
`

`

`
`Table 2.2.4.1-1.
`
`Summary of Treatment Differences for Ocular Itching Following
`Ophthalmic Administration of Bepotastine Besilate 1.0%, 1.5% and
`Placebo in Studies ISTA-BEPO-CS01 and CL-S&E-0409071-P
`– Per Protocol Populationa
`
`Visit
`
`Treatment
`
`N
`
`5
`(15 min)
`
`4
`(8 hr)
`
`78
`70
`
`74
`64
`
`78
`68
`
`Treatment Difference
`(Placebo – Active)
`Time Points
`5 min
`1.4
`1.6
`0.22
`1.2
`1.5
`0.05
`0.8
`1.0
`0.31
`
`7 min
`1.3
`1.4
`0.24
`1.1
`1.3
`0.06
`0.9
`0.9
`0.75
`
`3 min
`1.4
`Bepotastine besilate 1.0%
`1.5
`Bepotastine besilate 1.5%
`1.0%/1.5% Comparisonbc
`0.28
`1.1
`Bepotastine besilate 1.0%
`1.4
`Bepotastine besilate 1.5%
`1.0%/1.5% Comparisonbd
`0.07
`0.6
`Bepotastine besilate 1.0%
`3B
`0.8
`Bepotastine besilate 1.5%
`(16 hr)
`1.0%/1.5% Comparisonbe
`0.18
`a ITT populations (both observed data and LOCF) showed similar results.
`b Compared using 2-sample t-test.
`c p = 0.0019
`d p = 0.0023
`e p = 0.0932
`Source: Integrated Summary of Efficacy
`
`Summary of Treatment Differences for Conjunctival Hyperemia
`Following Ophthalmic Administration of Bepotastine Besilate 1.0%,
`1.5% and Placebo in Studies ISTA-BEPO-CS01 and CL-S&E-0409071-
`P – Per Protocol Populationa
`
`
`Table 2.2.4.1-2.
`
`
`
`
`
`
`
`
`
`
`
`Visit
`
`Treatment
`
`N
`
`78
`70
`
`74
`64
`
`78
`68
`
`Treatment Difference
`(Placebo – Active)
`Time Points
`5 min
`0.5
`0.4
`0.35
`0.3
`0.3
`0.91
`0.3
`0.1
`0.08
`
`7 min
`0.4
`0.3
`0.62
`0.2
`0.2
`0.83
`0.3
`0
`0.06
`
`3 min
`0.7
`Bepotastine besilate 1.0%
`5
`0.6
`Bepotastine besilate 1.5%
`
`1.0%/1.5% Comparisonbc
`0.25
`
`0.4
`Bepotastine besilate 1.0%
`4
`0.3
`Bepotastine besilate 1.5%
`
`1.0%/1.5% Comparisonbd
`0.50
`
`0.4
`Bepotastine besilate 1.0%
`3B
`0.1
`Bepotastine besilate 1.5%
`
`1.0%/1.5% Comparisonbe
`0.03
`
`a ITT populations (both observed data and LOCF) showed similar results.
`b Compared using 2-sample t-test.
`c p = 0.1618
`d p = 0.0047
`e p < 0.0001
`Source: Integrated Summary of Efficacy
`
`
`For further discussion of the efficacy comparison of the two bepotastine besilate ophthalmic
`solution strengths, refer to the Medical Officer’s and Biostatistician’s reviews of NDA 22-288.
`
`
`
`
`
`9
`
`

`

`2.2.4.2. What are the characteristics of the exposure-response relationships (dose-
`response, concentration-response) for safety?
`
`
`Summaries of treatment-emergent adverse events reported the pivotal trials for bepotastine
`besilate are presented in Tables 2.2.4.2-1 and 2.2.4.2-2. Based on the applicant’s analysis of
`safety, in Study ISTA-BEPO-CS01 there were no significant differences in the safety profiles
`between the two bepotastine besilate formulations. In Study CL-S&E-0409071-P, more adverse
`events occurred in the bepotastine besilate ophthalmic solution 1.0% treatment group (19/44) than
`in the bepotastine besilate ophthalmic solution 1.5% treatment group (1/43). However, there
`were no apparent trends with respect to the type of adverse events across treatment groups.
`
`Table 2.2.4.2-1.
`
`Treatment-Emergent Adverse Events Reported in Study ISTA-BEPO-
`CS01
`
`
`
`Adverse Event
`
`0
`0
`0
`
`6
`1
`
`Ocular AEs
`Eye Irritation
`Conjunctival Cyst
`Foreign Body Sensation
`Non-Ocular AEs
`Dysgeusia
`Respiratory, thoracic, and
`mediastinal disorders (all)
`0
`Gastrointestinal Disorders (all)
`2
`Nasopharyngitis
`1
`Lymphadenopathy
`0
`Anxiety
`1
`Cyst Removal
`Source: Clinical Study Report ISTA-BEPO-CS01
`
`
`Bepotastine Besilate 1.0%
`(N = 36)
`
`N
`
`Bepotastine Besilate 1.5%
`(N = 35)
`
`N
`
`%
`
`%
`
`0
`0
`0
`
`16.7
`2.8
`
`0
`5.6
`2.8
`0
`2.8
`
`1
`1
`0
`
`3
`3
`
`2
`0
`0
`1
`0
`
`2.9
`2.9
`0
`
`8.6
`8.6
`
`5.7
`0
`0
`2.9
`0
`
`
`
`10
`
`

`

`Table 2.2.4.2-2.
`
`
`
`Adverse Event
`
`Bepotastine Besilate 1.0%
`(N = 44)
`
`%
`
`N
`
`2
`1
`0
`1
`0
`
`Ocular AEs
`Eye Irritation
`Dry Eye
`Eye Pain
`Eye Pruritis
`Keratitis
`Non-Ocular AEs
`5
`Nasopharyngitis
`2
`Taste Perversion
`1
`Nasal Congestion
`1
`Headache
`1
`Migraine
`1
`Cough
`1
`Pharyngolaryngeal Pain
`0
`Postnasal Drip
`1
`Nausea
`0
`Joint Sprain
`1
`Rotator Cuff Syndrome
`Source: Clinical Study Report CL-S&E-0409071-P
`
`For further discussion of the safety comparison of the two bepotastine besilate ophthalmic
`solution strengths, refer to the Medical Officer’s review of NDA 22-288.
`
`
`Treatment-Emergent Adverse Events Reported in Study CL-S&E-
`0409071-P
`
`Bepotastine Besilate 1.5%
`(N = 43)
`
`N
`
`%
`
`4.5
`2.3
`0
`2.3
`0
`
`11.4
`4.5
`2.3
`2.3
`2.3
`2.3
`2.3
`0
`2.3
`0
`2.3
`
`2
`0
`0
`0
`1
`
`3
`2
`2
`0
`0
`0
`0
`1
`0
`1
`0
`
`4.7
`0
`0
`0
`2.3
`
`7.0
`4.7
`4.7
`0
`0
`0
`0
`2.3
`0
`2.3
`0
`
`2.2.4.3. Is the dose and dosing regimen selected by the sponsor consistent with the
`known relationship between dose-concentration-response, and are there any
`unresolved dosing or administration issues?
`
`
`
`There are no unresolved dosing or administration issues. The proposed dose and dosing regimen
`for Bepreve™ (bepotastine besilate ophthalmic solution), 1.5%, one drop into the affected eye(s)
`twice a day (BID), is consistent with the known relationship between dose-response for reduction
`of ocular itching. Both bepotastine besilate ophthalmic solutions (1.0% and 1.5%) were
`efficacious for reduction of ocular itching, and clinical benefit was seen with bepotastine besilate
`ophthalmic solution 1.5% for reduction of CAC-induced ocular itching compared to placebo for a
`duration of action of at least 16 hours. Since there were no significant differences in the safety
`profiles between the two bepotastine besilate formulations, selection of the 1.5% strength is
`acceptable from a clinical pharmacology perspective, based on the applicant’s analyses. For
`further discussion of the efficacy comparison of the two bepotastine besilate ophthalmic
`solution strengths, refer to the Medical Officer’s and Biostatistician’s reviews of NDA 22-288.
`
`
`
`
`11
`
`

`

`
`2.2.5. What are the PK characteristics of the drug and its major metabolite?
`
`
`2.2.5.1. Systemic Exposure Following Ocular Administration
`
`
`The extent of systemic exposure of bepotastine following topical ophthalmic administration of
`bepotastine besilate 1.0% and 1.5% ophthalmic solution was evaluated in one multiple-dose
`pharmacokinetic (PK) study in healthy adults (Study SNJ-TO-02). Study SNJ-TO-02 was a
`Phase 1 open-label study in 12 healthy adult male who received one drop of 1.0% or 1.5%
`SNJ-1773 ophthalmic solution to both eyes four times daily for seven days in sequential fashion.
`
`Plasma concentration-time profiles for bepotastine following ophthalmic administration of
`SNJ-1773 bilaterally four times daily for seven days in healthy male subjects are presented in
`Figure 2.2.5.1-1. A summary of plasma concentrations of bepotastine following ophthalmic
`administration of SNJ-1773 bilaterally four times daily for seven days in healthy male subjects is
`presented in Table 2.2.5.1-1. Following ophthalmic administration of SNJ-1773 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 increased
`proportional to dose; Cmax values for 1.0% and 1.5% SNJ-1773 following four times daily
`bilateral ophthalmic administration for 7 days were 5.138 ± 2.503 ng/mL and 7.335 ±
`1.876 ng/mL, respectively. Plasma concentrations at 24 hours post-instillation were the below
`quantifiable limit (2 ng/mL) in 11/12 subjects in the two dose groups.
`
`
`
`
`12
`
`

`

`
`Figure 2.2.5.1-1.
`
`Mean Plasma Concentration-Time Profiles for Bepotastine Besilate
`Following Ophthalmic Administration of SNJ-1773 Bilaterally Four
`Times Daily for Seven Days in Healthy Male Subjects
`
`
`
`
`
`
`SNJ-1773 = bepotastine besilate ophthalmic solution
`Source: SNJ-TO-02 Study Report, Section 11.4.1
`
`
`The estimated maximum total daily dose of bepotastine besilate administered in Study
`SNJ-TO-02 is approximately 4 mg for the 1.0% solution and 6 mg for the 1.5% solution. The
`proposed DOSAGE AND ADMINISTRATION of Bepreve™ (bepotastine besilate ophthalmic
`solution, 1.5%) is to instill one drop into the affected eye(s) twice a day (BID). The estimated
`maximum total daily dose for this proposed regimen is approximately 3 mg. Thus, the
`anticipated systemic exposure with the proposed regimen is expected to be less than that observed
`in Study SNJ-TO-02. In addition, 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
`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.
`
`
`2.2.5.2. What other characteristics of drug absorption, distribution, metabolism, and
`excretion are known and applicable to the NDA review for the ophthalmic
`drug product?
`
`
`The extent of protein binding of bepotastine was determined from blood samples obtained from
`healthy adult male volunteers enrolled in a bioequivalence study conducted in Japan to support
`the oral formulation of bepotastine besilate (Study TNB-TO-04). Subjects received one 10 mg
`tablet, blood samples were collected at 1 and 2 hours post-dose, and protein binding was
`determined via ultrafiltration. The plasma protein binding of bepotastine was approximately 55%
`and independent of bepotastine concentration over a range of 60 to 170ng/mL.
`
`
`
`13
`
`

`

`In vitro metabolism studies with human liver microsomes demonstrated that bepotastine is
`minimally metabolized by CYP450 isozymes.
`
`The urinary excretion of bepotastine was investigated in a Phase 1 single dose escalation study
`conducted in Japan with the oral formulation of bepotastine besilate (Study TNB-TO-01).
`Following single oral doses ranging from 2.5 to 40 mg, approximately 76 to 88% of the
`bepotastine dose was excreted in urine by 24 hours. Two minor metabolites were detected,
`accounting for about 0.3% and 1% of the original dose and were only observed with bepotastine
`doses of 20 mg or higher.
`
`2.3. Intrinsic Factors
`Not applicable.
`
`2.4. Extrinsic Factors
`In vitro studies of the effect of bepotastine besilate on the metabolism of various cytochrome
`P450 substrates for CYP3A4, CYP2C9, and CYP2C19 demonstrated that bepotastine does not
`inhibit the activity of CYP3A4, CYP2C9, and CYP2C19. Although certain cytochrome P450
`enzymes were not studied (CYP1A2, CYP2C8, CYP2D6), systemic concentrations following
`ophthalmic administration are expected to be low, such that metabolic drug interactions are not
`expected with the ophthalmic product.
`
`2.5. General Biopharmaceutics
`Not applicable.
`
`2.6. Analytical Section
`
`2.6.1. How are the active moieties identified and measured in the clinical pharmacology and
`biopharmaceutics studies?
`
`
`Plasma concentrations of bepotastine were determined via a high performance liquid
`chromatography (HPLC) method with UV-detection for both the ophthalmic PK study (SNJ-TO-
`02) and the single oral dose escalation study (TNB-TO-01) (Validation Study Reports SNJ-TO-06
`and TNB-HE-03, respectively). Urine concentrations of bepotastine were also determined via
`HPLC with UV-detection in Study TNB-TO-01.
`
`The analytical methods used for the two studies were similar. For purposes of development of
`the ophthalmic solution formulation of bepotastine besilate, the HPLC method used for the oral
`development program was modified and validated in order to obtain more sensitive quantitation
`at low bepotastine concentrations in human plasma.
`
`2.6.2. For all moieties measured, is free, bound, or total measured? What is the basis for that
`decision, if any, and is it appropriate?
`
`
`Total bepotastine concentrations were measured in plasma of healthy subjects in Studies
`SNJ-TO-02 and TNB-TO-01. The measurement of total concentrations of bepotastine for
`purposes of supporting the current application and determining systemic exposure following
`ophthalmic administration is appropriate.
`
`
`
`2.6.3. What bioanalytical methods are used to assess concentrations?
`
`
`
`14
`
`

`

`
`Plasma and urine concentrations of bepotastine were determined via a high performance liquid
`chromatography (HPLC) method with UV-detection.
`
`
`2.6.3.1. What is the range of the standard curve? How does it relate to the requirements
`for clinical studies? What curve fitting techniques are used?
`
`
`The calibration curve for the HPLC assay utilized for determination of systemic concentrations
`following ophthalmic administration (Study SNJ-TO-02) ranged from 2 to 300 ng/mL for
`bepotastine in human p