CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`206276Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`

`

`Clinical Investigator Financial Disclosure NDA 206276
`Review Template
`
`Application Number: 206276
`Submission Date(s): July 30, 2014
`Applicant: Alcon Laboratories
`Product: Olopatadine hydrochloride 0.7%
`
`Reviewer: Wiley A. Chambers, MD
`Date of Review: December 14, 2014
`Covered Clinical Study (Name and/or Number): C-10-126
`
`Was a list of clinical investigators provided:
`
`Yes
`
`(Request list from
` No
`applicant)
`
`Total number of investigators identified: 3
`Number of investigators who are sponsor employees (including both full-time and part-time
`employees): 0
`
`Number of investigators with disclosable financial interests/arrangements (Form FDA 3455):
`
`0 I
`
`f there are investigators with disclosable financial interests/arrangements, identify the
`number of investigators with interests/arrangements in each category (as defined in 21 CFR
`54.2(a), (b), (c) and (f)):
`Compensation to the investigator for conducting the study where the value could be
`influenced by the outcome of the study:
`Significant payments of other sorts:
`Proprietary interest in the product tested held by investigator:
`Significant equity interest held by investigator in sponsor of covered study:
`Is an attachment provided with details
`Yes
` No
`(Request details from
`of the disclosable financial
`applicant)
`interests/arrangements:
`(Request information
` No
`Is a description of the steps taken to
`from applicant)
`minimize potential bias provided:
`Number of investigators with certification of due diligence (Form FDA 3454, box 3) 0
`Is an attachment provided with the
`Yes
` No
`(Request explanation
`reason:
`from applicant)
`
`Yes
`
`NDA 206276 Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`1
`
`Reference ID: 3672611
`
`

`

`Covered Clinical Study (Name and/or Number): C-12-053
`
`Was a list of clinical investigators provided:
`
`Yes
`
`(Request list from
` No
`applicant)
`
`Total number of investigators identified: 6
`Number of investigators who are sponsor employees (including both full-time and part-time
`employees): 0
`
`Number of investigators with disclosable financial interests/arrangements (Form FDA 3455):
`
`0 I
`
`f there are investigators with disclosable financial interests/arrangements, identify the
`number of investigators with interests/arrangements in each category (as defined in 21 CFR
`54.2(a), (b), (c) and (f)):
`Compensation to the investigator for conducting the study where the value could be
`influenced by the outcome of the study:
`Significant payments of other sorts:
`Proprietary interest in the product tested held by investigator:
`Significant equity interest held by investigator in sponsor of covered study:
`Is an attachment provided with details
`Yes
` No
`(Request details from
`of the disclosable financial
`applicant)
`interests/arrangements:
`(Request information
` No
`Is a description of the steps taken to
`from applicant)
`minimize potential bias provided:
`Number of investigators with certification of due diligence (Form FDA 3454, box 3) 0
`Is an attachment provided with the
`Yes
` No
`(Request explanation
`reason:
`from applicant)
`
`Yes
`
`NDA 206276 Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`2
`
`Reference ID: 3672611
`
`

`

`Covered Clinical Study (Name and/or Number): C-12-028
`
`Was a list of clinical investigators provided:
`
`Yes
`
`(Request list from
` No
`applicant)
`
`Total number of investigators identified: 15
`Number of investigators who are sponsor employees (including both full-time and part-time
`employees): 0
`
`Number of investigators with disclosable financial interests/arrangements (Form FDA 3455):
`
`1 I
`
`f there are investigators with disclosable financial interests/arrangements, identify the
`number of investigators with interests/arrangements in each category (as defined in 21 CFR
`54.2(a), (b), (c) and (f)):
`Compensation to the investigator for conducting the study where the value could be
`influenced by the outcome of the study: 0
`Significant payments of other sorts: 1
`Proprietary interest in the product tested held by investigator: 0
`Significant equity interest held by investigator in sponsor of covered study: 0
`Is an attachment provided with details
`Yes
` No
`(Request details from
`of the disclosable financial
`applicant)
`interests/arrangements:
`(Request information
` No
`Is a description of the steps taken to
`from applicant)
`minimize potential bias provided:
`Number of investigators with certification of due diligence (Form FDA 3454, box 3) 0
`Is an attachment provided with the
`Yes
` No
`(Request explanation
`reason:
`from applicant)
`
`Yes
`
`NDA 206276 Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`3
`
`Reference ID: 3672611
`
`

`

`The applicant has adequately disclosed financial interests/arrangements with clinical
`investigators. The one reported interest is not likely to raise questions about the integrity
`of the data because the studies were multicenter, masked trials and the one investigator
`with a potential interest was responsible for a small percentage of the overall application.
`The applicant reports that they took the following steps to minimize potential bias:
`
` The studies were double-masked in which patients were randomized sequentially
`at each investigational center to receive 1 of 2 (in C-12-028), 3 (in C-10-126) or
`4 (in C-12-053) masked study drugs.
`
` For each study, a list of sequential subject numbers was generated by a member of
`the Alcon SAS programming group not involved in the conduct of the study or
`had any contact with study subjects or investigators. Each subject number was
`associated with a treatment according to a random process. Only once all study
`data was verified, validated and the database locked, individual subject data were
`unmasked.
`
` As a double-masked study, the patients, the Investigators, the investigational
`center staff, the Sponsor, and the clinical monitors were not aware of the
`treatment assigned to the individual study patients.
`
` All study drugs were identical in appearance and supplied in masked bottles with
`identical packaging and labeling.
`
` To minimize any potential Investigator bias, designated study site staff personnel
`administered the first dose of study medication in the subject’s eyes during Visit
`1 in C-12-028 and at all dosing visits for studies C-10-126 (Visits 3A, 4A and 5)
`and C-12-053 (Visits 3A and 4).
`
` All efficacy and safety variables were assessed by masked observers.
`
` The treatment code was not broken at any time during any of the studies by either
`the investigator or the Sponsor.
`
` Frequent on-site monitoring was performed during the conduct of the studies to
`ensure compliance with protocol guidelines.
`
`NDA 206276 Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`4
`
`Reference ID: 3672611
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`12/14/2014
`
`Reference ID: 3672611
`
`

`

`Clinical Review of NDA 206276
`
`Application Type
`Application Number(s)
`Priority or Standard
`
`NDA
`206276
`Priority
`
`Submit Date(s)
`Received Date(s)
`PDUFA Goal Date
`Review Division
`
`July 30, 2014
`July 30, 2014
`January 30, 2015
`Division of Transplant and Ophthalmology Products
`
`Reviewer Name Wiley A. Chambers, MD
`Review Completion Date
`September 15, 2014
`
`Established Name
`(Proposed) Trade Name
`Therapeutic Class
`
`Applicant
`
`Olopatadine Hydrochloride Ophthalmic Solution 0. 7%
`Pazeo
`Relatively selective histamine H1 antagonist and an inhibitor of
`the release of histamine from the mast cells
`Alcon Research Ltd
`
`Dosing Regimen
`Indication(s)
`
`One drop in each affected eye once a day
`Treatment of ocular itching associated with allergic
`conjunctivitis.
`Template Version: March 6, 2009
`
`Reference ID: 3624796
`
`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT .................................................. 4
`1.1 Recommendation on Regulatory Action .......................................................................... 4
`1.2 Risk Benefit Assessment .................................................................................................. 4
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies................ 4
`1.4 Recommendations for Postmarket Requirements and Commitments.............................. 4
`INTRODUCTION AND REGULATORY BACKGROUND ................................................ 4
`2.1
`Product Information.......................................................................................................... 4
`2.2
`Tables of Currently Available Treatments for Proposed Indications............................... 4
`2.3 Availability of Proposed Active Ingredient in the United States ..................................... 4
`Important Safety Issues With Consideration to Related Drugs -None. ............................ 5
`2.4
`2.5
`Summary of Presubmission Regulatory Activity Related to Submission........................ 5
`ETHICS AND GOOD CLINICAL PRACTICES................................................................... 5
`3.1
`Submission Quality and Integrity..................................................................................... 5
`3.2 Compliance with Good Clinical Practices........................................................................ 5
`Financial Disclosures- See separate review of Financial Disclosure. ............................. 5
`3.3
`SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................................... 5
`4.1 Chemistry Manufacturing and Controls ........................................................................... 5
`4.2 Clinical Microbiology....................................................................................................... 7
`4.3
`Preclinical Pharmacology/Toxicology ............................................................................. 8
`4.4 Clinical Pharmacology ................................................................................................... 10
`4.4.1 Mechanism of Action .............................................................................................. 10
`Pharmacodynamics – Not directly measured in humans......................................... 11
`4.4.2
`4.4.3
`Pharmacokinetics..................................................................................................... 11
`SOURCES OF CLINICAL DATA ....................................................................................... 13
`5.1
`Tables of Studies/Clinical Trials .................................................................................... 13
`5.2 Review Strategy.............................................................................................................. 14
`5.3 Discussion of Individual Studies/Clinical Trials............................................................ 14
`6 REVIEW OF EFFICACY ..................................................................................................... 21
`6.1
`Indication - Ocular Itching ............................................................................................. 21
`6.1.1 Methods................................................................................................................... 21
`6.1.2 Demographics – All trials........................................................................................ 21
`6.1.3
`Subject Disposition.................................................................................................. 24
`6.1.4 Analysis of Primary Endpoint - Itching .................................................................. 26
`7 REVIEW OF SAFETY.......................................................................................................... 30
`7.1 Methods .......................................................................................................................... 30
`7.1.1
`Studies/Clinical Trials Used to Evaluate Safety...................................................... 30
`
`3
`
`4
`
`5
`
`Reference ID: 3624796
`
`2
`
`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`7.1.2
`7.1.3
`
`Categorization of Adverse Events........................................................................... 31
`Pooling of Data Across Studies/Clinical Trials to Estimate and Compare Incidence
`- N/A........................................................................................................................ 31
`7.2 Adequacy of Safety Assessments................................................................................... 31
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of Target
`Populations .............................................................................................................. 31
`7.3 Major Safety Results ...................................................................................................... 32
`7.3.1 Deaths -None .......................................................................................................... 32
`7.3.2 Nonfatal Serious Adverse Events -None................................................................ 32
`7.3.3 Dropouts and/or Discontinuations –None related to study medication................... 32
`Significant Adverse Events –None.......................................................................... 32
`7.3.4
`7.4
`Supportive Safety Results............................................................................................... 32
`Common Adverse Events –see Table in 7.1.2......................................................... 32
`7.4.1
`Laboratory Findings -No significant finding........................................................... 32
`7.4.2
`7.4.3 Vital Signs -No significant findings. ....................................................................... 32
`Electrocardiograms (ECGs) -Not performed........................................................... 32
`7.4.4
`7.4.5
`Special Safety Studies/Clinical Trials ..................................................................... 32
`7.5 Other Safety Explorations - None................................................................................... 33
`7.6 Additional Safety Evaluations........................................................................................ 33
`7.6.1 Human Carcinogenicity -No human studies have been conducted. ........................ 33
`7.6.2 Human Reproduction and Pregnancy Data ............................................................. 34
`7.6.3
`Pediatrics and Assessment of Effects on Growth.................................................... 34
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound – None. .................... 35
`POST-MARKETING EXPERIENCE................................................................................... 35
`8
`9. LABELING............................................................................................................................... 36
`
`Reference ID: 3624796
`
`3
`
`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`NDA 206276, Olopatadine hydrochloride ophthalmic solution, 0.7% is recommended to be
`approved for the treatment of ocular itching with the labeling attached to this review.
`
`1.2 Risk Benefit Assessment
`Olopatadine hydrochloride ophthalmic solution, 0.7% has demonstrated efficacy in the treatment
`of ocular itching with minimal safety risks. The benefits are considered to outweigh the risks.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
`Routine postmarketing surveillance is recommended.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`There are no recommended postmarketing commitments or requirements.
`2 Introduction and Regulatory Background
`
`2.1 Product Information
`Olopatadine is a sterile, multi-dose ophthalmic solution containing olopatadine for topical administration
`to the eyes. The formulation includes povidone, polyethylene glycol 400, hydroxypropyl methylcellulose
`hydroxypropyl-gamma-cyclodextrin, boric acid, mannitol, and benzalkonium chloride as
`
`preservative.
`
`2.2 Tables of Currently Available Treatments for Proposed Indications
`
`Lastacaft
`Optivar
`Bepreve
`Elestat
`Alocril
`Pataday
`Alamast
`Acular
`Emadine
`Alrex
`Patanol
`
`Alcaftadine
`Azelastine Hydrochloride
`Bepotastine
`Epinastine Hydrochloride
`Nedocromil sodium
`Olopatadine hydrochloride
`Pemirolast potassium
`Ketorolac tromethamine
`Emedastine difumarate
`Loteprednol etabonate
`Olopatadine hydrochloride
`
`Ocular itching
`Ocular itching
`Ocular itching
`Ocular itching
`Ocular itching
`Ocular itching
`Ocular itching
`Ocular itching
`Allergic conjunctivitis
`Allergic conjunctivitis
`Allergic conjunctivitis
`
`2.3 Availability of Proposed Active Ingredient in the United States
`The active ingredient in the formulation, Olopatadine, is the same as in the US approved products,
`PATADAY™ 0.2% (NDA 21-545) and PATANOL Ophthalmic Solution, 0.1% (NDA 20-688).
`
`Reference ID: 3624796
`
`4
`
`(b) (4)
`
`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`2.4 Important Safety Issues With Consideration to Related Drugs -None.
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`Clinical studies were conducted under IND 60,991. Two Pre-NDA meetings were held between Alcon
`and the Agency. One meeting was held on July 30, 2012, and the second was held on August 26, 2013.
`3 Ethics and Good Clinical Practices
`3.1 Submission Quality and Integrity
`There is no evidence that the submitted studies were not conducted in accordance with acceptable clinical
`ethical standards.
`
`3.2 Compliance with Good Clinical Practices
`The clinical studies included in this application appear to be in compliance with Good Clinical Practices.
`Several of the investigators have been inspected in the past by the Agency.
`
`Protocol C-10-126:
`Torkildsen:
`97 Subjects;
`Macejko:
`55 subjects
`Bergmann:
`50 subjects;
`
` INDs;
`INDs;
` INDs;
`
`Protocol C-12-053:
`McLaurin: 100 subjects;
`Torkildsen: 74 subjects
`Rice: 53 subjects;
`
` INDs;
`
`INDs;
`
`Protocol C-12-028
`Meier:
`40 subjects;
`Rand:
`40 subjects;
`Sall:
`40 subjects;
`
`INDs;
`IND;
`INDs;
`
`VAI 2009; NAI 2006
`VAI 2009
`NAI 2009
`
`NAI 2012
`VAI 2009; NAI 2006
`No inspections
`
`NAI 09
`No inspections
`VAI 13; VAI 10; VAI 10; NAI 03; NAI 99; NAI 97
`
`3.3 Financial Disclosures- See separate review of Financial Disclosure.
`
`4 Significant Efficacy/Safety Issues Related to Other Review Disciplines
`4.1 Chemistry Manufacturing and Controls
`Olopatadine HCl Ophthalmic Solution, 0.7% is supplied in a low density polyethylene (LDPE) white oval
`bottle with
`dispensing plug and
` closure. The product has a 2.5 mL fill trade size
`and a 0.5 mL fill sample size. The filled containers are labeled and the 0.5 mL sample size is placed in a
`.
`
`Reference ID: 3624796
`
`5
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`(b)
`(6)
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`(b)
`(6)
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`(b)
`(6)
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`(b)
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`(b)
`(6)
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`(b)
`(6)
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`(b) (6)
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`(b) (4)
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`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`Composition of Olopatadine Ophthalmic Solution, 0.7% (FIDa
`
`)
`
`Component
`
`% w/v
`
`Function
`
`B
`
`0.776
`
`Active ingredient
`
`Olopatadine Hydrochloride
`Hydroxypropyl-Gamma- Cyclodextrind
`Povidone
`PEG 400
`Hypromellose
`Mannitol
`Boric Acid
`Benzalkonium Chloride
`Sodium Hydroxide and/or Hydrochloric
`Acid
`Purified Water
`a FID = Formulation Identification Number
`b 0.776% Olopatadine hydrochloride is equivalent to 0.7% Olopatadine free base.
`c Tested by In-house monograph which includes specifications tighter than those in the USP.
`d
`e Non-compendial
`
`0.015f
`
`pH 7.2
`
`
`
`Preservative
`pH adjust
`
`Compendial
`Status
`USPc
`NOCe
`USP
`NF
`USP
`USP
`NF
`NF
`NF
`
`USP
`
`Reviewer's Comments: The functions listed in the table above have been provided by the applicant. I do
`not agree with the characterization of mannitol
`. I believe it is better characterized as
`.
`
`Reference ID: 3624796
`
`6
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`Proposed Specifications for Olopatadine Ophthalmic Solution, 0.7%
`
`Specification
`Positive
`Positive
`% Label
`
`NMT % of active
`NMT % of active
`NMT % of active
`NMT % of active
`NMT % of active
`NMT % of active
`NMT % of active
`Positive
`% Label
`
` mOsm/kg
` mPa.s
`
`Test
`Olopatadine Identity (HPLC)a
`Olopatadine Identity (TLC)a
`Olopatadine Assay (HPLC)
`Olopatadine Impurities (HPLC)b:
`
`Impurity @ RRT
`Impurity @ RRT
`Any Single Unspecified Impurityc
`Total Impurities
`Benzalkonium Chloride Identity (HPLC)a
`Benzalkonium Chloride Assay (HPLC)
`pH (Potentiometric)
`Osmolality (Freezing Point Depression)
`Viscosity, Liquid
`Appearance (Visual):
`Color
`Clarity
`Precipitate
`
`Particulate Matter by HIAC
`
`Colorless to Light Yellow (B9 to Y3)
`NMT Ph. Eur. II
`None
`particles/mL ≥
`NMT
`NMT particles/mL ≥
`NMT particles/mL ≥
`< EU/mL
`Meets USP Requirements
`
`µm
`µm
`µm
`
`Bacterial Endotoxinsa
`Sterilityd
`a Release test only.
`bReport any impurity ≥ % of active except drug substance synthetic impurities.
`c Includes
`and others
`d Sterility testing will not be routinely conducted on production lots except at release. However, if tested, samples will
`comply with USP Requirements.
`NMT = Not more than
`
`Reviewer's Comments: Acceptable, although the Bacterial Endotoxin specification is not necessary.
`
`4.2 Clinical Microbiology
`Not applicable for this application.
`
`Reference ID: 3624796
`
`7
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`(b) (4)
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`(b)
`(4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b)
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`(4)
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`(b) (4)
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`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`4.3 Preclinical Pharmacology/Toxicology
`
`Alcon Research, Ltd. (Alcon) developed PATANOL® (olopatadine hydrochloride ophthalmic solution),
`0.1% for the treatment of allergic conjunctivitis (NDA 20-688). PATADAY™ (Olopatadine Ophthalmic
`Solution), 0.2% was subsequently developed to provide a once daily treatment regimen for itching
`associated with allergic conjunctivitis (NDA 21-545). PATANASE® (Olopatadine 0.6%) was developed
`for the treatment of nasal allergy symptoms (NDA 21-861). The currently proposed product (olopatadine
`hydrochloride ophthalmic solution, 0.7%) was intended to increase the duration of efficacy over the
`existing marketed products (PATANOL and PATADAY).
`
`Formulation Comparison between PATANOL, PATADAY, and Olopatadine HCl Solution, 0.7%
`Component
`Concentration (% w/v)
`Olopatadine
`PATADAY
`HCl Solution, 0.7%
`
`PATANOL
`
`0.776 a
`
`0.222 b
`
`0.111 c
`
`Olopatadine Hydrochloride
`Benzalkonium Chloride
`Hydroxypropyl-γ-cyclodextrin
`Edetate Disodium
`Povidone K29/32
`PEG 400
`Hydroxypropyl Methylcellulose (2910)
`Sodium Chloride
`Mannitol
`Boric Acid
`Dibasic Sodium Phosphate, Anhydrous
`Sodium Hydroxide and Hydrochloric Acid
`Purified Water
`a Equivalent to 0.7% Olopatadine free base
`b Equivalent to 0.2% Olopatadine free base
`c Equivalent to 0.1% Olopatadine free base
`adjusted based on assay results
`d
`
`No significant interaction was noted between olopatadine (10 μM) and α-adrenergic, muscarinic
`cholinergic, dopamine. Neuropharmacological studies indicate that olopatadine at oral doses as high as
`300 mg/kg, did not inhibit motor coordination, phenylbenzoquinone induced writhing, reserpine induced
`blepharoptosis or physostigmine induced lethality, nor did it exhibit any anticonvulsant activity.
`
`The effects of olopatadine (3-100 mg/kg) on the circulatory system (i.e., electrocardiogram (ECG), heart
`rate and blood pressure) were investigated following oral administration in conscious dogs. Over the dose
`range 3-30 mg/kg, oral administration of olopatadine did not affect ΔQTc. No significant effects on blood
`pressure were observed at olopatadine oral doses as high as 100 mg/kg. No significant change in heart rate
`
`Reference ID: 3624796
`
`8
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`or prolongation of the QT interval was observed when olopatadine administered by oral route (30 mg/kg)
`was used in combination with the CYP3A4 inhibiting drug itraconazole administered orally (100 mg/kg).
`
`To support the development of Olopatadine HCl Solution, 0.7%, a nonclinical ocular tissue distribution
`study was conducted to characterize the ocular distribution and systemic pharmacokinetics of olopatadine
`following single bilateral topical ocular instillation of 0.2% PATADAY or Olopatadine HCl Solution,
`0.7% (Clinical Formulation) to male New Zealand White (NZW) rabbits a). Plasma and ocular tissues
`(aqueous humor, choroid, cornea, bulbar conjunctiva, iris-ciliary body (ICB), whole lens and retina) were
`collected in a sparse fashion up to 24 hours post-dose to measure AL-4943 using a validated LC tandem
`mass spectrometry (LC/MS/MS) method. Olopatadine was absorbed into the eye and reached maximal
`levels within 30 minutes to 2 hours for most ocular tissues and plasma except lens (Tmax: 4.0 hours to 8.0
`hours). Tissues associated with the site of dosing, i.e., conjunctiva and cornea had the highest
`concentrations of olopatadine in both PATADAY (609 ng/g and 720 ng/g) and Olopatadine HCl Solution,
`0.7% (3000 ng/g and 2230 ng/g) treatment group, respectively. The mean Cmax estimates in aqueous
`humor, choroid, ICB and lens increased with increasing concentrations of olopatadine.
`
`A two-week topical ocular study of two prototype 0.7% olopatadine ophthalmic formulations was
`conducted in pigmented rabbits (NZW x New Zealand Red (NZR): F1-Cross rabbits). Additionally, a 3-
`month repeated topical ocular dose study using pigmented rabbits was conducted with the 0.7%
`olopatadine ophthalmic solution formulation proposed for marketing in order to qualify the use of the
`excipients by the ocular route of administration. These studies were conducted in accordance to GLP
`regulation. Five non-GLP local tolerance studies using either NZW or pigmented rabbits were conducted
`with various prototype formulations of 0.7% olopatadine ophthalmic solutions to evaluate the topical
`irritation potential as well as the ocular toxicity potential of the higher concentration formulation.
`
`Species
`Study design
`
`Daily dose (mg/day or mg/kg) (Sex)
`
`N
`
`Analyte
`
`Systemic exposure
`AUC(0-4hr)
`Cmax
`[ng·h/mL]
`[ng/mL]
`0.215
`0.108
`12.7
`0.241
`0.0999
`15.2
`0.200
`0.135
`15.1
`
`0.629
`0.0876
`34.0
`0.681
`0.0730
`39.2
`0.546
`0.0598
`37.4
`
`Rabbit
`2 week topical ocular
`
`Rabbit
`3 month topical ocular
`
`4 AL-24956
`AL-38189
`AL-4943
`4 AL-24956
`AL-38189
`AL-4943
`4 AL-24956
`AL-38189
`AL-4943
`AL-4943 (Olopatadine) and its Metabolites, AL-24956 (M1) and AL-38189 (M3)
`a Based on an average drop size of 52.6 µLb Based on an average drop size of 49.1 µL
`
`0.7% HD Olopatadine
`with SBCD
`(2.95 mg/day)a (M/F)
`0.7% HD Olopatadine
`with HPBCD (2.75 mg/day)b
`(M/F)
`High Dose Olopatadine
`Ophthalmic Solution, 0.7%
`
`Reference ID: 3624796
`
`9
`
`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`Olopatadine Nonclinical Studies Submitted to Previous Olopatadine Applications
`
`Repeat Dose
`
`Genotoxicity
`
`Type of Study Duration of Dosing Route of Admin Species
`Single Dose
`Single dose
`Oral, IV, Topical
`Mouse, Rat, Rabbit,
`Ocular
`Dog
`Oral
`Rat, Dog
`4-, 13-, 52-week
`4-week, 1-, 3-, 6-mon Topical Ocular
`Rabbit, Monkey
`In vitro
`In vitro
`Ames, Chrom. Ab.
`Micronucleus
`Oral
`Mouse
`78-, 104-week
`Oral/Diet
`Mouse, Rat
`Seg I
`Oral
`Rat
`Seg II
`Oral
`Rat, Rabbit
`Seg III
`Oral
`Rat
`1 day
`Topical Ocular
`Rabbit
`Local Tolerance
`Intradermal injection / topical challenges
`Guinea Pig
`Sensitization
`Oral/IP, Oral/IM
`Mouse, Guinea Pig
`Antigenicity
`Topical Ocular
`1 day
`Rabbit
`Impurities
`Degradation Products Ames, Mouse Lymphoma, SHE cell,
`In vitro, Mouse,
`Micronucleus, 28-day SC, 26-week SC,
`Rabbit
`1-month Topical Ocular, 1-day Oral
`
`Carcinogenicity
`Reproductive and
`Developmental
`
`Reviewer's Comments:
`Oral doses of 1 mg/kg/day of olopatadine in rats have resulted in plasma CMAX levels ranging from
`208-339 ng/mL and plasma AUC of 431-1437 ng.hr/mL. The CMAX and AUC levels have been shown to be
`dose proportional for oral doses between 1mg/kg and 25 mg/kg. Plasma levels for doses above 25 mg/kg
`have not been reported in the application and do not appear to have been measured.
`
`The CMAX levels noted above, following oral dosing of 1 mg/kg/day in rats, are 145-230 times the CMAX
`level seen in humans following a topical ophthalmic dose to humans. A 1 mg/kg oral olopatadine dose in
`rats resulted in an AUC level that was 50-160 times the level seen following a human ophthalmic dose.
`Subjects in the human study averaged 70.6 kg and had an average body service 1.8 meter squared. If
`calculated on a mg/kg basis, with a drop size of 0.04 mL, the ratio is approximately 125 ( 1 mg/kg/day
`divided by 0.008mg/kg/day). If calculated on a mg/m2basis, the ratio is approximately 19.5 (6
`mg/m2divided by 0.308 mg/m2).
`
`4.4 Clinical Pharmacology
`4.4.1 Mechanism of Action
`Olopatadine is a relatively selective histamine H1 antagonist and it inhibits the release of histamine from
`the mast cells.
`
`Reference ID: 3624796
`
`10
`
`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`4.4.2
`
`4.4.3
`
`Pharmacodynamics – Not directly measured in humans
`
`Pharmacokinetics
`
`A Randomized, Double-Masked, Vehicle-Controlled, Multiple-Dose Safety and Pharmacokinetic Study of
`AL-4943A Ophthalmic Solution, 0.77% Following Topical Ocular Administration in Healthy Normal
`Subjects
`
`PK Parameters
`
`N
`Cmax (ng/mL)a
`
`Olopatadine 0.7% Pharmacokinetics on Day 1 and Day 7
`Single Dose (Day 1)
`Multiple Dose (Day 7)
`Japanese
`Non-Japanese
`Japanese
`Non-Japanese
`12
`12
`10
`12
`1.59
`1.71
`1.48
`1.42
`(0.810-3.64)
`(0.624-4.12)
`(0.787-2.47)
`(0.613-4.50)
`2.00
`2.00
`2.00
`1.50
`Tmax (hr)b
`(0.50-4.02)
`(0.25-4.00)
`(0.50-8.00)
`((0.25-4.00)
`AUC0-12
`8.62
`9.48
`8.48
`8.95
`(4.96-18.2)
`(4.05-18.4)
`(5.13-15.5)
`(3.72-21.2)
`(ng*hr/mL)a
`2.79
`3.01
`3.03c
`3.61
`t1/2 (hr)
`(2.13-5.78)
`(2.05-5.35)
`(2.13-3.59)
`(2.28-7.77)
`a: Cmax and AUC0-12 expressed as geometric mean and range (min to max);
`b: Tmax expressed as median and range (min to max)
`c: t1/2 expressed as arithmetic mean with n = 7 for Japanese subjects
`Source: Table 14.2.1.-13 and Table 14.2.1-14
`
`Mean (SD) AL-4943 Plasma Concentration Versus Time Profiles on Day 1 and Day 7
`
`Non-Japanese
`
`Day 1 (n = 12)
`Day 7 (n = 12)
`
`0
`
`6
`4
`2
`Time (hours)
`
`8
`
`10
`
`12
`
`10
`
`1
`
`0.1
`
`* 0.01
`
`0.001
`12
`
`11
`
`Japanese
`
`Day 1 ( n = 12)
`Day 7 (n = 10)
`
`*
`
`0
`
`2
`
`6
`4
`Time (hours)
`*n = 9 for 8 and 12 hour time point on Day 7
`
`8
`
`10
`
`10
`
`1
`
`0.1
`
`0.01
`
`0.001
`
`AL-4943PlasmaConcentration(ng/mL)
`
`Reference ID: 3624796
`
`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`
`Individual and Geometric Mean AL-4943 Cmax Estimates on Day 1 and Day 7
`
`Japanese
`Individual C
`max
`Mean C
`max
`
`6
`
`5
`
`4
`
`3
`
`2
`
`1
`
`0
`
`25
`
`AL-4943MaximumPlasmaConcentration(ng/mL)
`
`(ng*h/mL)
`
`0-12
`
`AL-4943AUC
`
`20
`
`15
`
`10
`
`5
`
`0
`
`20
`
`15
`
`10
`
`5
`
`0
`
`Day 7
`Day 1
`Treatment Day
`Source = Tables 14.2.1.-13 and 14.2.1.-14 and 16.2.6.-9
`
`Day 1
`Day 7
`Treatment Day
`
`In this study the average body surface area was 1.82 m2. The average weight was 70.6 kg.
`
`Reference ID: 3624796
`
`12
`
`Non-Japanese
`Individual Cmax
`Mean Cmax
`
`6
`
`5
`
`4
`
`3
`
`2
`
`1
`
`0
`
`30
`
`25
`
`Day 7
`Day 1
`Treatment Day
`
`Non-Japanese
`Individual AUC0-12
`Mean AUC
`0-12
`
`Day 7
`Day 1
`Treatment Day
`Source = Tables 14.2.1.-13 and 14.2.1.-14 and 16.2.6.-9
`Individual and Geometric Mean AL-4943 AUC0-12 Estimates on Day 1 and Day 7
`30
`Japanese
`Individual AUC0-12
`Mean AUC0-12
`
`

`

`Clinical Review of NDA 206276
`Wiley A. Chambers, MD
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`5 Sources of Clinical Data
`5.1 Tables of Studies/Clinical Trials
`Safety and Efficacy Studies in Patients with Allergic Conjunctivitis
`
`Study Number Design
`
`Ages
`
`Arms
`
`C-10-127
`
`Phase 1
`Safety and
`comfort
`C-1