CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`206276Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`Summary Review for Regulatory Action
`
`Date
`From
`
`Subject
`NDA Number
`Related IND
`Applicant Name
`Date of Submission
`Date of Receipt
`Review Type
`PDUFA Goal Date
`Proprietary Name /
`Established (USAN) Name
`Drug Class
`
`Formulation
`Presentation
`Use
`Proposed Indication
`
`Action for Application
`
`See electronic stamp date
`Renata Albrecht, MD
`Division of Transplant and Ophthalmology Products
`Division Director Summary Review
`NDA 206276
`IND 60991
`Alcon Research Ltd.
`July 30, 2014
`July 30, 2014
`Priority (includes pediatric data)
`January 30, 2015
`PAZEO
`Olopatadine hydrochloride ophthalmic solution, 0.7%
`Relatively selective histamine H1 antagonist, inhibitor
`of histamine release from mast cells
`Ophthalmic solution
`2.5 mL fill volume in 4 mL bottle
`
`One drop in each affected eye once daily
`Treatment of ocular itching associated with allergic
`conjunctivitis
`Approval
`
`Reference ID: 3694683
`
`1
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`Names of discipline reviewers
`
`Material Reviewed/Consulted
`OAP Action Package, including:
`Medical Officer Review
`CDTL Review
`Statistical Review
`Pharmacology/Toxicology Review
`Clinical Pharmacology Review
`OPQ
`
`Wiley Chambers 9/15/2014, 12/14/2014
`Bill Boyd 1/29/2015
`Yunfan Deng, Yan Wang 1/2/2015
`Aaron Ruhland, Lori Kotch 12/31/2014
`Gerlie Gieser, Philip Colangelo 10/16/2014
`Libaniel Rodriguez, Balajee Shanmugam, Rapti
`Madurawe 12/22/2014
`Stephen Langille, Bryan Riley 1/5/2015
`Banu Zolnik, Elsbeth Chikhale 12/23/2014
`Acceptable (CMC review)
`Roy Blay 12/11/2014, 1/7/2015
`Rachna Kapoor 12/9/2014
`Karen Townsend 12/10/2014
`Rachna Kapoor, Yelena Maslov 11/19/2014
`Christine Corser 1/6/2015
`George Greeley 12/05/2014
`Matt Bacho 12/16/2014
`Lois Almoza
`
`Quality Microbiology Review
`Biopharmaceutics Review, OPQ
`OC/Facilities Inspection
`OSI/DGCPC
`OSE/DMEPA Proprietary Name
`Letter
`OSE/DMEPA Labeling Review
`OPDP/DPDP (formerly DDMAC)
`Pediatric Review Committee
`Pediatric Exclusivity
`Project Manager
`OND=Office of New Drugs,
`CDTL=Cross-Discipline Team Leader
`OPQ = Office of Product Quality
`OSI/DGCPC=Office of Scientific Investigations/Division of Good Clinical Practice Compliance
`(formerly Division of Scientific Investigation (DSI)
`OSE= Office of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`OPDP/DPDP=Office of Prescription Drug Promotion/Division of Professional Drug Promotion;
`formerly, DDMAC=Division of Drug Marketing, Advertising and Communication
`
`Reference ID: 3694683
`
`2
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`Table of Contents:
`
`1.
`
`2.
`
`3.
`
`Summary and Recommendations................................................................. 4
`1.1 Deficiencies...........................................................................................................4
`1.2
`Post-Marketing Studies: ........................................................................................4
`1.3 Other Issues...........................................................................................................4
`Background.............................................................................................. 4
`2.1 NDA Submission ..................................................................................................5
`2.2
`Priority Review .....................................................................................................5
`CMC/Product Quality Microbiology ............................................................ 6
`Product Quality .....................................................................................................6
`3.1
`Product Quality Microbiology ..............................................................................6
`3.2
`Biopharmaceutics – BA/BE Waiver .....................................................................6
`3.3
`3.4 USP nomenclature.................................................................................................7
`Nonclinical Pharmacology/Toxicology......................................................... 7
`4.
`Clinical Pharmacology/Biopharmaceutics..................................................... 8
`5.
`Clinical Microbiology/Immunology............................................................. 8
`6.
`Clinical/Statistical-Efficacy ........................................................................ 8
`7.
`Safety.................................................................................................... 13
`8.
`Advisory Committee Meeting ................................................................... 14
`9.
`Pediatrics............................................................................................... 14
`10.
`Other Relevant Regulatory Issues .............................................................. 14
`11.
`Compliance Inspection ....................................................................................14
`11.1
`Office of Scientific Investigation (OSI) Audits...............................................14
`11.2
`Financial Disclosure ........................................................................................15
`11.3
`Labeling ................................................................................................ 15
`12.
`Decision/Action/Risk Benefit Assessment .................................................. 15
`13.
`Regulatory Action............................................................................................15
`13.1
`Risk Benefit Assessment .................................................................................15
`13.2
`Recommendation for other Postmarketing Requirements (PRMs) and Commitments
`13.3
`(PMCs) 16
`
`Reference ID: 3694683
`
`3
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`1.
`
`Summary and Recommendations
`
`Pazeo (olopatadine hydrochloride ophthalmic solution) 0.7% is a histamine (H1) receptor
`antagonist that inhibits the mast cells from releasing histamine. It is proposed for the treatment of
`ocular itching associated with allergic conjunctivitis.
`
`The Indications and Usage section, and the Dosage and Administration section of labeling will
`provide the following information:
`
`INDICATIONS AND USAGE
`1
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7% is indicated for the
`treatment of ocular itching associated with allergic conjunctivitis.
`
`2 DOSAGE AND ADMINISTRATION
`The recommended dosage of PAZEO is to instill one drop in each affected eye once a day.
`
`All disciplines recommend approval. Product labeling, including carton and container labels have
`been finalized. The proprietary name PAZEO was found acceptable by DMEPA. OSI
`recommended that data are reliable. The Office of Compliance recommended the manufacturing
`facilities are acceptable.
`
`Deficiencies
`1.1
`None, the application will be approved.
`
`1.2
`None
`
`1.3
`None
`
`Post-Marketing Studies:
`
`Other Issues
`
`2. Background
`
`Allergic conjunctivitis is a reaction to various antigens and is characterized by itching and redness
`of the eye.
`
`There are currently various products approved for use in allergic conjunctivitis. Some are labeled
`for ocular itching only. Others are labeled for allergic conjunctivitis, because the clinical studies
`demonstrated efficacy in both reducing ocular itching and ocular redness (conjunctivitis).
`
`Lastacaft
`Optivar
`Bepreve
`Elestat
`Alocril
`
`Alcaftadine (#)
`Azelastine Hydrochloride (#)
`Bepotastine (#)
`Epinastine Hydrochloride (#)
`Nedocromil sodium (*)
`
`Ocular itching
`Ocular itching
`Ocular itching
`Ocular itching
`Ocular itching
`
`4
`
`Reference ID: 3694683
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`Olopatadine hydrochloride (*#)
`Pataday
`Pemirolast potassium (*)
`Alamast
`Ketorolac tromethamine (##)
`Acular
`Emedastine difumarate (#)
`Emadine
`Loteprednol etabonate (**)
`Alrex
`Olopatadine hydrochloride (*#)
`Patanol
`Source: Medical Officer Review p.4 (modified)
`(#) H1 histamine receptor antagonist
`(*) Mast cell stabilizer
`(##) NSAID
`(**) Corticosteroid
`
`Ocular itching
`Ocular itching
`Ocular itching
`Allergic conjunctivitis
`Allergic conjunctivitis
`Allergic conjunctivitis
`
`Olopatadine is approved under three Alcon NDAs:
` PATANOL (olopatadine hydrochloride ophthalmic solution) 0.1% is indicated for the
`treatment of the signs and symptoms of allergic conjunctivitis. It is dosed as one drop in
`each affected eye two times per day at an interval of 6 to 8 hours. The NDA 20-688 was
`approved December 18, 1996. The IND is IND 44216.
` PATADAY (olopatadine hydrochloride ophthalmic solution) 0.2%, is indicated for the
`treatment of ocular itching associated with allergic conjunctivitis. It is dosed as one drop in
`each affected eye once a day. The NDA 21-545 was approved December 22, 2004. The
`IND is IND 60991.
` PATANASE (olopatadine hydrochloride) Nasal Spray 0.6% is indicated for the relief of the
`symptoms of seasonal allergic rhinitis. NDA 21-861 was approved April 15, 2008.
`
`2.1
`
`NDA Submission
`
`The drug was studied under IND 60,991. Two pre-NDA meetings were held with the Division.
`
`During the July 30, 2012, pre-NDA meeting, topics of discussion included: need for new NDA of
`the new formulation, need for two studies to claim superiority, need for clinical data and not
`modeling to support an application; adequacy of PK study, six-week safety study in 300 subjects
`> 2 years old, defer comments on labeling, no anticipated need for additional nonclinical studies,
`need for ocular distribution study, additional stability data, comparison of current and previous
`formulations, additional CMC information.
`
`During the August 26, 2013, pre-NDA meeting, topics of discussion included: the clinical studies,
`primary endpoints, content and format of the application, statistical analysis plan, labeling,
`datasets, the pediatric written request, cross-referencing other approved olopatadine products in the
`NDA, and possible trade names; statistical comments for study C-12-053 were included in the
`meeting minutes.
`
`2.2
`
`Priority Review
`
`The application contains results from pediatric studies and is therefore given a priority review.
`
`Reference ID: 3694683
`
`5
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`3. CMC/Product Quality Microbiology
`
`See complete CMC review, Microbiology Sterility review and Biopharmaceutics review.
`
`3.1
`
`Product Quality
`
`The reviewers conclude the NDA provides adequate information to assure the identity, strength,
`purity, and quality of the drug product. All CMC issues have been resolved satisfactorily and there
`are no outstanding issues. The Office of Compliance has given an acceptable recommendation for
`both the drug substance manufacturing facility
`
`and the drug product manufacturing facility (Alcon Research, LTD., Fort Worth, Texas and Alcon-
`Covreour nv, Puurs, Belgium).
`
`Olopatadine hydrochloride ophthalmic solution, 0.7% solution contains: Active: 7.76 mg
`olopatadine hydrochloride equivalent to 7 mg olopatadine. Inactives: povidone; hydroxypropyl-
`gamma-cyclodextrin; polyethylene glycol 400; hydroxypropyl methylcellulose; boric acid;
`mannitol; benzalkonium chloride 0.015% (preservative); hydrochloric acid/sodium hydroxide (to
`adjust pH); and purified water.
`
`The product is supplied in a low density polyethylene (LDPE) white oval bottle with LDPE
`dispensing plug and polypropylene (PP) closure. This container/closure system is the same as use
`for PATANOL and PATADAY by Alcon. The product has a 2.5 mL fill trade size in a 4 mL
`bottle. A 0.5 mL fill size is planned as a professional sample size.
`
`The shelf life is 104 weeks (24 months) and it is supported by the updated 78 weeks of stability
`data provided.
`
`3.2
`
`Product Quality Microbiology
`
`The drug product will be
`
` filled into 4 ml LDPE dropper bottles.
`
`
`
`
`
`The applicant provided a satisfactory summary of the container closure integrity
`effectiveness test methods and results, description of the manufacturing process and process
`controls, information on the
`operation at both drug product manufacturing
`facilities and the component sterilization facilities, summary of the drug product specifications,
`test methods and acceptance criteria; and summary of the stability protocol and stability data.
`The reviewer concluded the applicant has presented adequate information to mitigate risks outlined
`in the initial product quality microbiology risk assessment.
`
`
`
`3.3
`
`Biopharmaceutics – BA/BE Waiver
`
`Reference ID: 3694683
`
`6
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`The Biopharmaceutics review notes that the applicant requested a waiver per 21 CFR 320.22(b)(1),
`however, the applicant conducted a PK study thus a waiver request is not applicable (see Section
`5. Clinical Pharmacology).
`
`3.4
`
`USP nomenclature
`
`The USP Nomenclature Monograph, <1121>, states that product strength is linked to the active
`moiety. The concentration of olopatadine hydrochloride is 0.77% in the formulation. The
`concentration of olopatadine in the formulation is 0.7%. After internal discussion, CMC
`confirmed the name and concentration should be: PAZEO (olopatadine hydrochloride ophthalmic
`solution) 0.7%.
`
`Comment:
`The OPQ CMC reviewers recommend approval of the application from their perspective.
`4. Nonclinical Pharmacology/Toxicology
`
`See Pharmacology/Toxicology reviews.
`
`The reviewer notes that Alcon conducted pharmacology, comparative ocular
`distribution/pharmacokinetic and ocular toxicity studies of olopatadine hydrochloride ophthalmic
`solution, 0.7% to support the new formulation and higher concentration of olopatadine
`hydrochloride compared to the previously approved formulations. The studies showed:
`
` A dose dependent increase in conjunctival and intraocular distribution for olopatadine
`hydrochloride, 0.7% compared to PATADAY®
`In pigmented rabbits, no adverse or toxic effects were attributed to olopatadine, 0.7% when
`administered up to four times daily for 3 months. This dose correlates with an approximate
`4-fold margin over the proposed clinical dose.
`
`
`
`All excipients are qualified for topical ophthalmic administration except hydroxypropyl-γ-
`cyclodextrin and povidone
` The applicant conducted a 3-month ocular toxicology
`study with the to-be-marketed formulation which qualifies the excipients at the proposed levels for
`topical ophthalmic administration.
`
`For this submission, the applicant conducted one preclinical efficacy pharmacology study, which
`compared efficacy of PATADAY (olopatadine hydrochloride ophthalmic solution) 0.2% with that
`of olopatadine hydrochloride, 0.7% in a preclinical model of histamine-induced vascular
`permeability. Study results indicated that olopatadine hydrochloride, 0.7% significantly suppresses
`allergic conjunctival symptoms compared to PATADSY and vehicle control.
`
`Comment: The Pharmacology/Toxicology (P/T) reviewers recommend approval. The labeling
`recommendations were incorporated; the Risk Summary section was streamlined so as not to be
`redundant with the complete summary of studies in the Animal Data section.
`
`Reference ID: 3694683
`
`7
`
`(b) (4)
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`5. Clinical Pharmacology/Biopharmaceutics
`
`See Clinical Pharmacology review.
`
`The reviewer notes that the sponsor conducted PK Study C-11-036 to determine the plasma
`exposures to olopatadine and its two (N-oxide and mono-desmethyl) metabolites following single
`and repeated topical ocular administration of the proposed commercial ophthalmic solution in 24
`healthy adult subjects; 19 subjects had a complete set of PK profiles on Days 1 and 7. No apparent
`accumulation of olopatadine was observed following repeated topical ocular administration of the
`proposed product for 7 days.
`
`The mean steady state plasma olopatadine Cmax and AUC0-12 measured with PAZEO in this PK
`study were lower (by 90% to 93%, and by 85% to 88%, respectively) than that reported in adult
`healthy subjects and seasonal allergic rhinitis patients following administration of PATANASE
`(olopatadine hydrochloride 0.6%; Alcon) Nasal Spray given 2 sprays per nostril twice daily for 14
`days. The N-oxide metabolite of olopatadine (M3) was detected in less than 10% of the total
`plasma samples in approximately half of the study participants; the maximum plasma
`concentration was 0.174 ng/mL measured during the first 4 hours post-dosing. Plasma
`concentrations of desmethyl olopatadine (M1) were below the LLOQ (0.05 ng/mL) of the PK
`assay.
`
`In healthy subjects, topical ocular dosing of 1 drop of PAZEO once daily for 7 days into both eyes
`resulted in mean ± SD (range) steady state plasma olopatadine Cmax and AUC0-12 of 1.6 ± 0.9
`ng/mL (0.6 to 4.5 ng/mL) and 9.7 ± 4.4 ng*h/mL (3.7 to 21.2 ng*h/mL), respectively. The
`olopatadine Cmax and AUC0-12 after the first dose were similar to those measured on day 7 in these
`subjects, suggesting that there was no systemic accumulation of olopatadine after repeated topical
`ocular dosing with PAZEO. The median (range) time to achieve peak olopatadine concentrations
`(Tmax) was 2.0 hours (0.25 to 4 hours). The mean ± SD (range) elimination half-life of olopatadine
`was 3.4 ± 1.2 hours (2 to 8 hours). N-oxide olopatadine (M3) was detected during the first 4 hours
`after bilateral topical ocular dosing of PAZEO in approximately half of the subjects and in less
`than 10% of the total plasma samples collected, at concentrations not exceeding 0.121 ng/mL on
`day 1 and 0.174 ng/mL on day 7. None of the plasma samples from these subjects had mono-
`desmethyl olopatadine (M1) concentrations that were above the lower limit of quantitation (0.05
`ng/mL) of the PK assay.
`
`Comment: The reviewers recommend approval from the Clinical Pharmacology perspective;
`labeling revisions have been incorporated in labeling.
`6. Clinical Microbiology/Immunology
`
`Not Applicable
`7. Clinical/Statistical-Efficacy
`
`See clinical reviews and biostatistics reviews.
`
`Reference ID: 3694683
`
`8
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`The following table summarizes the features of the three Phase 3 studies submitted in support of
`the application. These included two conjunctival antigen challenge (CAC) studies to support the
`efficacy of the product and one Phase 3 safety study to provide six weeks of adverse reaction data.
`
`Study Number Design
`
`Ages
`
`Arms
`
`18 years of
`age or older
`
`Olopatadine HCl, 0.7%
`
`Olopatadine, 0.2%
`
`C-10-126
`
`Phase 3
`Efficacy CAC
`
`C-12-053
`
`Phase 3
`Efficacy CAC
`
`Randomized, double
`masked, parallel-
`group, active and
`vehicle controlled
`study
`
`Randomized, double
`masked, parallel-
`group, active and
`vehicle controlled
`study
`
`18 years of
`age or older
`
`C-12-028
`
`Phase 3
`Safety
`
`Randomized, double
`masked, parallel-
`group, vehicle
`controlled study
`
`2 years of age
`or older
`
`Numbe
`r of
`Subjec
`66
`
`68
`
`68
`
`98
`
`Dosing
`
`Duration
`
`1 drop per
`eye
`
`1 drop per
`eye
`
`3 non-
`consecutive
`doses over 3
`weeks
`
`2 non-
`consecutive
`doses over 2
`weeks
`
`6 weeks
`
`1 drop per
`eye once
`daily
`
`Vehicle
`
`Olopatadine HCl, 0.7%
`
`Olopatadine HCl, 0.2%
`
`99
`
`Olopatadine HCl, 0.1%
`
`Vehicle
`
`Olopatadine HCl, 0.7%
`
`Vehicle
`
`99
`
`49
`
`330
`
`169
`
` and its
`Clinical studies (C-10-126, C-12-028 and C-12-053) used the same, final formulation for PAZEO (FID
`Vehicle (FID
`Two studies (C-10-126 and C-12-053) had PATADAY as an active comparator and used the same,
`marketed formulation for PATADAY (FID
`Source: adapted from Medical Officer Review
`
`The CAC efficacy studies, C-10-126 and C-12-053, were multicenter, randomized, double-
`masked, vehicle controlled, parallel-group studies and used the CAC model. Then Medical Officer
`notes that the CAC design has been used to support the majority of drug products approved for the
`treatment of ocular itching. The details of the study procedure are included in the clinical review.
`In brief, patients with an allergic history were conjunctively challenged in both eyes with
`progressively higher doses of antigen until they demonstrated a ≥2+ itching and redness reaction.
`These patients returned for a second visit in which the dose which elicited a ≥2+ reaction was
`administered and only patients who demonstrated a reproducible ≥2+ reaction continued in the
`study. Patients returned for a third visit, during which the test drug product was administered to
`both eyes and after 24 hours, the antigen which reproducibly elicited a ≥2+ reaction was again
`administered. The patient’s itching reactions were recorded at 3, 5 and 7 minutes after antigen
`administration, the patient’s redness reactions were recorded 7, 15 and 20 minutes after antigen
`administration. The patient’s fourth visit was a repeat of the third visit except that the time after
`test product administration was reduced to 16 hours. The patient’s fifth visit was a repeat of the
`third visit, except that the time after test product administration was reduced to 27 minutes.
`
`The study designs were similar for both studies with the exception that C-12-053 did not include
`the 16 hour duration efficacy evaluation visit and had an additional active comparator, PATANOL.
`Both studies evaluated the same efficacy endpoints (itching and redness) for the onset of action
`
`9
`
`Reference ID: 3694683
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`and the 24 hours duration of action. The randomization ratio in C-10-126 was 1:1:1 and in C-12-
`053, it was 2:2:2:1 for PAZEO 0.7%: PATADAY: PATANOL: Vehicle.
`
`Both studies were conducted in patients at least 18 years of age with a history of seasonal and/or
`perennial allergic conjunctivitis for at least 1 year prior to study entry and a positive allergic skin
`test within 24 months prior to study entry. Study C-12-053 had PATADAY, PATANOL and
`vehicle as comparators; however, PATANOL was dosed only once daily (instead of the approved
`twice-a-day regimen) at Visit 3A (the day before the 24-hour duration-of-action efficacy
`evaluation) and Visit 4.
`
`The primary efficacy variable for both studies was patient-evaluated ocular itching severity scores
`(assessed using a 0-4 scale with 0.5 unit increments: 0 = none, 4 = incapacitating itch). In Study C-
`10-126, the primary efficacy endpoints were patient-evaluated ocular itching at 3, 5, and 7 minutes
`post-CAC at both Visits 4B (16-hour duration-of-action) and 5 (onset-of-action). In Study C-12-
`053, the primary efficacy endpoints were patient-evaluated ocular itching at 3, 5, and 7 minutes
`post-CAC at both Visit 3B (24-hour duration-of-action) and Visit 4 (onset-of-action).
`
`In past CAC Studies, differences of approximately 1 unit between test product and vehicle
`observed in the majority of time points (two out of three in the case of these studies) has been
`considered clinically significant.
`
`Secondary efficacy objectives included: to demonstrate superiority of PAZEO over vehicle and
`PATADAY at the 24-hour duration-of-action timepoint and to demonstrate superiority to vehicle
`for conjunctival redness associated with allergic conjunctivitis.
`
`The majority of patients completed the two CAC studies as well as the Phase 3 safety study, C-12-
`028.
`
`Study
`
`C-10-126
`C-12-053
`C-12-028
`TOTAL
`
`PAZEO (N)
`Randomized
`Completed (%)
`63
`93
`329
`485 (98%)
`
`66
`98
`331
`495
`
`Vehicle Control (N)
`Randomized
`Completed (%)
`60
`48
`166
`274 (96%)
`
`68
`49
`169
`286
`
`Results for Ocular Itching
`Efficacy results for ocular itching are shown in the table below:
`
`In both studies, PAZEO was significantly better (p-value<0.0001) compared to vehicle for treating
`ocular itching associated with allergic conjunctivitis at onset-of-action, and 24-hour duration-of-
`action.
`
`In Study C-10-126, at 24-hour duration-of-action, PAZEO was superior to PATADAY for the
`treatment of ocular itching associated with allergic conjunctivitis. In Study C-12-053, PAZEO was
`superior to PATADAY for ocular itching associated with allergic conjunctivitis at 24-hour
`duration-of-action at 2 (3 and 5 minutes) out of 3 post CAC time points. The point estimate for the
`
`10
`
`Reference ID: 3694683
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`treatment difference at 7 minutes post-CAC was in favor of PAZEO but did not demonstrate
`statistical significance.
`
`Itching Scores by Treatment Group and Treatment Difference* in Mean Itching
`Time Point
`Olopatadine, 0.77%
`PATADAY*
`Vehicle
`(Olopatadine, 0.2%)
`(N = 68)
`
`(N = 66)
`
`(N = 68)
`
`STUDY
`C-10-126
`
` Onset
`
`Average
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
` 16h
`
`Average
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
` 24h
`
`Average
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
`Mean
`0.46
`
`Mean
`0.54
`
`0.36
`
`0.53
`
`0.48
`
`0.75
`
`0.70
`
`0.79
`
`0.75
`
`1.04
`
`0.93
`
`1.10
`
`1.09
`
`0.39
`
`0.61
`
`0.61
`
`0.96
`
`0.87
`
`1.04
`
`0.98
`
`1.48
`
`1.41
`
`1.52
`
`1.50
`
`Difference (95% CI)
`-0.08
`(-0.37, 0.21)
`-0.02
`(-0.31, 0.26)
`-0.08
`(-0.39, 0.22)
`-0.13
`(-0.44, 0.17)
`-0.21
`(-0.49, 0.07)
`-0.17
`(-0.44, 0.11)
`-0.24
`(-0.55, 0.07)
`-0.23
`(-0.54, 0.08)
`-0.44
`(-0.72, -0.16)
`-0.48
`(-0.76, -0.20)
`-0.42
`(-0.72, -0.12)
`-0.41
`(-0.72, -0.10)
`
`Mean
`1.98
`
`1.90
`
`2.06
`
`1.97
`
`2.20
`
`2.20
`
`2.27
`
`2.13
`
`2.55
`
`2.54
`
`2.62
`
`2.50
`
`Difference (95% CI)
`-1.51
`(-1.81, -1.23)
`-1.54
`(-1.82, -1.25)
`-1.53
`(-1.84, -1.22)
`-1.49
`(-1.80, -1.18)
`-1.45
`(-1.73, -1.17)
`-1.50
`(-1.77, -1.23)
`-1.48
`(-1.79, -1.16)
`-1.38
`(-1.69, -1.07)
`-1.51
`(-1.79, -1.24)
`-1.61
`(-1.88, -1.33)
`-1.51
`(-1.81, -1.21)
`-1.41
`(-1.72, -1.11)
`
`(N = 98)
`
`(N = 99)
`
`(N = 49)
`
`Study
`C-12-053
` Onset
`
`Average
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
` 24h
`
`Average
`
` 3 mins
`
` 5 mins
`
` 7 mins
`
`0.52
`
`0.38
`
`0.53
`
`0.65
`
`1.16
`
`1.01
`
`1.22
`
`0.56
`
`0.47
`
`0.61
`
`0.61
`
`1.40
`
`1.33
`
`1.48
`
`1.91
`
`1.91
`
`1.99
`
`1.82
`
`2.27
`
`2.30
`
`2.37
`
`-1.39
`-0.05
`(-1.62, -1.16)
`(-0.24, 0.14)
`-1.53
`-0.09
`(-1.76, -1.30)
`(-0.28, 0.09)
`-1.46
`-0.08
`(-1.71, -1.22)
`(-0.29, 0.12)
`-1.17
`0.04
`(-1.45, -0.90)
`(-0.18, 0.26)
`-1.11
`-0.24
`(-1.40, -0.82)
`(-0.48, -0.00)
`-1.29
`-0.31
`(-1.60, -0.97)
`(-0.57, -0.06)
`-1.15
`-0.26
`(-1.46, -0.84)
`(-0.51, -0.01)
`-0.89
`-0.16
`2.14
`1.41
`1.25
`(-1.22, -0.57)
`(-0.42, 0.11)
`* Mean score estimates, treatment differences and corresponding 95% confidence intervals (CIs) were based on analysis of repeated measures
`using a mixed model with itching scores from each eye (left or right) as the dependent variable and fixed effect terms for investigator, treatment,
`eye-type (left or right), time, and treatment-by-time interaction.;
`The ocular itching score range is 0-4, where 0 is none and 4 is incapacitating itch.
`
`Reference ID: 3694683
`
`11
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`Reference ID: 3694683
`
`12
`
`(b) (4)
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`8.
`Safety
`
`See the clinical and statistical reviews.
`
`The reviewers summarize that safety information for this application is primarily derived from
`Study C-12-028, a 6 week, multicenter, randomized, double-masked, vehicle-controlled, parallel-
`group study. Subjects at risk for developing allergic conjunctivitis, at least 2 years of age or older
`with asymptomatic eyes at the time of study entry were randomized in a 2:1 ratio to PAZEO or
`vehicle, respectively. Subjects younger than 6 years of age were randomized from one
`randomization schedule; subjects 6 years of age or older were randomized from another
`randomization schedule.
`
`All randomized subjects received 1 drop of either PAZEO or vehicle in both eyes for 6 weeks.
`Safety variables and assessments included best-corrected visual acuity, slit-lamp, intraocular
`pressure (IOP), dilated fundus evaluations, pulse, blood pressure, and adverse events.
`
`At the Baseline Visit (Day 0) and at each subsequent office visit (Week 1, Week 3, Week 6),
`best-corrected visual acuity was measured and slit-lamp evaluations were performed for the
`eyelids, conjunctiva, cornea, iris/anterior chamber, and lens. At the Baseline Visit (Day 0) and at
`the last office visit (Week 6), IOP was measured, a dilated fundus examination (DFE) of the
`vitreous, retina/macula/choroid, and optic nerve was performed, and vital signs (pulse and blood
`pressure) were taken. At each office visit and during telephone contacts at Weeks 2, 4, and 5,
`adverse events and dosing compliance were recorded and concomitant medications updated. The
`Exit Visit occurred via telephone contact at Week 7. Adverse events were recorded and
`concomitant medications updated.
`
`The following safety information was obtained from the study:
`
` There were no deaths or serious adverse reactions reported.
` Two subjects entered with negative pregnancy test and became pregnant despite use of
`spermicide with barrier. Both delivered babies without congenital anomalies after the
`study.
` Fifty one pediatric patients between ages 2 through 16 years of age (median 5 years) were
`enrolled.
` There were no clinically significant changes noted in Visual Acuity, Intraocular Pressure,
`Slit Lamp or fundus exam in the studies. There were no significant differences in vital
`signs.
` Adverse events were comparable in the two arms
`
`Study 12-028
`Adverse Events
`Deaths
`Discontinue due to Adverse
`Event
`Vision blurred
`
`PAZEO
`
`N=330
`0
`0
`
`Vehicle
`N=169
`0
`2
`
`1.2%
`
`16
`
`4.8%
`
`7
`
`4.1%
`
`13
`
`Reference ID: 3694683
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`Dry eye
`Corneal Staining
`Dysgeusia
`Abnormal sensation in eye
`Nasopharyngitis
`Upper respiratory tract infection
`Conjunctival staining
`Eye pruritus
`Headache
`Eye irritation
`Ligament sprain
`Cough
`Conjunctival hemorrhage
`Diarrhea
`Gastroenteritis viral
`
`11
`8
`8
`7
`6
`6
`6
`5
`5
`1
`1
`1
`0
`0
`0
`
`3.3%
`2.4%
`2.4%
`2.1%
`1.8%
`1.8%
`1.8%
`1.5%
`1.5%
`0.3%
`0.3%
`0.3%
`
`5
`7
`0
`7
`3
`3
`1
`2
`3
`5
`2
`2
`2
`2
`2
`
`3%
`4.1%
`
`4.1%
`1.8%
`1.8%
`0.6%
`1.2%
`1.8%
`3%
`1.2%
`1.2%
`1.2%
`1.2%
`1.2%
`
`Reviewer Comment:
`I agree there are no safety issues to preclude approval.
`9. Advisory Committee Meeting
`There were no efficacy and safety issues raised by this application to bring before the Advisory
`Committee. Olopatadine is not a new molecular entity.
`10. Pediatrics
`The application was presented before the Pediatric Review Committee (PeRC) on November 12,
`2014. PeRC concurred with the applicant’s request for a partial waiver for children less than two
`years of age because necessary studies are impossible or highly impractical, e.g., because the
`number of patients in that age group is so small or geographically dispersed.
`
`Pediatric exclusivity was granted on December 16, 2014, based on the Pediatric Exclusivity
`Board’s determination that the information submitted met the terms of the Pediatric Written
`Request.
`11. Other Relevant Regulatory Issues
`
`11.1 Compliance Inspection
`Overall the Office of Compliance found that facilities are acceptable as noted in the CMC review.
`
`11.2 Office of Scientific Investigation (OSI) Audits
`Two investigators were inspected and classified as NAI. OSI concluded the data generated by
`these clinical sites appear adequate in support of the indication.
`
`14
`
`Reference ID: 3694683
`
`

`

`NDA 206276
`PAZEO (olopatadine hydrochloride ophthalmic solution) 0.7%
`Proposed Indication: Ocular Itching Associated With Allergic Conjunctivitis
`
`Financial Disclosure
`11.3
`The financial disclosure information was reviewed by the Medical Officer, who notes the one
`investigator with an interest enrolled a small percentage of patients and is unlikely to impact the
`integrity of the data. In add