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

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`Indication:
`
`Applicant:
`
`Review Division:
`
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`Disclaimer
`
`206276
`SDN014 (eCTD013)
`1/22/2015
`1/22/2015
`Olopatadine hydrochloride ophthalmic solution,
`0.77%
`Treatment of signs and symptoms of allergic
`conjunctivitis
`Alcon Research Ltd
`6201 South Freeway MS TC 45
`Fort Worth, TX 76134
`Division of Transplant and Ophthalmology
`Products
`Aaron M Ruhland, PhD
`Lori Kotch, PhD, DABT
`Renata Albrecht, MD
`Lois Almoza
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 206276 are owned by Alcon Research Ltd or are data
`for which Alcon Research Ltd has obtained a written right of reference.
`Any information or data necessary for approval of NDA 206276 that Alcon Research Ltd
`does not own or have a written right to reference constitutes one of the following: (1)
`published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug,
`as reflected in the drug’s approved labeling. Any data or information described or
`referenced below from reviews or publicly available summaries of a previously approved
`application is for descriptive purposes only and is not relied upon for approval of NDA
`206276.
`
`Reference ID: 3693634
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`Executive Summary
`1
`Introduction
`1.1
`The subject of this NDA is olopatadine hydrochloride ophthalmic solution, 0.77%
`administered as a once daily topical ocular drop for the treatment of ocular itching
`associated with allergic conjunctivitis. A nonclinical review of the approvability of the
`NDA application has been conducted (dated 12-31-2014). This review represents
`reconsideration of Section 8 of the labeling following a counterproposal by the applicant.
`Specifically, the applicant contends that labeling language in Section 8 describing
`increased embryolethality and cleft palate in rats following oral administration of 60
`mg/kg olopatadine during gestation falls within or near historical control values. The
`applicant submitted historical control data from nonclinical embryo-fetal studies to
`support these arguments .
`
`1.2 Brief Discussion of Nonclinical Findings
` The applicant’s argument that increased embryolethality following daily oral
`olopatadine doses of 60 mg/kg in pregnant rats falls within the historical control
`range is supported by the data submitted. The FDA proposed labeling has been
`amended in support of these findings.
` The applicant’s argument that
`
`
`
`. The FDA proposed labeling has
`not been amended in support of these findings.
`It was suggested in internal discussion that
`
`
`
` be
`
`deleted from the labeling to reduce potential confusion when comparing this
`multiple to that of the 1 mg/kg/day based on comparison of exposure (i.e. 45 –
`150 fold).
` The human exposure (AUC0-12) to Pazeo following the recommended dosing
`regimen reported in Section 12.3 of the labeling was changed based upon the
`Clinical Pharmacology reviewer’s calculations (changed from
` to
`9.7 ng∙hr/mL). The human AUC reported in Section 8 and resultant safety
`margin calculations have been revised to reflect this change.
` During ongoing revision, the applicant suggested the addition of the following
`statement to Section 8.3:
`o “An oral dose of 1 mg/kg olopatadine in rats resulted in a range of
`systemic plasma area under the curve (AUC) levels that were 45 to 150
`times higher than the observed human exposure [9.7 ng∙hr/mL] following
`administration of the recommended human ophthalmic dose.”
`
`1.3.
`
`Labeling
`
`Reference ID: 3693634
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`1.3.1 Former FDA proposed labeling (see letter dated 12-31-2014)
`
`8.1 Pregnancy
`
`Risk Summary
`There are no adequate or well-controlled studies with PAZEO in pregnant women.
`Olopatadine caused maternal toxicity and embryofetal toxicity in rats at levels 1080
`to 14,400 times the maximum recommended human ophthalmic dose (MRHOD)).
`There was no toxicity in rat offspring at
` times MRHOD. Olopatadine
`should be used during pregnancy only if the potential benefit justifies the potential
`risk to the fetus.
`
`Animal Data
`In a rabbit embryofetal study, rabbits treated orally at 400 mg/kg/day during
`organogenesis showed a decrease in live fetuses. This dose is 14,400 times the
`MRHOD, on a mg/m2 basis.
`
`An oral dose of 600 mg/kg/day olopatadine (10,800 times the MRHOD) was shown
`to be maternally toxic in rats, producing death and reduced maternal body weight
`gain. When administered to rats throughout organogenesis, olopatadine produced
` cleft palate at 60 mg/kg/day (1080 times the
`MRHOD), and reduced fetal weight in rats at 600 mg/kg/day. When administered to
`rats during late gestation and throughout the lactation period, olopatadine produced
`decreased neonatal survival at 60 mg/kg/day and reduced body weight gain in
`offspring at 4 mg/kg/day
`. A dose of 2 mg/kg/day olopatadine
`produced no toxicity in rat offspring. An oral dose of 1 mg/kg olopatadine in rats
`resulted in a range of systemic plasma area under the curve (AUC) levels that were
` times higher than the observed human exposure
` following
`administration of the recommended human ophthalmic dose.
`
`8.3 Nursing Mothers
`Olopatadine has been identified in the milk of nursing rats following oral
`administration. Oral administration of olopatadine doses at or above 4 mg/kg/day
`throughout the lactation period produced decreased body weight gain in rat
`offspring; a dose of 2 mg/kg/day olopatadine produced no toxicity. It is not known
`whether topical ocular administration could result in sufficient systemic absorption
`to produce detectable quantities in the human breast milk. Nevertheless, caution
`should be exercised when PAZEO is administered to a nursing mother.
`
`1.3.2. Applicant’s proposed amended labeling (SDN014; 1-22-2015)
`
`Blue double-underlined text represents applicant’s proposed additions to the labeling;
`Red strikethrough text represents applicant’s proposed deletions from the labeling:
`
`8.1 Pregnancy
`
`Reference ID: 3693634
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`Risk Summary
`There are no adequate or well-controlled studies with PAZEO in pregnant women.
`Olopatadine caused maternal toxicity and embryofetal toxicity in rats at levels
`10,
`0 to 14,400 times the maximum recommended human ophthalmic dose
`(MRHOD)). There was no toxicity in rat offspring at
` times MRHOD.
`Olopatadine should be used during pregnancy only if the potential benefit justifies
`the potential risk to the fetus.
`
`Animal Data
`In a rabbit embryofetal study, rabbits treated orally at 400 mg/kg/day during
`organogenesis showed a decrease in live fetuses. This dose is 14,400 times the
`MRHOD, on a mg/m2 basis.
`
`An oral dose of 600 mg/kg/day olopatadine (10,800 times the MRHOD) was shown
`to be maternally toxic in rats, producing death and reduced maternal body weight
`gain. When administered to rats throughout organogenesis, olopatadine produced
`decreased embryofetal viability and
`
`reduced fetal weight in rats at 600 mg/kg/day. When administered to
`rats during late gestation and throughout the lactation period, olopatadine produced
`decreased neonatal survival at 60 mg/kg/day and reduced body weight gain in
`offspring at 4 mg/kg/day
`. A dose of 2 mg/kg/day olopatadine
`produced no toxicity in rat offspring. An oral dose of 1 mg/kg olopatadine in rats
`resulted in a range of systemic plasma area under the curve (AUC) levels that were
` times higher than the observed human exposure
` following
`administration of the recommended human ophthalmic dose.
`
`8.3 Nursing Mothers
`Olopatadine has been identified in the milk of nursing rats following oral
`administration. Oral administration of olopatadine doses at or above 4 mg/kg/day
`throughout the lactation period produced decreased body weight gain in rat
`offspring; a dose of 2 mg/kg/day olopatadine produced no toxicity. It is not known
`whether topical ocular administration could result in sufficient systemic absorption
`to produce detectable quantities in the human breast milk. Nevertheless, caution
`should be exercised when PAZEO is administered to a nursing mother.
`
`1.3.3 Data submitted by applicant to support proposed labeling changes
`
`Morita, H., et al., 1987; “Spontaneous malformations in laboratory animals:
`Frequency of external, internal and skeletal malformations in rats, rabbits, and
`mice”, Cong Anom, 27: 147 – 206.
`
`Embryolethality
`
`Following review of data from Study A-89-52, an embryo-fetal toxicity study in rats
`submitted to support the NDA, it was concluded that the
` dose caused
`
`Reference ID: 3693634
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`increased embryo-fetal lethality with significantly higher death in the olopatadine treated
`group compared to control (7.2% vs 2.9%, respectively):
`
`Dose (mg/kg/day)
`# of dams
`Implantations
`Alive (% of implantations)
`Early death (% of
`implantations)
`Late death (% of
`implantations)
`B.W. (m, f)
`
`Control
`24
`314
`97
`2.9
`
`0
`
`60
`24
`340
`92.8*
`7.2*
`
`0
`
`200
`22
`308
`93.5*
`6.3*
`
`0.3
`
`3.1, 2.9
`
`3.1, 2.9
`
`3.0, 2.8
`
`600
`22
`324
`92.8
`7.2
`
`0
`2.8**,
`2.6**
`
`Oxatomide
`24
`354
`81.6**
`15.1**
`
`3.3**
`
`2.8**, 2.6**
`
`Historical data submitted by the applicant (Morita, et al.) were reviewed. The data in
`Wistar rats were derived from two common strains: JCL and SLC. In JCL:Wistar rats,
`mean (range) fetal mortality among 1327 dams was 6% (2.5 – 15.8%). In SLC:Wistar
`rats, fetal mortality among 1232 dams was 4.5% (2.5 – 22.5%). While embryolethality
`in the olopatadine treated rats was significant higher than controls, the results fall within
`the published historic range.
`
` The data support this
`
`argument.
`
`Cleft Palate
`In Study A-89-52, cleft palate was reported in 2 fetuses (2 litters) treated with
`olopatadine (both instances occurred in the 60 mg/kg treated group). Across all
`olopatadine treated groups, this represents an incidence of 2/905 (0.22%) among all
`treated fetuses or 2/68 (2.9%) among all treated litters. These data were compared to
`the historical data submitted by the applicant (Morita, et al.).
`
`In JCL:Wistar rats, a total of 2 instances of cleft palate were reported among 18,205
`fetuses analyzed (0.011%).
`If an average litter size of 10 fetuses is assumed, this
`represents an incidence of 2/1820 litters (0.11%). Therefore, the incidence of 0.22% of
`fetuses or 2.9% of litters reported for the olopatadine treated groups represents an
`increase of 20-fold and 26-fold over the historical rate among fetuses and litters,
`respectively.
`
`In SLC:Wistar rats, one (1) instance of cleft palate was reported among 10,713 fetuses
`analyzed (0.0093%). If an average litter size of 10 fetuses is assumed, this represents
`an incidence of 1/1071 litters (0.093%). Therefore, the incidence of 0.22% of fetuses or
`2.9% of litters reported for the olopatadine treated groups represents an increase of 24-
`fold and 31-fold, respectively, over the historical rate.
`
`Therefore, it is concluded that olopatadine treatment was associated with an increase in
`the incidence of cleft palate compared to the concurrent controls in the study and
`
`Reference ID: 3693634
`
`(b) (4)
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`historical control data submitted by the applicant. The labeling will remain unchanged to
`reflect these data.
`
`1.3.4 Revised FDA labeling
`
`8.1 Pregnancy
`
`Risk Summary
`There are no adequate or well-controlled studies with PAZEO in pregnant women.
`Olopatadine caused maternal toxicity and embryofetal toxicity in rats at levels 1080
`to 14,400 times the maximum recommended human ophthalmic dose (MRHOD).
`There was no toxicity in rat offspring at
`45 to
`150 times MRHOD.
`Olopatadine should be used during pregnancy only if the potential benefit justifies
`the potential risk to the fetus.
`
`Animal Data
`In a rabbit embryofetal study, rabbits treated orally at 400 mg/kg/day during
`organogenesis showed a decrease in live fetuses. This dose is 14,400 times the
`MRHOD, on a mg/m2 basis.
`
`An oral dose of 600 mg/kg/day olopatadine (10,800 times the MRHOD) was shown
`to be maternally toxic in rats, producing death and reduced maternal body weight
`gain. When administered to rats throughout organogenesis, olopatadine produced
`cleft palate at 60 mg/kg/day (1080 times the
`MRHOD), and decreased embryofetal viability and reduced fetal weight in rats at
`600 mg/kg/day. When administered to rats during late gestation and throughout the
`lactation period, olopatadine produced decreased neonatal survival at 60 mg/kg/day
`and reduced body weight gain in offspring at 4 mg/kg/day
`. A
`dose of 2 mg/kg/day olopatadine produced no toxicity in rat offspring. An oral dose
`of 1 mg/kg olopatadine in rats resulted in a range of systemic plasma area under
`the curve (AUC) levels that were
`45 to
`150 times higher than the observed
`human exposure [
`9.7 ng∙hr/mL] following administration of the recommended
`human ophthalmic dose.
`
`8.3 Nursing Mothers
`Olopatadine has been identified in the milk of nursing rats following oral
`administration. Oral administration of olopatadine doses at or above 4 mg/kg/day
`throughout the lactation period produced decreased body weight gain in rat
`offspring; a dose of 2 mg/kg/day olopatadine produced no toxicity. An oral dose of 1
`mg/kg olopatadine in rats resulted in a range of systemic plasma area under the
`curve (AUC) levels that were 45 to 150 times higher than the observed human
`exposure [9.7 ng∙hr/mL] following administration of the recommended human
`ophthalmic dose. It is not known whether topical ocular administration could result
`in sufficient systemic absorption to produce detectable quantities in the human
`breast milk. Nevertheless, caution should be exercised when PAZEO is
`administered to a nursing mother.
`
`Reference ID: 3693634
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`AARON M RUHLAND
`01/28/2015
`
`LORI E KOTCH
`01/28/2015
`
`Reference ID: 3693634
`
`

`

`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY NDA REVIEW AND EVALUATION
`
`Application number:
`Supporting document/s:
`Applicant’s letter date:
`CDER stamp date:
`Product:
`
`Indication:
`
`Applicant:
`
`Review Division:
`
`Reviewer:
`Supervisor/Team Leader:
`Division Director:
`Project Manager:
`Disclaimer
`
`206276
`N001
`7/30/2014
`7/30/2014
`Olopatadine hydrochloride ophthalmic solution,
`0.77%
`Treatment of signs and symptoms of allergic
`conjunctivitis
`Alcon Research Ltd
`6201 South Freeway MS TC 45
`Fort Worth, TX 76134
`Division of Transplant and Ophthalmology
`Products
`Aaron M Ruhland, PhD
`Lori Kotch, PhD, DABT
`Renata Albrecht, MD
`Lois Almoza
`
`Except as specifically identified, all data and information discussed below and
`necessary for approval of NDA 206276 are owned by Alcon Research Ltd or are data
`for which Alcon Research Ltd has obtained a written right of reference.
`Any information or data necessary for approval of NDA 206276 that Alcon Research Ltd
`does not own or have a written right to reference constitutes one of the following: (1)
`published literature, or (2) a prior FDA finding of safety or effectiveness for a listed drug,
`as reflected in the drug’s approved labeling. Any data or information described or
`referenced below from reviews or publicly available summaries of a previously approved
`application is for descriptive purposes only and is not relied upon for approval of NDA
`206276.
`
`Reference ID: 3681271
`
`1
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`TABLE OF CONTENTS
`
`1
`
`3
`
`EXECUTIVE SUMMARY ......................................................................................... 3
`1.1
`INTRODUCTION.................................................................................................... 3
`1.2
`BRIEF DISCUSSION OF NONCLINICAL FINDINGS ...................................................... 3
`1.3
`RECOMMENDATIONS............................................................................................ 3
`2 DRUG INFORMATION ............................................................................................ 6
`2.1
`DRUG................................................................................................................. 6
`2.2
`RELEVANT INDS, NDAS, BLAS AND DMFS........................................................... 7
`2.3
`DRUG FORMULATION ........................................................................................... 7
`2.4
`COMMENTS ON NOVEL EXCIPIENTS....................................................................... 8
`2.5
`PROPOSED CLINICAL POPULATION AND DOSING REGIMEN ...................................... 8
`STUDIES SUBMITTED............................................................................................ 8
`3.1
`STUDIES REVIEWED............................................................................................. 8
`3.2
`STUDIES NOT REVIEWED ..................................................................................... 9
`3.3
`PREVIOUS REVIEWS REFERENCED...................................................................... 10
`PHARMACOLOGY................................................................................................ 11
`4.1
`PRIMARY PHARMACOLOGY................................................................................. 11
`4.2
`SECONDARY PHARMACOLOGY............................................................................ 12
`4.3
`SAFETY PHARMACOLOGY................................................................................... 12
`PHARMACOKINETICS/ADME/TOXICOKINETICS .............................................. 12
`5.1
`PK/ADME........................................................................................................ 12
`6 GENERAL TOXICOLOGY..................................................................................... 17
`6.1
`REPEAT-DOSE TOXICITY.................................................................................... 17
`7 GENETIC TOXICOLOGY ...................................................................................... 23
`
`4
`
`5
`
`8 CARCINOGENICITY ............................................................................................. 23
`
`9 REPRODUCTIVE AND DEVELOPMENTAL TOXICOLOGY ................................ 24
`
`10
`
`INTEGRATED SUMMARY AND SAFETY EVALUATION................................. 30
`
`Reference ID: 3681271
`
`2
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`1
`
`Executive Summary
`
`Introduction
`1.1
`The subject of this NDA is olopatadine hydrochloride ophthalmic solution, 0.77%
`administered as a once daily topical ocular drop for the treatment of ocular itching
`associated with allergic conjunctivitis. Olopatadine hydrochloride ophthalmic solution is
`currently approved as a topical ocular formulation in Patanol® (0.1%, BID) and
`Pataday® (0.2%, QD). The applicant conducted pharmacology, comparative ocular
`distribution/pharmacokinetic and ocular toxicity studies of olopatadine hydrochloride
`ophthalmic solution, 0.77% to support the new formulation and higher concentration of
`olopatadine hydrochloride compared to the previously approved formulations.
`
`1.2 Brief Discussion of Nonclinical Findings
` A dose dependent increase in conjunctival and intraocular distribution was
`reported for olopatadine, 0.77% compared to Pataday®
`In a 90-day repeat-dose ocular toxicity study, no toxicity, ocular or systemic, was
`attributed to olopatadine, 0.77% administered bilaterally. This dose correlates
`with an approximate 4-fold margin over the proposed clinical dose.
`1.3 Recommendations
`
`
`
`1.3.1 Approvability
` P/T recommends approval
`
`1.3.2
`
`Labeling
`
`1.3.2.1 Applicant’s version of labeling
`
`Blue double-underlined text represents additions to the Pataday® labeling; red
`strikethrough text represents deletions from the Pataday® labeling:
`
`8 USE IN SPECIFIC POPULATIONS
`
`8.1 Pregnancy
`
`Pregnancy
`
`
`
`Reference ID: 3681271
`
`3
`
`(b) (4)
`
`(b) (4)
`
`2 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`2
`
`Drug Information
`
`2.1 Drug
`CAS Registry Number: 113806-05-6
`
`Generic Name: Olopatadine hydrochloride ophthalmic solution, 0.77%
`
`Reference ID: 3681271
`
`6
`
`(b) (4)
`
`

`

`NDA 206276
`
`Code Name: Pazeo
`
`Aaron M Ruhland
`
`Chemical Name: {(11Z)-11-[3-(dimethylamino)propylidene]-6,11-
`dihydrodibenzo[b,e]oxepin-2-yl}acetic acid
`
`Molecular Formula/Molecular Weight: C21H23NO3 / 337.4 g/mol
`
`Structure or Biochemical Description:
`
`Pharmacologic Class: Histamine-1 receptor inhibitor
`
`2.2 Relevant INDs, NDAs, BLAs and DMFs
` DMF
` NDA 20-688: Patanol®, olopatadine hydrochloride ophthalmic solution, 0.1%
`o Approved: 12-18-1996
`IND 44,216: Patanol®
`
` NDA 21-545: Pataday®, olopatadine hydrochloride ophthalmic solution, 0.2%
`o Approved: 12-22-2004
`IND 60,991, Pataday®
`
`2.3 Drug Formulation
`Component
`Olopatadine hydrochloride
`Hydroxypropyl-gamma
`cyclodextrin
`Povidone
`Polyethylene glycol
`Hypromellose
`Mannitol
`Boric Acid
`Benzalkonium chloride
`Sodium hydroxide and/or
`hydrochloric acid
`Purified water
`
`% w/v
`0.776
`
`Function
`Active ingredient
`
`0.015
`qs to pH 7.2
`
`Preservative
`pH adjustment
`
`Formulation comparison of Pazeo® with Patanol® and Pataday®:
`
`Reference ID: 3681271
`
`7
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`Pazeo®
`(olopatadine
`HCl Solution,
`0.77%)
`0.776
`
`Pataday®
`
`Patanol®
`
`0.222
`
`0.111
`
`Component
`
`Olopatadine HCl
`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
`
`2.4 Comments on Novel Excipients
`All excipients are qualified for topical ophthalmic administration except hydroxypropyl-γ-
`cyclodextrin and povidone K29/32
`. 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.
`
`
`Proposed Clinical Population and Dosing Regimen
`2.5
`The recommended dose is one drop in each affected eye once a day. In the nonclinical
`sections of the labeling, the applicant bases calculated safety margins on a 0.035 mL
`drop size. The daily dose per eye is 270 µg/eye/day (540 µg/day total daily dose if
`administered bilaterally).
`
`3
`
`Studies Submitted
`
`3.1
`
`Studies Reviewed
`
`Reference ID: 3681271
`
`8
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`Pharmacology
` Report TDOC-0016656: Preclinical pharmacology of high-dose (0.7%)
`olopatadine (AL-4943A) in an in vivo model of ocular allergy
`
`Pharmacokinetics
` Report TDOC-0015572: Single dose ocular distribution comparison study
`between 0.2% Pataday® versus 0.77% high dose olopatadine (final formulation)
`in NZW male rabbits
` Report TDOC-0013348: Toxicokinetics of AL-4943, AL-24956 (M1) and AL-
`38189 (M3) in toxicology study N-10-166: AL-4943 (high dose olopatadine): two-
`week topical ocular irritation and systemic toxicity study in pigmented rabbits
` Report TDOC-0015752: Toxicokinetics of AL-4943 in toxicology study N-11-110:
`AL-4943AQ (high dose olopatadine): three-month QID topical ocular irritation and
`systemic toxicity study in pigmented rabbits
`
`Toxicology
` Single dose toxicity
`o Report TDOC-0001715: Seventy two-hour ocular evaluation of
`olopatadine HCl nasal spray following single-dose administration in New
`Zealand White rabbits
` Repeat dose toxicity
`o Report TDOC-0013437: AL-4943A (high dose olopatadine): two-week
`topical ocular irritation and systemic toxicity study in pigmented rabbits
`o Report TDOC-0015211: AL-4943A (high dose olopatadine): three-month
`QID topical ocular irritation and systemic toxicity study in pigmented
`rabbits
`
`3.2
`
`Studies Not Reviewed
`
`Pharmacology
` Report 019:39900:0895: Effect of olopatadine on contralateral eye responses in
`a model of histamine-induced vascular permeability
`
`Safety Pharmacology
` on the sleep-wakefulness cycle of cats
` Report 1156: Effects of
` Report 137:30:0700: Effects of olopatadine hydrochloride on cloned hERG
`channels
` Report 89-121(Y): Pharmacological properties of
`and peripheral nervous systems
`
`4679- effects on the central
`
`Pharmacokinetics
` Report TDOC-0009658: Validation of an HPLC tandem mass spectrometry
`(HPLC/MS/MS) method for the determination of olopatadine (AL-4943), M1,M2
`and M3 in human plasma (K2EDTA) at tandem labs
`
`Reference ID: 3681271
`
`9
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`(b) (4)
`
`(b) (4)
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
` Report TDOC-0015730: Olopatadine (AL-4943), M1 (AL-24956) and M3 (AL-
`38189) human K2EDTA plasma concentrations for Alcon Study C-11-036
`
`Repeat dose toxicity
` Systemic administration
`o Report A-90-92: Toxicological study of
`toxicity study of
` in dogs
`
`o Report A-90-82: 52-week chronic oral toxicity study of
`
`a 52-week chronic oral
`
` in rats
`
` Ocular administration
`o Report 102:38520:0895: Six month chronic topical ocular irritation and
`systemic toxicity evaluation of AL-4943A ophthalmic solution in primates
`o Report 030:38520:0395: Six-month topical ocular irritation and systemic
`toxicity evaluation of AL-4943A ophthalmic solution in rabbits
`
`Genotoxicity
` Report A-88-147: Toxicological study of
`of
` on CHL cells in vitro
` Report A-88-93: Toxicological study of
`assay of
` Report A-90-17: Micronucleus test of
`
`chromosomal aberration test
`
`bacterial reverse mutation
`
` administered orally to mice
`
`Carcinogenicity
` Report 92/KKY009/1065: Oncogenicity study by dietary administration to CD-1
`mice for 78 weeks
` Report 93/KKY008/0386:
`to F-344 rats for 104 weeks
`
` Oncogenicity study by dietary administration
`
`Reproductive and developmental toxicity
` Report A-89-26: Toxicological study of
`rats
` Report A-89-52: Reproduction study of
` in rats
` Report A-89-59: Reproduction study of
` in rabbits
`
`Fertility study of
`
` in
`
` – Teratogenicity study of
`
`Teratogenicity study of
`
`Previous Reviews Referenced
`3.3
` NDA 20-688: Patanol®, olopatadine hydrochloride ophthalmic solution, 0.1%
`o Pharm/Tox review conducted by Asoke Mukherjee, Ph.D. (review dated 7-
`16-1996)
` NDA 21-545: Pataday®, olopatadine hydrochloride ophthalmic solution, 0.2%
`o Pharm/Tox review conducted by Maria Rivera, Ph.D. (review dated 2-24-
`03).
`
`Reference ID: 3681271
`
`10
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`4
`
`Pharmacology
`
`4.1
`
`Primary Pharmacology
`
`Olopatadine is a H1 receptor antagonist, an inhibitor of pro-inflammatory mediator
`release from human conjunctival mast cells, and an inhibitor of histamine stimulated
`cytokine production by human conjunctival epithelial cells. Most of the nonclinical
`studies to determine the pharmacologic properties of olopatadine were previously
`submitted under NDA 20-688 and 21-545. 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 HCl
`Solution, 0.77% in a preclinical model of histamine-induced vascular permeability. Study
`results indicated that olopatadine, 0.77% significantly suppresses allergic conjunctival
`symptoms compared to Pataday and vehicle control.
`
`TDOC-0016656: Preclinical pharmacology of high-dose (0.7%) olopatadine (AL-
`4943A) in an in vivo model of ocular allergy
`
`Male Hartley VAF guinea pigs (250–300 g) received a single inferior subconjunctival
`injection of 300 ng histamine dissolved in saline to the right eye. Groups were given a
`20 μL topical drop of olopatadine, 0.77%, olopatadine, 0.2% (Pataday) or corresponding
`vehicle to the right eye at 30 minutes or 24 hours prior to histamine challenge. At 30
`minutes post challenge, guinea pigs were euthanized and the area of vascular leakage
`determined. Olopatadine exhibited significantly greater anti-allergy efficacy in vivo
`when administered topically in a 0.7% solution as compared with PATADAY®
`(olopatadine, 0.2%) or vehicle control, when administered either 30 minutes or 24 hours
`before histamine challenge.
`
`Reference ID: 3681271
`
`11
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`Secondary Pharmacology
`4.2
`Studies describing secondary pharmacology of olopatadine and its metabolites were
`previously reviewed under NDA 20-688 (Patanol) or NDA 21-545 (Pataday®). Briefly,
`
`The major olopatadine metabolites across species (including humans) are the N-
`oxide and N-desmethyl metabolites. Both metabolites showed affinity for the
`histamine H1 receptor but at lower concentrations than calculated for olopatadine.
`Weak interactions with the serotonin 5HT2A receptor and norepinephrine
`transporter were also observed. The N-oxide was evaluated for its ability to inhibit
`the release of histamine from human conjunctival mast cells. Inhibition was
`observed with an IC50 value of 3.07 mM. Comparing to the IC50 of 559 µM obtained
`for olopatadine in a separate study, the N-oxide showed lower potency than the
`parent compound. These findings, together with the low plasma levels detected for
`both metabolites, support that these metabolites are not expected to contribute
`significantly to olopatadine efficacy or side effects.
`
`Safety Pharmacology
`4.3
`The effect of olopatadine (3, 10, 30, 100 mg/kg) on electrocardiogram, heart rate and
`blood pressure was determined in conscious dogs. Olopatadine significantly prolonged
`QTc by 20 – 40 msec at dose of 100 mg/kg. At the same dose, heart rate was also
`significantly increased while systolic blood pressure was decreased. At doses of 30
`mg/kg or higher, olopatadine increased diastolic blood pressure. It is thought that
`olopatadine prolongation of the QTc interval was caused by the increase in heart rate.
`In a study to determine the effect of olopatadine on the central and peripheral nervous
`systems, olopatadine showed a sedative effect in mice at the highest dose tested, 300
`mg/kg.
`
`The doses at which these effects occurred are greatly in excess of therapeutic
`ophthalmic doses. Therefore, olopatadine is not expected to cause significant adverse
`effects in humans following topical ocular administration of 0.77% olopatadine
`hydrochloride ophthalmic solution
`5
`Pharmacokinetics/ADME/Toxicokinetics
`
`5.1
`
`PK/ADME
`
`Studies describing the pharmacokinetics, absorption, distribution, metabolism and
`excretion of olopatadine and its metabolites were previously reviewed under NDA 20-
`688 (Patanol) or NDA 21-545 (Pataday®). Briefly (from review of NDA 21-545):
`
`Absorption: Following i.v. administration, the elimination olopatadine from plasma
`was relatively rapid with a t½ of 0.7 hr in rabbits, 5 hr in rats, 7 hr in dogs, and 10
`
`Reference ID: 3681271
`
`12
`
`

`

`NDA 206276
`
`Aaron M Ruhland
`
`hr in monkeys. The oral bioavailability of olopatadine was high, ranging from 70%
`in the rat to 100% in the monkey. In rats and dogs, both Cmax and AUC increased in
`a dose-proportional manner over a dose range of 0.3 to 3 mg/kg/day. The volume
`of distribution at steady-state was moderately low, 1 – 2 L/kg. After a topical ocular
`dose of 0.15% olopatadine ophthalmic solution in rabbits, maximal plasma levels of
`10 ng/mL were reached by 30 minutes, The elimination t½ of olopatadine from
`plasma following the topical ocular dose was similar to that observed following an
`i.v. dose (0.8hr).
`
`Distribution: Ocular tissue distribution studies following a topical ocular dose of
`the 0.15% 14C-olopatadine ophthalmic solution in rabbits showed that radioactivity
`was absorbed into the eye and reached maximal tissue levels within 0.5 to 1 hour.
`Tissues at the site of dosing (i.e. cornea and conjunctiva