CENTER FOR DRUG EVALUATION AND
`
`RESEARCH
`
`~ APPLICA TION NUMBER:
`
`2 1 -994
`
`PHARMACOLOGY REVIEW I
`
`

`

` DEPARTMENT OF HEALTH AND HUMAN SERVICES.
`
`PUBLIC HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`PHARMACOLOGY/TOXICOLOGY REVIEW AND EVALUATION
`
`NDA NUMBER:
`
`SERIAL NUMBER:
`DATE RECEIVED BY CENTER:
`
`PRODUCT:
`
`INTENDED CLINICAL POPULATION:
`
`SPONSOR:
`
`21-994
`
`000
`
`1 1/2 1/2005
`
`TravatanOZ '
`
`Reduction of elevated intraoeular hressure (IOP) in
`patients with open angle glaucoma or ocular
`hypertension
`Alcon Universal Ltd, PO Box 62, Bosch 69, CH-
`6331 Hunenberg, Switzerland
`Authorized US Agent: Alcon Laboratories, Inc.,
`6201 South‘Freeway, Fort Worth, TX 76134-2009
`
`”(1
`
`DOCUMENTS REVIEWED:
`
`'
`
`Vol. 4.1-4.4
`
`REVIEW DIVISION:
`
`Division of Anti-Infective and Ophthalmology v
`
`PHARM/TOX REVIEWER:
`
`PHARM/TOX SUPERVISOR:
`
`DIVISION DIRECTOR:
`
`PROJECT MANAGER:
`
`Products (HEB—520)
`
`Zhou Chen, MD, PhD
`
`' Terry Peters, DVM
`
`Janice SOreih, MD
`
`Mike Puglisi
`
`Date of review submission to Division File System (DFS): March 2, 2006
`
`Appears ThisWay
`On Original
`
`

`

`TABLE OF CONTENTS
`
`EXECUTIVE SUMMARY 3
`
`2.6 PHARMACOLOGY/TOXICOLOGY REVIEW ................................................... 4
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY................................................................... 4
`
`2.6.2 PHARMACOLOGY ......................................................................................................... 6
`2.6.2.1
`Brief summary .................................................................. 6
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY......................................,................... 6
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS ...................................................... ..... 6
`2.6.4.1
`Brief summary ....................................................................................................................... 6
`2.6.4.2
`Distribution ............................................................................................................................ 7
`
`2.6.5 PHARMACOKINETICS TABULATED SUMMARY ................................................. 8 '
`
`2.6.6 TOXICOLOGY...........................................z..;.................................. 8
`2.6.6.1
`Overall toxicology summary ............................... -. ................................................................. 8
`2.6.6.2
`Single-dose toxicity ........................................................................................... .................... 8
`2.6.6.3
`Repeat-dose toxicity ............................................................................................................ 14
`2.6.6.4
`Genetic toxicology .................................. ............................................................................ 19
`2.6.6.5
`Carcinogenicity ...............................................................\. ................................................... l 9
`2.6.6.6
`Reproductive and developmental toxicology ...................................................................... 21
`2.6.6.7
`Local tolerance .........................................._. ......................................................................... 22
`2.6.6.8
`Special toxicology studies ................................................................................................... 22
`2.6.6.9
`Discussion and Conclusions
`.................................................................................. 26
`
`2.6.7 TOXICOLOGY TABULATED SUMMARY
`
`......................... 26
`
`OVERALL CONCLUSIONS AND RECOMMENDATIONS 26
`
`APPENDIX/ATTACHNIENTS ................................................................................................. 27
`
`Appears This Way
`On Original
`
`2
`
`

`

`
`Reviewer: Zhou Chen,_P_h.D.
`
`NDA No. 21—994
`
`EXECUTIVE SUMMARY
`
`Recommendations
`
`A. Recommendationon approvability
`
`An “approval” is recommended for this NDA application.
`
`B. Recommendation for nonclinical studies
`
`No recommendation is necessary.
`
`C. Recommendations on labeling
`
`No reCommendation is necessary. The proposed labeling is acceptable.
`
`II.
`
`Summary of nonclinical findings
`
`A. Brief overview of nonclinical findings
`
`Travoprost is approved asTravatan® in 2001 for'th’e reduction'ofIOP in patients
`with open angel glaucoma or ocular hypertension. In the current NDA
`application, the sponsor proposed a new benzalkonium chloride-free (BAC-free)
`formulation. The sponsor indicated that benzalkonium chloride in IOP-lowering
`medications had been implicated in exerting a deleterious effect on the
`conjunctiva that resulted in altered pustoperative wound healing. In nonclinical
`. studies, the new formulation, Travatan® Z, showed a similar toxicity profile as the
`marketed formulation, Travatan®. The drug showed a low irritation potential
`when administered topically to the rabbit eye. Regarding ocular absorption, the
`new formulation seems to have a lower absorption.
`
`B. Pharmacologic activity
`
`Travoprost (AL—6221), an isopropyl ester derivative of the free acid AL-5848, is
`believed to be hydrolyzed to the free acid by ester hydrolase enzymes located in
`the cornea and appears in the aqueous humor as the free acid. AL—5848 is a
`highly selective and potent agonist at the prostanoid FP receptor (PGFZOL
`receptor) with a Ki of 52 nM and a fiinctional potency (EC50) of 4 nM. In animal
`studies, travoprost produced a dose-related reduction of IOP, and once daily
`dosing with travoprost lowered [GP to a similar degree as BID dosing.
`
`C. Nonclinical safety issues relevant to clinical use
`
`No safety issues were raised comparing the Travatan® Z formulation with the
`marketed formulation.
`
`

`

`Reviewer: Zhou Chen, PhD.
`
`.
`
`NDA No. 21-994
`
`2.6 PHARMACOLOGY/TOXICOLOGYREVIEW
`
`2.6.1
`
`INTRODUCTION AND DRUG HISTORY
`
`NDA number:
`Review number:
`
`21—944
`000
`
`Sequence number/date/type of submission: 000/November 18,2005/CommercialNDA
`Information to sponsor: Yes (
`)No ( X)
`Sponsor and/or agent: Alcon Universal Ltd.., PO Box 62, Bosch 69, CH—6331
`Hunenberg, Switzerland
`Authorized US Agent: Alcon Laboratories, Inc, 6201 South Freeway, Fort Worth, TX
`76134—2009
`
`Manufacturer for drug substance: The Dow Chemical Company, 1803 Building,
`Midland, Michigan 48674 as well as Mitchell Cotts
`Chemicals, PO. Box 6, Steanard Lane, Mirfield,
`West Yorkshire WF14 8QB, UK
`
`Reviewer name: Zhou Chen, M.D., PhD.
`Division name: Anti—Infective and Ophthalmology Products
`HFD #: HFD—520
`_ " ‘
`'
`'
`Review completion date: March 1, 2006
`
`'
`
`Drug:
`
`Trade name: Travatan®Z
`
`Generic name: Travoprost ophthalmic solution, 0.004%
`Code name: AL-6221
`'
`
`Chemical name: (Z)--7—[( 1R2R, 3R,-5S)3 ,5dihydroxy--2—[( 1E,3R)——3—hydroXy—~4—
`[(a, Cl, oc——trifluoro-m--isopropyl-tolyl)oxy]- l—
`butenyl]cyclopentyl]-5-heptenoate
`CAS registry number: 157283-68-6
`-
`Molecular formula/molecular weight: C26H35F3O6; MW=500.55
`Structure:
`
`‘
`
` Travo . rosl AL~6221
`
` Relevant INDs/NDAs/DMFS: DMF‘.‘
`
`,IND
`
`51,000; NDA 21-257
`
`Drug class: PGqu analogue
`
`

`

`
`
` Reviewer: Zhou Chen PhD. NDA No. 21-994
`
`“g'ed‘e’”
`
`'
`
`%(w/v)
`9-.004
`
`I Intended clinical population: Reduction of elevated intraocular pressure (IOP) in
`patients with open angle glaucoma or ocular hypertension
`Clinical formulation:
`
`Travoprost Ophthalmic Solution, 0.004%
`Compendial desi ation
`Nonmom-endial
`
`
`
`Route of administration:
`Ocular, topical
`Proposed use: 1 drop (25 ul) per eye, once daily (Total dose could be 2 ug/patient/day or
`0.04 ug/kg for a 50 kg adult)
`
`Disclaimer: Tabular and graphical information are constructed by the reviewer unless
`cited otherwise.
`
`Studies reviewed within this submission:
`
`_
`Pharmacology:
`All pharmacology studies were reviewed under NDA 21—257 (Travatan®). For detailed
`review information, please check pharmacology/toxicology review of NDA 21-257.
`
`Pharmacokinetics: -
`
`TDOC—0001791: Ocular bioavailability comparison of two travoprost formulations in
`New Zealand White rabbits: Travatan® and Travatan®BAC—free
`
`Other PK studies were reviewed under NDA 21—257. For detailed review information,
`please check pharmacology/toxicology review of NDA 21~257.
`
`Toxicology:
`
`TDOC—0003457: One-day topical ocular irritation evaluation of Travatan® BAC-free
`ophthalmic solution in rabbits
`TDOC-0003351: One—day exaggerated topical ocular irritation evaluation of Travatan®
`BAC—free (travoprost, 0.004%) ophthalmic formulations (FIDs 107670 and 107074) in
`New Zealand White rabbits
`
`TDOC-0003456: Three month topical ocular irritation and toxicity study of Travatan®
`BAC-free1n New Zealand White rabbits
`
`012430-0101. Two week topical ocular irritation toxicity evaluation of w
`ophthalmic solution in New Zealand White rabbits
`051-30-0601: One month topical ocular irritation and systemic toxicity evaluation of AL-
`
`6221'(travoprost) ;
`- 1mpurity using New Zealand rabbits
`
`

`

`
`
` Reviewer: Zhou Chen Ph.D. '- NDA No. 21—994
`
`
`
`Other toxicity studies were reviewed under NDA 21-257. For detailed review
`information, please check pharmacology/toxicology review of NDA 21—257.
`
`Studies not reviewed within this submission:
`
`Ia
`
`2.6.2 PHARMACOLOGY
`
`2.6.2.1 Brief summary
`
`Travoprost (AL-6221), an isopropyl ester derivative of the free acid AL-5 848, is believed
`to be hydrolyzed to the free acid by ester hydrolase enzymes located in the cornea and to
`appear in the aqueous humor as the free acid. AL—5848 isa highly selective and potent
`agonist at the prostanoid FP receptor (PGF20L receptor) with a Ki for binding to the FP
`receptor of 52 nM and a fimctional potency (ECSO) of 4 nM. In animal studies, travoprost
`produced a dose~related reduction of IOP, and once daily dosing with travoprost lowered
`[GP to a similar extent as BID dosing.
`
`All pharmacology studiers were submitted under NDA 21—257..For detailed
`pharmacology study reviews, please see Review and Evaluation of Pharmacology and
`Toxicology Data for NDA 21-257 (October 2000).
`
`>45!
`
`2.6.3 PHARMACOLOGY TABULATED SUMMARY
`
`Not applicable
`
`2.6.4 PHARMACOKINETICS/TOXICOKINETICS
`
`2.6.4.1 Brief summary V
`
`In an ocular bioavailability comparison study conducted in NZW rabbits, Travatan® '
`BAC-free formulation (Travatan® Z) provided lower‘ intraocular concentrations and AUC
`values of active AL—5848 compared to Travatan®. The reason is not clear. It is possible
`that benzalkonium chloride may facilitate resorption of AL-5 848 from the tear through
`the corneal epithelium.
`
`

`

`
`
`Reviewer: Zhou Chen Ph.D.. NDA No. 21—994
`
`[Reviewer’s comments: Several PK studies were conducted with 3I-I—labeled drug.
`Usually HC is preferred because 3H incorporates into body fluids easily and the accuracy _
`of PK parameters is affected.)
`
`1
`
`Following topical ocular administration of 3H-AL-622l in rabbits, the drug was absorbed
`into the eye with highest concentrations noted in the anterior tissues (iris-ciliary body and
`aqueous humor; Tmax: 1-2 hr). In most ocular tissues, the drug was rapidly eliminated
`with half-life of 0.4—2.6 hr. In both rabbit and monkey studies, systemic exposure to the
`drug was very low after topical ocular administration.
`
`The extent of binding of the drug to rat, monkey and human plasma proteins was similar
`at approximately 80%. Over the concentration range of 0.01 to 100 ng/ml, the percent of
`bound drug for these species was independent of drug concentration.
`
`' Systemically, travoprost free acid was rapidly and extensively oxidized to inactive
`metabolites. Biotransformations included [3——oxidation of the 0L(carboxylic acid) chain to
`give 1,,2 3 ,4-tetranor analogs, oxidation of the lS-hydroxyl moiety, as well as reduction
`of the 13,14 double bond. The metabolites identified included 1,2 3,4-tetranor-l3, 14-
`dihydro-l 5-oxo-AL—5848, 1.,2-dinor—13,l4-dihydro-lS-oxo-AL-5848, l,2,3,4—tetranor-
`15-.oxo-AL-5848 and 1,2-dinor—l 5-oxo-AL—5 848.
`
`In rats, rabbits and dogs following intravenous administration of 3H-AL—6221, plasma
`concentrations of radioactivity decreased in a biphasic manner with half—lives for
`radioactivity elimination of 35, 48 and 26 hr for rats, rabbits and dogs, respectively. In
`rats, 95% of a subcutaneous radiolabeled dose was eliminated within 24 hours. The
`
`major route of elimination was via the bile (61%).
`
`Only one ocular bioavailability comparison study was submitted with this NDA package.
`All other PK studiers were submitted under NDA 21—257. For detailed reviews for these
`
`PK studies, pleasesee Review and Evaluation of Pharmacology and Toxicology Data for
`NDA 21—257 (October 2000).
`
`* 2.6.4.2 Distribution
`
`TDOC-0001791: Ocular bioavailability comparison of two travoprost formulations
`in New Zealand White rabbits: Travatan® and Travatan® BAC-free
`
`The purpose of this study was to determine the relative ocular bioavailability of AL-5848,
`the pharmacologically active metabolite of travoprost, in male New Zealand White
`rabbits following a single topical ocular administration (30 pl) of Travatan® ophthalmic
`solution to the right eye and Travatan® BAC-free to the left eye. Aqueous humor andiris-
`ciliary body were sampled from 6 rabbits per time point at 025, 0.5, l, 2, 4, and 6 hr after
`dosing. AL-5848 concentrations were determined using validated HPLC/MS/MS
`
`procedures with a lower limit of quantitation (LLOQ) of
`_ ng/g foriris-
`. ciliary body and »’-——--ng/ml for aqueous humor.
`
`

`

`
`Reviewer: Zhou Chen PhD.
`_
`‘
`NDA No. 21-994
`
`The results of this study (see table below) showed that in both aqueous humor and iris-
`ciliary body, the Cmax and AUC values for Travatan® BAC-free were lower than those
`for Travatan®. Travatan® BAC-free provided lower intraocular concentrations of active
`AL-5 848 compared to Travatan®. The reason of the loWer intraocular uptake of AL-S 848
`from Travatan® BAC-free is not clear. It is possible that benzalkonium chloride facilitates
`resorption of AL-S 848 from the tear through the corneal epithelium. In clinical studies,
`Travatan® containing 0.002%, 0.004% and 0.006% travoprost provided similar IOP-
`lowering effects. The sponsor indicated that the BAC-free formulation might provide
`similar IOP-lowering effects to Travatan® in human patients.
`
`AL-5848 concentrations in rabbit ocular tissues treated with Travatan and Travatan BAC-free
`
`
`(mean i SD)
`Aqueous humor
`Iris-ciliary body
`
`
`
`Travatan BAC~free
`Travatan BAG-free
`Travatan
`
`
`
`—_m 527:! .69
`4.08:1.56
`77
`-____- l
`.
`1
`
`
`
`
`
`--_—E 177th!
`I37i0-9
`* Percentage of the values for Travatan
`
`. _
`
`77
`
`2.6.5 PHARMACOKINETICS TABULATED SUMIVIARY
`
`Not applicable
`
`2.6.6 TOXICOLOGY
`
`2.6.6.1 Overall toxicology summary
`
`Many ocular and systemic toxicity studies were conducted under NDA 21-25 7. Topical
`ocular administration of travoprost in monkeys resulted in an increased palpebral fissure,
`noted clinically as “big eye”, and increased iridal pigmentation In a 6-month rat study
`with repeated daily subcutaneousadministration of travoprost, treatment—related
`mortalities were noted at 100 rig/kg (600 ug/mz). Microscopic bone changes (endosteal
`fibrosis and hyperostosis) were noted at doses > 30 ug/kg (180 ug/mz). These doses were '
`apprdximately lZl-fold above the highest human daily dose (1.48 rig/m2). Therefore,.
`travoprost was generally considered as safe and well tolerated.
`
`Two one-day studies and one three—month ocular toxicity study in NZW rabbits were
`included in this NDA submission. In these studies, BAC-free formulation was compared
`with the marketed Travatan®. Both formulations showed similar safety profiles with a
`very low ocular irritation potential. No biologically relevant toxicity was noted.
`
`2.6.6.2 Single-dose toxicity
`
`TDOC-0003457: One—day topical ocular irritation evaluation of Travatan® BAC-
`free ophthalmic solution in rabbits
`
`

`

`
`
` Reviewer: Zhou Chen PhD. NDA No. 21-994
`
`Key study findings: Travatan®. BAC-free ophthalmic solution showed a low ocular
`irritation potential and elicited minimal to moderate discomfort in the treated eyes.
`Similar findings were also seen in' the marketed drug Travatan®.
`
`7‘ T
`
`Document #: TDOC-0003457
`Protocol #: N—0.4-137
`-
`Study Aim: To determine the ocular irritation potential of Travatan® BAC-free
`ophthalmic solution in NZW rabbits following an exaggerated one—day dosing regimen
`Compound/Vehicle: Travatan® BAC-free ophthalmic solution vehicle (group 1),
`Travatan® BAC-free ophthalmic solution (Lot #: 04-37157—1, Group 2) and. Travatan®
`
`
`(marketed dru, Lot #: 50393F, Grou -
`ll i ll l
`|
`r I l1ll
`
`
`TravzmnBAC-freew _,
`Ingredient (% w/v)
`7 7
`BAC-ree veicle
`
`04-37
`o.. a:
`
`i
`i
`T__—"T" 04—37157—1
`‘ L—6221
`0.004_
`
`
`'ol 0
`l 40 h dro_enated castor oil
`
`‘1
`r
`
`Boric Acid, NF
`orbitol, NF
`ro 1ene_lycol, USP
`inc chloride, USP
`aOH, NF and/or HCl, NF
`Purified H20
`
`
`vet/3r"
`
`
`L,
`
`J
`
`L;
`
`_)
`
`.n‘
`
`«Vi
`
`Dose & Route: Two drops (30 ul each)/eye, right eyes, every 30 min for a total of 10
`applications
`V
`'
`H _
`.
`_.
`;.
`.
`Animals: New Zealand. White rabbits, 4-month old, weighing 3.0—3.4 kg, 3/sex/group
`Study Location: Alcon Laboratory, Inc., 6201 South Freeway, Fort Worth, TX 76134
`Compliance with GLP/QAU: Yes
`.
`Study Initiation: 8/30/2004
`Study Design: Test articles or vehicle was applied to the right eye (two 30 it] drops) of
`each rabbit every 30 min for a total of 10 applications. The left eye served as the
`untreated control. The day of dosing was designated, as Day 1.
`
`Observations and times:
`
`-
`
`Mortality, morbidity, and daily observations: 2x/day
`Biomicroscopic examination: Pretest and Days 1 (one hr after the last dose), 2, 3, and 4
`Ocular comfort examination:-After the ISI and last doses on Day 1
`Body weight: Pretest and Day 4
`
`Results:
`
`Mortality and clinical Observations: No deaths occurred and no remarkable clinical signs
`were noted.
`
`Slit lamp biomicroscopy examination: Conjunctival congestion data are summarized in
`the table below. On Day «1 at one hr after the last dosing, moderate conjunctival
`congestion (score = 2) in the right eye was noted in 1/6 vehicle control rabbits, 2/6 rabbits
`in BAC-free group, and 3/6 rabbits in marketed Travatan® group. In addition, rabbits in
`marketed Travatan® group also showed moderate conjunctival congestion on Day 3 (1/6),
`and minimal conjunctival discharge on Day 3 (1/6). All other ocular parameters evaluated
`
`

`

`
`Reviewer: Zhou ChenLPhD.
`
`NDA No. 21-994
`
`were unremarkable throughout the study It seemed that Travatan® BAC—free treated
`' animals did not show additional biomicroscopical findings beyond the levels1n control
`and Travatan® treated animals.
`
`
`
`Mean Score of Conunctival Congestionin Rabbits
`-— g
`Left eyes
`
`
` _ , 0
`
`
`incidence
`0/3
`0/3
`
`Mean
`0.3
`.
`Incidence
`
`
`
`m-
`1/3
`1/3
`fl
`
`Incidence
`
`
`o 3
`
`Incidence
`2/3
`2/3
`1/3
`0/3
`1/3
`Mean
`.
`0
`O
`1.0
`_
`1
`.
`.
`‘
`’
`Incidence
`2/3
`0/3
`'0/3
`3/3
`[/3
`
`'
`
`Ocular comfort evaluation: The scores were 2.00, 2.33, and 1.66 for vehicle, BAC-free,
`and marketed Travatan® groups, corresponding to minimal discomfort, minimal—
`moderate discomfort, and minimal discomfort, respectively.
`
`Body weights: Normal.
`
`In summary, New Zealand White rabbits were topically treated with vehicle, Travatan®
`BAC-free ophthalmic solution and Travatan® ophthalmic solution 10 times a day for one
`day and observed for 4 additional days. Travatan® BAC-frec ophthalmic solution showed
`a low ocular irritation potential and minimal to moderate discomfort in the treated eye.
`Similar findings were seen in animals treated with vehicle alone and the marketed
`Travatan® ophthalmic solution.
`
`«:5
`
`TDOC—0003351: One-day exaggerated topical ocular irritation evaluation of
`Travatan® BAC—free (travoprost, 0.004%) ophthalmicjformulations (Fle 107670
`and 107074) in New Zealand White rabbits
`
`Key study findings: No significant ocular irritation and toxicity was seen with
`Travatan® BAC—free ophthalmic formulations tested in this study under exaggerated
`dosing conditions.
`
`Document #: TDOC-000335l
`.
`Protocol #: N-05-042
`Study Aim: To determine the acute topical ocular irritation potential of various BAC-free
`ophthalmic vehicles containing travoprost in NZW rabbits following an exaggerated one—
`day dosing regimen
`Compound/Vehicle: Two Travatan® BAC-free ophthalmic formulations and one vehicle
`(see table below). Lot 04-38249-1 (FID 107047) was the same as the proposed clinical
`' formulation.
`'
`
`10
`
`

`

`
`
`Reviewer: Zhou Chen Ph.D. NDA No. 21-994
`
`
`Ingredient (% w/v)
`Vehicle for FID [07670
`Travamno BAC-free
`Travatan" BAG-free
`
`
`
`
`ID #
`~
`108555
`107670
`107047
`
`
`.
`05-40085-1
`05-40084-1
`04-38249—1
`
`
`
`0.004
`
`a, 7 w a 7'
`1....
`0.004
`
` Pol ox 1-40 h dro-_enated castor oil
`_
`
`
`
`
`
`)
`
`
`
`
`‘3‘
`Dose & Route: One drop (30 rib/eye, right eyes, every30min for a total of 10"“
`
`applications (Two drops were given for the first three applications.)
`Animals: New Zealand White rabbits, 4—9 months old, weighing 3.0-4.3 kg, 3/sex/group
`Study Location: Alcon Laboratory, lnc., 6201 South Freeway, Fort Worth, TX 76134
`Compliance with GLP/QAU: Yes
`Study Initiation: 7/16/2005
`Study Design: Drugs or vehicle was applied to the right eye of each rabbit every 30 min
`for a total of 10 applications. The lefi eye served as the untreated control. The day of
`
`dosin_ was desi nated as Da
`1.
`
`
`
`3
`1 untreated control
`
`
`
`
`
`
`2 Vehicle
`' -—14
`
`
`3 FID l07670 formulation
`
`
`4 FID 107047 formulation
`
`
`Observations and times:
`Mortality, morbidity, and daily observations: Twice daily
`Body weights: Weekly
`Ophthalmic biomicroscopic examinations: Pretest, 1 and 24‘hr after the last dose, and on,
`Days 4, 7 and 14
`Necropsy: After at least 14 days of observation. All animals were examined for external
`abnormalities.
`
`Histopathology: Ocular tissues (eyes and adnexa) only
`
`Results:
`
`Clinical observations: No mortality occurred during the study. No toxicologically
`significant clinical signs'were noted. Two Group 3 females and one Group 4 male had red
`(congested) right eyes on Day 1 which were thought to be treatment-related. The sponsor
`indicated exaggerated dosing was expected to-causesome congestiOn in the
`travoprost—treated animals.
`
`Body weights: No abnormal findings in body weights were noted.
`
`Biomicroscopic evaluations: Corneal cloudiness, neovascularization, aqueous flare, light
`reflex abnormalities, and fluorescein staining were not seen in any of the treatment
`groups. Isolated incidences of iritis (one Group 1‘ male, right eye, and one Group 3 male,
`both eyes)’ were observed and were not considered as drug-related. Multiple incidences of
`
`11
`
`

`

`
`
`Reviewer: Zhou Chen PhD. NDA No. 21-994W
`
`conjunctival congestion, swelling, and discharge were noted during the study andare
`described below.
`
`Conjunctival congestion: Minimal conjunctival congestion (score :1) was seen in
`all groups in both eyes during all observation time~points, indicating that the congestion
`might be spontaneous, or due to scratch or other stimulations but not drug—induced. At
`one hr after dosing, moderate conjunctival congestion (score = 2) was seen in the right
`eye in one Group 1 animal, two Group 3 animals, and three Group~4 animals. It seemed
`that animals receiving travoprost had a slightly higher incidence of moderate congestion
`and greater mean scores at one hr after dosing (see table below) when compared to
`controls. Moderate conjunctiva] congestion was also seen in both eyes approximately
`evenly across all control and treatment groups on Days 4, -7 and 14, suggesting that the
`congestion was not drug-related. Marked congestion (score = 3) was only seen in one '
`Group 2 (vehicle Control) male. The sponsor indicated that travoprost was known to
`cause hyperemia clinically and the increased incidence at one hrafter dosing was not an
`unexpected finding.
`‘
`
`Summaryof Conjunctival Congestioflmean score and incidence
`
`
`Right (treated) eyes
`
`
`
`
`rou
`se
`Pretest
`24 hr
`Day 14
`03
`9
`mean
`0
`
`incidence
`1/3
`0/3
`
`
`6‘
`mean
`0.7
`1.7
`
`
`
`
`incidence
`2/3
`3/3
`
`g
`mean
`1.0
`17
`
`
`
`incidence
`3/3
`3/3
`
`- 6‘
`mean
`0.7
`1.0
`
`incidence
`2/3
`2/3
`
`
`mean
`0
`0.7
`
`
`
`incidence
`0/3
`1/3
`6'
`mean
`0.3
`07
`
`incidence
`1/3
`2/3
`
`mean
`0.7
`1.0
`
`
`incidence
`2/3
`3/3
`6‘
`mean
`1 0
`incidence
`3/3
`
`
` l/3
`
` 0 3
`
`Conjunctival swelling: Numerous instances of minimal (score = l) conjunctiva]
`' swelling were observed on Day 14 (see table below). Findings were distributed across all
`treatment and control groups in both eyes. Two instances of moderate (score = 2)
`conjunctival discharge were observed on Day 14 ofthe left eye of one Group 1 male and
`the right eye of one Group 2 female. The distribution of findings did not indicate any
`treatment-related association.
`
`12
`
`

`

`
`Reviewer: Zhou Chen, PhD.
`'
`
`‘
`
`NDA No. 21—994
`
`
`
`Left eyes
`
`
`mean
`incidence
`
`mean
`
`
`incidence
`
`
`incidence
`mean
`
`
`incidence
`
`
`
`
`
`incidence
`
`mean
`incidence
`
`incidence
`
`Conjunctival discharge: A single instance of minimal discharge (score = 1) in the
`left eye of Group 1 male animal was observed on Day 4. Numerous instances of minimal
`conjunctiva] discharge, observed on Day 14, were distributed across all treatment and
`control groups in both eyes. The distribution of findings did not indicate any treatment—
`related association.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`incidence
`mean
`
`incidence
`
`The sponsor indicated that the numerous instances of conjunctival congestion,
`» swelling and discharge on Day 14 were distributed relatively evenly across all treatment
`and control groups and were found in both eyes. The reasons might be that slit-lamp
`evaluations were performed after a weekend in which the cage pans were not changed.
`The urine vapor, which is slightly irritating, might cause the-increase in these findings.
`Also, previous slit-lamp evaluations on Days 4 and 7 did not reveal any ocular adverse
`effects, suggesting the Day 14 findings were unrelated to treatment. The reviewer agrees
`that the Day 14 findings are not treatment-related.
`
`Lens: One Group 4 female animal was identified to have an early‘focal opacity at
`the axial junction of the nucleus and anterior cortex in the left eye. A second female
`
`13
`
`

`

`
`
`
`Reviewer: Zhou Chen PhD.
`.
`
`.
`
`NDA No. 21-994
`
`animal in the same group had a faint ring—shaped opacity on the posterior capsule in both
`eyes.'These findings were not considered treatment-related.
`
`Necropsy: No treatment-related abnormal findings were noted.
`
`Histopathology: No microscopic lesions considered related to administration of the
`vehicle or test article formulations were noted in eyes or ocular adnexa of male or female
`rabbits. The few changes including mononuclear cell infiltration, Harderian gland
`atrophy, eyelid epidermal hyperplasia, retinal fold formation were seen in both eyes of
`control and treated groups with similar incidence and severity, and were all considered
`incidental and unrelated to treatment.
`
`In summary, New Zealand White rabbits were topically treated with vehicle, two
`Travatan® BAC-free ophthalmic formulations 10 times a day for one day and observed
`for 14 days. Conjunctival congestion was seen in all groups but a slightly high incidence
`and greater mean score was noted in drug—treated groups. The sponsor indicated that
`travoprost was known to cause hyperemia clinically and the increased incidence at one hr
`after dosing was not an unexpected finding. Conjunctival congestion, swelling and
`‘
`discharge were also observed in other examination times with similar distribution and
`severity, and were not considered as drug-related. No other toxicologically findings were
`noted. In conclusion, Travatan®~BAC-free ophthalmic formulations-shoWed a low ocular
`irritation potential in the treated eye. No significant ocular toxicity was seen.
`
`2.6.6.3 Repeat-dose toxicity
`
`TDOC-0003456; Three month topical ocular irritation ahd toxicity study of
`Travatan® BAC—free in New Zealand White rabbits
`
`«1:5
`
`Key study findings: Travatan® BAC-free ophthalmic solution exhibited a very low
`ocular irritation potential in this three month rabbit study.
`
`Document #: TDOC—0003456
`Protocol #: N-46-167 .
`Study Aim: To evaluate the ocular irritation and systemic toxicity potential ofTravatan®
`BAC-free ophthalmic solution,-0.004%, following topical ocular administration, three
`times daily, to New Zealand White rabbits for three months
`Compound/Vehicle: Travatan® vehicle, Travatan® BAC-free vehicle, Travatan®, 0.004%,
`Travatan® BAC—free, 0.004%, 0r Travatan® BAC-free vehicle plus 5X ZnClz. Travatan®
`BAC-free, 0.004% is the same as the proposed clinical drug formulation.
`
`' Appears This Way
`On Original
`
`14
`
`

`

`
`Reviewer: Zhou Chen, PhD.
`
`'
`
`NDA'No. 21-994
`
`Ingredient (% w/v)
`Travatan" (marketed product)
`Travatano BAC—free
`Travatana BAC-free vehicle
`plus 5x ZnCIz
`
`j
`92860
`~-
`I
`107047
`.|
`107884
`. 04-38249—103-500565- I 04—38236-1
`
`
`0.004
`0.004
`.
`—
`
`Polyox l 40 h dro_enated castor oil
`
`Boric Acid, NF
`_-
`
`
`
`Dose & Route: Two drops (25 u] each)/eye, right eyes, three times daily x 3 months (91
`days for males and 92 days for females)
`v
`Animals: New Zealand White rabbits, 3—4 months old, weighing 2.9-3.3 kg, 5/sex/group
`Study Location: Alcon Laboratory, Inc., 6201 South Freeway, Fort Worth, TX 76134
`Compliance with GLP/QAU: Yes
`Study Initiation: 12/9/2004
`
`I Grou .
`—
`
`
`
` l Travatan vehicle 5
`
`
`
`2 Travatan BAC—free vehicle
`'
`~
`5
`
`
`3 Travatan (marketed product)
`5
`
`
`4 Travatan BAC-free
`5
`
`5 Travatan BAC-free vehicle_p_lus 5x ZnClz
`
`
`Observations and times:
`
`Daily observations: Twice daily
`Body Weights: Weekly
`Ophthalmic biomicroscopic examinations: Pretest, Weeks 1, 3, 5, 9 and I3
`Pachymetry, IOP and indirect ophthalmoscopic examinations: Pretest and Week 13
`Clinical pathology: Week 13
`Necropsy: All animals
`Histopathology: All animals. See Histopathology Inventory Table
`
`Results:
`
`Clinical observations: No drug-related abnormal findings were noted. Detailed health
`examinations showed pustules or reddened areas in urogenital regions in several vehicle
`treated animals (3 in Group I and 2 in Group 5) and in one Group 3 (Travatan®) animal.
`One male rabbit in Group 5 (Travatan® BAC—free vehicle plus 5X ZnCIz) exhibited a
`swollen eye (OD) on Day 52, which was diagnosed as subpalpebral conjunctiva] edema.‘
`Normal dosing was suspended while the eye was treated with Bion Tears®. Normal
`dosing resumed on Day 55. This ocular finding was resolved by Day 59. One Group 5
`female eXhibited a reddened iris (OS) and was later found to have a granuloma in its left
`iris. None of these findings were considered drug—related.
`
`15
`
`*It!
`
`

`

`
`
`Reviewer: Zhou Chen PhD. NDA No. 21-994 -
`
`
`
`Body weights: Body weight gain data are summarized in the table below. Although body
`weight gain in the drug—treated groups (Groups 3 and 4) was lower than in vehicle-treated
`groups, the final body weights were similar. The differences in body weight gain were
`not considered as toxicologically significant.
`
` 4
`
`
`
`
`
`3.06i 0.1 1
`3.03: 0.08
`3.181 0.04
`3.12: 0.15
`314 i009
`
`
`
`
`_———-——
`-_--m--m__—
`“-__ .
`
`_M .
`Female
`
`
`
`3.123: 0.13
`3.06: 0.05
`Pretreatment
`.
`3_l4+ 0 09
`
`
`
`
`~
`Week l3
`3.521: 0.18
`3.641: 0.18
`3.481 0.11
`
`
`
`
` 100 95.6 96.7 %GroulBWatW13
`
`
`0.50
`Bod weiht _ain
`
`% Group l BW gain
`
`
`
`
`
`Pretreatmen
`
`
`
`
`
`
`
`
`Ophthalmic examinations:
`
`Biomicroscopic examinations: Minimal conjunctival congestion (score = l) was
`seen in all groups in both eyes during all observation time—points with similar incidence.
`‘ Moderate conjunctival congestion (score = 2) was seen in one Groupfll animal (Week 9,
`left eye), one Group 3 animal (Week 13, both eyes), and one Group 4 animal (Week 9,
`right eye with moderate conjunctival discharge). One Group 5 female was found to have
`a granuloma present in the iris stroma in the untreated eye during Week 13. This
`abnormality elicited moderate conjunctival congestion (grade of 2), conjunctival swelling
`(grade of 2), conjunctival discharge (grade of 1),.aqueous flare (grade of 2) and iritis
`(grade of 4). Marked swelling and congestion was observed in the iris as well as a
`shallow peripheral anterior chamber. None of the findings were considered as
`drug-related.
`‘
`
`Indirect ophthalmoscopic examinations: No remarkable indirect ophthalmoscopy
`findings were noted at the Week 13 examination.
`
`Pachymetry: N0 remarkable findings were noted in pachymetric examinations.
`
`IOP: IOP data are summarized in the table below. No toxicologically significant
`.
`findings were noted. The sponsor indicated that at the one month interval, the IOP
`measured in female Group 5 rabbits (Travatan® BAC—free vehicle plus 5X ZnClz) was
`statistically significantly lower in the treated eye (OD, -15.3%) and untreated eye (OS, —
`18.6%) respectively, than was measured in Travatan® vehicle—treated female rabbits.
`However, the IOP values for this group were lower than the other groups before
`treatment. Therefore, this finding is not biolo