CENTER FOR DRUG EVALUATION AND
`
`'
`
`RESEARCH
`
`APPLICA TION NUMBER:
`
`2 1 -9 94
`
`CLINICAL PHARMACOLOGY AND
`
`BIOPHARMACEUTICS REVIEW! S 2
`
`

`

`OFFICE OF CLINICAL PHARMACOLOGY REVIEW
`
`NDA#
`
`21—994
`
`PRODUCT
`
`Travoprost (TRAVATAN® Z/AP/AF; TBD)
`
`FORMULATION
`'
`,
`
`Ophthalmic solution, 0.004%, benzalkonium chloride (BAC) free _
`formulation
`
`SUBMISSION DATE(S)
`
`18NOV2005
`
`SUBMISSION TYPE
`
`505(b)(2) application
`
`SPONSOR
`
`Alcon Research, Ltd.‘
`
`OCPB DIVISION
`
`DCP4
`
`'
`
`0ND DIVISION
`
`DAIOP
`
`REVIEWER
`
`’
`
`Kimberly L. Bergman, PharmD.
`
`TEAM LEADER
`Venkateswar R. Jarugula, PhD.
`
`
`TABLE OF CONTENTS
`
`.
`
`1
`
`i
`
`,.
`
`.
`
`1
`
`1.
`
`EXECUTIVE SUMMARY .................................................................................................................. 1
`
`1.1.
`1.2.
`1.3.
`
`RECOMMENDATION ...................................................................i................................................... 2
`PHASE [V COMMITMENTS ............................................................................................................ 2
`SUMMARY OF IMPORTANT CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS FINDINGS. 2
`
`2. QUESTION BASED REVIEW................................................. 4
`2.1.
`GENERAL A'ITRIBUTES OF THE DRUG ...............-..................................................................V......... 4
`2.2.
`GENERAL BIOPHARMACEUTICS .................................................................................................... 5
`
`3.
`
`LABELING RECOMMENDATIONS ................................................................................................ 9
`
`4. APPENDICES......................................................................................... 10
`
`Value"
`
`1. EXECUTIVE SUMMARY
`
`Travoprost is the isopropyl ester prodrug of a potent and selective FP prostaglandin receptor
`agonist. It is in the pharmacological class of PGFZUL agonists that includes the [OP-lowering
`agents latanoprost and bimatoprost, marketed in the United States as XALATAN® and
`LUMIGAN®, respectively. Prostaglandin analogues are believed to lower intraocular
`pressure by increasing the outflow of aqueous humor via trabecular meshwork and '
`uveoscleral pathways.
`
`TRAVATAN® BAC—free is an ophthalmic solution composed of travoprost (AL—622 l) at a
`concentration Of 0.004%. This is the same active ingredient and at the same concentration as
`in TRAVATAN® (NDA 21-257), which was approved by the FDA in March 2001. Unlike
`
`

`

`’
`TRAVATAN, which contains 0.015% benzalkonium chloride (BAC) as a preservative,
`TRAVATAN BAC-free is preserved in the bottle with a buffered ionic system. TRAVATAN
`BAC—free is proposed to be marketed as an alternate formulation to TRAVATAN.
`
`The proposed dosage and indication for TRAVATAN BAC-free is the same as that approved
`for TRAVATAN: once—daily topical ocular therapy for the reduction of elevated intraocular
`pressure in patients with open-angle glaucoma or ocular hypertension whorare intolerant of
`other intraocular pressure loWering medications or insufficiently responsive (failed to achieve
`target [OP determined after multiple measurements over time) to another intraocular pressure
`lowering medication.
`
`The current submission for TRAVATAN BAC-free is a 505b(2) NDA and is based on the
`previously approved NDA for TRAVATAN, which included two Phase ll pivotal clinicaltrials,
`dose-response studies, an adj unctive-use study, and clinical pharmacology and pharmacokinetic
`studies. The clinical development plan for TRAVATAN® BAC—free ophthalmic solution
`included one Phase [II safety and efficacy study (C-04- l 7) designed to demonstrate therapeutic
`bioequivalence of the BAC—free formulation of travoprost ophthalmic solution, 0.004% to the
`marketed formulation of travoprost ophthalmic solution, 0.004% (TRAVATAN), both dosed
`once—daily in the evening in patients with open—angle glaucoma or ocular hypertension. The
`Sponsor’s request for a waiver from the requirements for submission of in Vivo pharmacokinetic
`bioavailability/ bioequivalence data is acceptable based on the consideration that the differences
`in formulation between TRAVATAN and TRAVATAN BAC—free formulations are not expected
`to influence the limited systemic availability of travoprost, and the therapeutic. bioequivalence
`established in Alcon Study C-04-l 7.
`
`1.1. Recommendation
`
`The Clinical Pharmacology and Biopharmaceutics information provided by the Applicant is
`' acceptable.
`
`1.2. Phase IV Commitments
`
`No phase lV commitments are recommended.
`
`1.3. Summary of Important Clinical Pharmacology and Biopharmaceutics Findings
`
`The active component of TRAVATAN BAC-free, travoprost, is an approved therapeutic
`agent for the reduction 'of elevated intraocular pressure (lOP) in patients with open—angle
`glaucoma or ocular hypertension. The clinical pharmacology, safety, and efficacy of travoprost
`have been established in NDA 21-257 [TRAVATAN (travoprost ophthalmic solution), 0.004%].
`The current NDA for TRAVATAN® BAC-free ophthalmic solution included one Phase Ill safety
`and efficacy study (C-04—l7) designed to demonstrate therapeutic bioequivalence of the
`BAC—free formulation of travoprost ophthalmic solution, 0.004% to the marketed formulation of
`travoprost ophthalmic solution, 0.004% (TRAVATAN), with both dosed once-daily in the
`evening in patients with open-angle glaucoma or ocular hypertension. The concentration of
`travoprost in TRAVATAN BAC-free formulation is the same as that of the previously approved
`and marketed product TRAVATAN. Alterations in formulation were made to TRAVATAN to
`develop a formulation that meets USP preservation criteria and does not contain a conventional
`preservative, specifically BAC.
`I
`'
`
`

`

`The Sponsor has not performed any clinical pharmacology assessments of TRAVATAN BAC-
`free Ophthalmic Solution, as differences between TRAVATAN and TRAVATAN BAC-free
`formulations are not expected to influence the systemic availability of travoprost. During
`development of TRAVATAN, the Sponsor conducted 4 Phase I trials to fully characterize the
`steady—state plasma pharmacokinetics of travoprost (AL-6221) and AL-S 848 (the active acid
`metabolite of travoprost) in healthy Caucasian (C-99-08) and male Japanese (C-OO-IS) subjects,
`as well as in patients with renal (C-99-97) or hepatic (C—00—05) impairment.
`In addition, the
`Sponsor conducted a pharmacokinetic and drug-drug interaction trial with TRAVATAN,
`travoprost 0.004%/timolol 0.5% ophthalmic solution and timolol 0.5% ophthalmic solution
`(C-02-35). For additional information on the clinical pharmacology of TRAVATAN and detailed
`assessments of these Phase 1 studies, please refer to the Clinical Pharmacology and
`Biopharmaceutics reviews under NDA 21-257 (original submissions dated'07JUL2000,
`26DEC2000, and 28JUN2002) and NDA 21—699 (original submission dated 13NOV2003).
`
`*
`
`From a Clinical Pharmacology perspective, the requirements for submission of in vivo
`pharmacokinetic bioavailability/bioequivalence data can be waived based on:
`1) consideration that the alterations between TRA VATAN and TRAVATAN BAC-free
`
`formulations are minor and not expected to significantly influence the limited systemic
`exposure of travoprost that was observed with the original approved formulation, and
`2) therapeutic bioequivalence established in the safety and efficacy study of TRAVATAN
`'BAC—free Ophthalmic Solution versus TRAVATAN Ophthalmic Solution (Alcon Study
`C-04-l7).
`
`Appears This Way
`On Original
`
`4.39%“
`
`

`

`2. QUESTION BASED REVIEW
`
`2.1. General'Attributes of the Drug
`
`Since this submission is a 505b(2) NDA with changes in preservative to the approved
`formulation, only relevant questions from the QC? question-based review (QBR) format are
`addressed below.
`
`2.1.1. What are the highlights ofthe chemistry and physical-chemical properties ofthe drug
`substance and theformulation ofthe drug product?
`
`Travoprost, the active ingredient in TRAVATAN® BAC-free, has been previously approved in
`Alcon’s NDA 21-257 for TRAVATAN® (travoprost ophthalmic solution) 0.004%. The
`chemical structure and physical-chemical properties of travoprost are shown below:
`
`Structural Formula: C26H35F305
`
`Chemical Structure:
`
`
`
`..a‘s*
`
`MW”
`
`Chemical Names:
`
`[lR-[1u(Z),ZB(lE,3R*),3(1,5a]]—7-[3,5-Dihydroxy-2—[3—hydroxy—4—[3-(trifluoromethyl)
`1.
`phenoxy]— l -butenyl]cyclopentyl]—5 —heptenoic acid, l—methylethylester
`
`2. (Z)-7-[(lR,2R,3R,SS)-3,5-Dihydroxy-2-[(1E;3 R)—3—hydroxy—4-[(a,a,a-trifluoro-m-
`isopropyltolyl)oxy]— l -butenyl]cyclopentyl]-5-heptenoate
`
`Relative Molecular Mass: 500.55
`
`The physical and chemical properties of travoprost are described in NDA 21—257 for
`TRAVATAN [Volume 2; Section 4.A.l (Drug Substance)].
`
`2.1.2. What is the proposed mechanism ofdrug action and therapeutic indication?
`
`Travoprost is the isopropyl ester prodrug of a potent and selective FP prostaglandin receptor
`agonist.
`It is in the pharmacological class of PGFZu agonists that includes the [OP-lowering
`agents latanoprost and bimatoprost, marketed in the UnitedStates as XALATAN® and ’
`LUMIGAN®, respectively. Prostaglandin analogues are believed to lower intraocular
`pressure by increasing the outflow ofaqueous humor via trabecular meshwork and
`uveoscleral pathways.
`
`

`

`The proposed indication for TRAVATAN BAC—free is the same as that approved
`for TRAVATAN: once-daily topical ocular therapy for the reduction of elevated intraocular
`pressure in patients with open-angle glaucoma or ocular hypertension who are intolerant of
`other intraocular pressure lowering medications or insufficiently responsive (failed to achieve
`target IOP determined after multiple measurements over time) to another intraocular pressure
`lowering medication.
`
`2.1.3. What is the proposed dosage and route ofadministration?
`
`The proposed dosage for TRAVATAN BAC—free is the same as that approved for TRAVATAN:
`the recommended dosage is one drop in the affected eye(s) once-daily in the evening. The dosage
`of TRAVATAN® Z ophthalmic solution should not exceed once-daily since it has been shown
`that more frequent administration of travoprost may decrease the intraocular pressure lowering
`effect. Reduction of intraocular pressure starts approximately 2 hours after administration of
`travoprost. The maximum effect is observed 12 hours after administration and is maintained
`throughout the day.
`
`2.2. General Biopharmaceutics
`
`TRAVATAN BAC—free (travoprost ophthalmic solution) 0.004% (i.e., TRAVATAN BAC-free)
`isa sterile, preserved aqueousSo‘lution formulated for topical ophthalmic application.
`The formulation contains 0.004% travoprost, which is the same concentration approved in
`TRAVATAN (travoprost ophthalmic solution) 0.004% (NDA ,2_lj-257). TRAVATAN BAC—free
`is formulated such that it does not contain the quaternary ammonium compound benzalkonium
`chloride and preservative aid disodium edetate that are present in TRAVATAN.
`
`The quantitative composition of the proposed product is shown in the following table
`(Table 2.2-1):
`f
`
`Table 2.2—1
`
`Composition of TRAVATAN BAC-free Ophthalmic Solution
`
`
`Travo rost (AL06221)
`
`.
`
`Non-com-endial
`IPE
`_
`Altemgzngggnhmom'
`
`=
`
`Active
`
`‘3
`
`.
`
`
`
`
`Co mpendial
`
`
`Designation
`Component
`Purpose
`
`
`
`Polyoxyl 40 Hydrogenated
`Castor on (HCO-40)
`
`
`
`
`Propylene Glycol
`Sorbitol
`
`
`Zinc Chloride
`
`
`
`Sodium Hydroxide and/or
`Hydrochloric Acid
`Purified Water
`
`-
`>
`3 Adjust to I based on purity of the raw material.
`
`b The combination'of 'm _ provide the w Jaoacitv. Preservation of the drug
`product in the container is achieved by the _ www-vwwwfwww WWM“‘
`~—-—
`
`i
`i
`,
`
`' USP
`{l
`
`
`
`Kl
`
`\\
`
`

`

`2.2.]. What data support or do not support a waiver ofin vivo BE data?
`
`The Sponsor requested a waiver from the requirements for submission of in vivo pharmacokinetic
`bioavailability/bioequivalence data. This request is supported by the following rationale:
`
`l.
`
`.The drug product is an ophthalmic solution applied topically to the eye and is intended
`only for local therapeutic effect. The drug product contains the same active ingredient, '
`travoprost, in the same concentration, 0.004% that is the basis of an approved full New
`Drug Application, 21-257 [TRAVATAN (travoprost ophthalmic solution) 0.004%].
`Differences between TRAVATAN and TRAVATAN BAC-free formulations are not
`
`expected to influence the systemic availability of travoprost. -
`
`2.- Bioequivalence was established in an vivo therapeutic bioequivalence study of
`TRAVATAN ‘BAC-free Ophthalmic SOlution versus TRAVATAN (Alcon study C—04-
`17) designed to compare the {OP-lowering efficacy of TRAVATAN BAC-free
`Ophthalmic Solution (dosed once-daily) to TRAVATAN (dosed once-daily) using an
`accepted criterion of clinical relevance, 1.5 mmHg.
`
`2.2.1L1. Comparative Composition in Support ofa Waiver ofIn Vivo BE Data
`
`The comparativecomposition of the proposed product TRAVATAN BAC-free and the
`, previously approved formulation TRAVATAN is shown in the following table (Table 221—1):
`
`Table 2.2.1.14
`
`Comparative Composition of TRAVATAN BAC:free and TRAVATAN
`Ophthalmic Solutions (W/V%)
`
`
`'
`
`.
`
`TRAVATAN®
`
`Y”
`
`_
`
`”'7
`
`0.904
`
`.1
`
`
`ITRAVATAN®
`
`BAC-free
`Component
`
`0.004
`
`
`' Travoprost (AL06221)
`Polyoxyl 4O Hydrogenated
`Castor Oil (HCO-40)
`Tromethamine
`
`
`Boric Acid
`
`
`
`
`
`
`Sodium Hydroxide and/or
`Hydrochloric Acid
`
`Purified Water
`
`.
`
`1
`
`
`
`
`*
`
`
`
`
` Lt...)
`
`The Concentration of travoprost (the active ingredient)in TRAVATAN BAC-free formulation15
`the same as that of the previously approved and marketed product TRAVATAN Alterations1n
`formulation were made to TRAVATAN to develop a formulation that meets USP preservation
`criteria and does not contain a conventional preservative specifically BAC.
`In addition, the
`formulation was modified to remove EDTA and mannitol, and to include propylene glycol zinc
`chloride and sorbitol Also WWWMMWMM.mma-‘MWWWWWW
`Similar to TRAVATAN, this formulation contains #7 polyoxyl 40 hydrogenated castor oil for
`
`W
`
`\\
`
`

`

`
`
`. ,gW-RWWxvi“): any‘32;11«33‘WQWvabwmvééxéfibfshflfiy-fla
`
`Although differences between the composition of TRAVATAN BAC—free and TRAVATAN may
`alter the ocular penetration of travoprost, the differences in excipients are not expected to
`influence the limited systemic availability of travoprost that was observed with the original
`approved forrnulation. This assessment is further supported by the safety and efficaCy findings
`from Alcon Study C-O4—17.
`’
`
`2.2.1.2. In Vivo Therapeutic Bioequivalence Study in Support ofa Waiver ofIn Vivo
`BE Data
`
`The Sponsor has conducted an in vivo therapeutic bioequivalence study of TRAVATAN BAC-
`free Ophthalmic Solution versus TRAVATAN (Alcon Study C—04-17) to compare the [OP-
`. lowering efficacy of the two formulations (dosed once-daily in the evening) This study was
`designed as an equivalence trial with statistical power to demonstrate equivalence1n IOP
`loWering efficacy between TRAVATAN BAC—free and TRAVATAN using an accepted criterion
`of clinical relevance, 1.5 mmHg. This multicenter, randomized, double-masked, parallel group,
`active-controlled study enrolled 690 patients with open-angle glaUCOma or ocular hypertension,
`age 18 years or older, which included a total of 344 patients exposed to once daily TRAVATAN
`BAC- free for a duration of 3 months. Efficacy and safety data were collected at Week 2, Week 6,
`and Month 3 [OP was assessed at 8 AM, 10 AM, and 4 PM at all study visitsAll enrolled
`patients were followed for up to three months.
`'
`.,
`.
`.
`
`Efficacy results from Alcon Study C—O4-l7 indicated that the 95% confidence limits for
`differences in mean [OP were <1.5 mmHg, demonstrating that TRAVATAN BAC-free is
`equivalent to TRAVATAN in [OP—lowering efficacy. Differences in mean IOP between
`TRAVATAN BAC—free and TRAVATAN ranged from -0.3 to +012 mmHg in both the per
`protocol and intent-to-treat analyses. There were no statistically significant differences in mean
`IOP at baseline between treatment groups. Mean LOP reductions in the per protocol and intent—t0-
`treat analyses ranged from 7.3 to 8.5 mmHg for TRAVATAN BAC-free and from 7.4 to
`8.4 mmHg for TRAVATAN. The maximum mean IOP reductions for TRAVATAN BAC—free
`(8.5 mmHg) and TRAVATAN (8.4 mmHg) correspond to approximate 31% [OP reductions in
`each group. Confidence limits for the treatment group differences were within :|:0.8 mmHg at
`9 of 9 study visits and times in both the per protocol and intent-to-treat analyses.
`
`Safety data from Alcon Study C-04-l7 demonstrated a similar safety profile comparing therapy
`with TRAVATAN BAC-free t0 TRAVATAN based upon a review of adverse events and an
`assessment of ocular safety parameters.
`In both the TRAVATAN BAC-free and the
`TRAVATAN treatment groups, the most frequently reported, treatment—related adverse event was
`ocular hyperemia, occurring at incidences of 6. 1% and 9.0%,‘respectively. A comparison of the
`adverse events observed with TRAVATAN BAC-free to those observed with TRAVATAN
`
`revealed no unexpected types of events.
`
`Overall, efficacy and safety findings from Alcon Study C-04- 17 indicate that the two
`formulations are therapeutically bioequivalent. For a detailed assessment of safety and efficacy
`results from Study C-04- 17, please refer to the Clinical review of the NDA.
`
`In summary, from a Clinical Pharmacology perspective, a waiver from the requirements for
`submission of in vivo pharrnacokinetic bioavailability/bioequivalence data is acceptable based on:
`1) consideration that the alterations in formulation between TRAVATAN and TRAVATAN
`
`t‘t
`
`\\
`
`

`

`. BAC—free formulations are not expected to influence the limited systemic availability of
`travoprost, and 2) therapeutic bioequivalence established in the safety and efficacy study of
`TRAVATAN BAC-free Ophthalmic Solution versus TRAVATAN Ophthalmic Solution
`(Alcon Study C—04—l7).
`
`Appears This. Way
`On Original
`
`ll
`
`‘\
`
`

`

`3. LABELING RECOMMENDATIONS
`
`The following changes reflect Clinical Pharmacology Reviewer recommendations to the proposed
`labeling (recommendations appear in bold italicized underlined age).
`
`CLINICAL PHARMACOLOGY
`
`Pharmacokinetics/Pharmacodynamics
`
`_
`Absorption:
`Travoprost is absorbed through the cornea and is hydrolyzed to the active free acid. Data
`
`from four multiple dose .pharmacokinetic studies 'WWW
`
`‘
`,.
`‘ _(totaling 107 subjects) have shown that plasma concentrations of the free
`acid are below 0.01 ng/ml (the quantitation limit of the assay) in two-thirds of the
`subjects. In those individuals with quantifiable plasma concentrations (N=3 8), the mean
`plasma Cmax was 0.018 i 007 ng/ml (ranged 0.01 to 0.052 ng/mL) and was reached within
`30 minutes. From these studies, travoprost is estimated to have a plasma half-life of 45
`minutes. There was no difference in plasma concentrations between Days 1 and 7,
`indicating ”MWNWWW”:W” that there was no significant accumulation.
`
`Appears This WOV
`oh Original
`
`

`

`4. APPENDICES
`
`For additional information on theclinical pharmacology of TRAVATAN, please refer to the
`Clinical Pharmacology and Biopharmaceutics reviews of submissions under NDA 21-257
`(original Submissions dated 07JUL2000, 26DEC2000, and ZSJUNZOOZ) and NBA 21-699
`(original submission dated l3NOV2003).
`
`Appears This Wdy
`On Original
`
`H
`
`.V‘
`
`10
`
`

`

`This is a representation of an electronic record that was signed electronically and
`this page is the manifestationof the electronic signature.
`
`Kimberly Bergman
`6/28/2006 02:14:11 PM
`BIOPHARMACEUTICS
`
`Venkateswar Jarugula
`6/28/2006 03:08:28 PM
`BIOPHARMACEUTICS
`
`Appears This Way \‘
`On Original
`
`