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`
`J.5 l,
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`
`2
`03
`1
`
`ACADEMY•OF
`
`OPHTHALMOLOGY
`
`Volume 103 Number 1
`January 1996
`
`ISSN 0161-6420
`
`Oohthalmology
`BML 1st & 2nd Floors
`UC San Diego
`Received on: 02- 13-96
`
`Micro Labs Exhibit 1040
`Micro Labs v. Santen Pharm. and Asahi Glass
`IPR2017-01434
`
`

`

`Opht~~ology
`
`American Academy of Ophthalmology
`
`The objecti11e of the American Academy of Ophthalmology in publishing its journal, Ophthalmology,
`is to pro11ide opportunities for the free exchange of ideas and information. The Academy accepts
`no responsibility for any statements published in Ophthalmology. These statements are to be
`attributed solely to their authors and are not, by the fact of their publication in Ophthalmology
`or ownership of copyright, necessarily those of the Academy or Ophthalmology or
`indicati11e of Academy 11iews or policy or editorial concurrence.
`
`Editor-in-Chief
`Don Minckler*
`Los Angeles, CA
`
`Associate Editor
`Rohit Varma*
`Los Angeles, CA
`
`Douglas R. Anderson
`Miami, FL
`George B. Bartley
`Rochester, MN
`RoyW. Beck
`Tampa, FL
`Mark S. Blumenkranz
`Menlo Park, CA
`*James D. Brandt
`Sacramento, CA
`J. Brooks Crawford
`San Francisco, CA
`Susan H. Day
`San Francisco, CA
`
`Editorial Board
`
`Robert C. Drews
`Clayton, MO
`*Robert Folberg
`Iowa City, IA
`William R. Freeman
`La Jolla, CA
`Brenda L. Gallie
`Toronto, Canada
`Peter Hamilton
`London, England
`Glenn J. Jaffe
`Durham, NC
`
`*Robert E. Kalina
`Seattle, WA
`Yoshiaki Kitazawa
`Gifu, Japan
`Ronald Klein
`Madison, WI
`Richard Alan Lewis
`Houston, TX
`Maureen G. Maguire
`Philadelphia, PA
`*Joel S. Mindel
`New York, NY
`
`Editorial Staff
`
`Ann Dawson
`Karyn Crislip
`Sherril Nixon
`Sue Gertson
`
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`Production Editor
`Editorial Assistant
`Reference Librarian
`
`• Member, Editorial Advisory Committee
`
`David C. Musch
`Ann Arbor, MI
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`Nashville, TN
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`San Francisco, CA
`Roger F. Steinert
`Boston, MA
`*Alan Sugar
`Ann Arbor, MI
`Andrea C. Tongue
`Lake Oswego, OR
`Thomas A. W C'!ingeist
`Iowa City, IA
`
`Ophthalmology (ISSN 0161 -6420) is published 13 times a year (monthly except September, in which two issues are published) for the American Academy of Ophthalmology,
`Inc., by Lippincott-Raven Publishers, 12107 Insurance Way, Hagerstown, MD 21740. Business offices are located at 227 East Washington Square, Philadelphia, PA 19106.
`© Copyright 1996 by the American Academy of Ophthalmology, Inc. Printed in the U .S.A. Second-class postage paid at Hagerstown, Maryland, and at additional mailing
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`POSTMASTER: Send address changes to Ophthalmology, P.O . Box 1550, Hagerstown, MD 21741.
`@J Text printed on acid-free paper.
`
`~tion
`
`15
`
`,armaceutlcala
`
`irporation
`·, NY 14623, U.S.A.
`
`Micro Labs Exhibit 1040-2
`
`

`

`Comparison of Latanoprost and
`Timolol in Patients with Ocular
`Hypertension and Glaucoma
`A Six-month, Masked, Multicenter Trial in
`the United States
`
`Carl B. Camras, MD, the United States Latanoprost Study Group*
`
`Purpose: Latanoprost, a new prostaglandin analogue, was compared with timolol
`for ocular hypotensive efficacy and side effects.
`Methods:
`In a multicenter, randomized, double-masked, parallel group study, 268
`patients with ocular hypertension or early primary open-angle glaucoma received either
`0.005% latanoprost once daily or 0.5% timolol twice daily for 6 months. All except ten
`patients from each group successfully completed the study.
`lntraocular pressure (IOP) was significantly (P < 0.001) reduced and main(cid:173)
`Results:
`tained by both medications without evidence of a long-term drift over 6 months. Com(cid:173)
`paring 6-month with baseline diurnal IOP values, the IOP reduction (mean ± standard
`deviation) achieved with latanoprost (-6.7 ± 3.4 mmHg) was significantly (P < 0.001)
`greater than that produced with timolol (-4.9 ± 2.9 mmHg). Four patients treated with
`timolol and none treated with latanoprost were withdrawn from the study because of
`inadequate IOP control. Pulse rate was significantly reduced with timolol, but not with
`latanoprost. Slightly more conjunctiva! hyperemia appeared in latanoprost-treated com(cid:173)
`pared with timolol-treated eyes. Fewer subjective side effects occurred in latanoprost(cid:173)
`treated eyes. Both eyes of a patient with a characteristic, concentric iris heterochromia
`(darker centrally) at baseline showed a definite, photographically documented increase
`in pigmentation during latanoprost treatment, making the irides uniformly darker. Three
`additional patients treated with latanoprost were suspects for this color change. Oth(cid:173)
`erwise, no significant difference between treatment groups occurred in visual acuity,
`slit-lamp examination, blood pressure, and laboratory values.
`Conclusion: Latanoprost has the potential for becoming a new first-line treatment
`for glaucoma Ophthalmology 1996; 103: 138-147
`
`phen)
`the gr,
`and si
`analo,
`less th
`at the
`ful in
`tant tc
`numt
`penoc
`onists
`poten
`,8-blO<
`ical tt
`Th
`ficacy
`13,14
`-1-iso
`timol,
`ocula1
`
`Pati• -
`
`Patie
`
`Patie1
`States
`patier
`press1
`single
`exam1
`for th
`remai
`ment ·
`eye;(:
`hyper
`persio
`IOP,
`drugt
`field I
`1ft
`their 1
`befon
`onists
`cholir
`Pa1
`any o
`age;c
`feedin
`glaucc
`speci6
`would
`narro,
`intrac
`out fr
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`natio1
`tact le
`other
`
`I .
`
`\
`
`Originally received: October 27, 1994.
`Revision accepted: August 31 , 1995.
`From the Department of Ophthalmology, University of Nebraska Medical
`Center, Omaha.
`* Members of the United States Latanoprost Study Group are listed in
`the Appendix at the end of this article.
`Presented in part at the Glaucoma Society of the International Congress
`of Ophthalmology in Quebec City, Canada, June 1994, and as a poster
`at the American Academy of Ophthalmology Annual Meeting, San
`Francisco, November 1994.
`Also submitted for publication, in part, in Glaucoma Update V, Kriegl(cid:173)
`stein GK, ed, Springer-Verlag Berlin Heidelberg, which has limited dis(cid:173)
`tribution.
`
`138
`
`Several prostaglandin (PG) prodrugs and analogues are
`potent, effective, and well-tolerated ocular hypotensive
`agents in patients with ocular hypertension or glaucoma.1·2
`23 the 17-
`Of these agents evaluated in clinical trials,3-
`
`,
`
`Supported by a grant from Pharmacia Pharmaceuticals, Uppsala, Sweden.
`Dr. Camras is a consultant to Pharmacia Ophthalmics, Uppsala, Sweden,
`and to Alcon Laboratories, Fort Worth, Texas. None of the authors has
`a proprietary interest in the development or marketing of any drug used
`in this study or in any competing drug.
`Reprint requests to Carl B. Camras, MD. Department of Ophthalmology,
`University of Nebraska Medical Center, 600 South 42nd St, Omaha, NE
`68198-5540.
`
`Micro Labs Exhibit 1040-3
`
`

`

`Camras · Latanoprost and Timolol with Ocular H ypertension and Glaucoma
`
`phenyl-substituted PGF20 analogues apparently provide
`the greatest separation between ocular hypotensive efficacy
`21
`24
`and side effects.8•11 •12•15-
`- 26 Previous studies with these
`·
`analogues have followed only small groups of patients for
`less than 3 months (Alm et al, unpublished data; presented
`at the 199 3 AR VO Annual Meeting). However, to be use(cid:173)
`ful in treating chronic open-angle glaucoma, it is impor(cid:173)
`tant to evaluate a drug for efficacy and side effects in large
`numbers of patients undergoing treatment for extended
`periods of time. Because nonselective ,8-adrenergic antag(cid:173)
`onists are currently the first-line treatment for glaucoma,
`potentially new therapeutic agents may be compared with
`,8-blockers to establish their relative usefulness in the clin(cid:173)
`ical therapy of glaucoma.
`This multicenter, randomized study compares the ef(cid:173)
`ficacy and side effects of 0.005% latanoprost (PhXA4 l;
`13,14 - dihydro - 17 - phenyl - 18,19,20 - trinor - PGF20
`-1-isopropyl ester) applied topically once daily with 0.5%
`timolol given twice daily for 6 months to patients with
`ocular hypertension or glaucoma.
`
`Patients and Methods
`
`Patients
`Patients were recruited from 17 centers in the United
`States. To be eligible for the study, at least one eye of each
`patient had to meet the following criteria: ( 1) intraocular
`pressure (IOP) of at least 22 mmHg with no more than a
`single ocular hypotensive medication during the screening
`examination; (2) if only one eye of a patient was eligible
`for the study, the expectation that the other eye would
`remain controlled either without treatment or with treat(cid:173)
`ment with the same experimental agent used in the eligible
`eye; (3) diagnosis of primary open-angle glaucoma, ocular
`hypertension, exfoliation syndrome, or pigmentary dis(cid:173)
`persion syndrome; (4) expectation by the investigator that
`IOP would remain adequately controlled with a single
`drug treatment for 6 months without optic nerve or visual
`field progression.
`If treated for their elevated IOP, patients discontinued
`their medication for a minimum of the following intervals
`before the baseline day: 3 weeks for ,8-adrenergic antag(cid:173)
`onists, 2 weeks for adrenergic agonists, and 5 days for
`cholinergic agonists or carbonic anhydrase inhibitors.
`Patients were ineligible for inclusion into the study for
`any of the following reasons: younger than 40 years of
`age; currently pregnant, considering pregnancy, or breast
`feeding; use of any ocular medications other than for
`glaucoma; diagnosis of any glaucoma type other than
`specified in the inclusion criteria; advanced glaucoma that
`would be at risk for progression during the washout period;
`narrow angles or presence of peripheral anterior synechiae;
`intraocular surgery or argon laser trabeculoplasty carried
`out fewer than 6 months before the study; corneal ab(cid:173)
`normalities or other problems preventing reliable appla(cid:173)
`nation tonometry; inability to temporarily suspend con(cid:173)
`tact lens use for the duration of the study; active eye disease
`other than ocular hypertension or primary open-angle
`
`glaucoma; ocular inflammation less than 3 months before
`the study; known allergy or contraindication to any med(cid:173)
`ications used in the study (specifically, contraindications
`to .8-blockers, including congestive heart failure, sinus
`bradycardia, second- or third-degree atrioventricular
`block, chronic obstructive pulmonary disease, bronchial
`asthma, etc.); if treated orally with medications known to
`affect IOP, the expectation that the type or dosage of these
`drugs would not change during the course of the study;
`any unstable medical condition; history of noncompliance
`or unreliability; or inability to adhere to the protocol de(cid:173)
`sign.
`
`Protocol
`
`After obtaining appropriate informed consent and ap(cid:173)
`proval by the Institutional Review Board at each center,
`a medical history was taken from each subject, including
`a list of all systemic medications each was receiving. A
`complete ophthalmologic history and examination was
`performed on each patient within 4 weeks of the onset of
`the study (Table 1).
`The protocol used during the 6-month study is de(cid:173)
`scribed in Table 1. On the baseline day, all of the param(cid:173)
`eters indicated in Table 1 were assessed. Patients were
`assigned to treatment by computer-generated randomiza(cid:173)
`tion, stratified for each center and performed in blocks
`within each center. Neither the examiners nor the subjects
`were informed of the identity of the drop received during
`the course of the study.
`Beginning in the evening of the baseline day, one drop
`(approximately 35 µI} of either 0.005% latanoprost or 0.5%
`timolol was applied topically to one or both eyes (all eli(cid:173)
`gible eyes) of each of 268 patients. Each patient received
`two bottles, one carefully labeled for use each morning at
`8:00 AM, and the other for the evening at 8:00 PM. The
`timolol-assigned group of patients received timolol for
`both doses each day. The latanoprost-assigned group of
`patients received active latanoprost at 8:00 PM and the
`vehicle (0.02% benzalkonium chloride, 0.5% monosodium
`phosphate monohydrate, 0.6% disodium hydrogen phos(cid:173)
`phate dihydrate, and 0.4% sodium chloride) at 8:00 AM
`each day. Treatment was continued for 6 months. At 0.5,
`1.5, 3, 4.5, and 6 months, the parameters specified in
`Table 1 were recorded. Patients were told not to take their
`study medications on the morning of their return visits.
`After their 8:00 AM examination, their study drops were
`administered by the study coordinator or by the patient.
`The treatment code was not broken by the manufacturer
`until the last patient completed the study and until all
`case report forms were completed and reviewed for ac(cid:173)
`curacy.
`Adverse events were monitored carefully throughout
`the study. An adverse event was defined as any undesirable
`event occurring in a subject, regardless if it were considered
`related to the investigational drug. A serious adverse event
`was defined as potentially fatal, life threatening, sight
`threatening, permanently disabling, requiring hospital(cid:173)
`ization, cancer, or a drug overdose.
`
`139
`
`are
`;ive
`1. 1.2
`17-
`
`den.
`den,
`. has
`1sed
`
`ogy,
`NE
`
`Micro Labs Exhibit 1040-4
`
`

`

`Ophthalmology Volume 103, Number 1, January 1996
`
`Table 1. Timing of Evaluation
`
`Baseline
`12 Noon 4 PM
`
`8AM
`
`2 Wks
`
`1.5 Mos
`
`3 Mos
`
`4 .5Mos
`
`8AM
`
`8AM
`
`8AM
`
`8AM
`
`8AM
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Within
`4Wks
`of
`Baseline
`X
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`Evaluation
`
`Visual fields*
`Subjective side
`effectst
`Conjunctiva!
`hyperemiaf
`Slit-lamp
`biomicroscopy§
`lntraocular
`pressure II
`Blood pressure
`and pulse rate
`(resting)
`Color
`photography of
`iris
`Blood and urine
`analysis**
`
`6Mos
`12 Noon 4 PM
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`X
`
`* Two visual fields (Humphrey 24-2 or 30-2, or Octopus G-1) required within 6 months before baseline day, at least one of which was done within 4
`weeks of baseline.
`t Blurred vision, photophobia, itching, burning, stinging, tearing, dryness, foreign body sensation, eye pain, and eyelid pain or discomfort.
`t Based on a relative scale of 0, 0.5, 1.0, 1.5, 2.0, 2.5, and 3.0 by comparing with standard photographs showing no (0), mild (1), moderate (2), and
`severe (3) hyperemia.
`§ Undilated and dilated slit-lamp biomicroscopic examination of the cornea, anterior chamber, iris, and lens.
`II Goldmann applanation tonometer taking three replicate measurements for each eye using the same calibrated tonometer at each visit.
`,r Complete blood count, differential, platelet count, cholesterol (total, HDL, and LDL), triglycerides, total protein, glucose, creatinine, urea nitrogen,
`bilirubin, alkaline phosphatase, SGOT, SGPT, sodium, potassium, calcium, and chloride.
`** Including evaluation for albumin and sugar.
`
`Demographics and Withdrawals
`
`Of the 268 patients initially enrolled, 128 were assigned
`to the latanoprost group and 140 to the timolol group.
`No significant difference in age, sex, race, family history
`of glaucoma, number of eyes treated per patient, iris color,
`diagnosis or previous medical therapy existed between
`the two groups of patients (Tables 2 and 3). Ten patients
`from each group dropped out of the study for the reasons
`indicated in Table 4. Four patients receiving timolol and
`none receiving latanoprost were withdrawn from the study
`because of inadequate IOP control (Table 4).
`
`Data Analysis
`
`A two-tailed, paired or unpaired Student's t test was used
`as appropriate for statistical evaluation of differences between
`treatment and baseline values or between the latanoprost
`and timolol groups. Differences in diurnal IOP values be(cid:173)
`tween the latanoprost and timolol groups were determined
`using analysis of covariance with treatment groups and cen(cid:173)
`ters as factors and baseline I0Ps as covariants. If both eyes
`of a patient were treated, a mean value of the two eyes was
`
`used for analysis. Protocol violations prevented inclusion of
`at least one IOP measurement from each of 24 patients
`treated with latanoprost and 26 treated with timolol. Overall,
`11 patients had one measurement excluded, 28 had 2 ex(cid:173)
`cluded, 5 had 3 excluded, I had all except baseline mea(cid:173)
`surements excluded (instilled study medication before the
`8:00 AM IOP measurement on each visit), and 5 had all
`excluded (because of insufficient washout of previous fl(cid:173)
`blocker therapy). Thirty of these patients had the 12:00 noon
`and 4:00 PM measurements on their 6-month visit excluded
`because of failure to receive the 8:00 AM dose of the study
`medication on that day. When analyzed by including, rather
`than excluding, the I0Ps during protocol violations, the sig(cid:173)
`nificance of the findings did not change.
`
`Results
`
`lntraocular Pressure
`
`Compared with .baseline measurements, both latanoprost
`and timolol caused a significant (P < 0.00 I) reduction of
`IOP throughout the duration of therapy (Figs I and 2).
`
`140
`
`Tal
`
`Age (
`Mt
`Ra
`Sex
`M
`F
`Race
`WJ
`Bia
`Hi:
`As
`Famil
`
`SD =
`*Yalu
`
`Fron
`each
`cant)
`pare<
`meai
`duce
`by 4.
`base)
`tors i
`timo
`hype
`thera
`
`Co~
`In gi
`sligh1
`mole
`a rel:
`grade
`(Tab
`
`Iris t
`
`A de
`of I c
`of th
`three
`grou1
`these
`base!
`ter h
`stron
`and :
`centr
`riphe
`four
`
`Micro Labs Exhibit 1040-5
`
`

`

`Camras · Latanoprost and Timolol with Ocular Hypertension and Glaucoma
`
`Table 2. Demographic Characteristics of Patients*
`
`Characteristics
`
`Age (yrs)
`Mean± SD
`Range
`Sex
`M
`F
`Race
`White
`Black
`Hispanic
`Asian
`Family history of glaucoma or
`ocular hypertension
`
`Timolol
`(n = 140)
`
`Latanoprost
`(n = 128)
`
`63 ± 11
`33-90
`
`56 (40)
`84 (60)
`
`91 (65)
`38 (27)
`10 (7)
`1 (1)
`52 (37)
`
`61 ± 12
`30-89
`
`58 (45)
`70 (55)
`
`94 (73)
`27 (21)
`6 (5)
`1 (1)
`43 (34)
`
`SD = standard deviation .
`• Values in parentheses are percentages.
`
`From 2 weeks to 6 months, the IOP remained stable in
`each treatment group (Fig I). Latanoprost was a signifi(cid:173)
`cantly (P < 0.00 I) more effective hypotensive agent com(cid:173)
`pared with timolol (Figs I and 2). At 6 months, diurnal
`measurements (mean ± standard error) of IOP were re(cid:173)
`duced by 6.7 ± 3.4 mmHg (27%) with latanoprost and
`by 4.9 ± 2.9 mmHg (20%) with timolol compared with
`baseline measurements (Fig 2). None of the following fac(cid:173)
`tors significantly altered the effect of either latanoprost or
`timolol on IOP: sex, age, race, iris color, diagnosis (ocular
`hypertension versus glaucoma), or previous use of medical
`therapy (including ~-blockers) for glaucoma.
`
`Conjunctival Hyperemia
`
`In general, mean conjunctiva! hyperemia was graded
`slightly higher in latanoprost-treated compared with ti(cid:173)
`molol-treated eyes throughout the course of therapy. On
`a relative scale of O to 3, latanoprost-treated eyes were
`graded at 0.4 and timolol-treated eyes at 0.3 for hyperemia
`(Table 5).
`
`Iris Color
`
`A definite change in iris color was observed in both eyes
`of I of the 128 patients treated with latanoprost and none
`of the 140 patients treated with timolol. An additional
`three patients (both eyes of each) from the latanoprost
`group were suspects for these color changes. All four of
`these patients showed a concentric heterochromia on
`baseline photographs, with the stroma around the sphinc(cid:173)
`ter having a darker appearance than the peripheral iris
`stroma. Sixty of the 128 patients treated with latanoprost
`and 56 of the 140 treated with timolol showed this con(cid:173)
`centric heterochromia at baseline. Darkening of the pe(cid:173)
`ripheral iris stroma occurred or was suspected in these
`four patients, producing a more uniform iris color. The
`
`iris color change was suspected as early as 4.5 months
`after initiation of treatment. Nevi, or freckles of the iris,
`were not affected by latanoprost treatment.
`
`Other Ocular Side Effects and Adverse Events
`
`Serious ocular adverse events did not occur in any patient
`in either the latanoprost or timolol group. Otherwise, 20
`ocular adverse events occurred in IO (8%) of the 128 pa(cid:173)
`tients in the latanoprost group and 17 events in 16 ( 11 % )
`of the 140 patients in the timolol group (Table 6). These
`ocular adverse effects included apparent worsening of the
`visual fields in one patient from each group.
`Ocular signs and symptoms, excluding the adverse
`events, were reported at least once during the 6 months
`of treatment by 62 (48%) and 85 (61 %) of the patients
`treated with latanoprost and timolol, respectively (Table
`7). Stinging, itching, foreign body sensation, and tearing
`occurred more frequently in the timolol group, whereas
`blurred vision and dry eye were more common in the
`latanoprost group (Table 7).
`With the exception of 4.5-month visit, at which time
`28 (20%) patients treated with timolol and 17 (13%)
`treated with latanoprost reported ocular symptoms, no
`
`Table 3. Baseline Characteristics of the Pairs of
`Eyes of Each Patient*
`
`Characteristics
`
`No. of eyes treated per patient
`One eye
`Both eyes
`Iris color
`Brown
`Blue/ green/ gray
`Hazel
`Diagnosis
`Ocular hypertension
`Primary open-angle
`glaucoma
`Exfoliation
`Pigmentary dispersion
`Different diagnosis OD
`versus OS
`No. of glaucoma medications
`per patient
`
`0
`1
`2
`3
`Glaucoma therapy
`/J-adrenergic blocker
`Adrenergic agonist
`Cholinergic agonist
`CAI
`Other
`
`Timolol
`(n = 140)
`
`Latanoprost
`(n = 128)
`
`20 (14)
`120 (86)
`
`21 (16)
`107 (84)
`
`71 (51)
`52 (37)
`17 (12)
`
`90 (64)
`45 (32)
`
`2 (1)
`1 (1)
`2 (1)
`
`52 (37)
`67 (48)
`19 (14)
`2 (1)
`
`78 (56)
`8 (6)
`8 (6)
`5 (4)
`7 (5)
`
`68 (53)
`44 (34)
`16 (13)
`
`80 (63)
`39 (30)
`
`3 (2)
`3 (2)
`3 (2)
`
`56 (44)
`49 (38)
`21 (16)
`2 (2)
`
`71 (55)
`6 (5)
`8 (6)
`6 (5)
`1 (1)
`
`OD = right eye; OS = left eye; CAI = carbonic anhydrase inhibitors.
`• Values are no. (%).
`
`141
`
`PM
`
`X
`
`X
`
`X
`
`X
`
`n 4
`
`md
`
`en,
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`of
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`
`Micro Labs Exhibit 1040-6
`
`

`

`Ophthalmology Volume 103, Number 1, January 1996
`
`Table 4. Numbers of and Reasons for Patient Withdrawals from Study
`
`Treatment
`Latanoprost (n = 128)
`Timolol (n = 140)
`
`Completions
`118 ·
`130
`
`Withdrawals*
`
`Inadequate
`IOP
`Control
`
`0
`4
`
`Ocular
`Reasons
`2t
`2t
`
`Systemic
`Medical
`Reasons
`4§
`311
`
`Non medical
`Reasons
`4'
`1 ••
`
`IOP = intraocular pressure.
`* Not necessarily related to treatment.
`t Including allergic blepharoconjunctivitis.
`t Including swelling of eyelids and allergic conjunctivitis.
`§ Including palpitations, peptic ulcer symptoms, and maculopapular rash (two patients).
`II Including palpitations, shortness of breath with subsequent bypass surgery, and status post mastectomy for breast cancer.
`11 Including left country for family emergency, lost to follow-up, moved out of state, and dropped out due to time constraints.
`** Patient decided to withdraw from study without specifying a reason.
`
`significant difference in ocular symptoms were reported
`between the two groups throughout the course of ther(cid:173)
`apy.
`Superficial punctate keratopathy (SPK) was reported
`in 17 (13%) patients treated with latanoprost and in 25
`( 18%) treated with timolol. In two of these patients from
`each group, SPK was found only at baseline before any
`study drug was applied. In two other patients treated
`with latanoprost, SPK was found at all visits, including
`baseline. In some patients, the SPK may have resulted
`from frequent tonometry and instillation of local an(cid:173)
`esthetic drugs.
`Neither timolol nor latanoprost altered any of the fol(cid:173)
`lowing compared with baseline measurements: visual
`acuity, refraction, or slit-lamp biomicroscopic examina(cid:173)
`tion, including anterior chamber flare or cellular response.
`
`Systemic Side Effects and Adverse Events
`
`Serious adverse events occurred in 8 (6%) of the 128 pa(cid:173)
`tients treated with latanoprost, and in 10 (7%) of the 140
`treated with timolol (Table 6). Of these patients with se(cid:173)
`rious events, two may have been exacerbated by the treat(cid:173)
`ment. Both patients were receiving timolol: one with
`shortness of breath, requiring discontinuation of the study
`drug, and the other with sick sinus syndrome with syncope
`(Table 6).
`Excluding serious adverse events, 18 ( 14%) patients re(cid:173)
`ceiving latanoprost reported 20 additional nonocular ad"
`verse events, and 23 (16%) patients receiving timolol re(cid:173)
`ported 33 events (Table 6). In addition to these adverse
`events, 34 (27%) of the patietits treated with latanoprost
`reported 4 7 nonocular signs and symptoms, and 22 ( 16%)
`
`• Latanoprost
`• Timolol
`
`......... ... iii
`!!! ''• • .. , ... ......... ,
`*
`*
`
`iii
`iii
`... ..... ..... . ..... !!! ................ ... !!!
`
`25
`
`21
`
`19
`
`......
`Cl :c
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`E
`-~ 23
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`Q)
`
`17
`
`0 0.5
`
`1.5
`
`3
`
`4.5
`
`6
`
`Time (months)
`
`Figure 1. Effect of 0.005% latan(cid:173)
`oprost (n = 128) applied once
`daily (at 8:00 PM) and 0.5% ti(cid:173)
`molol (n = 140) applied twice
`daily{at 8:00 AM and 8:00 PM) on
`intraocular pressure (IOP) as de(cid:173)
`termined at 8:00 AM (12 hours
`after the last dose) in patients
`with ocular hypertension or
`glaucoma. The IOP of patients
`with protocol violations were not
`included (see the Patients and
`Methods section). If both eyes of
`a patient were treated, a mean
`value of both eyes was used. Each
`value represents a mean ± stan(cid:173)
`dard error of the mean. All values
`were significantly (P < 0.001) re(cid:173)
`duced compared with baseline
`measurements. Asterisks = a sig(cid:173)
`nificant (P < 0.001) further re(cid:173)
`duction of IOP produced by la(cid:173)
`tanoprost compared with timolol.
`
`142
`
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`
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`...
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`
`of tho
`and S)
`He.
`opros·
`(mear
`75 ± I
`8). Ne
`ues (l
`group
`
`Disc1 -The re
`
`applie
`hypot,
`The c
`molal
`paten
`tainec
`6 mor
`fects c
`traoct
`blood
`is sigr
`prost.
`conju
`feet is
`tients
`Th,
`and 1
`and 2•
`time I
`Both c
`with n
`
`' l
`
`I
`
`l
`
`Micro Labs Exhibit 1040-7
`
`

`

`'ical
`1S
`
`pa-
`140
`se(cid:173)
`!at-
`1ith
`1dy
`)pe
`
`re(cid:173)
`ad.
`re(cid:173)
`:rse
`·ost
`i%)
`
`' OSt
`
`Camras · Latanoprost and Timolol with Ocular Hypertension and Glaucoma
`
`0 Latanoprost, Baseline
`• Latanoprost, Month 6
`C Timolol, Baseline
`• Timolol, Month 6
`
`······
`
`··· ··· .,., ,
`
`.. ...... Q
`
`/
`
`. ·
`
`Figure 2. Diurnal effect of
`latanoprost and timolol on ~~-
`IOP as determined on base·
`line day and after 6 months
`of treatment. Also see legend
`of Figure 1.
`
`22
`
`20
`
`18
`
`16
`
`C,
`J:
`E
`
`(/)
`(/)
`
`~
`:::,
`(J
`0
`
`- 26
`E 24 -Q) ... :::,
`4) ... a. ...
`(U ... -s:
`
`8:00
`
`12:00
`
`16:00
`
`Time of Day (hours)
`
`of those treated with timolol reported 35 nonocular signs
`and symptoms.
`Heart rate did not change significantly in the latan(cid:173)
`oprost group. However, in the timolol group, heart rate
`(mean± SD) was significantly (P < 0.001) reduced from
`7 5 ± l Oto 71 ± l O beats per minute at 6 months (Table
`8). Neither blood pressure (Table 8) nor laboratory val(cid:173)
`ues (blood or urine) changed significantly in either
`group.
`
`Discussion
`
`The results of this study show that 0.005 % latanoprost
`applied topically once daily is a more effective ocular
`hypotensive agent than 0.5% timolol applied twice daily.
`The concentration of latanoprost is l / l 00 that of ti(cid:173)
`molol; therefore, latanoprost is at least l 00-fold more
`potent than timolol. The hypotensive effect is main(cid:173)
`tained, without any evidence of drift, from 2 weeks to
`6 months of treatment. More subjective ocular side ef(cid:173)
`fects occur with timolol compared with latanoprost. In(cid:173)
`traocular inflammatory effects do not occur. Although
`blood pressure is not altered in either group, heart rate
`is significantly reduced by timolol, but not by latano(cid:173)
`prost. Although latanoprost produces slightly more
`conjunctiva! hyperemia than timolol, this mild side ef(cid:173)
`fect is well tolerated and virtually unnoticed by the pa(cid:173)
`tients.
`The study design includes IOP measurements at 4, 8,
`and 12 hours after the last dose of timolol, and 12, 16,
`and 20 hours after the last dose of latanoprost. At each
`time point, latanoprost was more effective than timolol.
`Both drugs provide approximately 24 hours oflOP control
`with minimal diurnal fluctuation. Unlike other drugs with
`
`a shorter duration of action, such as pilocarpine, dorzo(cid:173)
`lamide, or apraclonidine, there is no appreciable peak or
`trough effect after each dose of timolol or latanoprost.
`Therefore, the greater efficacy of latanoprost compared
`with timolol is unlikely due to differences in the timing
`of the IOP measurements.
`Of the PG analogues reported in clinical trials, latan(cid:173)
`oprost appears to provide the best separation between
`ocular hypotensive efficacy and side effects. PGF2a tro(cid:173)
`- 6 15-
`methamine salt,27·28 PGF2a-l -isopropyl ester,4
`propionate-PGF2a- l -isopropyl ester (diester),7 PGD2,9
`BW245C,9 PGE2 analogue, 3 and UF-021 10 either do not
`effectively reduce IOP or produce unacceptable side ef(cid:173)
`fects. Of these analogues, PGD2,9 BW245C,9 and the PGE2
`analogue3 were found to cause an initial mean rise in IOP
`of as much as 4 mmHg during the first 2 hours after ad(cid:173)
`ministration. Although IOP was not measured during the
`first few hours after latanoprost administration in the cur(cid:173)
`rent study, other publications demonstrate that the 17-
`phenyl-substituted PGF2a analogues (latanoprost or its
`epimeric mixture PhXA34) do not raise IOP at any time
`after administration.8·11·12·15-21 Although many of the
`subjective side effects and conjunctival hyperemia were
`assessed 12 to 20 hours after the last latanoprost dose in
`the current study, previous studies indicate that side effects
`are no different in the first, compared with second, 12
`hours after administration of PhXA34 or latano(cid:173)
`prost. 8· 11 • 16· 17·21 Evening, rather than morning, adminis(cid:173)
`tration of latanoprost was chosen to potentially block an
`early morning diurnal spike of IOP, not to reduce side
`effects. The time course and the magnitude of the con(cid:173)
`junctiva! hyperemia after PhXA348·11 or latanoprost16·17·21
`are distinctly different from that occurring after other PG
`analogues.1-7·9•27·28 The peak hyperemia occurs earlier,
`usually within the first hour, and is much greater in mag(cid:173)
`nitude with the latter analogues.
`
`143
`
`Micro Labs Exhibit 1040-8
`
`

`

`Ophthalmology Volume 103, Number 1, January 1996
`
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