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`Volume 103 Number 11
`November 1996
`
`ISSN 0161-6420
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`

`

`Ophthalmology
`
`Journal of the
`American Academy of Ophthalmology
`
`The objective of the American Academy of Ophthalmology in publishing its journal, Ophthalnwlogy, is to
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`
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`Don Minckler*
`Los Angeles, C A
`
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`Rohit Varma*
`Los Angeles, CA
`
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`Miami, FL
`George B. Bartley
`Rochester, MN
`Roy W. 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
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`@) Text printed on acid-free paper.
`
`Micro Labs Exhibit 1039-2
`
`

`

`Latanoprost, a Prostaglandin
`Analog, for Glaucoma Therapy
`Efficacy and Safety after 1 Year of
`Treatment in 198 Patients
`
`Carl B. Camras, MD ,1 Albert Alm, MD, 2 Peter Watson, MD ,3
`Johan Stjernschantz, MD, 4 the Latanoprost Study Groups*
`
`Purpose: To determine efficacy and safety of latanoprost, a prostaglandin analog
`for glaucoma, during 1 year of treatment.
`Methods: After baseline measurements, 0.005% latanoprost was topically applied
`once daily for 12 months in patients from Scandinavia, the United Kingdom, and the
`United States who had elevated intraocular pressure (IOP). Diagnoses included ocular
`hypertension, chronic open-angle glaucoma, exfoliation syndrome, and pigment disper(cid:173)
`sion syndrome. Treatment was masked for the first 6 months and open-label during the
`second 6 months.
`Results: Of the 272 patients initially enrolled, withdrawals were due to inadequate
`IOP control (1%) , increased iris pigmentation (5%) , other ocular problems (3%) , systemic
`medical problems (3%), and nonmedical reasons (14%). Latanoprost significantly (P <
`0.0001) reduced diurnal IOP from 25.3 ::t:: 3.0 mmHg (mean ::t:: standard deviation) at
`baseline to 17.4 ::t:: 2.7 mmHg (32% reduction) at 12 months in the 198 patients who
`completed 1 year of treatment. The IOP reduction was maintained at a consistent level
`throughout the 12 months without evidence of drift, and was not affected by sex, age,
`race, or eye color. Overall, latanoprost caused a possible or definite increase in iris
`pigmentation in 12% of the 272 patients, all of whom had multicolored irides at baseline.
`One half of these patients with increased pigmentation withdrew before completing 1
`year of therapy. Visual field, optic disc cupping, visual acuity, refractive error, conjunctiva!
`hyperemia, aqueous flare, anterior chamber cellular response, lens examination, blood
`pressure, heart rate, blood tests, and urinalysis were not appreciably altered.
`Conclusion: Latanoprost safely and effectively reduces IOP for 1 year in patients
`of diverse nationalities, providing further evidence for its usefulness in chronic glaucoma
`therapy. Ophthalmology 1996; 103: 1916-1924
`
`Originally received: October 30, 1995.
`Revision accepted: July I 7, 1996.
`
`1 Department of Ophthalmology, University of Nebraska Medical Cen(cid:173)
`ter, Omaha.
`2 Department of Ophthalmology, University Hospital, Uppsala, Sweden .
`3 Addenbrooke's Hospital , Cambridge, England.
`
`4 Pharmacia & Upjohn, Uppsala, Sweden.
`
`* Members of the Latanoprost Study Groups are listed in the Appendix
`at the end of this article.
`
`Presented in part at the American Academy of Ophthalmology Annual
`Meeting, Atlanta Oct/Nov 1995 .
`Supported by a grant from Pharmacia and Upjohn, Uppsala, Sweden.
`Drs. Camras and Alm are consultants to Pharmacia & Upjohn, Uppsala,
`Sweden. Dr. Stjernschantz is employed by Pharmacia & Upjohn. Mr.
`Watson has no financial interest in Pharmacia & Upjohn . None of the
`authors have a proprietary interest in the development or marketing of
`any drug used in this study or any competing drug.
`Reprint requests to Carl B. Camras, MD, Department of Ophthalmology,
`University of Nebraska Medical Center, 600 South 42nd St, Omaha,
`NE 68 198-5540.
`
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`Camras et al · Latanoprost for Glaucoma Therapy
`
`Latanoprost, a prodrug of a 17-phenyl-substituted prosta(cid:173)
`glandin (PG)F2a analog, when topically applied once daily
`at a concentration of 0.005%, is as effective and well toler(cid:173)
`ated as 0.5% timolol applied twice daily for 6 months in
`randomized, double-masked studies evaluating more than
`800 patients with ocular hypertension or glaucoma. 1
`6
`-
`However, to effectively treat chronic glaucoma, efficacy
`and safety must be demonstrated for more prolonged peri(cid:173)
`ods of time.
`To provide this important longer-term information, this
`report describes the safety and efficacy of the first 198
`patients who completed 1 year of treatment with 0.005%
`latanoprost topically applied once daily. These patients
`were recruited from three different parts of the world,
`enabling an international comparison of the relative effi(cid:173)
`cacy and side effects of latanoprost.
`
`Methods
`
`Patients were recruited from 10 centers in Scandinavia,
`14 centers in the United Kin'gdom (UK), and 13 centers
`in the United States (US). 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 during treatment with no more than a single ocular
`hypotensive medication during the screening examina(cid:173)
`tion; (2) diagnosis of primary open-angle glaucoma, ocu(cid:173)
`lar hypertension, exfoliation syndrome, or pigment dis(cid:173)
`persion syndrome. If treated for their elevated IOP, pa(cid:173)
`tients discontinued their medication for a minimum of the
`following intervals before the baseline day: 3 weeks for
`beta-adrenergic antagonists, 2 weeks for adrenergic ago(cid:173)
`nists, and 5 days for cholinergic agonists or carbonic
`anhydrase inhibitors. Patients previously treated with
`beta-adrenergic antagonists were not eligible to partici(cid:173)
`pate in the studies in Scandinavia or the UK, but were
`still eligible for the study in the US . Patients were ineligi(cid:173)
`ble for any of the following reasons: (1) younger than 40
`years of age; (2) use of any ocular medications other than
`for glaucoma; (3) advanced glaucoma that would be at
`risk for progression during the washout period or during
`treatment with a single ocular hypotensive medication;
`( 4) ocular conditions, including a history of acute angle(cid:173)
`closure glaucoma, severe eye trauma, intraocular surgery
`or argon laser trabeculoplasty within 6 months, severe dry
`eye syndrome, or ocular inflammation/infection within 3
`months; and/or (5) any unstable medical condition.
`The first 6 months of the study were carried out in a
`randomized, double-masked fashion, with either 0.005%
`latanoprost applied once daily or 0.5% timolol applied
`twice daily to one or both eyes (depending on eligibility)
`for each patient. The latanoprost-assigned patients received
`active latanoprost at 8:00 PM and the vehicle at 8:00 AM
`each day for 6 months in the UK and US . In Scandinavia,
`the patients taking latanoprost were divided randomly into
`two groups. One group received the active latanoprost at
`8:00 AM for the first 3 months, and at 8:00 PM for the
`second 3 months. The other group received latanoprost at
`8:00 PM for the first 3 months and at 8:00 AM for the
`
`second 3 months. Each center used standard procedures to
`assess the parameters that were evaluated. 1
`3 Details of the
`-
`6-month, masked trial are described further in previous
`5
`publications. 1
`-
`After completion of 6 months of treatment, all centers
`were encouraged to give their subjects the option of con(cid:173)
`tinuing treatment with latanoprost in an open-label fash(cid:173)
`ion for an additional 6 months. Each patient was given the
`option of applying 0.005% latanoprost once daily either in
`the morning (at approximately 8:00 AM) or the evening
`(at approximately 8:00 PM), with their choice of treatment
`time remaining unaltered during the course of the second
`6-month, open-label trial. The patients receiving latano(cid:173)
`prost in the morning were instructed not to take their
`drops in the morning of an examination day. Instead, the
`latanoprost was administered after their examination.
`Patients returned for visits at 6 1
`/2 , 8, 10, and 12 months
`of treatment. Subjective side effects, visual acuity, refrac(cid:173)
`tion (if a change in visual acuity occurred), conjunctiva!
`hyperemia, slit-lamp biomicroscopy, IOP, and magnified
`color photography of the iris were assessed or performed
`on each visit in the morning. In addition, at the 12-month
`visit, the examination included automated visual field
`(Humphrey 24-2 or 30-2 [Allergan Humphrey, San Lean(cid:173)
`dro, CA], Octopus G 1
`[Interzeag, Schlieren, Switzer(cid:173)
`land] , or Competer [Bara Elektronik AB , Lund, Sweden]);
`dilated ophthalmoscopy, including assessment of the
`cup:disc ratio; blood pressure; heart rate; and diurnal
`(8:00 AM, 12:00 noon, and 4:00 PM) assessments of sub(cid:173)
`jective side effects, conjunctiva! hyperemia, slit-lamp bio(cid:173)
`microscopy, and IOP.
`The iris photographs were reviewed by an independent
`panel of two or three ophthalmologists or scientists who
`were not investigators or examiners of any of the patients.
`The panel usually decided as a group whether a definite
`or suspect darkening of iris color occurred. The slightest
`suggestion of a change in pigmentation, including slight
`darkening or enlargement of a pre-existing brown area,
`was considered a change.
`If the investigators believed that the latanoprost inade(cid:173)
`quately controlled the IOP, they were given the option of
`adding 0.25% or 0.5% timolol once or twice daily to
`their patients' regimen. If the addition of timolol did not
`adequately control the IOP, the patients were discontinued
`from the study and treated at the discretion of their oph(cid:173)
`thalmologist.
`Adverse events were monitored carefully throughout
`the study. An adverse event was defined as any undesir(cid:173)
`able event occurring to a subject, whether or not it was
`considered related to the investigational drug. A serious
`adverse event was defined as potentially fatal, life threat(cid:173)
`ening, sight threatening, permanently disabling, requiring
`hospitalization, cancer, or a drug overdose.
`Blood samples collected at baseline and after 6 and 12
`months of treatment were analyzed for the following:
`hematocrit level, hemoglobin level, mean corpuscular
`volume, mean corpuscular hemoglobin level, mean cor(cid:173)
`puscular hemoglobin concentration, erythrocyte count,
`leukocyte count, differential count, platelets, prothrom(cid:173)
`bin, partial thromboplastin time, serum cholesterol level
`
`1917
`
`Micro Labs Exhibit 1039-4
`
`

`

`Ophthalmology Volume 103, Number 11 , November 1996
`
`Table 1. International Distribution and Reasons for Withdrawal from the Group of 272 Patients Who
`Began Therapy with Latanoprost by April 30, 1993.*
`
`Reason for Withdrawal
`
`Inadequate
`/OP
`Completed Comro!
`
`Systemic Option of
`Increased Other
`Ocular Medical Withdrawing
`Iris
`at 6 Mos
`Pigment Reasonst Reasons
`
`Know ledge about
`Increased Iris
`Pigment§
`
`Other
`Nonmedical
`Reasons
`
`Scandinavia
`United Kingdom
`United States
`Total
`
`88
`60
`50
`198 (73%)
`
`1
`2
`0
`3 (1 %)
`
`5
`6
`3
`14 (5%)
`
`5
`3
`1
`9 (3%)
`
`3
`3
`3
`9 (3%)
`
`6+
`JO
`3
`19 (7%)
`
`14+
`0
`0
`14 (5%)
`
`0
`1
`5
`6 (2%)
`
`Total
`
`122 (45%)
`85 (31%)
`65 (24%)
`272 (100%)
`
`%
`Withdrawal
`
`28
`29
`24
`27
`
`·)
`
`lOP = intraocular pressure.
`* Values are number of patients.
`t Includes blurred vision, photophobia, tearing, eye pain, punctate epithelial erosions, conjunctiva! hyperemia, chemosis, stinging, embolus in retinal
`artery, central retinal vein occlusion, branch retinal vein occlusion, and diabetic retinopathy.
`:j: One of these patients was later found to show increased iris pigmentation.
`§ Patients decided to withdraw after being informed that other patients in the study developed increased iris pigmentation.
`
`(total, high-density lipoprotein, low-density lipoprotein),
`serum triglycerides, serum proteins, glucose value, creati(cid:173)
`nine level, urea level, bilirubin level, alkaline phospha(cid:173)
`tase, SGOT, SGPT, sodium, potassium, calcium, and
`chloride. Urinalysis included assessment of protein and
`glucose.
`
`Results
`
`One hundred ninety-eight patients successfully completed
`1 year of therapy with latanoprost by April 30, 1994.
`These 198 patients represent a subset of a total of 272
`patients who began treatment with latanoprost in the ran(cid:173)
`domized, masked study by April 30, 1993, and therefore
`had the potential of completing I year of treatment by
`April 30, 1994. Overall, the withdrawal rate was slightly
`less in the US compared with the other geographic areas
`
`(Table 1). Of the 272 patients, 3 (1 %) were withdrawn
`because of inadequate IOP control, all within the first
`3 months of therapy (Tables I and 2). Excluding iris
`pigmentation, nine patients (3%) dropped out because of
`the development of adverse ocular side effects. Of these
`nine patients, six (67%) withdrew within the first 3
`months, and 8 (89%) within the first 6 months of therapy
`(Tables I and 2). Symptoms or signs that may have repre(cid:173)
`sented an allergic or toxic reaction developed in only
`three of these nine patients (1 % overall incidence) . Of
`the 74 patients who withdrew from the study, 39 (53 %)
`dropped out for nonmedical reasons, which included cen(cid:173)
`ter deciding not to participate in the second 6-month,
`open-label trial; patients electing the option not to con(cid:173)
`tinue treatment during the second 6 months; information
`that an increase in iris pigmentation occurred in other ·
`patients; and lost to follow-up because of moving or trav(cid:173)
`eling.
`
`,,
`Table 2. Timing of and Reasons for Withdrawal of the 74 Patients Who Began Therapy with Latanoprost
`by April 30, 1993 but Did Not Complete 1 Year of Treatment*
`
`Reason for Withdrawal
`
`Tim:: of
`Withdrawal
`(mos)
`
`:s:3
`> 3 and :s:6
`> 6 and :s:9
`>9
`Total
`
`Inadequate
`IOP
`Control
`
`3
`0
`0
`0
`3 (4%)
`
`Increased
`Iris
`Pigment
`
`0
`2
`10
`2
`14 (19%)
`
`Other
`Ocular
`Reasonst
`
`6
`2
`1
`0
`9 (1 2%)
`
`Systemic
`Medical
`Reasons
`
`6
`3
`0
`0
`9 (12%)
`
`Option of
`WirJulrawing
`at 6 Mos
`
`Knowledge about
`Increased Iris
`Pigment
`
`Other
`Nonmedical
`Reasons
`
`0
`19:j:
`0
`0
`19 (26%)
`
`0
`3
`10:j:
`1
`14 (19%)
`
`3
`3
`0
`0
`6 (8%)
`
`Total
`
`18 (24%)
`32 (43%)
`21 (28%)
`3 (4%)
`74 (100%)
`
`!OP = intraocular pressure.
`* Values are number of patients. These 74 patients are a subset of the total 272 patients who began treatment by April 30, 1993.
`t Includes blurred vision, photophobia, tearing, eye pain, punctate epithelial erosions, conjunctiva! hyperemia, chemosis, stinging, embolus in retinal
`artery, central retinal vein occlusion, branch retinal vein occlusion, and diabetic retinopathy.
`:j: One of these patients was later found to show increased iris pigmentation.
`
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`

`

`Camras et al · Latanoprost for Glaucoma Therapy
`
`T able 3. Demographics of Patients Completing 1 Year of Therapy
`
`Scandinavia
`(n = 88)
`
`United Kingdom
`(n = 60)
`
`United States
`(n = 50)
`
`Total
`(n = 198)
`
`Gender
`Men
`W ome n
`Age (yrs)
`Mean :!:: SD
`Range
`Race
`White
`Black
`Hispanic
`
`37
`51
`
`68 :!:: 9
`44-85
`
`88
`0
`0
`
`40
`20
`
`66 :t 9
`41-81
`
`60
`0
`0
`
`24
`26
`
`61 :!:: 12
`40-89
`
`33
`13
`4
`
`101 (51 %)
`97 (49%)
`
`66 :!:: 10
`40-89
`
`181 (91 %)
`13 (7%)
`4 (2%)
`
`Forty-four percent of the 198 patients completing l year
`of treatment were from Scandinavia, with the remainder
`approximately evenly divided between the UK and US (Ta(cid:173)
`ble I). There were twice as many men compared with
`women in the UK, but approx.1mately one half of the 198
`patients were men from all three regions combined (Table
`3). Mean age was 66 years, with patients slightly younger
`in the US. All patients from Scandinavia and the UK were
`white, whereas one third from the US were nonwhite (pre(cid:173)
`dominantly African-American) (Table 3).
`More patients from the UK and US had ocular hyper(cid:173)
`tension as opposed to primary open-angle glaucoma,
`whereas those from Scandinav ia were approximately
`equally divided between these two groups (Table 4). Ex(cid:173)
`foliative glaucoma was present in 15% of patients from
`Scandinavia, but in less than I% of patients from the UK
`and US. Unilateral treatment was given to approximately
`one fifth of patients overall, ranging from one third of
`patients in Scandinavia to only 4% of those in the US .
`Because of the difference in selection criteria among the
`geographic regions, none of the patients from Scandinavia
`
`or the UK, but two thirds of the patients from the US,
`were treated previously with beta-adrenergic blockers
`(Table 4). As specified by the protocol, all patients from
`the UK and the US took latanoprost in the evening during
`the first 6 months, whereas patients from Scandinavia
`were evenly divided between morning and evening dos(cid:173)
`ing. However, two thirds of patients decided on morning
`dosing during the second 6 months.
`Intraocular pressure was significantly (P < 0.0001)
`reduced by 8 ± 3 mmHg (mean ± standard deviation;
`32%) during the course of treatment (Figs 1 and 2). The
`IOP reduction did not significantly change comparing 6-
`and 12-month values. The reduction of diurnal IOP mea(cid:173)
`surements from baseline was more pronounced in Scandi(cid:173)
`navia (from 25 .5 :±: 3.0 mmHg to 16.8 ± 2.5 mmHg) and
`the UK (from 25.5 :±: 3.0 mmHg to 17.7 ± 2.4 mmHg),
`compared with the US (from 24.9 :±: 2.9 mmHg to 18.0
`± 3.1 mmHg) at 1 year. Sex/ age, race, previous glaucoma
`ther<}py, or eye color djd not affect the IQP response. Of
`the 198 patients, 1216%) received timolol in addition to
`the latanoprost. Even if the uncontrolled IOP of these 12
`
`!
`
`l,1
`
`(
`i
`
`T able 4. Baseline Characteristics of the Pairs of Eyes of Each Patient
`Completing 1 Year of Therapy
`
`Scandinavia
`(n = 88)
`
`United Kingdom
`(n = 60)
`
`United States
`(n = 50)
`
`Total
`(n = 198)
`
`Diagnosis
`Ocular hypertension
`Primary open-angle glaucoma
`Exfoliation glaucoma
`Pigmentary glaucoma
`Mixed types
`No. of eligible eyes receiving
`treatment per patient
`1 eye
`Both eyes
`Prior glaucoma therapy
`/3-Ad renergic blocker
`Adrenergic agon ist
`C holine rgic agonise
`Carbonic anh ydrase inhibitor
`
`36
`35
`13
`l
`3
`
`29
`59
`
`0
`2
`5
`2
`
`35
`23
`0
`0
`2
`
`13
`47
`
`0
`4
`2
`0
`
`26
`18
`I
`2
`3
`
`2
`48
`
`33
`3
`4
`3
`
`97 (49%)
`76 (38%)
`14 (7%)
`3 (2%)
`8 (4%)
`
`42 (21 %)
`156 (79%)
`
`33 (17%)
`9 (5%)
`11 (6%)
`5 (3%)
`
`1919
`
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`
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`1ese
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`pre(cid:173)
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`tion
`ther
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`
`11
`%)
`%)
`%)
`, )
`0%)
`
`tinal
`
`Micro Labs Exhibit 1039-6
`
`

`

`Ophthalmology Volume 103, Number 11 , November 1996
`
`IOP(mmHg)
`27
`
`25
`
`23
`
`21
`
`19
`
`17
`
`15
`0 ~.,.......,.---.---r---,-----r---r---r----.----,--
`10
`6 6.5
`12
`3
`4.5
`8
`0 0.5 1.5
`
`Duration of treatment (Months)
`
`Figure 1. Effect on intraocular pressure (!OP) of 0.005% latanoprost ap(cid:173)
`plied once daily to one or both eyes in each of 198 patients with elevated
`!OP completing 1 year of therapy. Each point represents the mean !OP
`of 184 to 198 patients, with limits of±: standard error of the mean. All
`values during treatment were significantly (P < 0.0001) reduced compared
`with baseline measurements.
`
`patients before the addition of timolol was carried forward
`through the 12 months of therapy, the latanoprost-induced
`IOP reduction would not be significantly altered. In the
`42 patients receiving unilateral therapy, the IOPs in the
`contralateral untreated eyes were not significantly altered
`during the course of the study.
`Ten patients had serious adverse events, none of which
`were believed to be secondary to the latanoprost treatment
`(Table 5). The incidence of adverse events was not differ(cid:173)
`ent comparing the first 6 months with the second 6 months
`of treatment. In general, patients recovered from most
`adverse events without sequela, except for the increase
`in iris pigmentation.
`In addition to the 14 patients who withdraw from the
`study because of increased iris pigmentation before com(cid:173)
`pleting 1 year of therapy, and the 2 additional patients who
`withdrew for other reasons and later had this increased
`pigmentation (Tables 1 and 2), 6 (3%) of the 198 patients
`completing l year of therapy definitely showed this change,
`and an additional 10 patients (5%) were suspects (Table
`6). Therefore, 22 (8%) of the 272 patients who began
`treatment by April 30, 1993, had a definite increase in
`iris pigmentation. As a worse-case scenario analysis by
`including all definite and suspect cases, and by adding
`to the 198 patients only those 16 patients with increased
`pigmentation who withdrew before completing 1 year of
`treatment, without including any other patient who with(cid:173)
`drew, 32 (15%) of 214 patients demonstrated a possible or
`definite increase in iris pigmentation. Of these 32 patients,
`baseline iris color was blue/gray-brown in 7 (22%), green(cid:173)
`brown in 22 (69%), and yellow-brown in 3 (9%). An in(cid:173)
`crease in iris pigmentation was not observed in any patient
`with the following baseline iris colors: blue/gray, blue/
`gray with slight brown, or brown. The pigmentary changes
`occurred more frequently in patients in the UK than those
`
`1920
`
`'
`in either Scandinavia or the US (Table 6). The pigmentary
`change usually was noted between 6 and 12 months of
`treatment, at which time the patient was withdrawn from
`treatment (Table 2). A retrospective review of the photo(cid:173)
`graphs of these patients demonstrated that the first subtle
`evidence of increased iris pigmentation often occurred a
`few months earlier. Variability in photographic technique
`occasionally necessitated two sets of photographs to con(cid:173)
`firm apparent changes. Iris nevi and freckles, carefully doc(cid:173)
`umented photographically at baseline, did not change with
`latanoprost treatment.
`Ocular symptoms and signs were graded as mild with
`few exceptions. The symptoms and signs were reported
`more frequently during the first 6 months than during the
`second 6 months of therapy. Overall , mean conjunctiva!
`hyperemia was graded as slight at baseline, and did not
`appreciably change throughout the course of therapy (Ta(cid:173)
`ble 7) . No change in mean visual acuity or refractive error
`occurred during the course of therapy. During the 12
`months of treatment, slight aqueous flare was noted at
`least once in three patients (2% ). A few cells in the ante(cid:173)
`rior chamber were observed at least once at baseline or
`during the 12 months of therapy in ten patients (5 %), two
`of whom had cells observed on the baseline day. No
`appreciable changes were observed for any of the follow(cid:173)
`ing: cup:disc ratio; visual fields; eyelids; conjunctiva; cor(cid:173)
`nea; iris (except for pigmentation); lens; vitreous; retina;
`blood pressure; heart rate; and blood and urine analyses.
`Because only three visual fields were obtained on each
`patient (at baseline, 6 months, and 1 year), definite pro(cid:173)
`gressive changes were difficult to determine in view of
`inherent variability. However, no obvious progressive
`glaucomatous defects were apparent.
`
`Discussion
`
`This study demonstrates that latanoprost applied once
`daily safely and effectively reduces IOP for 1 year in
`
`I
`
`\
`t
`I
`
`I
`
`27
`
`26
`
`25
`
`24
`
`23
`
`22
`
`21
`
`20
`
`19
`
`18
`
`-0 - Baseline
`
`-
`---•--
`
`6Monlhs
`12 Months
`
`J::-~--------------7!: __ 1--------------------- i
`
`ci
`:c
`E g
`w
`a:
`::,
`U)
`U)
`w
`a:
`a.
`a: cc
`
`.J
`::,
`0
`0
`cc
`a: ...
`
`~ 17
`
`16
`
`8:00am
`
`12:00 noon
`
`4:00pm
`
`TIME OF DAY (hours)
`
`Figure 2. Diurnal intraocular pressure measurements at baseline and after
`6 and 12 months of treatment with 0.005% latanoprost applied once daily
`to 198 patients with elevated intraocular pressure. Each point represents
`the mean of 198 patients with limits of ±: standard error of the mean.
`There was no significant difference comparing 6- and 12-month values.
`
`pat
`COi
`de1
`to
`wi
`pn
`lar
`1 o/.
`du
`pa
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`wi
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`q1
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`B
`B
`B
`C
`C
`I:
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`
`*
`
`Micro Labs Exhibit 1039-7
`
`

`

`ttary
`s of
`'rom
`1oto-
`1btle
`ed a
`ique
`con(cid:173)
`doc(cid:173)
`with
`
`with
`•rted
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`ti val
`not
`(Ta(cid:173)
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`: 12
`d at
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`No
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`!ach
`pro(cid:173)
`v of
`sive
`
`mce
`r in
`
`Camras et al · Latanoprost for Glaucoma Therapy
`
`Table 5. Number of Patients with Adverse Events Not Necessarily Related to
`Treatment) in Those Completing 1 Year of Therapy
`
`Scandinavia
`(n = 88)
`
`United Kingdom
`(n = 60)
`
`United States
`(n = 50)
`
`Total
`(n = 198)
`
`,;
`
`Serious*
`Oculart
`Nonocular
`Not serious+
`Oculart
`Nonocular
`
`0
`5
`
`10
`15
`
`0
`2
`
`20
`15
`
`0
`3
`
`0
`12
`
`0
`10§
`
`30
`42
`
`.,...'>..
`* Defined as potentially fatal, life-threatening, sight threatening, permanently disabling, requiring hospitalization,
`cancer, or a drug overdose.
`t Patients wi th ocula;· adverse events are indicated only if the event occurred in an eye treated with latanoprost.
`t Twelve patients had both ocular and nonocular adverse events; 23 patients had more than one adverse event.
`§ Includes abdominal pain, broken right hip, surgery for inguinal hernia, esophageal cancer, angina pectoris, chest
`pain, breast cancer, hospitalization for liver biopsy, gynecomastia, and hospitalization for colon resection for abscess.
`
`patients with ocular hypertension and open-angle glau(cid:173)
`coma. The IOP reduction was maintained without evi(cid:173)
`dence of drift during the 1 year of treatment. The 30%
`to 35% reduction of IOP is comparable to that achieved
`with nonselective beta-adrenergic blockers and verifies
`previous randomized, masked studies demonstrating simi(cid:173)
`lar efficacy compared with timolol for 6 months. 1-6 Only
`1 % of the 272 patients receiving latanoprost dropped out
`due to inadequate IOP control, and only 6% of the 198
`patients completing 1 year of treatment were given sup(cid:173)
`plemental timolol to maintain adequate control. In con(cid:173)
`trast, IOP was reduced by 14% after 1 year of treatment
`with dorzolamide in an open-label trial.7 In a 1-year study
`evaluating dorzolamide and betaxolol, 10% to 15% of
`patients dropped out because of insufficient IOP reduc(cid:173)
`tion, and another 30% to 35% required supplemental med(cid:173)
`ications to achieve adequate control.8 Of prostaglandin
`analogs evaluated in clinical trials, latanoprost offers the
`greatest separation between ocular hypotensive efficacy
`and adverse side effects.6
`The exceedingly low drop-out rate secondary to inade(cid:173)
`quate IOP control (1 %) or ocular reasons other than in-
`
`creased iris pigmentation (3 % ) is at least as low as that
`found with nonselective beta-blockers9 and considerably
`better than the drop-out rates found in long-term trials
`with the following medications: epinephrine, 35% to
`50%10·11 ; pilocarpine, approximately 90% of patients
`younger than 30 years of age or with significant cataracts;
`apraclonidine, 15% to 50%12- 16 ; and oral carbonic anhy(cid:173)
`drase inhibitors, 50%.17 Unlike epinephrine or apracloni(cid:173)
`dine, which frequently produce allergic or toxic reactions
`requiring discontinuation of treatment, latanoprost pro(cid:173)
`duced an allergic reaction in no more than l % of the
`272 patients evaluated in this study. Unlike the known
`potential systemic side effects of beta-adrenergic blockers
`on pulmonary and cardiac function, latanoprost has not
`been demonstrated to, and is not expected to, produce
`any systemic side effects, based on pharmacokinetic con(cid:173)
`siderations.18·19
`This study demonstrates that an increase in iris pig(cid:173)
`mentation occurs in 8% to 15% of eyes, beginning 3 to
`12 months after initiation of treatment. This pigmentary
`change occurred more frequently in the UK than in either
`Scandinavia or the US, perhaps due to the greater num-
`
`hs
`
`T able 6. Incidence of Possible Increase in Iris Pigmentation Relative to Baseline Iris Color in Those
`Pati