CLINICAL TRIALS

SECTION EDITOR: ROY W. BECK, MD, PhD

A Randomized Trial Assessing Dorzolamide

in Patients With Glaucoma Who Are Younger
Than 6 Years
Elyssa Z. Ott, BS; Monte D. Mills, MD; Santiago Arango, MD; Albert J. Getson, PhD;
Christopher A. Assaid, PhD; Ingrid A. Adamsons, MD, MPH;
for the Pediatric Dorzolamide Study Group

Objective: To evaluate dorzolamide hydrochloride in Results: One younger patient (1.8%) of 56 randomized
patients younger than 6 years who have an elevated in- to dorzolamide discontinued concomitant therapy be-
traocular pressure or glaucoma. cause of bradycardia. Two older patients (3.0%) of 66 dis-
continued dorzolamide because of ocular adverse expe-
Design: A 3-month, controlled, randomized, double- riences. The most frequent ocular adverse experiences
masked, multicenter, clinical trial. Patients were ran- were discharge and ocular hyperemia (younger cohort)
domized to 2% dorzolamide 3 times daily or timolol ma- and ocular hyperemia and burning/stinging (older co-
leate gel-forming solution (0.25% for patients ⬍2 years hort). At week 12, the mean change in intraocular pres-
and 0.5% for patients ⱖ2 but ⬍6 years) once daily plus sure for dorzolamide was statistically significant from base-
placebo twice daily. If the intraocular pressure was not line (−7.3 mm Hg [−20.6%] and −7.1 mm Hg [−23.3%])
controlled through monotherapy, younger patients re- in the younger and older cohorts, respectively; P⬍.001
ceived concomitant dorzolamide 3 times daily and 0.25% for both.
timolol gel-forming solution once daily and older pa-
tients received a fixed combination of 2% dorzolamide Conclusion: Dorzolamide was generally well tolerated
and 0.5% timolol twice daily. The primary safety vari- and demonstrated efficacy for up to 3 months in pa-
able was the proportion of patients who discontinued tients younger than 6 years.
therapy for a drug-related adverse experience. Intraocu-
lar pressure reduction was a secondary measure. Arch Ophthalmol. 2005;123:1177-1186

P
EDIATRIC GLAUCOMA ENCOM- a treatment for pediatric glaucoma,1-3 al-
passes a wide range of dis- thoughadverseeffectshavebeenaproblem.4,5
eases, including primary con- Thetopicalcarbonicanhydraseinhibitordor-
genital glaucoma, glaucoma zolamide hydrochloride (Trusopt; Merck &
associated with congenital Co, Inc, Whitehouse Station, NJ) has been
Author Affiliations: ocular anomalies such as aniridia or Sturge- studied in pediatric glaucoma patients and
Departments of Clinical Weber syndrome, and secondary glau- has had good tolerability and has lowered
Research (Ms Ott) and
coma following intraocular surgery or ocu- IOP,4,6,7 although not as much as oral acet-
Biostatistics (Drs Getson and
Assaid), and Clinical Risk lar inflammation. Surgical therapy is azolamide.5 However, the information pro-
Management and Safety preferable for the treatment of primary vided by these reports is less than compre-
Surveillance (Dr Adamsons), congenital glaucoma and many of the glau- hensive. Donohue and Wilensky4 described
Merck Research Laboratories, comas associated with congenital anoma- 4 infants who were followed up for an un-
West Point, Pa; Department of lies. Medications can be useful in reduc- specified period, and did not specify whether
Ophthalmology, Children’s ing intraocular pressure (IOP) until other glaucoma therapies were taken con-
Hospital of Philadelphia, surgery can be performed and in cases in comitantly. Three studies observed a few pe-
Philadelphia, Pa (Dr Mills); and which there has been a limited or poor re- diatric patients (n=11, 9, and 6) who re-
Clinica Oftalmologia Sandiego,
sponse to surgery. Medications may play ceived dorzolamide as concomitant therapy
Medellin, Colombia
(Dr Arango).
a greater role in the treatment of some ac- for about 6 months5,6 or up to 2 years.7
Group Information: A list of quired secondary forms of glaucoma, such Meyer et al8 reported a 3-month study that
members of the Pediatric as inflammatory glaucoma. included pediatric glaucoma patients as a
Dorzolamide Study Group Systemic carbonic anhydrase inhibitors, subpopulation (unknown sample size). A
appears on page 1185. primarily acetazolamide, have been used as sixth publication described retrospective

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 cases in 15 infants and children treated before, in be- ocular laser therapy up to 3 months before study start. Other
tween, or after failure of surgical intervention.9 These re- reasons for exclusion included any contraindication to timo-
ports provide encouraging evidence of the value of dor- lol or carbonic anhydrase inhibitors, known severe or serious
zolamide in the treatment of pediatric glaucoma. Additional hypersensitivity to sulfonamides, concomitant systemic or topi-
information, through a randomized controlled trial, on the cal medications known to affect IOP unless therapy remained
constant throughout the study, history or evidence of im-
efficacy and tolerability of dorzolamide would be informa- paired renal function, and participation in a study involving
tive. The US Food and Drug Administration recently un- an investigational drug within 4 weeks.
dertook an initiative to encourage evaluation of the safety Before enrolling in the study, patients discontinued any topi-
and efficacy of a broad range of marketed medications in cal or systemic ocular hypotensive medications for at least 24
pediatric patients. As part of that initiative, Merck & Co, hours before study day 1. A longer washout of ocular hypo-
Inc, submitted a pediatric study request to the Food and tensive medication was available at the discretion of the inves-
Drug Administration and subsequently received a written tigator according to the following schedule: 21 days for topi-
request from the Food and Drug Administration for a pe- cal ␤-blockers, ␣-agonists, topical prostaglandin analogues, and
diatric study of dorzolamide. The written request in- oral or topical carbonic anhydrase inhibitors; 7 days for epi-
cluded specifications regarding the patient population, num- nephrine or dipivefrin; and 72 hours for pilocarpine, carba-
ber of patients, comparator medications, safety and efficacy chol, or echothiophate iodide. Patients were also required to
undergo a complete physical examination within 3 months of
measurements, and study duration. The study that was con- study start to ensure that the patient was generally healthy. Af-
ducted was designed to meet the request of the Food and ter this washout period, patients returned to the clinic on day
Drug Administration. 1 for baseline examinations. On day 1, if the patient was eli-
This trial was designed to prospectively evaluate the gible and met the enrollment criterion of an IOP of 22 mm Hg
safety and efficacy of 2% dorzolamide 3 times daily (TID) or higher in 1 or both eyes, the patient was then randomly as-
in children (aged 1 week-⬍6 years) with pediatric glau- signed in a 2:1 ratio to masked treatment with dorzolamide or
coma or elevated IOP. The active comparator for this study timolol GS. Treatment assignment was determined by a com-
was timolol maleate gel-forming solution (GS) (Timoptic- puter-generated allocation schedule that was prepared by a
XE; Merck & Co, Inc). The size of the timolol GS group Merck & Co, Inc, staff member who was not involved in the
was not determined by the goal of detecting clinically analysis of the study results. Patients aged 1 week to younger
than 2 years (hereafter referred to as the younger patients or
meaningful differences between the 2 treatments with suf- cohort) received either 2% dorzolamide TID or 0.25% timolol
ficient statistical power. It was reasoned that if dorzol- GS once daily plus placebo twice daily. Patients 2 years or older
amide was tolerated in at least 3 of 4 pediatric patients, but younger than 6 years (hereafter referred to as the older pa-
the drug would have utility in this age group. There- tients or cohort) received either 2% dorzolamide TID or 0.5%
fore, the primary hypothesis was that in pediatric pa- timolol GS once daily plus placebo twice daily. If during the
tients, the true proportion of patients who will discon- study the investigator determined that the IOP was not con-
tinue therapy due to a drug-related adverse experience trolled, the study therapy was changed to open-label concomi-
was 25% or less when the initial treatment was 2% dor- tant therapy of 2% dorzolamide TID and 0.25% timolol GS once
zolamide TID for up to 3 months. This hypothesis was daily (10 minutes after the first drop) for younger patients and
evaluated separately for the younger than 2 years cohort to open-label therapy of the fixed combination of 2% dorzol-
amide hydrochloride and 0.5% timolol maleate (Cosopt; Merck
and the 2 years and older but younger than 6 years & Co, Inc) twice daily for older patients. Because of concerns
cohort. about the systemic adverse effects of timolol in young chil-
dren, the younger cohort was assigned the lower concentra-
METHODS tion of 0.25% timolol GS therapy, while the older cohort was
assigned the higher concentration of 0.5% timolol GS therapy.
The data analyzed and presented include data from masked
PROCEDURES monotherapy for safety and efficacy. Limited patient account-
ing and safety data are also provided for open-label concomi-
This was a 3-month, double-masked, in-house–masked, ran- tant or combination therapy and are indicated as such.
domized, active treatment, controlled study conducted at 22 All study medications for the masked and open-label phases
sites in the United States and 13 sites in Latin America, Eu- were provided by the sponsor (Merck & Co, Inc, Whitehouse
rope, Egypt, and the Philippines. All sites received ethical re- Station, NJ) as sterile ophthalmic solutions in identical con-
view committee approval of the protocol, and informed con- tainers labeled with the patient’s allocation number (for masked
sent was obtained for each patient from a parent or legal guardian therapy only) and instillation instructions. A sealed disclo-
before beginning the study. Male and female patients, aged 1 sure envelope, which identified the treatment group for each
week to younger than 6 years, with an elevated IOP of 22 mm Hg allocation number when unsealed, was kept in a secure loca-
or higher and the diagnosis of glaucoma or ocular hyperten- tion at the site. In the event of an emergency requiring the iden-
sion were eligible for enrollment. Neonates were required to tification of test drug, the disclosure envelope could have been
be at least 36 weeks’ gestational age. Among the ocular condi- opened to determine the treatment group. No allocation num-
tions for which patients were excluded were the use of con- bers were unmasked during the study by the investigators or
tinuous wear contact lenses (use of daily wear lenses was per- by sponsor personnel directly involved with the study. An in-
mitted); history or evidence of goniotomy or trabeculotomy dividual not otherwise involved in the study monitored pa-
within 1 month of study start; filtration or implantation sur- tient accrual. Parents or legal guardians of the patients were
gery, cyclodestructive surgery, or history or evidence of sig- instructed to instill the medications in the morning, after-
nificant ocular trauma within 3 months of study start; evi- noon, and evening at consistent times throughout the entire
dence of acute or recent ocular inflammation and/or infection study. Study visits occurred on day 1 and weeks 1, 4, and 12.
within 1 month of study start; chronic conjunctivitis; chronic If a change in therapy was required at week 1 or 4, the patient
keratitis; or lacrimal deficiency. Patients may have had intra- returned to the clinic for follow-up at week 2 or 5, respec-

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 tively. If at weeks 2 or 5 the IOP was not controlled, then the spect to the primary safety end point, if the upper limit of the
patient was discontinued from the study. Physicians were re- 95% confidence interval for patients receiving dorzolamide who
quested to measure each patient’s IOP at consistent times discontinued therapy was 25% or less. Data for the remaining
throughout the study, and the method of measurement was left safety measures are descriptively summarized.
to their discretion. The IOP was measured by 1 of 3 methods The primary efficacy (IOP) analysis was based on the all-
(Goldmann, TonoPen, or Perkins tonometry), and physicians patients-treated population, which consisted of all patients as
were asked to use the same method for each patient through- randomized (regardless of actual age) who had a baseline IOP
out the study. Two readings per eye were required for Gold- and at least 1 subsequent efficacy measurement. The IOP-
mann and Perkins tonometry, and the average value was re- lowering effect of dorzolamide was characterized by summa-
ported. Two IOP readings with a 5% confidence level were rizing IOP values by study visit, in addition to summary sta-
required for TonoPen tonometry, except when this confi- tistics for change from baseline and percentage change from
dence was not achieved and then 3 or 4 isolated readings were baseline. The change from baseline was calculated using the
taken, and the average value was reported. Patient coopera- patient’s “worse eye,” which was defined as the eye with the
tion and whether sedation was used during the IOP measure- higher IOP on day 1. If the IOP was the same for both eyes on
ment were also reported. Intraocular pressure, ocular signs, vi- day 1, the right eye was selected. This analysis included a 95%
sual acuity, alertness, vital signs, and adverse experiences were confidence interval on the difference between treatment groups
measured and recorded at each visit. Patient alertness was as- for mean change and mean percentage change from baseline
sessed using a 5-point scale (responds readily to name spoken based on the student t distribution. Missing data at week 12
in normal tone, lethargic response to name spoken in normal were estimated by the last-observation-carried-forward method,
tone, responds only after name is called loudly and/or repeat- which uses previous time-matched observations occurring within
edly, responds only after mild prodding or shaking, does not the study period. As noted previously, the sample sizes were
respond to mild prodding or shaking) that was adapted from not determined by the need to detect clinically meaningful dif-
the validated Observer’s Assessment of Alertness/Sedation Scale.10 ferences between the 2 treatments in IOP.
The drug relationship of all adverse experiences was assessed
by the investigator; adverse experiences were considered drug
related if they were assessed as possibly, probably, or defi- RESULTS
nitely related. Additional measurements performed at pre-
study or day 1 and poststudy visits included a physical exami- DEMOGRAPHICS
nation (if not performed within the past 3 months), dilated
ophthalmoscopy, corneal diameter measurement, and the chem-
istry laboratory test of venous total carbon dioxide (CO2) level Table 1 provides the baseline demographic character-
(serum). Since oral carbonic anhydrase inhibitors induce meta- istics of the study population. A total of 83 patients
bolic acidosis, total CO2 level was included as a special safety were enrolled in the younger cohort, 56 of whom were
variable to assess the effect of dorzolamide on serum bicarbon- randomized to dorzolamide. Approximately twice as
ate levels in a pediatric population. many male as female patients were randomized to each
treatment group. The mean baseline IOPs were 32.6
STATISTICAL ANALYSIS and 29.9 mm Hg in the dorzolamide and timolol GS
treatment groups, respectively. A total of 101 patients
The primary hypothesis of the study was that among pediatric were enrolled in the older cohort, 66 of whom were ran-
patients, the true proportion of patients who discontinued
therapy because of a drug-related adverse experience was 25%
domized to dorzolamide. Comparable proportions of
or less when the initial treatment was 2% dorzolamide TID for male and female patients were randomized to each
up to 3 months. It was reasoned that if dorzolamide was tol- treatment group. The mean baseline IOPs were 28.7
erated in at least 3 of 4 pediatric patients, the drug would have and 30.3 mm Hg in the dorzolamide and timolol GS
utility in this age group. A sample size of approximately 50 pa- treatment groups, respectively. For both cohorts, com-
tients randomized to dorzolamide in each cohort was se- parable distributions between treatment groups were
lected. With 50 patients, if the observed proportion of pa- observed for race, iris color, and age. The most common
tients who discontinued therapy because of a drug-related glaucoma causes were congenital glaucoma and apha-
adverse experience was 15%, then the primary hypothesis would kic glaucoma. Table 2 provides data on specific glau-
be supported because the upper limit of the 95% confidence coma causes for the study population. There were more
interval would be 24.9%.
The analysis of the primary study end point was based on
patients in the older cohort with other glaucoma causes
the all-patients-as-treated analysis population, which in- who received dorzolamide. Included in these other
cluded all patients who were randomized to double-masked causes are 2 patients in the dorzolamide group and 1
therapy and received at least 1 dose of study therapy. Patients patient in the timolol GS group with the cause of glau-
were analyzed according to the treatment received and accord- coma and 2 patients in both treatment groups with the
ing to the age cohort to which they actually belonged at study cause of pseudophakia. In addition, each of the follow-
start, irrespective of the cohort to which they were random- ing causes was reported in 1 patient in the dorzolamide
ized (patients enrolled who were ⬎6 years at randomization group but in no patients in the timolol GS group: ocu-
were counted in the older cohort). locerebrorenal syndrome, surgical aphakia, corticoste-
The primary safety end point was the observed proportion roid-induced glaucoma, microphthalmos, corneal
of patients in each age cohort who discontinued therapy with
dorzolamide because of a drug-related adverse experience. An
opacity, retinopathy of prematurity, retinal surgery,
exact (Clopper-Pearson11) 95% confidence interval on the pri- and vitreous surgery.
mary end point was calculated by age cohort (for patients ini- Previous glaucoma surgery was reported for approxi-
tially treated with dorzolamide) to document an acceptable safety mately 40% of patients in the younger cohort, 23 (41.1%)
profile. The prespecified decision rule stated that the safety pro- patients randomized to dorzolamide and 11 (40.7%) ran-
file for an age cohort would be declared acceptable, with re- domized to timolol GS. Previous glaucoma surgery was

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 Table 1. Baseline Demographic Characteristics*

Those ⬍2 y Those ⱖ2 y-⬍6 y

2% Dorzolamide Group 0.25% Timolol GS Group 2% Dorzolamide Group 0.5% Timolol GS Group
Characteristic (n = 56) (n = 27) (n = 66) (n = 35)
Sex
Male 35 (62.5) 20 (74.1) 33 (50.0) 18 (51.4)
Female 21 (37.5) 7 (25.9) 33 (50.0) 17 (48.6)
Race/nationality
Asian 5 (8.9) 2 (7.4) 5 (7.6) 2 (5.7)
Black 4 (7.1) 2 (7.4) 4 (6.1) 1 (2.9)
White 16 (28.6) 7 (25.9) 23 (34.8) 14 (40.0)
Egyptian 8 (14.3) 4 (14.8) 8 (12.1) 4 (11.4)
Hispanic 22 (39.3) 11 (40.7) 26 (39.4) 12 (34.3)
Other 1 (1.8) 1 (3.7) 0 2 (5.7)
Age, mo
Mean (SD) 9.7 (6.5) 11.5 (6.4) 46.9 (14.5) 48.2 (15.8)
Range 1-23 0.25-22 24-77 24-83
Iris color
Blue 10 (17.9) 8 (29.6) 9 (13.6) 7 (20.0)
Brown 20 (35.7) 9 (33.3) 19 (28.8) 7 (20.0)
Dark brown 22 (39.3) 8 (29.6) 26 (39.4) 15 (42.9)
Green 0 0 1 (1.5) 0
Hazel 1 (1.8) 0 6 (9.1) 3 (8.6)
Other† 3 (5.4) 2 (7.4) 5 (7.6) 3 (8.6)
Baseline IOP in the worse eye, mm Hg
Mean (SD) 32.6 (11.1) 29.9 (8.6) 28.7 (7.4) 30.3 (6.5)
Range 17.3-64 14-48.7 18-55 22-45.5

Abbreviations: GS, gel-forming solution; IOP, intraocular pressure.

*Data are given as number (percentage) of each group unless otherwise indicated. Percentages may not total 100 because of rounding. Dorzolamide was
administered as dorzolamide hydrochloride, and timolol as timolol maleate.
†Aniridia or unable to evaluate.

Table 2. Patients With Specific Glaucoma Causes*

Those ⬍2 y Those ⱖ2 y-⬍6 y

2% Dorzolamide Group 0.25% Timolol GS Group 2% Dorzolamide Group 0.5% Timolol GS Group
Glaucoma Cause (n = 56) (n = 27) (n = 66) (n = 35)
Aniridia 2 (3.6) 1 (3.7) 1 (1.5) 2 (5.7)
Glaucoma
Aphakic 6 (10.7) 5 (18.5) 11 (16.7) 10 (28.6)
Congenital 32 (57.1) 14 (51.9) 38 (57.6) 15 (42.9)
Iridocorneal mesenchymal dysgenesis 7 (12.5) 3 (11.1) 5 (7.6) 3 (8.6)
Sturge-Weber syndrome 8 (14.3) 2 (7.4) 4 (6.1) 2 (5.7)
Other† 2 (3.6) 2 (7.4) 12 (18.2) 3 (8.6)

Abbreviation: See Table 1.

*Data are given as number (percentage) of each group. Patients could have had more than 1 reason for glaucoma diagnoses. Dorzolamide was administered as
dorzolamide hydrochloride, and timolol as timolol maleate gel-forming solution.
†Includes surgical aphakia, chromosome abnormality, glaucoma, corticosteroid-induced glaucoma, macular hypoplasia, microphthalmos, oculocerebrorenal
syndrome, corneal opacity, pseudophakia, retinopathy of prematurity, spherophakia, retinal surgery, and vitreous surgery.

reported more frequently for the patients in the older co- masked monotherapy and 22 (26.5%) while undergo-
hort, 41 (62.1%) patients randomized to dorzolamide and ing open-label concomitant therapy. Seventeen patients
22 (62.9%) randomized to timolol GS. from the younger cohort discontinued therapy. In the
older age cohort, 19 patients were screened but not ran-
PATIENT ACCOUNTING domized. Of the remaining 101 patients, 81 (80.2%) com-
pleted the study, 62 (61.4%) while undergoing masked
Patient accounting is detailed in Figure 1A for the monotherapy and 19 (18.8%) while undergoing open-
younger cohort and in Figure 1B for the older cohort. In label combination therapy. Twenty patients from the older
the younger cohort, 13 patients were screened but not cohort discontinued therapy. The most frequent reason
randomized. Of the remaining 83 patients, 66 (79.5%) for discontinuation in both age cohorts was “IOP not con-
completed the study, 44 (53.0%) while undergoing trolled; patient went to surgery” (10 [58.8%] of 17 pa-

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 A Patients Screened
(N = 96)
Screen Failures
(n = 13)
Patients
Randomized
1 Lost to Follow-up Completed Completed 2 Clinical AE
(n = 28) (n = 16)
4 IOP Not Controlled; 2% Dorzolamide 0.25% Timolol 1 IOP Not Controlled;
Patient Went to Surgery (n = 28) (n = 27) Other Medication Prescribed
1 Other Discontinued Discontinued
(n = 6) (n = 3)

4 IOP Not Controlled; Completed Open-Label Therapy Open-Label Therapy Completed

Patient Went to Surgery (n = 15) (n = 22) (n = 8) (n = 7)
1 IOP Not Controlled;
1 IOP Not Controlled;
Other Medication Prescribed Discontinued Discontinued Patient Went to Surgery
1 Other (n = 7) (n = 1)

B Patients Screened
(N = 120)
Screen Failures
(n = 19)
Patients
Randomized
1 Withdrew Consent Completed Completed 2 Clinical AE
(n = 41) (n = 21)
2 Clinical AE 2% Dorzolamide 0.25% Timolol 1 IOP Not Controlled;
(n = 66) (n = 35) Patient Went to Surgery
3 IOP Not Controlled; Discontinued Discontinued
Patient Went to Surgery
(n = 6) (n = 3)

Completed Open-Label Therapy Open-Label Therapy Completed 2 IOP Not Controlled;

5 IOP Not Controlled; (n = 12) (n = 7) Patient Went to Surgery
(n = 19) (n = 11)
Patient Went to Surgery
1 IOP Not Controlled;
2 IOP Not Controlled; Other Medication Prescribed
Other Medication Prescribed Discontinued Discontinued
(n = 7) (n = 4) 1 Other

Figure 1. Patient accounting in those younger than 2 years (A) and in those 2 years and older but younger than 6 years (B). Dorzolamide was administered as
dorzolamide hydrochloride, and timolol as timolol maleate gel-forming solution (GS). AE indicates adverse event; and IOP, intraocular pressure.

tients in the younger cohort and 11 [55.0%] of 20 pa- continued study therapy because of a drug-related adverse
tients in the older cohort). The most frequent reasons experience. In the older age cohort, 2 patients (3.0%) ini-
given for nonrandomization in both cohorts were an IOP tially randomized to dorzolamide discontinued study
lower than the enrollment criterion (4 patients in the therapy while taking dorzolamide because of the drug-
younger cohort and 7 patients in the older cohort) and related adverse experiences of eye pain, ocular hyper-
withdrawal of consent (3 patients in the younger cohort emia, ocular burning/stinging, or ocular itching. The re-
and 4 patients in the older cohort). Five patients were sulting 95% confidence interval for the true proportion
randomized to the incorrect age cohort: 3 who were older of discontinuations was 0.4% to 10.5%. One patient (2.9%)
than 2 years were randomized to the younger cohort, and initially randomized to the timolol GS treatment group
2 who were older than 6 years were randomized to the discontinued study therapy because of the drug-related
older cohort. adverse experience of ocular hyperemia. Thus, for both
age cohorts, because the upper bounds of the 95% con-
SAFETY fidence intervals were each less than 25%, it could be con-
cluded that dorzolamide was generally well tolerated in
In the younger cohort, 1 patient (1.8%) who was ini- patients younger than 6 years with an elevated IOP or
tially randomized to dorzolamide discontinued study glaucoma.
therapy while undergoing open-label dorzolamide plus Table 3 summarizes the clinical adverse experi-
timolol GS therapy because of a drug-related adverse ex- ences for both age cohorts. In both cohorts, approxi-
perience. This patient discontinued therapy because of mately equal numbers of patients in both treatment groups
bradycardia, which was determined by the investigator had a clinical adverse experience or a drug-related ad-
to be related to the timolol GS therapy. The resulting 95% verse experience. Table 4 provides the most common
confidence interval for the true proportion of discon- adverse experiences for the younger and older cohorts.
tinuations was 0.1% to 9.6%. None of the 27 patients ini- The most common adverse experiences for both treat-
tially randomized to the timolol GS treatment group dis- ment groups were fever, cough, and upper respiratory

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 Table 3. Clinical Adverse Experience Summary (Masked Monotherapy)*

Those ⬍2 y Those ⱖ2 y-⬍6 y

2% Dorzolamide 0.25% Timolol GS 2% Dorzolamide 0.5% Timolol GS

Group Group Group Group
Group (n = 56) (n = 27) (n = 66) (n = 35)
Those with ⱖ1 adverse experience 42 (75.0) 17 (63.0) 50 (75.8) 24 (68.6)
Those with drug-related adverse experiences† 8 (14.3) 4 (14.8) 17 (25.8) 8 (22.9)
Those with serious adverse experiences 6 (10.7) 1 (3.7) 3 (4.5) 1 (2.9)
Those who discontinued because of an adverse experience 0 2 (7.4) 2 (3.0) 2 (5.7)
Those who discontinued because of a drug-related adverse experience 0‡ 0 2 (3.0) 1 (2.9)
Those who discontinued because of a serious adverse experience 0 1 (3.7) 0 0

Abbreviation: See Table 1.

*Data are given as number (percentage) of each group. Patients could belong to more than 1 group. Dorzolamide was administered as dorzolamide
hydrochloride, and timolol as timolol maleate gel-forming solution.
†Determined by the investigator to be possibly, probably, or definitely drug related.
‡The one patient who discontinued because of the drug-related adverse experience of bradycardia discontinued while undergoing open-label concomitant
therapy. This table only represents the masked monotherapy phase of the study.

Table 4. Patients With Specific Clinical Adverse Events (Incidence ⬎5% in ⱖ1 Treatment Group)
in Both Age Cohorts (Masked Monotherapy)*

Dorzolamide Group Timolol GS Group

Adverse Event Overall Drug Related Overall Drug Related

Those ⬍2 y†
Fever 14 (25.0) 0 5 (18.5) 0
Anorexia 3 (5.4) 0 0 0
Diarrhea 10 (17.9) 0 1 (3.7) 0
Vomiting 3 (5.4) 0 0 0
Bronchitis 2 (3.6) 0 2 (7.4) 0
Nasal congestion 3 (5.4) 0 0 0
Cough 12 (21.4) 0 6 (22.2) 0
Upper respiratory tract infection 7 (12.5) 0 4 (14.8) 0
Influenza 4 (7.1) 0 1 (3.7) 0
Pneumonia 3 (5.4) 0 0 0
Rash 4 (7.1) 1 (1.8) 1 (3.7) 1 (3.7)
Eye discharge 3 (5.4) 2 (3.6) 3 (11.1) 0
Ocular hyperemia 4 (7.1) 3 (5.4) 3 (11.1) 1 (3.7)
Eye irritation 0 0 2 (7.4) 0
Those ⱖ2 y-⬍6 y‡
Fever 11 (16.7) 0 9 (25.7) 1 (2.9)
Diarrhea 7 (10.6) 0 4 (11.4) 0
Vomiting 6 (9.1) 0 1 (2.9) 0
Headache 7 (10.6) 0 2 (5.7) 1 (2.9)
Somnolence 1 (1.5) 0 2 (5.7) 2 (5.7)
Cough 10 (15.2) 1 (1.5) 3 (8.6) 0
Upper respiratory tract infection 12 (18.2) 1 (1.5) 5 (14.3) 0
Influenza 7 (10.6) 0 2 (5.7) 0
Rhinitis 4 (6.1) 0 1 (2.9) 0
Rhinorrhea 5 (7.6) 0 3 (8.6) 0
Eye burning/stinging 9 (13.6) 8 (12.1) 3 (8.6) 3 (8.6)
Conjunctivitis 2 (3.0) 1 (1.5) 2 (5.7) 0
Eye discharge 0 0 4 (11.4) 1 (2.9)
Ocular hyperemia 7 (10.6) 5 (7.6) 6 (17.1) 3 (8.6)
Eye pain 4 (6.1) 2 (3.0) 2 (5.7) 2 (5.7)
Tearing 0 0 3 (8.6) 0

Abbreviation: See Table 1.

*Data are given as number (percentage) of each group. Dorzolamide was administered as dorzolamide hydrochloride, and timolol as timolol maleate
gel-forming solution.
†N = 56 for the 2% dorzolamide group, and N = 27 for the 0.25% timolol GS group.
‡N = 66 for the 2% dorzolamide group, and N = 35 for the 0.5% timolol GS group.

tract infections. The most frequently reported ocular ad- ocular burning/stinging for the older cohort. Although
verse experiences were ocular discharge and ocular hy- many patients (approximately 75% in both age cohorts)
peremia for the younger cohort and ocular hyperemia and reported an adverse experience, only 14.3% and 25.8%

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 reported an adverse experience that was considered re- younger age cohort experienced malnutrition, vomit-
lated to dorzolamide therapy for the younger and older ing, diarrhea, and fever around the time the laboratory
cohorts, respectively. None of the drug-related adverse test was performed. In the older cohort, one patient ex-
experiences reported during treatment with mono- perienced decreased capillary PCO2 (the incorrect labo-
therapy, either dorzolamide or timolol GS, was consid- ratory test was performed) (baseline, 5.1 kPa; week 12,
ered serious by the investigators. Few of the drug- 4.3 kPa; normal range, 4.8-6.1 kPa) while undergoing dor-
related adverse experiences were systemic. zolamide monotherapy. Both of these events were con-
Vital sign measurements were summarized for each sidered by the investigators to be drug related.
treatment group, and the mean changes from baseline to
the end of monotherapy were calculated. For the younger EFFICACY
cohort, the mean changes were comparable between treat-
ment groups (dorzolamide vs timolol) for systolic blood The IOP summary statistics on monotherapy for both age
pressure (−1.1 vs 0.3 mm Hg), diastolic blood pressure cohorts are provided in Table 5. Figure 2 and Figure 3
(−1.6 vs −1.2 mm Hg), and respiratory rate (−1.7/min vs display the IOP treatment means and SEs for the younger
−1.4/min). An unexpected increase in the mean pulse rate and older cohorts, respectively. For the patients in the
in the timolol group was seen (−2.0 vs 10.6 beats/min). younger cohort, the mean baseline IOP was higher in the
For the older cohort, comparable mean changes were seen dorzolamide group than in the timolol GS group (32.6
between treatment groups (dorzolamide vs timolol) for vs 29.9 mm Hg). Statistically significant (P⬍.001) de-
the vital signs of systolic blood pressure (0.7 vs −2.9 creases in IOP were seen at week 1 through 12 with both
mm Hg), diastolic blood pressure (−0.4 vs −2.4 mm Hg), treatments. At week 12, the mean decreases (mean per-
and respiratory rate (−0.5/min vs 0.0/min). The mean centage changes) in IOP for the dorzolamide and timo-
changes in pulse rate were 0.9 and −4.9 beats/min for the lol GS groups were −7.3 mm Hg (−20.6%) and −7.8
dorzolamide and timolol groups, respectively. mm Hg (−24.9%), respectively. The 95% confidence in-
For the alertness assessment, in both cohorts, nearly terval for the mean difference between the 2 treatments
all of the patients responded readily at baseline and week at week 12 was −3.4 to 4.5. Because the confidence in-
12. Two patients in the younger cohort experienced a terval includes 0, this indicates a similar effect for both
worsening of alertness; in one patient treated with timo- therapies.
lol GS, the assessment was performed during an exami- For the patients in the older cohort, the mean base-
nation under anesthesia, and, while no cause was pro- line IOP was slightly higher in the timolol GS group than
vided for the other patient (who was treated with in the dorzolamide group (30.3 vs 28.7 mm Hg). Statis-
concomitant therapy), the investigator did not believe that tically significant (P⬍.001) decreases in IOP were seen
this was an adverse experience. No patients in the older at week 1 through 12 with both treatments. At week 12,
cohort experienced a worsening in alertness. the mean decreases (mean percentage changes) in IOP
Changes in corneal diameter for the younger and older for the dorzolamide and timolol GS groups were −7.1
cohorts were small overall and were comparable across mm Hg (−23.3%) and −7.4 mm Hg (−25.3%), respec-
treatment groups (±0.1 mm). No statistically significant tively. The 95% confidence interval for the mean differ-
changes from baseline were observed (younger cohort, ence between the 2 treatments at week 12 was −2.5 to
P=.8; older cohort, P = .4). The number of emergent or 3.2. Because the confidence interval includes 0, this in-
worsening signs reported (from a slitlamp or dilated oph- dicates a similar effect for both therapies. As noted ear-
thalmoscopic examination) was similar between treat- lier, the study was not necessarily powered to find a dif-
ment groups in the younger and older cohorts. The most ference in treatment effect between the 2 medications.
common sign reported in the younger cohort was cor-
neal enlargement, which occurred in 3 patients receiv-
ing dorzolamide monotherapy. This was reported in pa- COMMENT
tients who were 5, 8, and 10 months old who were
reported to have developed mild, moderate, or severe cor- This study demonstrated acceptable safety of dorzol-
neal enlargement, respectively, during the study. The cor- amide in patients younger than 6 years. The primary hy-
neal diameter measurements that were recorded at base- pothesis of the study was confirmed, namely, that the true
line and week 12 for each of these patients were as follows: proportion of patients who discontinued therapy be-
13.5 mm and 13.75 mm; 12.0 mm and 11.5 mm; and cause of a drug-related adverse experience was less than
12 mm and 12 mm, respectively. Thus, the more objec- 25%. In the younger cohort, the proportion (95% con-
tive corneal evaluation showed no, or a minimal, change. fidence interval) of patients who discontinued therapy
The most common sign reported in the older cohort was because of drug-related adverse experiences was 1.8%
conjunctival hyperemia, which occurred in 3 patients re- (0.1%-9.6%); and in the older cohort, it was 3.0% (0.4%-
ceiving timolol monotherapy. All other signs were re- 10.5%). Previously published studies of 2% dorzol-
ported in 1 or 2 patients in either cohort. amide in pediatric patients found the medication to be
There were 2 laboratory adverse events, 1 in each co- well tolerated, with few adverse effects.4-9,12 The safety
hort. In the younger cohort, one patient experienced de- profile of dorzolamide in this study is consistent with that
creased venous total CO2 (baseline, 26.4 mmol/L; week reported in the earlier smaller pediatric studies. To our
12, 16.3 mmol/L; normal range, 20-28 mmol/L) while re- knowledge, this prospective, randomized, controlled study
ceiving concomitant therapy. In addition to this labora- is the largest of its kind in pediatric patients. This may
tory adverse experience, the same patient from the be in part because of the difficulty in performing such

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 Table 5. The IOP Summary Statistics in the Worse Eye (Masked Monotherapy)*

Visit, wk Treatment No. of Patients Baseline Value† Study Value† Change‡§ % Change§ 㥋
Those ⬍2 y¶
1 2% Dorzolamide 46 34.07 (11.61) 24.05 (10.06) −10.0 (10.77) −27.4
0.25% Timolol GS 22 31.15 (9.02) 23.15 (8.19) −8.0 (8.24) −23.8
4 2% Dorzolamide 53 33.16 (11.29) 24.30 (9.58) −8.9 (8.15) −25.7
0.25% Timolol GS 24 30.26 (8.98) 22.67 (7.75) −7.6 (8.11) −23.8
12 2% Dorzolamide 58 32.60 (11.03) 25.33 (9.38) −7.3 (8.69) [−9.51 to −5.03] −20.6 (−26.3 to −15.0)
0.25% Timolol GS 27 29.88 (8.59) 22.03 (7.32) −7.8 (8.23) [−10.90 to −4.74] −24.9 (−32.7 to −17.2)
Those ⱖ2 y-⬍6 y#
1 2% Dorzolamide 59 28.49 (7.40) 21.32 (7.95) −7.2 (5.97) −24.8
0.5% Timolol GS 29 30.26 (6.76) 22.19 (7.57) −8.1 (7.03) −26.3
4 2% Dorzolamide 60 28.22 (6.81) 20.96 (6.31) −7.3 (6.26) −24.5
0.5% Timolol GS 30 30.16 (6.63) 21.97 (7.09) −8.2 (4.22) −28.0
12 2% Dorzolamide 63 28.54 (7.49) 21.49 (6.78) −7.1 (6.74) [−8.72 to −5.39] −23.3 (−28.9 to −17.8)
0.5% Timolol GS 34 30.25 (6.61) 22.85 (8.97) −7.4 (6.74) [−9.67 to −5.13] −25.3 (−33.2 to −17.4)

Abbreviations: See Table 1.

*This was an all patients–treated analysis/last-observation-carried-forward approach. Dorzolamide was administered as dorzolamide hydrochloride, and timolol
as timolol maleate gel-forming solution.
†Data are given as mean (SD).
‡Data are given as mean (SD) [95% confidence interval].
§P⬍.001 for within-group changes from baseline (paired t test).
㛳Data are given as mean (95% confidence interval).
¶The mean (95% confidence interval) change between the 2% dorzolamide group and the 0.25% timolol GS group was 0.57 (−3.39 to 4.54), and the mean
(95% confidence interval) percentage change was 4.30 (−5.66 to 14.26).
#The mean (95% confidence interval) change between the 2% dorzolamide group and the 0.5% timolol GS group was 0.34 (−2.50 to 3.18), and the mean (95%
confidence interval) percentage change was 1.95 (−7.71 to 11.62).

36 36
2% Dorzolamide Hydrocloride 2% Dorzolamide Hydrocloride
34 0.25% Timolol Maleate GS 34
0.25% Timolol Maleate GS
32 32
Mean IOP, mm Hg

Mean IOP, mm Hg

30 30
28 28
26 26
24 24
22 22
20 20
18 18
0 1 4 12 0 1 4 12
Sample Size Study Week Sample Size Study Week
2% Dorzolamide Group 58 46 53 58 2% Dorzolamide Group 63 59 60 63
0.25% Timolol GS Group 27 22 24 27 0.25% Timolol GS Group 34 29 30 34

Figure 2. Mean (SE) intraocular pressure (IOP) in the worse eye by Figure 3. Mean (SE) intraocular pressure (IOP) in the worse eye by
treatment group for those younger than 2 years at baseline and at each study treatment group for those 2 years and older but younger than 6 years at
visit for masked monotherapy (all patients–treated analysis/last-observation- baseline and at each study visit for masked monotherapy (all
carried-forward approach). GS indicates gel-forming solution. patients–treated analysis/last-observation-carried-forward approach).
GS indicates gel-forming solution.

large studies in a pediatric population. In fact, this study burning/stinging was the most commonly reported ocu-
was planned only as a US study when enrollment began lar adverse experience.13 For the most part, the safety pro-
on November 14, 2000. Because of slow enrollment, the file of dorzolamide in this pediatric study reflected that
study was expanded worldwide and the last patient com- seen in adult studies.14,15 Systemic drug-related adverse
pleted the study on January 15, 2003. experiences were infrequently reported in adult and pe-
The most common adverse experiences reported in diatric populations.
both treatment groups were common childhood ill- Secondary measures assessed during the study, in-
nesses for these age groups, and most were not consid- cluding vital signs, visual acuity, and alertness, also sup-
ered drug related. The most common drug-related ad- ported the safety of dorzolamide and timolol GS in these
verse experiences reported for dorzolamide in this study patients. The few adverse experiences (n=2) reported for
were ocular hyperemia (5.4%) in younger patients and venous total CO2 and capillary PCO2 for patients treated
ocular burning/stinging (12.1%) in older patients. The with dorzolamide demonstrates systemic safety in this
higher incidence of burning/stinging in the older group patient population. One of these reports was in the set-
may reflect that the younger age cohort was preverbal. ting of malnutrition, vomiting, diarrhea, and fever, which
Local adverse effects were also the most common drug- could also have adversely affected the child’s electrolyte
related adverse experiences in adults in whom ocular imbalance.

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 The Pediatric Dorzolamide Study Group use has been limited by the relatively high incidence of
systemic adverse effects.5 In one adult study,16 in which
timolol was given adjunctively with dorzolamide or
Norman Aquino, MD, Manila, Philippines; Santiago
Arango, MD, Medellin, Colombia; David Coats, MD, acetazolamide, the efficacy between the 2 groups was
Houston, Tex; Janusz Czajkowski, MD, Lodz, Poland; similar, with acetazolamide demonstrating an approxi-
Pedro Debess, MD, Caracas, Venezuela; Mohammed El mately 1–mm Hg advantage over dorzolamide. In con-
Sada, MD, Cairo, Egypt; Ales Filous, MD, Prague, trast, adverse events were reported more frequently and
Czech Republic; Nikica Gabric, MD, Zagreb, Croatia; discontinuation rates were higher in patients receiving
Flor Galvez, MD, Lima, Peru; Sai Gandham, MD, acetazolamide, indicating that dorzolamide possessed
Albany, NY; David Godfrey, MD, Dallas, Tex; Federico significantly better tolerability.
Hermes, MD, Ciudad, Guatemala; Maria Hurtado, MD, In summary, 2% dorzolamide TID taken for up to 3
Bogota, Colombia; Joseph Kubacki, MD, Philadelphia, months was generally well tolerated and demonstrated
Pa; Gregg Lueder, MD, St Louis, Mo; Michael May,
efficacy in pediatric patients younger than 6 years with
MD, Aurora, Colo; Norman Medow, MD, New York,
NY; Monte D. Mills, MD, Philadelphia; David Plager, an elevated IOP or glaucoma. In addition, 2% dorzol-
MD, Indianapolis, Ind; Jaroslav Rehurek, MD, Brno, amide monotherapy seemed to be comparable in safety
Czech Republic; Manuel Rodriquez Almaraz, MD, in this study population to that reported in previous adult
Mexico City, Mexico; John Samples, MD, Portland, studies14,15 and comparable in efficacy to that reported
Ore; Colin Scher, MD, San Diego, Calif; Jonathan Song, in the published pediatric literature.5
MD, Los Angeles, Calif; Manuela Spagarino, MD, Cara-
cas, Venezuela; C. Gail Summers, MD, Minneapolis,
Minn; M. Edward Wilson, MD, Charleston, SC; Ken- Submitted for Publication: June 11, 2004; final revi-
neth Wright, MD, Los Angeles; and Johan Zwaan, MD, sion received April 26, 2005; accepted May 14, 2005.
San Antonio, Tex. Merck & Co, Inc, Personnel: Ingrid Correspondence: Ingrid A. Adamsons, MD, MPH, Merck
A. Adamsons, MD, MPH; Elyssa Z. Ott, BS; Coleen Research Laboratories, Inc, BLX-30, PO Box 4, West Point,
Clineschmidt; Scott Reines, MD, PhD; Cynthia Rusk; PA 19486.
Albert J. Getson, PhD; Michael Nessly, MS; Christopher Financial Disclosure: At the time of this study, Ms Ott
A. Assaid, PhD; and Charles Liss.
and Drs Getson, Assaid, and Adamsons were employees
of Merck & Co, Inc, and potentially own stock and/or
hold stock options in the company; and Drs Mills and
The IOP-lowering effect of dorzolamide seen in this Arango have received research grants from Merck &
study was statistically significant and was comparable to Co, Inc.
the IOP-lowering effect of 27% reported in the 6-month Funding/Support: This study was supported by Merck
study in children by Portellos et al.5 This is the only & Co, Inc.
other study in the literature, to our knowledge, to report Previous Presentation: This study was presented at
a numeric value for IOP reduction in a pediatric popula- the Association for Research in Vision and Ophthal-
tion. All other studies found in the literature for this mology Annual Meeting; April 28, 2004; Ft Lauderdale,
population stated there was a general IOP reduction, but Fla.
no values were typically provided. 4,6-8,12 The IOP- Acknowledgment: We thank Sharon Freedman, MD
lowering effects in this study and in the study by Portel- (Duke University Eye Center, Durham, NC), Michael
los et al were greater than those that have been seen in Kass, MD (Department of Ophthalmology, Washington
adults.13 In this pediatric study, the mean changes (mean University School of Medicine, St Louis, Mo), and David
percentage changes) in IOP at week 12 in younger and Walton (Boston, Mass) for their scientific advice.
older patients were −7.3 mm Hg (−20.6%) and −7.1
mm Hg (−23.3%), respectively, compared with a change REFERENCES
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From the Archives of the ARCHIVES

S ulzer stated that in France, the law on the subject

gave an indemnity of one half of the loss in wages
for partial disability caused by the accident and two thirds
of a year’s wages for total disability. Most countries have
laws similar in principle.

Reference: Sulzer A. Estimation of the value of a lost or

injured eye as regards the question of damages. Arch Oph-
thalmol. 1905:179.

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