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Ocular Hypotensive Efficacy of 0.25% Levobunolol Instilled Once Daily
Ocular Hypotensive Efficacy of 0.25% Levobunolol Instilled Once Daily THADDEUS WANDEL, MD,* DEBORAH FISHMAN, MD,* GARY D. NOVACK, PhD,tt ELAINE KELLEY, BS,t KUANKUAN S. CHEN, MSt
Abstract: The authors evaluated the efficacy of once-daily treatment with levobunolol in patients with primary open-angle glaucoma or ocular hypertension in an open-labeled, two-phase titration clinical trial. All patients started the study using 0.25% levobunolol administered once daily for 3 months (phase I). If a patient's intraocular pressure (lOP) was not controlled with this concentration of levobunolol, the concentration was increased to 0.5% administered once daily for 3 months (phase II). During phase I, a significant reduction in lOP was observed in 21 of the 29 patients (72%), with an average lOP reduction of 24%. During phase II, in six patients whose lOP was reduced inadequately with 0.25% levobunolol, one had a significant reduction in lOP with 0.5% levobunolol. The authors concluded that levobunolol, instilled once daily at a concentration of 0.25%, was effective in significantly reducing lOP in the majority of the patients evaluated. [Key words: beta-adrenergic antagonists, glaucoma, levobunolol, ocular hypertension.] Ophthalmology 95:252-255, 1988
Beta-blockers for the treatment of glaucoma are generally administered twice daily, although several reports indicate that some, such as timolol and levobunolol, are effective when instilled once daily at a concentration of 0.5%.1,2 Both of these agents, in the 0.25% concentration, have been reported to be effective in both singledrop and twice-daily studies. 3-6 From a compliance as well as a safety standpoint, reduction of both the frequency of dosing and the concentration of beta-blocker may be helpful. Therefore, we decided to evaluate 0.25% levobunolol administered once daily to determine ifthe lower concentration combined with less-frequent administration was effective in reducing elevated intraocular pressure (lOP).
From the Department of Ophthalmology: Albert Einstein School of Medicine, Montefiore Hospital, Bronx, Allergan Inc,t and the University of Califomia,:J: Irvine. Presented at the Annual Meeting of the Association for Research in Vision and Ophthalmology, May 1987. Reprint requests to Gary D. Novack, PhD, Allergan Inc, 2525 Dupont Drive, Irvine, CA 92715.
252
MATERIALS AND METHODS Study participants were patients with primary openangle glaucoma or ocular hypertension who had lOP values of at least 22 mmHg after a minimum washout period of 4 days (pilocarpine) or 14 days (epinephrine or beta-blockers). We excluded those who had cardiovascular or pulmonary contraindications to topical betablocker therapy, as well as women of child-bearing potential. All patients gave their informed consent before study entry. At baseline, we performed a complete eye examination consisting of visual acuity, lOP, biomicroscopy and ophthalmoscopy, and measured heart rate and blood pressure. Manual kinetic (Goldmann) or automated static threshold visual fields (Octopus) were obtained before study entry and again within 3 months of study completion. After the baseline examination, we instilled a drop of 0.25% levobunolol into the treated eye(s) of each patient and instructed them to continue this procedure once daily between 7:00 and 9:00. AM. Patients returned for follow-up examinations after 1 week and again monthly for 3 months. At these visits,
WANDEL et al
•
0.25% LEVOBUNOLOL ONCE DAILY
Table 1. Patient Characteristics and Diagnoses Characteristics Age (yrs) Mean ± SO 68.4 ± 14.0 34-91 Range Sex F M Race White Black Other Iris color Blue Green Brown Glaucoma diagnosis Open-angle glaucoma Ocular hypertension SO
=
No. of Patients
(%)
22 7
(76) (24)
21 6 2
(72) (21) (7)
15 1 13
(52) (3) (45)
16 13
(55) (45)
standard deviation. Table 2. Patient Disposition Patient Disposition
Phase I: 0.25% levobunolol once daily Entered Completed successfully Titrated to phase II Discontinued Adverse drug experience Phase II: 0.5% levobunolol once daily Entered Completed successfully Discontinued Lack of efficacy
No. of Patients
(%)
29 21 6
(100) (72) (21)
2
(7)
6 1
(100) (17)
5
(83)
we performed the same examinations completed at baseline with the exception of an ophthalmoscopic examination which was repeated only at the final visit. All follow-up examinations were performed in the morning before instillation of the study medication. Thus, the lOP values we measured were obtained approximately 24 hours after the last administration of the drug. This was an open-labeled titration study. Initially, patients received 0.25% levobunolol administered once daily (phase I). However, if we noticed that a patient's lOP was uncontrolled at this dosage level, we increased the concentration of levobunolol to 0.5% administered once daily (phase II). During phase II, we followed patients for an additional 3 months on the higher concentration of study medication. We defined significant lOP reduction as lOP values in the treated eye(s) 20% or more below pretreatment values. Reductions less than this were required to be
verified at two consecutive visits scheduled at least 24 hours apart. If we found a patient's lOP to be inadequately reduced during phase II, we stopped treatment with 0.5% levobunolol and initiated therapy with an alternative antiglaucoma medication. In addition, the protocol allowed for the investigator to terminate any patient from additional study participation whose lOP was judged to be sight-threatening from nerve head or visual field considerations. However, this latter criterion was not invoked in this study for any patient. All data from patients dropped from the study were included in the study analysis up to the time oftheir exit from the study. We analyzed the number of days that patients were adequately controlled under 0.25% levobunolol once-daily therapy by life-table methods with the Kaplan-Meier estimate. 7 We calculated the mean lOP using average lOP values from both treated eyes for each patient at each visit; if only one eye was treated, the lOP from the treated eye was used. Patients' data were excluded from the by-visit analyses if their actual visit deviated significantly from the schedule, or the patient took the study medication the morning of the visit. All visit data, irrespective of schedule variation, were included in the overall mean. Two-sided, 95% confidence intervals of mean lOP changes and percent changes in lOP were calculated based on the t distribution8 for phase I data only. Similar methods were used to analyze heart rate and systolic and diastolic blood pressure.
RESULTS We evaluated 29 patients with ocular hypertension or primary open-angle glaucoma whose characteristics and glaucoma diagnoses are shown in Table 1. The majority were white women with diagnoses almost evenly distributed between open-angle glaucoma and ocular hypertension. Twenty-one patients (72%) were treated successfully with 0.25% levobunolol administered once daily for the 3-month study period (Table 2). Six patients, however, had lOPs reduced inadequately with this concentration and they were treated subsequently with 0.5% levobun0101. Most of these efficacy failures occurred within the first 2 weeks of treatment (Fig 1). Of these six patients, only one patient achieved significant reduction in lOP with 0.5% levobunolol administered once daily and completed the 3 months of phase II. Before study entry, this patient had been controlled successfully with 0.5% timolol administered twice daily. The other five patients whose lOP was not adequately controlled by an increase in the concentration of levobunolol all had varied prior treatment histories: three patients had been controlled previously on two glaucoma medications (e.g., timolol in combination with either dipivefrin or pilocarpine); one patient was treated with timolol 0.5% administered twice daily; and one patient had not been treated previously. After their exit from the study, these five patients who were treatment 253
OPHTHALMOLOGY
•
FEBRUARY 1988 •
¥
VOLUME 95
•
NUMBER 2
30
E
;:;.
g,
~
0.9
~
Q)
> :;:; .Q
0.8
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<3
o
10
Table 3. Intraocular Pressure (mmHg): Mean Changes from Baseline Phase I (0.25% levobunolol) Week
No. of Patients
o(baseline)
1 4 8 12
Overall mean change =
Mean
SO
95% Confidence Intervals
26.2 -5.3 -6.4 -5.6 -7.2
3.2 3.4 2.3 2.9 2.8
(-6.9, (-7.5, (-7.0, (-8.5,
-3.7) -5.3) -4.1) -5.9)
12
Wee<.
85
t
g; $
80
&
75
0
70
t
(l)
29 20 20 18 20
8
4
Fig 2. Mean lOP (± standard error) of patients treated with 0.25% levobunolol administered once daily.
:r: c 0
(l)
65
~
60 0
8
4
12
-5.9
standard deviation.
failures at 0.25 and 0.5% levobunolol administered once daily were placed on 0.5% levobunolol administered twice daily. Adequate medical control of lOP was not observed in any of these patients. Two patients were discontinued from the study because of adverse experiences in phase I, although both had controlled lOP while taking 0.25% levobunolol instilled once daily. One patient experienced inflammation of the right eye probably due to an allergic reaction to the study medication. The second patient's reaction -flushing, dryness of the nose, and tachycardia-did not appear to be drug-related. Both patients discontinued treatment and neither chose to be rechallenged. As shown in Table 3 and Figure 2, mean decreases in lOP during phase I ranged from 5.3 (21.1%) to 7.2 mmHg (26.8%) from a mean baseline value of 26.2 mmHg. The overall mean decrease in lOP during phase I was 5.9 mmHg (23.6%). Intraocular pressure decreases ranged from 5 to 7 mmHg for the single patient whose lOP was reduced significantly during phase II. No changes in cup-disc ratio greater than 0.1 were observed, nor were there decreases in visual fields. No decreases in visual acuity greater than one line or worsening of slit-lamp findings were observed during the study period. As shown in Figures 3 and 4, during 254
o
Day
Fig 1. Life-table probability (Kaplan-Meier estimate) of successful treatment with 0.25% levobunolol administered once daily. Displayed is the probability of a patient's lOP being controlled adequately at given time points in the study. The probability of adequate control for the 3 months of the study was 78%.
SO
~+-----------~------------~----------~
20 30 40 50 60 70 80 90 100 110 120 130 140
Fig 3. Mean heart rate (± standard error) of patients treated with 0.25% levobunolol once daily.
O'l :r: E
150 140
&
130
~
120
::J
(f) (f)
ctu 0
..Q
100
m
90
0
80
c
(l)
~
Systolic
110
Diastolic
70 0
4
Week
8
12
Fig 4. Mean systolic and diastolic blood pressure (± standard error) of patients treated with 0.25% levobunolol administered once daily.
phase I, slight, nonsignificant decreases occurred in the mean heart rate and blood pressure. A few patients had clinically significant decreases in heart rate (~15%) and systolic (~20 mmHg) or diastolic blood pressure (~1O mmHg) at a few visits. Because of the limited exposure time in phase II, few data are available for relative comparisons of systemic effects produced by the 0.25 and 0.5% concentrations.
WANDEL et al
•
0.25% LEVOBUNOLOL ONCE DAILY
DISCUSSION We found that 0.25% levobunolol was an effective ocular hypotensive agent during the 3 months of this study. The efficacy was similar to that seen in previous reports for 0.25,0.5, 1% levobunolol administered twice daily5,6,9 and 0.5 to 1% levobunolol administered once daily? For the six patients (21 %) who were titrated from the 0.25 to the 0.5% concentration of levobunolol, one patient's lOP was significantly reduced on the higher concentration for a period of 3 months. The small sample size of patients receiving 0.5% levobunolol limits any definitive conclusions, although results from twice-daily studies with 0.25% levobunolol suggest that increasing the concentration to 0.5% levobunolol is helpful in some patients. 6 Levobunolol 0.25% did not have a significant effect on mean heart rate or blood pressure. In this study, mean decreases of up to 0.8 beats per minute were observed with once-daily treatment with 0.25% levobuno101. In other studies, treatment with 0.5% levobunolol administered once daily caused maximum decreases in mean heart rate of 2.2 beats per minute and treatment with 0.5% levobunolol administered twice daily produced mean heart rate decreases up to 6.4 beats per minute. 9 Thus, this lower concentration oflevobunolol may have more of a reduced systemic effect than higher concentrations in some patients.
The results of this study indicate that instillation of 0.25% levobunolol, once daily, may be an effective ocular hypotensive agent in some patients with open-angle glaucoma and ocular hypertension.
REFERENCES 1. Yalon M, Urinowsky E, Rothkoff L, et al. Frequency of timolol administration. Am J Ophthalmol1981; 92:526-9. 2. Wandel T, Charap AD, Lewis RA, et al. Glaucoma treatment with once-daily levobunolol. Am J Ophthalmol1986; 101 :298-304. 3. Zimmerman TJ, Kaufman HE. Timolol: dose response and duration of action. Arch Ophthalmol1977; 95:605-7. 4. Partamian LG, Kass MA, Gordon M. A dose-response study of the effect of levobunolol on ocular hypertension. Am J Ophthalmol1983; 95:229-32. 5. Long D, Zimmerman T, Spaeth G, et al. Minimum concentration of levobunolol required to control intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension. Am J Ophthalmol 1985; 99:18-22. 6. Boozman FW, Foerster RJ, Allen RC, et al. The long-term efficacy of twice-daily 0.25% levobunolol and timolol. ARVO Abstracts. Invest Ohthalmol Vis Sci 1987; (Suppl)28:267. 7. Lee ET. Statistical Methods for Survival Data Analysis. Belmont, CA: Lifetime Learning Publications, 1980; 75-87. 8. Snedecor GW, Cochran WG. Statistical Methods, 7th ed. Ames, Iowa: Iowa State University Press, 1980; 54-6. 9. The Levobunolol Study Group. Levobunolol: a beta-adrenoceptor antagonist effective in the long-term treatment of glaucoma. Ophthalmology 1985; 92:1271-6.
255
Abstract: The authors evaluated the efficacy of once-daily treatment with levobunolol in patients with primary open-angle glaucoma or ocular hypertension in an open-labeled, two-phase titration clinical trial. All patients started the study using 0.25% levobunolol administered once daily for 3 months (phase I). If a patient's intraocular pressure (lOP) was not controlled with this concentration of levobunolol, the concentration was increased to 0.5% administered once daily for 3 months (phase II). During phase I, a significant reduction in lOP was observed in 21 of the 29 patients (72%), with an average lOP reduction of 24%. During phase II, in six patients whose lOP was reduced inadequately with 0.25% levobunolol, one had a significant reduction in lOP with 0.5% levobunolol. The authors concluded that levobunolol, instilled once daily at a concentration of 0.25%, was effective in significantly reducing lOP in the majority of the patients evaluated. [Key words: beta-adrenergic antagonists, glaucoma, levobunolol, ocular hypertension.] Ophthalmology 95:252-255, 1988
Beta-blockers for the treatment of glaucoma are generally administered twice daily, although several reports indicate that some, such as timolol and levobunolol, are effective when instilled once daily at a concentration of 0.5%.1,2 Both of these agents, in the 0.25% concentration, have been reported to be effective in both singledrop and twice-daily studies. 3-6 From a compliance as well as a safety standpoint, reduction of both the frequency of dosing and the concentration of beta-blocker may be helpful. Therefore, we decided to evaluate 0.25% levobunolol administered once daily to determine ifthe lower concentration combined with less-frequent administration was effective in reducing elevated intraocular pressure (lOP).
From the Department of Ophthalmology: Albert Einstein School of Medicine, Montefiore Hospital, Bronx, Allergan Inc,t and the University of Califomia,:J: Irvine. Presented at the Annual Meeting of the Association for Research in Vision and Ophthalmology, May 1987. Reprint requests to Gary D. Novack, PhD, Allergan Inc, 2525 Dupont Drive, Irvine, CA 92715.
252
MATERIALS AND METHODS Study participants were patients with primary openangle glaucoma or ocular hypertension who had lOP values of at least 22 mmHg after a minimum washout period of 4 days (pilocarpine) or 14 days (epinephrine or beta-blockers). We excluded those who had cardiovascular or pulmonary contraindications to topical betablocker therapy, as well as women of child-bearing potential. All patients gave their informed consent before study entry. At baseline, we performed a complete eye examination consisting of visual acuity, lOP, biomicroscopy and ophthalmoscopy, and measured heart rate and blood pressure. Manual kinetic (Goldmann) or automated static threshold visual fields (Octopus) were obtained before study entry and again within 3 months of study completion. After the baseline examination, we instilled a drop of 0.25% levobunolol into the treated eye(s) of each patient and instructed them to continue this procedure once daily between 7:00 and 9:00. AM. Patients returned for follow-up examinations after 1 week and again monthly for 3 months. At these visits,
WANDEL et al
•
0.25% LEVOBUNOLOL ONCE DAILY
Table 1. Patient Characteristics and Diagnoses Characteristics Age (yrs) Mean ± SO 68.4 ± 14.0 34-91 Range Sex F M Race White Black Other Iris color Blue Green Brown Glaucoma diagnosis Open-angle glaucoma Ocular hypertension SO
=
No. of Patients
(%)
22 7
(76) (24)
21 6 2
(72) (21) (7)
15 1 13
(52) (3) (45)
16 13
(55) (45)
standard deviation. Table 2. Patient Disposition Patient Disposition
Phase I: 0.25% levobunolol once daily Entered Completed successfully Titrated to phase II Discontinued Adverse drug experience Phase II: 0.5% levobunolol once daily Entered Completed successfully Discontinued Lack of efficacy
No. of Patients
(%)
29 21 6
(100) (72) (21)
2
(7)
6 1
(100) (17)
5
(83)
we performed the same examinations completed at baseline with the exception of an ophthalmoscopic examination which was repeated only at the final visit. All follow-up examinations were performed in the morning before instillation of the study medication. Thus, the lOP values we measured were obtained approximately 24 hours after the last administration of the drug. This was an open-labeled titration study. Initially, patients received 0.25% levobunolol administered once daily (phase I). However, if we noticed that a patient's lOP was uncontrolled at this dosage level, we increased the concentration of levobunolol to 0.5% administered once daily (phase II). During phase II, we followed patients for an additional 3 months on the higher concentration of study medication. We defined significant lOP reduction as lOP values in the treated eye(s) 20% or more below pretreatment values. Reductions less than this were required to be
verified at two consecutive visits scheduled at least 24 hours apart. If we found a patient's lOP to be inadequately reduced during phase II, we stopped treatment with 0.5% levobunolol and initiated therapy with an alternative antiglaucoma medication. In addition, the protocol allowed for the investigator to terminate any patient from additional study participation whose lOP was judged to be sight-threatening from nerve head or visual field considerations. However, this latter criterion was not invoked in this study for any patient. All data from patients dropped from the study were included in the study analysis up to the time oftheir exit from the study. We analyzed the number of days that patients were adequately controlled under 0.25% levobunolol once-daily therapy by life-table methods with the Kaplan-Meier estimate. 7 We calculated the mean lOP using average lOP values from both treated eyes for each patient at each visit; if only one eye was treated, the lOP from the treated eye was used. Patients' data were excluded from the by-visit analyses if their actual visit deviated significantly from the schedule, or the patient took the study medication the morning of the visit. All visit data, irrespective of schedule variation, were included in the overall mean. Two-sided, 95% confidence intervals of mean lOP changes and percent changes in lOP were calculated based on the t distribution8 for phase I data only. Similar methods were used to analyze heart rate and systolic and diastolic blood pressure.
RESULTS We evaluated 29 patients with ocular hypertension or primary open-angle glaucoma whose characteristics and glaucoma diagnoses are shown in Table 1. The majority were white women with diagnoses almost evenly distributed between open-angle glaucoma and ocular hypertension. Twenty-one patients (72%) were treated successfully with 0.25% levobunolol administered once daily for the 3-month study period (Table 2). Six patients, however, had lOPs reduced inadequately with this concentration and they were treated subsequently with 0.5% levobun0101. Most of these efficacy failures occurred within the first 2 weeks of treatment (Fig 1). Of these six patients, only one patient achieved significant reduction in lOP with 0.5% levobunolol administered once daily and completed the 3 months of phase II. Before study entry, this patient had been controlled successfully with 0.5% timolol administered twice daily. The other five patients whose lOP was not adequately controlled by an increase in the concentration of levobunolol all had varied prior treatment histories: three patients had been controlled previously on two glaucoma medications (e.g., timolol in combination with either dipivefrin or pilocarpine); one patient was treated with timolol 0.5% administered twice daily; and one patient had not been treated previously. After their exit from the study, these five patients who were treatment 253
OPHTHALMOLOGY
•
FEBRUARY 1988 •
¥
VOLUME 95
•
NUMBER 2
30
E
;:;.
g,
~
0.9
~
Q)
> :;:; .Q
0.8
::J
E
<3
o
10
Table 3. Intraocular Pressure (mmHg): Mean Changes from Baseline Phase I (0.25% levobunolol) Week
No. of Patients
o(baseline)
1 4 8 12
Overall mean change =
Mean
SO
95% Confidence Intervals
26.2 -5.3 -6.4 -5.6 -7.2
3.2 3.4 2.3 2.9 2.8
(-6.9, (-7.5, (-7.0, (-8.5,
-3.7) -5.3) -4.1) -5.9)
12
Wee<.
85
t
g; $
80
&
75
0
70
t
(l)
29 20 20 18 20
8
4
Fig 2. Mean lOP (± standard error) of patients treated with 0.25% levobunolol administered once daily.
:r: c 0
(l)
65
~
60 0
8
4
12
-5.9
standard deviation.
failures at 0.25 and 0.5% levobunolol administered once daily were placed on 0.5% levobunolol administered twice daily. Adequate medical control of lOP was not observed in any of these patients. Two patients were discontinued from the study because of adverse experiences in phase I, although both had controlled lOP while taking 0.25% levobunolol instilled once daily. One patient experienced inflammation of the right eye probably due to an allergic reaction to the study medication. The second patient's reaction -flushing, dryness of the nose, and tachycardia-did not appear to be drug-related. Both patients discontinued treatment and neither chose to be rechallenged. As shown in Table 3 and Figure 2, mean decreases in lOP during phase I ranged from 5.3 (21.1%) to 7.2 mmHg (26.8%) from a mean baseline value of 26.2 mmHg. The overall mean decrease in lOP during phase I was 5.9 mmHg (23.6%). Intraocular pressure decreases ranged from 5 to 7 mmHg for the single patient whose lOP was reduced significantly during phase II. No changes in cup-disc ratio greater than 0.1 were observed, nor were there decreases in visual fields. No decreases in visual acuity greater than one line or worsening of slit-lamp findings were observed during the study period. As shown in Figures 3 and 4, during 254
o
Day
Fig 1. Life-table probability (Kaplan-Meier estimate) of successful treatment with 0.25% levobunolol administered once daily. Displayed is the probability of a patient's lOP being controlled adequately at given time points in the study. The probability of adequate control for the 3 months of the study was 78%.
SO
~+-----------~------------~----------~
20 30 40 50 60 70 80 90 100 110 120 130 140
Fig 3. Mean heart rate (± standard error) of patients treated with 0.25% levobunolol once daily.
O'l :r: E
150 140
&
130
~
120
::J
(f) (f)
ctu 0
..Q
100
m
90
0
80
c
(l)
~
Systolic
110
Diastolic
70 0
4
Week
8
12
Fig 4. Mean systolic and diastolic blood pressure (± standard error) of patients treated with 0.25% levobunolol administered once daily.
phase I, slight, nonsignificant decreases occurred in the mean heart rate and blood pressure. A few patients had clinically significant decreases in heart rate (~15%) and systolic (~20 mmHg) or diastolic blood pressure (~1O mmHg) at a few visits. Because of the limited exposure time in phase II, few data are available for relative comparisons of systemic effects produced by the 0.25 and 0.5% concentrations.
WANDEL et al
•
0.25% LEVOBUNOLOL ONCE DAILY
DISCUSSION We found that 0.25% levobunolol was an effective ocular hypotensive agent during the 3 months of this study. The efficacy was similar to that seen in previous reports for 0.25,0.5, 1% levobunolol administered twice daily5,6,9 and 0.5 to 1% levobunolol administered once daily? For the six patients (21 %) who were titrated from the 0.25 to the 0.5% concentration of levobunolol, one patient's lOP was significantly reduced on the higher concentration for a period of 3 months. The small sample size of patients receiving 0.5% levobunolol limits any definitive conclusions, although results from twice-daily studies with 0.25% levobunolol suggest that increasing the concentration to 0.5% levobunolol is helpful in some patients. 6 Levobunolol 0.25% did not have a significant effect on mean heart rate or blood pressure. In this study, mean decreases of up to 0.8 beats per minute were observed with once-daily treatment with 0.25% levobuno101. In other studies, treatment with 0.5% levobunolol administered once daily caused maximum decreases in mean heart rate of 2.2 beats per minute and treatment with 0.5% levobunolol administered twice daily produced mean heart rate decreases up to 6.4 beats per minute. 9 Thus, this lower concentration oflevobunolol may have more of a reduced systemic effect than higher concentrations in some patients.
The results of this study indicate that instillation of 0.25% levobunolol, once daily, may be an effective ocular hypotensive agent in some patients with open-angle glaucoma and ocular hypertension.
REFERENCES 1. Yalon M, Urinowsky E, Rothkoff L, et al. Frequency of timolol administration. Am J Ophthalmol1981; 92:526-9. 2. Wandel T, Charap AD, Lewis RA, et al. Glaucoma treatment with once-daily levobunolol. Am J Ophthalmol1986; 101 :298-304. 3. Zimmerman TJ, Kaufman HE. Timolol: dose response and duration of action. Arch Ophthalmol1977; 95:605-7. 4. Partamian LG, Kass MA, Gordon M. A dose-response study of the effect of levobunolol on ocular hypertension. Am J Ophthalmol1983; 95:229-32. 5. Long D, Zimmerman T, Spaeth G, et al. Minimum concentration of levobunolol required to control intraocular pressure in patients with primary open-angle glaucoma or ocular hypertension. Am J Ophthalmol 1985; 99:18-22. 6. Boozman FW, Foerster RJ, Allen RC, et al. The long-term efficacy of twice-daily 0.25% levobunolol and timolol. ARVO Abstracts. Invest Ohthalmol Vis Sci 1987; (Suppl)28:267. 7. Lee ET. Statistical Methods for Survival Data Analysis. Belmont, CA: Lifetime Learning Publications, 1980; 75-87. 8. Snedecor GW, Cochran WG. Statistical Methods, 7th ed. Ames, Iowa: Iowa State University Press, 1980; 54-6. 9. The Levobunolol Study Group. Levobunolol: a beta-adrenoceptor antagonist effective in the long-term treatment of glaucoma. Ophthalmology 1985; 92:1271-6.
255