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Timolol Hemihydrate vs Timolol Maleate to Treat Ocular Hypertension and Open-Angle Glaucoma
Timolol Hemihydrate vs Timolol Maleate to Treat Ocular Hypertension and Open-Angle Glaucoma HARVEY B. DuBINER, MD., RICHARD HILL, MD., HERBERT KAUFMAN, M.D., EDWIN U. KEATES, MD., THOM J. ZIMMERMAN, MD., ALAN I. MAN DELL, M.D., THOMAS K. MUNDORF, MD., ROBERT L. BAHR, MD., LOUIS W. SCHWARTZ, MD., ANNE W. TOWEY, MD., LAWRENCE M. HURVITZ, MD., RICHARD J. STARITA, M.D., JOSEPH W. SASSANI, MD., AULI ROPO, MD., RON GUNN, MS., AND WILLIAM C. STEWART, M.D. • PURPOSE: We compared the therapeutic efficacy and safety of timolol hemihydrate to timolol maleate in patients with ocular hypertension and chronic open-angle glaucoma. • METHODS: We conducted this three-month study as a multicentered, masked, parallel group comparison. Both the 0.25% and 0.5% concentra tions were evaluated against similar concentra tions of timolol maleate. Dosing was twice daily. An open-label, nine-month study followed the masked portion of the protocol, in which all patients received either 0.25% or 0.5% timolol Accepted for publication Dec. 4, 1995. From the Clayton Eye Center, Morrow, Georgia (Dr. DuBiner); University of California, Irvine, Irvine, California (Dr. Hill); LSU Eye Center, New Orleans, Louisiana (Dr. Kaufman); Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania (Dr. Keates); University of Louisville, Louisville, Kentucky (Dr. Zimmerman); pri vate practice, Memphis, Tennessee (Dr. Mandell); private practice, Charlotte, North Carolina (Dr. Mundorf); Brown University School of Medicine, Providence, Rhode Island (Dr. Bahr); Ophthalmic Associ ates, Lansdale, Pennsylvania (Dr. Schwartz); Park-Nicollet Medical Center, Minneapolis, Minnesota (Dr. Towey); private practice, Sarasota, Florida (Dr. Hurvitz); Glaucoma Associates of Texas, Dallas, Texas (Dr. Starita); Milton S. Hershey Medical Centet, Hershey, Pennsylva nia (Dr. Sassani); Employees of Leiras Oy (Dr. Ropo and Mr. Gunn); and Medical University of South Carolina, Charleston, South Carolina (Dr. Stewart). Investigators had a contractual agreement with Leiras Oy, Turku, Finland, the sponsor of this study. Reprint requests to William C. Stewart, M.D., Storm Eye Institute, Medical University of South Carolina, 171 Ashley Ave., Charleston, SC 29425-2236; fax: (803) 792-5193.
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hemihydrate. A total of 371 patients were included in both the 0.25% and 0.5% studies. • RESULTS: We found statistically similar intraoc ular pressures with both the 0.25% (18.3 and 18.6 mm Hg for the hemihydrate and maleate groups, respectively) and 0.5% (19.9 and 19.5 mm Hg for the hemihydrate and maleate groups, respectively) concentrations of timolol hemihy drate and timolol maleate after three months of masked treatment. Likewise, peak intraocular ef fect at two hours after taking the medication was statistically similar between medicines at both concentrations. Likewise, both ocular and system ic safety were similar between the maleate and hemihydrate preparations at both concentrations. In the nine-month open-label protocol, therapeu tic efficacy (19.9 and 19.1 mm Hg for the 0.25% and 0.5% concentrations, respectively) and safety of timolol hemihydrate were similar to effect and safety of the three-month protocol. • CONCLUSIONS: This study suggests that timolol hemihydrate had an ocular hypotensive efficacy and safety profile statistically equivalent to that of timolol maleate for up to three months of therapy. Timolol hemihydrate showed efficacy and safety similar to that observed within the first three months, for up to one year of therapy.
© AMERICAN JOURNAL OF OPHTHALMOLOGY 1996;121:522-528
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B
ETA-BLOCKERS HAVE BEEN USED TO TREAT GLAU-
coma and ocular hypertension for almost two decades.1'3 Although they are effective in de creasing the intraocular pressure, concerns persist over the side effects1'3 and cost of these medicines.4 Betaxolol (^-selective adrenergic blocker),5 carteolol (nonselective ß-blocker with partial agonism),6 and preservative-free timolol maleate have been intro duced commercially to help limit the side effects. In this study, we compared the therapeutic efficacy and side effects of timolol hemihydrate vs timolol maleate in a multicenter, randomized, masked, paral lel group comparison. Timolol hemihydrate has the potential advantages of simplifying the formulation process of timolol and eliminating the maleate salt.
PATIENTS AND METHODS WE INCLUDED IN THIS STUDY PATIENTS OVER 18 YEARS OF
age with ocular hypertension or chronic open-angle glaucoma. We defined ocular hypertension as an increased intraocular pressure (22 mm Hg or greater) with no observable glaucomatous changes in the visual field or optic disk. We defined chronic openangle glaucoma as an intraocular pressure of 22 mm Hg or greater, with glaucomatous optic disk changes (saucerization, notching, or rim thinning in the superior or inferior temporal portion of the optic disk) with or without perimetric evidence of glaucomatous visual field defects (nasal step or SeidePs, paracentral, or arcuate scotoma). All patients had open and normal angles by gonioscopy. Before entering the study, each patient signed an informed consent. At each study center, the study was approved by an institutional review board. Patients were excluded if any of the following were found in either eye: marked retinal or neurologic optic nerve disease, recent history of ocular trauma, infec tion or inflammation, corneal topography that pre vented reliable applanation tonometry, intraocular surgery in the past six months or laser ocular surgery in the past three months, best-corrected visual acuity of 20/100 or worse, a pupil that would not dilate sufficiently for examination of the optic disk and retina, contact lens wear, diseases adversely affected by a ß-adrenergic blocker (reactive airway disease or cardiac arrhythmia), any terminal illness, secondary VOL.121, No. 5
glaucomas (including pigment dispersion and exfolia tion glaucoma), hypersensitivity to a compound in the study medications, glaucoma that was advanced or required more than one medicine for intraocular pressure control, severe dry eyes, and therapy with an ot-adrenergic agonist. Pregnant or nursing women or premenopausal women not using birth control pills also were excluded. Two separate study protocols were performed. In one protocol, we evaluated the 0.25% maleate and hemihydrate solutions, and in the other, the 0.5% solutions. Patients were randomly assigned within each protocol to either timolol hemihydrate or timolol maleate in a double-masked, parallel group compari son over a three-month period. At the screening examination, we ensured that each patient met all exclusion and inclusion criteria before study enrollment. Qualified patients then un derwent an ocular examination, including inspection of the adnexa, Snellen visual acuity, manifest refrac tion, color vision testing (Farnsworth-Munsell 28hue color vision test), Schirmer's testing, slit-lamp biomicroscopy, and gonioscopy. After pharmacologie mydriasis, ophthalmoscopy was performed as well as visual field testing with either the Humphrey Field Analyzer program 30-2 or the Octopus program G-l. Blood pressure and pulse also were measured. All procedures were performed in the same manner throughout the study. At the screening examination, if patients qualified for the study, their current glaucoma medicine was discontinued for an appropriate washout period (three weeks for a ß-adrenergic blocker and two weeks for all other classes of glaucoma medicines) before they entered the active treatment portion of the trial. After the washout period, patients were required to have an intraocular pressure of between 22 and 34 mm Hg to enter the active treatment phase. If this condition was satisfied, the patient was provided with a masked medication bottle (0.25% or 0.5% timolol maleate or hemihydrate) according to a randomized number list. Patients were instructed to use one drop of this formulation in each eye every 12 hours, except on the morning of a study examination. At baseline, the initial drops of masked medicine were instilled, and two hours later blood pressure, pulse, and the intraocular pressure were measured.
TIMOLOL HEMIHYDRATE VS MALEATE FOR GLAUCOMA
523
TABLE 1 CHARACTERISTICS OF PATIENTS INCLUDED IN THIS STUDY
Mean ± S.D. age (yrs) Range <60 a=60 Gender Male Female Race White Nonwhite Iris color Brown/black Other Diagnosis Open-angle glaucoma Ocular hypertension
TIMOLOL
TIMOLOL
HEMIHYDRATE 0.25% (N = 91)
MALEATE 0.25%
TIMOLOL HEMIHYDRATE 0.5%
TIMOLOL MALEATE 0.5%
(N = 92)
(N = 93)
(N = 95)
NO. (%)
NO. (%)
NO. (%)
NO. (%)
61.2 ± 11.3 30-87 34(37) 57 (63)
58.6 ± 14.1 18-87 43 (47) 49 (53)
58.5 ± 14.5 26-83 42 (45) 51 (55)
62.1 ±11.6 28-88 36(38) 59 (62)
44 (48) 47 (52)
48 (52) 44 (48)
43 (46) 50 (54)
46 (48) 49 (52)
82(90) 9(10)
77(84) 15(16)
79 (85) 14(15)
79(83) 16(17)
42 (46) 49 (54)
47(51) 45 (49)
41 (44) 52 (56)
45 (47) 50 (53)
60 (66) 31 (34)
60 (65) 32 (35)
53(57) 40 (43)
58(61) 37 (39)
At the visits at weeks 1, 2, 4, and 8, after the masked study medicine was dispensed, visual acuity and applanation tonometry were measured and slitlamp biomicroscopy was performed. At week 4, two hours after medication was given, intraocular pres sure, blood pressure, and pulse were measured. At week 12, two hours after medication was given, intraocular pressure was measured before completion of an examination similar to that performed at the screening visit. At the conclusion of the week 12 examination, all patients were given the option to continue in a nine-month, open-label follow-up period using one drop of timolol hemihydrate in both eyes twice a day at the concentration (0.25% or 0.5%) used in the masked portion of the trial. At three and six months after enrolling in the open-label trial, patients were examined with the following tests: Snellen visual acuity, applanation tonometry, slit-lamp biomicrosco py, blood pressure, and pulse rate. At the nine-month open-label trial visit (one year after the beginning of active treatment), each patient had a final examina tion similar to that performed at the screening visit. Additionally, two hours after medication was given, intraocular pressure was measured before the exami nation with a dilated pupil. 524
Adverse events were recorded at each visit. Patients who were not controlled sufficiently by the study medication or who suffered an adverse event that was incompatible with the patient's clinical safety or lifestyle were discontinued from the study. Statistical analysis was performed for the primary efficacy variable of intraocular pressure by using a repeated measures analysis of variance. The average of the values for the right and left eyes was used for data analysis.7 An S.D. of 2.5 mm Hg was assumed to project the needed sample size for the study.8 The primary estimate of interest was that the lower 90% confidence interval, to establish equivalence between the test and reference study agents at the final visit, would not be greater than or equal to — 1 mm Hg. Vital signs also were analyzed with a repeated mea sures analysis. Safety data were analyzed with Fisher's exact test.9 An a level of 0.05 was used for all statistical tests.7
RESULTS BASELINE MEASUREMENTS FOR THE 371 PATIENTS EN-
rolled in both the 0.25% and 0.5% clinical protocols are given in Table 1. The only statistical difference
AMERICAN JOURNAL OF OPHTHALMOLOGY
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between the hemihydrate and maleate treatment groups was in mean age (P = .021). In the 0.25% study, the age for the timolol hemihydrate group was higher, whereas in the 0.5% study, the age for the timolol maleate group was higher. In Fig. 1, the intraocular pressure readings at baseline and for each visit at trough during the three-month masked comparison study are shown. No significant difference at any visit was observed between the two medicines for either concentration. For the 0.25% and 0.5% solutions, the 90% confi dence intervals for the difference between timolol
maleate and hemihydrate (intraocular pressure at the final visit of masked periods) were -0.912 to 0.518 and —0.591 to 0.814, respectively. Both concentra tions fulfilled the criteria for equivalence that the 90% confidence interval was not greater than or equal to — 1 mm Hg. At the end of the open-label portion of the trial (timolol hemihydrate treatment only), the trough intraocular pressure was 19.9 and 19.1 mm Hg for the 0.25% and 0.5% concentrations, respectively. Peak drug effect measured at two hours after medication was given is provided in Table 2. These measurements were statistically similar between both medicines for the 0.25% and 0.5% concentrations. Tables 3 and 4 provide ocular and systemic signs and symptoms noted in the study that occurred more than once or were life threatening. No ocular or systemic side effect reached statistical significance between medicines for either concentration. Three patients had an adverse event serious enough to discontinue the medicine, two patients who used timolol maleate (one with a myocardial infarction and one with bronchospasm as well as dyspnea) and one who used timolol hemihydrate (because of severe asthenia from pancreatic carcino ma). Eleven other patients (five receiving timolol hemihydrate and six receiving timolol maleate) had a serious adverse event during the masked portion of the study but which did not necessitate discontinuing
Timolol hemihydrate 0.25% Timolol maleate 0.25% T i m o l o l hemih.vdralc 0.5% T i m o l o l maleate 0.5% 0.
O
Weeks
Fig. 1 (DuBiner and associates). Intraocular pressure readings at baseline and for each visit during the masked portion of the study for 0.25% and 0.5% timolol maleate and timolol hemihydrate.
TABLE 2 PEAK EFFECTS (TWO HOURS AFTER DOSE) OF 0.25% AND 0.5% TIMOLOL SOLUTIONS ON INTRAOCULAR PRESSURE (MM He; MEAN * S.D.) TIMOLOL 0.25%
Baseline No. of patients After washout Peak effect Week 4 No. of patients Trough value Peak effect Week 12 No. of patients Trough value Peak effect
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TIMOLOL 0.5%
HEMIHYDRATE
MALEATE
HEMIHYDRATE
MALEATE
91 24.4 ± 0.2 17.5 ± 0.3
91 24.4 ± 0.3 17.2 ± 0.3
91 24.9 ± 0.3 16.5 ± 0.3
92 25.0 ± 0.3 16.6 ± 0.3
86 19.9 ± 0.3 17.7 ± 0.3
90 19.7 ± 0.2 17.5 ± 0.2
85 18.5 ± 0.4 17.3 ± 0.4
87 18.9 ± 0.3 17.8 ± 0.3
85 20.2 ± 0.3 17.8 ± 0.3
89 19.5 ± 0.3 17.5 ± 0.3
84 17.9 + 0.3 16.7 ± 0.3
80 18.2 ± 0.4 17.1 ± 0.4
TIMOLOL HEMIHYDRATE VS MALEATE FOR GLAUCOMA
525
TABLE 3 OCULAR ADVERSE EVENTS 0.5% TIMOLOL HEMIHYDRATE SYMPTOMS
Blepharitis Burning or stinging On instillation Continuous Corneal lesion Discharge from eye Discomfort of eye Dry eyes Epiphora Eyelid erythema Blurred vision Foreign body sensation Conjunctival hemorrhage Injection Itching Keratitis Photophobia Fluorescein staining Retinal hemorrhage Vitreous disorder
MALEATE
HEMIHYORATE
MALEATE
NO. (%)
NO. (%)
1 (1.1)
2 (2.2)
1 (1.1)
45 (49.5) 3 (3.2) 5 (5.4) 1 (1.1) 5 (5.4) 9 (9.7) 5 (5.4) 4 (4.3) 3 (3.3) 6 (6.5) 0 (0) 6 (6.5) 8 (8.6) 8 (8.6) 1 (1.1) 0 (0) 1 (1.1) 2 (2.2)
20 (22.0) 2 (2.2)
23 (25.0) 1 (1.1)
0 (0) 1 (1.1) 13(14.3) 12(13.2) 5 (5.5) 8 (8.8) 3 (3.3) 6 (6.6)
0 (0) 1 (2.2) 12(13.0) 6 (6.5) 3 (3.3) 6 (6.5) 0 (0) 6 (6.5) 0 (0) 15(16.3) 11 (12.0) 3 (3.3)
NO. (%)
NC
2 (2.2) 38(41.8) 3 (3.3) 3 (3.3) 1 (1.1) 10(11.0) 6 (6.5) 8 (8.8) 4 (4.4) 3 (3.3) 4 (4.4) 2 (2.2) 4 (4.4) 12(13.2) 6 (6.6) 1 (1.1) 1 (1.1) 1 (1.1) 0 (0)
the drug and was considered definitely or probably not related to the study medication. Adverse events in the open-label period were similar to those in the 12week masked period. Few notable changes occurred in visual field, optic disk, and visual acuity during the study. Three patients, who had normal visual fields at screening, had one eye progress to nerve fiber layer changes. Two patients had decreased visual acuity and visual field, one because of a vein occlusion and another from a diabetic vitreous hemorrhage. Vital signs data from the masked portion of the treatment trial are shown in Fig. 2. For both concen trations of both timolol maleate and hemihydrate, a significant overall reduction from baseline was ob served for the systolic (P = .030) and diastolic blood pressure (P = .019) as well as pulse rate (P < .001). Timolol maleate showed a greater reduction in pulse than timolol hemihydrate did at week 12 for both concentrations (P = .01). At the end of the nine-month open-label portion of the study, pulse (72.2/min for 0.25% and 70.2/min for 0.5%) and systolic (134.5 mm Hg for 0.25% and 526
0.25% TIMOLOL
>■
( % )
0 8 6 2 4 7 0 0
(0) (8.8) (6.6) (2.2) (4.4) (7.7) (0) (0)
1 (1-1) 3 (3.3) 0 (0) 2 (2.2)
130.6 mm Hg for 0.5%) and diastolic (81.5 mm Hg for 0.25% and 78.4 mm Hg for 0.5%) blood pressure levels were similar to levels observed during the masked portion of the trial (Fig. 2).
DISCUSSION IN THIS STUDY, WE EVALUATED A NEW FORMULATION OF
timolol prepared as a hemihydrate. We compared this medicine's efficacy in lowering the intraocular pres sure, as well as the ocular and systemic side effects, to that of timolol maleate. We found that timolol hemihydrate decreased the intraocular pressure from baseline to an extent statis tically similar to that of timolol maleate at both the 0.25% and 0.5% concentrations throughout the 12-week masked portion of the protocol. Additional ly, the peak intraocular pressure-decreasing effect two hours after taking the medication was similar be tween preparations for both the 0.25% and 0.5% concentrations. Ocular and systemic safety between medications
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TABLE 4 NONOCULAR ADVEflSE EVENTS 0.5% TIMOLOL
0.25% TIMOLOL
HEMIHYDRATE
MALEATE
HEMIHYDRATE
MALEATE
SYMPTOMS
NO. (%)
NO. (%)
NO. (%)
NO. (%)
Allergic reaction Asthenia Headache Chest pain Body pain Cardiac arrhythmia Bradycardia Systemic hypertension Myocardial infarction Constipation Peripheral edema Depression Dizziness Dry mouth Asthma Dyspnea Respiratory infection Nausea
3 (3.3) 0 (0) 8 (8.8)
3 (3.3) 1(1.1) 6 (6.5) 0 (0)
0 3 2 1 0 1 0 4
2 0 3 2 0 0 0 5 0 0 0 0 0 0
(2.2) (0) (3.3) (2.2) (0) (0) (0) (5.5) (0) (0) (0) (0) (0) (0)
0 0 0 0
(0) (0) (0) (0)
0 (0) 2(2.2) 0 (0) 0 (0) 1 (1.1) 0 (0) 1(1.1) 2 (2.2) 0 (0) 3 (3.3) 2 (2.2) 0 (0) 1(1.1) 3 (3.3) 2 (2.2)
1 2 2 2
(1-1) (2.2) (2.2) (2.2)
1 (1.1) 2 (2.2) 1 (1.1) 2 (2.2) 0 (0) 1 (1.1) 1 (1.1) 1(1.1) 2 (2.2) 0 (0)
Timolol hemihydrate 0.25%
s s
0 (0) 0 (0) 1 (1.1) 1(1.1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.1)
Timolol hemihydrale 0.25% 85
Timolol maleate 0.25%
X
(0) (3.3) (2.2) (1.1) (0) (1.1) (0) (4.4)
Timolol hemihydrate 0 3 %
e
Timolol maleate 0.5%
Timolol maleate 0.25% Timolol hemihydrale 0.5%
■" 82.5-
t a
77.5
75· 2
4
Weeks Timolol hemihydrale 0.25% Timolol maleate 0.25% Timolol hemihydrate 0.5%
Fig. 2 (DuBiner and associates). Graphs show mean and S.D. for systolic (top left) and diastolic (top right) blood pressure as well as pulse rate (bottom left) at each visit in the masked portion of the study. Data are shown for both concentrations of the hemihydrate and maleate timolol forms.
5 72-
6
71-
«5
I —r-
baseline
Weeks VOL.121, No. 5
12
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527
appeared to be similar for both the 0.25% and 0.5% concentrations. A reduced pulse rate was noted in patients treated with timolol maleate 0.25% compared with those treated with timolol hemihydrate, but it was believed not to be clinically important. Overall differences between formulations were inconsistent, and no clear trends were evident. Clinical deterioration (on the basis of optic disk, visual field, and visual acuity examinations) was observed in five patients who had a high degree of probability of worsening. These patients ostensibly had controlled intraocular pressure during the trial. Two of these patients had a vascular event (vitreous hemorrhage related to diabetic retinopathy and a hemiretinal vein occlusion), whereas three patients had a new-onset scotoma in the visual field. No confirmation visual fields were performed. No clear trends to a particular study medication associated with worsening of visual function were indicated. In the nine-month, open-label portion of the trial, patients were treated with timolol hemihydrate only. The intraocular pressure efficacy and safety findings were similar to those in the masked portion of the trial. Consequently, the ocular hypotensive effect and safety profile of timolol hemihydrate appear to be maintained over the first year of treatment. The timolol product studied in this clinical trial was manufactured according to a patented process that has several differences compared with previous formulation techniques. First, it simplifies the formu lation method for timolol by reducing the purification process for the more active S-enantiomer into a single crystallization step.10,11 Second, timolol hemihydrate eliminates the maleate buffer from the solution. In a recent article, Ball and Schneider4 commented that the average cost of commercially available timolol maleate in three diverse locations was $15.72 for a 5-ml bottle, $27.13 for a 10-ml bottle, and $38.31 for a 15-ml bottle. A simplified manufacturing process potentially could help reduce the cost of timolol to the pharmacy. The results of this study suggest that timolol hemihydrate has an ocular hypotensive efficacy and safety profile comparable to those of timolol maleate for both the 0.25% and 0.5% concentrations for up to three months of therapy. Timolol hemihydrate shows continued efficacy and safety for up to one year of therapy. 528
In this study, we found no clear advantage to timolol hemihydrate over timolol maleate in thera peutic efficacy or safety. However, the techniques (subjective grading of ocular signs and patientinitiated symptom reporting) used to evaluate adverse events in this study may not have been sensitive enough to detect subtle changes in the safety profile between the two medicines. Likewise, this study did not determine the long-term efficacy of timolol hemi hydrate compared with timolol maleate, for which ten-year follow-up studies are available.12 Further experience and study will help to determine the place of timolol hemihydrate in the therapeutic regi men of ocular hypertension and chronic open-angle glaucoma. ACKNOWLEDGMENT
Kay Hart, Ph.D., Data Inc., Hazel, Kentucky, provid ed statistical assistance.
REFERENCES 1. Zimmerman TJ, Harbin R, Pett M, Kaufman HE. Timolol and facility outflow. Invest Ophthalmol Vis Sci 1977; 16:623-4. 2. Lin L-L, Galin MA, Obstbaum SA, Katz I. Longterm timolol therapy. Surv Ophthalmol 1979;23:377-80. 3. Zimmerman TJ, Kaufman HE. Timolol: a ß-adrenergic blocking agent for the treatment of glaucoma. Arch Oph thalmol 1977;95:601-7. 4. Ball SF, Schneider E. Cost of ß-adrenergic blocking agents for ocular hypertension. Arch Ophthalmol 1992;110:654-7. 5. Berrospi AR, Leibowitz HM. Betaxolol: a new ß-adrenergic blocking agent for the treatment of glaucoma. Arch Oph thalmol 1982;100:943-6. 6. Stewart WC, Shields MB, Allen RC, Lewis RA, Cohen JS, Hoskins HD, et al. A three-month comparison of 1% and 2% carteolol and 0.5% timolol in open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol 1991;229:258-61. 7. Book SA. Essentials of statistics. New York: McGraw Hill, 1978:223-47. 8. Novack GD. Ophthalmic ß-blockers since timolol. Surv Ophthalmol 1987;31:307-27. 9. Swinscow TDV. Statistics at square one. London: British Medical Association, 1976:54-7. 10. Keates EU, Stone R. The effect of d-timolol on intraocular pressure in patients with ocular hypertension. Am J Ophthal mol 1984;98:73-8. 11. Liu JHK, Bartels SP, Neufeld AH. Effects of 1- and d-timolol on cyclic AMP synthesis and intraocular pressure in waterloaded, albino and pigmented rabbits. Invest Ophthalmol Vis Sci 1983;24:1276-82. 12. Goethals M. Ten-year follow-up of timolol-treated openangle glaucoma [summary]. Surv Ophthalmol 1989;33 Suppl:463-4·
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hemihydrate. A total of 371 patients were included in both the 0.25% and 0.5% studies. • RESULTS: We found statistically similar intraoc ular pressures with both the 0.25% (18.3 and 18.6 mm Hg for the hemihydrate and maleate groups, respectively) and 0.5% (19.9 and 19.5 mm Hg for the hemihydrate and maleate groups, respectively) concentrations of timolol hemihy drate and timolol maleate after three months of masked treatment. Likewise, peak intraocular ef fect at two hours after taking the medication was statistically similar between medicines at both concentrations. Likewise, both ocular and system ic safety were similar between the maleate and hemihydrate preparations at both concentrations. In the nine-month open-label protocol, therapeu tic efficacy (19.9 and 19.1 mm Hg for the 0.25% and 0.5% concentrations, respectively) and safety of timolol hemihydrate were similar to effect and safety of the three-month protocol. • CONCLUSIONS: This study suggests that timolol hemihydrate had an ocular hypotensive efficacy and safety profile statistically equivalent to that of timolol maleate for up to three months of therapy. Timolol hemihydrate showed efficacy and safety similar to that observed within the first three months, for up to one year of therapy.
© AMERICAN JOURNAL OF OPHTHALMOLOGY 1996;121:522-528
MAY
1996
B
ETA-BLOCKERS HAVE BEEN USED TO TREAT GLAU-
coma and ocular hypertension for almost two decades.1'3 Although they are effective in de creasing the intraocular pressure, concerns persist over the side effects1'3 and cost of these medicines.4 Betaxolol (^-selective adrenergic blocker),5 carteolol (nonselective ß-blocker with partial agonism),6 and preservative-free timolol maleate have been intro duced commercially to help limit the side effects. In this study, we compared the therapeutic efficacy and side effects of timolol hemihydrate vs timolol maleate in a multicenter, randomized, masked, paral lel group comparison. Timolol hemihydrate has the potential advantages of simplifying the formulation process of timolol and eliminating the maleate salt.
PATIENTS AND METHODS WE INCLUDED IN THIS STUDY PATIENTS OVER 18 YEARS OF
age with ocular hypertension or chronic open-angle glaucoma. We defined ocular hypertension as an increased intraocular pressure (22 mm Hg or greater) with no observable glaucomatous changes in the visual field or optic disk. We defined chronic openangle glaucoma as an intraocular pressure of 22 mm Hg or greater, with glaucomatous optic disk changes (saucerization, notching, or rim thinning in the superior or inferior temporal portion of the optic disk) with or without perimetric evidence of glaucomatous visual field defects (nasal step or SeidePs, paracentral, or arcuate scotoma). All patients had open and normal angles by gonioscopy. Before entering the study, each patient signed an informed consent. At each study center, the study was approved by an institutional review board. Patients were excluded if any of the following were found in either eye: marked retinal or neurologic optic nerve disease, recent history of ocular trauma, infec tion or inflammation, corneal topography that pre vented reliable applanation tonometry, intraocular surgery in the past six months or laser ocular surgery in the past three months, best-corrected visual acuity of 20/100 or worse, a pupil that would not dilate sufficiently for examination of the optic disk and retina, contact lens wear, diseases adversely affected by a ß-adrenergic blocker (reactive airway disease or cardiac arrhythmia), any terminal illness, secondary VOL.121, No. 5
glaucomas (including pigment dispersion and exfolia tion glaucoma), hypersensitivity to a compound in the study medications, glaucoma that was advanced or required more than one medicine for intraocular pressure control, severe dry eyes, and therapy with an ot-adrenergic agonist. Pregnant or nursing women or premenopausal women not using birth control pills also were excluded. Two separate study protocols were performed. In one protocol, we evaluated the 0.25% maleate and hemihydrate solutions, and in the other, the 0.5% solutions. Patients were randomly assigned within each protocol to either timolol hemihydrate or timolol maleate in a double-masked, parallel group compari son over a three-month period. At the screening examination, we ensured that each patient met all exclusion and inclusion criteria before study enrollment. Qualified patients then un derwent an ocular examination, including inspection of the adnexa, Snellen visual acuity, manifest refrac tion, color vision testing (Farnsworth-Munsell 28hue color vision test), Schirmer's testing, slit-lamp biomicroscopy, and gonioscopy. After pharmacologie mydriasis, ophthalmoscopy was performed as well as visual field testing with either the Humphrey Field Analyzer program 30-2 or the Octopus program G-l. Blood pressure and pulse also were measured. All procedures were performed in the same manner throughout the study. At the screening examination, if patients qualified for the study, their current glaucoma medicine was discontinued for an appropriate washout period (three weeks for a ß-adrenergic blocker and two weeks for all other classes of glaucoma medicines) before they entered the active treatment portion of the trial. After the washout period, patients were required to have an intraocular pressure of between 22 and 34 mm Hg to enter the active treatment phase. If this condition was satisfied, the patient was provided with a masked medication bottle (0.25% or 0.5% timolol maleate or hemihydrate) according to a randomized number list. Patients were instructed to use one drop of this formulation in each eye every 12 hours, except on the morning of a study examination. At baseline, the initial drops of masked medicine were instilled, and two hours later blood pressure, pulse, and the intraocular pressure were measured.
TIMOLOL HEMIHYDRATE VS MALEATE FOR GLAUCOMA
523
TABLE 1 CHARACTERISTICS OF PATIENTS INCLUDED IN THIS STUDY
Mean ± S.D. age (yrs) Range <60 a=60 Gender Male Female Race White Nonwhite Iris color Brown/black Other Diagnosis Open-angle glaucoma Ocular hypertension
TIMOLOL
TIMOLOL
HEMIHYDRATE 0.25% (N = 91)
MALEATE 0.25%
TIMOLOL HEMIHYDRATE 0.5%
TIMOLOL MALEATE 0.5%
(N = 92)
(N = 93)
(N = 95)
NO. (%)
NO. (%)
NO. (%)
NO. (%)
61.2 ± 11.3 30-87 34(37) 57 (63)
58.6 ± 14.1 18-87 43 (47) 49 (53)
58.5 ± 14.5 26-83 42 (45) 51 (55)
62.1 ±11.6 28-88 36(38) 59 (62)
44 (48) 47 (52)
48 (52) 44 (48)
43 (46) 50 (54)
46 (48) 49 (52)
82(90) 9(10)
77(84) 15(16)
79 (85) 14(15)
79(83) 16(17)
42 (46) 49 (54)
47(51) 45 (49)
41 (44) 52 (56)
45 (47) 50 (53)
60 (66) 31 (34)
60 (65) 32 (35)
53(57) 40 (43)
58(61) 37 (39)
At the visits at weeks 1, 2, 4, and 8, after the masked study medicine was dispensed, visual acuity and applanation tonometry were measured and slitlamp biomicroscopy was performed. At week 4, two hours after medication was given, intraocular pres sure, blood pressure, and pulse were measured. At week 12, two hours after medication was given, intraocular pressure was measured before completion of an examination similar to that performed at the screening visit. At the conclusion of the week 12 examination, all patients were given the option to continue in a nine-month, open-label follow-up period using one drop of timolol hemihydrate in both eyes twice a day at the concentration (0.25% or 0.5%) used in the masked portion of the trial. At three and six months after enrolling in the open-label trial, patients were examined with the following tests: Snellen visual acuity, applanation tonometry, slit-lamp biomicrosco py, blood pressure, and pulse rate. At the nine-month open-label trial visit (one year after the beginning of active treatment), each patient had a final examina tion similar to that performed at the screening visit. Additionally, two hours after medication was given, intraocular pressure was measured before the exami nation with a dilated pupil. 524
Adverse events were recorded at each visit. Patients who were not controlled sufficiently by the study medication or who suffered an adverse event that was incompatible with the patient's clinical safety or lifestyle were discontinued from the study. Statistical analysis was performed for the primary efficacy variable of intraocular pressure by using a repeated measures analysis of variance. The average of the values for the right and left eyes was used for data analysis.7 An S.D. of 2.5 mm Hg was assumed to project the needed sample size for the study.8 The primary estimate of interest was that the lower 90% confidence interval, to establish equivalence between the test and reference study agents at the final visit, would not be greater than or equal to — 1 mm Hg. Vital signs also were analyzed with a repeated mea sures analysis. Safety data were analyzed with Fisher's exact test.9 An a level of 0.05 was used for all statistical tests.7
RESULTS BASELINE MEASUREMENTS FOR THE 371 PATIENTS EN-
rolled in both the 0.25% and 0.5% clinical protocols are given in Table 1. The only statistical difference
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between the hemihydrate and maleate treatment groups was in mean age (P = .021). In the 0.25% study, the age for the timolol hemihydrate group was higher, whereas in the 0.5% study, the age for the timolol maleate group was higher. In Fig. 1, the intraocular pressure readings at baseline and for each visit at trough during the three-month masked comparison study are shown. No significant difference at any visit was observed between the two medicines for either concentration. For the 0.25% and 0.5% solutions, the 90% confi dence intervals for the difference between timolol
maleate and hemihydrate (intraocular pressure at the final visit of masked periods) were -0.912 to 0.518 and —0.591 to 0.814, respectively. Both concentra tions fulfilled the criteria for equivalence that the 90% confidence interval was not greater than or equal to — 1 mm Hg. At the end of the open-label portion of the trial (timolol hemihydrate treatment only), the trough intraocular pressure was 19.9 and 19.1 mm Hg for the 0.25% and 0.5% concentrations, respectively. Peak drug effect measured at two hours after medication was given is provided in Table 2. These measurements were statistically similar between both medicines for the 0.25% and 0.5% concentrations. Tables 3 and 4 provide ocular and systemic signs and symptoms noted in the study that occurred more than once or were life threatening. No ocular or systemic side effect reached statistical significance between medicines for either concentration. Three patients had an adverse event serious enough to discontinue the medicine, two patients who used timolol maleate (one with a myocardial infarction and one with bronchospasm as well as dyspnea) and one who used timolol hemihydrate (because of severe asthenia from pancreatic carcino ma). Eleven other patients (five receiving timolol hemihydrate and six receiving timolol maleate) had a serious adverse event during the masked portion of the study but which did not necessitate discontinuing
Timolol hemihydrate 0.25% Timolol maleate 0.25% T i m o l o l hemih.vdralc 0.5% T i m o l o l maleate 0.5% 0.
O
Weeks
Fig. 1 (DuBiner and associates). Intraocular pressure readings at baseline and for each visit during the masked portion of the study for 0.25% and 0.5% timolol maleate and timolol hemihydrate.
TABLE 2 PEAK EFFECTS (TWO HOURS AFTER DOSE) OF 0.25% AND 0.5% TIMOLOL SOLUTIONS ON INTRAOCULAR PRESSURE (MM He; MEAN * S.D.) TIMOLOL 0.25%
Baseline No. of patients After washout Peak effect Week 4 No. of patients Trough value Peak effect Week 12 No. of patients Trough value Peak effect
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TIMOLOL 0.5%
HEMIHYDRATE
MALEATE
HEMIHYDRATE
MALEATE
91 24.4 ± 0.2 17.5 ± 0.3
91 24.4 ± 0.3 17.2 ± 0.3
91 24.9 ± 0.3 16.5 ± 0.3
92 25.0 ± 0.3 16.6 ± 0.3
86 19.9 ± 0.3 17.7 ± 0.3
90 19.7 ± 0.2 17.5 ± 0.2
85 18.5 ± 0.4 17.3 ± 0.4
87 18.9 ± 0.3 17.8 ± 0.3
85 20.2 ± 0.3 17.8 ± 0.3
89 19.5 ± 0.3 17.5 ± 0.3
84 17.9 + 0.3 16.7 ± 0.3
80 18.2 ± 0.4 17.1 ± 0.4
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TABLE 3 OCULAR ADVERSE EVENTS 0.5% TIMOLOL HEMIHYDRATE SYMPTOMS
Blepharitis Burning or stinging On instillation Continuous Corneal lesion Discharge from eye Discomfort of eye Dry eyes Epiphora Eyelid erythema Blurred vision Foreign body sensation Conjunctival hemorrhage Injection Itching Keratitis Photophobia Fluorescein staining Retinal hemorrhage Vitreous disorder
MALEATE
HEMIHYORATE
MALEATE
NO. (%)
NO. (%)
1 (1.1)
2 (2.2)
1 (1.1)
45 (49.5) 3 (3.2) 5 (5.4) 1 (1.1) 5 (5.4) 9 (9.7) 5 (5.4) 4 (4.3) 3 (3.3) 6 (6.5) 0 (0) 6 (6.5) 8 (8.6) 8 (8.6) 1 (1.1) 0 (0) 1 (1.1) 2 (2.2)
20 (22.0) 2 (2.2)
23 (25.0) 1 (1.1)
0 (0) 1 (1.1) 13(14.3) 12(13.2) 5 (5.5) 8 (8.8) 3 (3.3) 6 (6.6)
0 (0) 1 (2.2) 12(13.0) 6 (6.5) 3 (3.3) 6 (6.5) 0 (0) 6 (6.5) 0 (0) 15(16.3) 11 (12.0) 3 (3.3)
NO. (%)
NC
2 (2.2) 38(41.8) 3 (3.3) 3 (3.3) 1 (1.1) 10(11.0) 6 (6.5) 8 (8.8) 4 (4.4) 3 (3.3) 4 (4.4) 2 (2.2) 4 (4.4) 12(13.2) 6 (6.6) 1 (1.1) 1 (1.1) 1 (1.1) 0 (0)
the drug and was considered definitely or probably not related to the study medication. Adverse events in the open-label period were similar to those in the 12week masked period. Few notable changes occurred in visual field, optic disk, and visual acuity during the study. Three patients, who had normal visual fields at screening, had one eye progress to nerve fiber layer changes. Two patients had decreased visual acuity and visual field, one because of a vein occlusion and another from a diabetic vitreous hemorrhage. Vital signs data from the masked portion of the treatment trial are shown in Fig. 2. For both concen trations of both timolol maleate and hemihydrate, a significant overall reduction from baseline was ob served for the systolic (P = .030) and diastolic blood pressure (P = .019) as well as pulse rate (P < .001). Timolol maleate showed a greater reduction in pulse than timolol hemihydrate did at week 12 for both concentrations (P = .01). At the end of the nine-month open-label portion of the study, pulse (72.2/min for 0.25% and 70.2/min for 0.5%) and systolic (134.5 mm Hg for 0.25% and 526
0.25% TIMOLOL
>■
( % )
0 8 6 2 4 7 0 0
(0) (8.8) (6.6) (2.2) (4.4) (7.7) (0) (0)
1 (1-1) 3 (3.3) 0 (0) 2 (2.2)
130.6 mm Hg for 0.5%) and diastolic (81.5 mm Hg for 0.25% and 78.4 mm Hg for 0.5%) blood pressure levels were similar to levels observed during the masked portion of the trial (Fig. 2).
DISCUSSION IN THIS STUDY, WE EVALUATED A NEW FORMULATION OF
timolol prepared as a hemihydrate. We compared this medicine's efficacy in lowering the intraocular pres sure, as well as the ocular and systemic side effects, to that of timolol maleate. We found that timolol hemihydrate decreased the intraocular pressure from baseline to an extent statis tically similar to that of timolol maleate at both the 0.25% and 0.5% concentrations throughout the 12-week masked portion of the protocol. Additional ly, the peak intraocular pressure-decreasing effect two hours after taking the medication was similar be tween preparations for both the 0.25% and 0.5% concentrations. Ocular and systemic safety between medications
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TABLE 4 NONOCULAR ADVEflSE EVENTS 0.5% TIMOLOL
0.25% TIMOLOL
HEMIHYDRATE
MALEATE
HEMIHYDRATE
MALEATE
SYMPTOMS
NO. (%)
NO. (%)
NO. (%)
NO. (%)
Allergic reaction Asthenia Headache Chest pain Body pain Cardiac arrhythmia Bradycardia Systemic hypertension Myocardial infarction Constipation Peripheral edema Depression Dizziness Dry mouth Asthma Dyspnea Respiratory infection Nausea
3 (3.3) 0 (0) 8 (8.8)
3 (3.3) 1(1.1) 6 (6.5) 0 (0)
0 3 2 1 0 1 0 4
2 0 3 2 0 0 0 5 0 0 0 0 0 0
(2.2) (0) (3.3) (2.2) (0) (0) (0) (5.5) (0) (0) (0) (0) (0) (0)
0 0 0 0
(0) (0) (0) (0)
0 (0) 2(2.2) 0 (0) 0 (0) 1 (1.1) 0 (0) 1(1.1) 2 (2.2) 0 (0) 3 (3.3) 2 (2.2) 0 (0) 1(1.1) 3 (3.3) 2 (2.2)
1 2 2 2
(1-1) (2.2) (2.2) (2.2)
1 (1.1) 2 (2.2) 1 (1.1) 2 (2.2) 0 (0) 1 (1.1) 1 (1.1) 1(1.1) 2 (2.2) 0 (0)
Timolol hemihydrate 0.25%
s s
0 (0) 0 (0) 1 (1.1) 1(1.1) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 1 (1.1)
Timolol hemihydrale 0.25% 85
Timolol maleate 0.25%
X
(0) (3.3) (2.2) (1.1) (0) (1.1) (0) (4.4)
Timolol hemihydrate 0 3 %
e
Timolol maleate 0.5%
Timolol maleate 0.25% Timolol hemihydrale 0.5%
■" 82.5-
t a
77.5
75· 2
4
Weeks Timolol hemihydrale 0.25% Timolol maleate 0.25% Timolol hemihydrate 0.5%
Fig. 2 (DuBiner and associates). Graphs show mean and S.D. for systolic (top left) and diastolic (top right) blood pressure as well as pulse rate (bottom left) at each visit in the masked portion of the study. Data are shown for both concentrations of the hemihydrate and maleate timolol forms.
5 72-
6
71-
«5
I —r-
baseline
Weeks VOL.121, No. 5
12
TIMOLOL HEMIHYDRATE VS MALEATE FOR GLAUCOMA
527
appeared to be similar for both the 0.25% and 0.5% concentrations. A reduced pulse rate was noted in patients treated with timolol maleate 0.25% compared with those treated with timolol hemihydrate, but it was believed not to be clinically important. Overall differences between formulations were inconsistent, and no clear trends were evident. Clinical deterioration (on the basis of optic disk, visual field, and visual acuity examinations) was observed in five patients who had a high degree of probability of worsening. These patients ostensibly had controlled intraocular pressure during the trial. Two of these patients had a vascular event (vitreous hemorrhage related to diabetic retinopathy and a hemiretinal vein occlusion), whereas three patients had a new-onset scotoma in the visual field. No confirmation visual fields were performed. No clear trends to a particular study medication associated with worsening of visual function were indicated. In the nine-month, open-label portion of the trial, patients were treated with timolol hemihydrate only. The intraocular pressure efficacy and safety findings were similar to those in the masked portion of the trial. Consequently, the ocular hypotensive effect and safety profile of timolol hemihydrate appear to be maintained over the first year of treatment. The timolol product studied in this clinical trial was manufactured according to a patented process that has several differences compared with previous formulation techniques. First, it simplifies the formu lation method for timolol by reducing the purification process for the more active S-enantiomer into a single crystallization step.10,11 Second, timolol hemihydrate eliminates the maleate buffer from the solution. In a recent article, Ball and Schneider4 commented that the average cost of commercially available timolol maleate in three diverse locations was $15.72 for a 5-ml bottle, $27.13 for a 10-ml bottle, and $38.31 for a 15-ml bottle. A simplified manufacturing process potentially could help reduce the cost of timolol to the pharmacy. The results of this study suggest that timolol hemihydrate has an ocular hypotensive efficacy and safety profile comparable to those of timolol maleate for both the 0.25% and 0.5% concentrations for up to three months of therapy. Timolol hemihydrate shows continued efficacy and safety for up to one year of therapy. 528
In this study, we found no clear advantage to timolol hemihydrate over timolol maleate in thera peutic efficacy or safety. However, the techniques (subjective grading of ocular signs and patientinitiated symptom reporting) used to evaluate adverse events in this study may not have been sensitive enough to detect subtle changes in the safety profile between the two medicines. Likewise, this study did not determine the long-term efficacy of timolol hemi hydrate compared with timolol maleate, for which ten-year follow-up studies are available.12 Further experience and study will help to determine the place of timolol hemihydrate in the therapeutic regi men of ocular hypertension and chronic open-angle glaucoma. ACKNOWLEDGMENT
Kay Hart, Ph.D., Data Inc., Hazel, Kentucky, provid ed statistical assistance.
REFERENCES 1. Zimmerman TJ, Harbin R, Pett M, Kaufman HE. Timolol and facility outflow. Invest Ophthalmol Vis Sci 1977; 16:623-4. 2. Lin L-L, Galin MA, Obstbaum SA, Katz I. Longterm timolol therapy. Surv Ophthalmol 1979;23:377-80. 3. Zimmerman TJ, Kaufman HE. Timolol: a ß-adrenergic blocking agent for the treatment of glaucoma. Arch Oph thalmol 1977;95:601-7. 4. Ball SF, Schneider E. Cost of ß-adrenergic blocking agents for ocular hypertension. Arch Ophthalmol 1992;110:654-7. 5. Berrospi AR, Leibowitz HM. Betaxolol: a new ß-adrenergic blocking agent for the treatment of glaucoma. Arch Oph thalmol 1982;100:943-6. 6. Stewart WC, Shields MB, Allen RC, Lewis RA, Cohen JS, Hoskins HD, et al. A three-month comparison of 1% and 2% carteolol and 0.5% timolol in open-angle glaucoma. Graefes Arch Clin Exp Ophthalmol 1991;229:258-61. 7. Book SA. Essentials of statistics. New York: McGraw Hill, 1978:223-47. 8. Novack GD. Ophthalmic ß-blockers since timolol. Surv Ophthalmol 1987;31:307-27. 9. Swinscow TDV. Statistics at square one. London: British Medical Association, 1976:54-7. 10. Keates EU, Stone R. The effect of d-timolol on intraocular pressure in patients with ocular hypertension. Am J Ophthal mol 1984;98:73-8. 11. Liu JHK, Bartels SP, Neufeld AH. Effects of 1- and d-timolol on cyclic AMP synthesis and intraocular pressure in waterloaded, albino and pigmented rabbits. Invest Ophthalmol Vis Sci 1983;24:1276-82. 12. Goethals M. Ten-year follow-up of timolol-treated openangle glaucoma [summary]. Surv Ophthalmol 1989;33 Suppl:463-4·
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