ORIGINAL STUDY
The Efficacy of a Latanoprost/Timolol Fixed Combination Versus Latanoprost and Timolol Gel-forming Solution Unfixed Combination on Daytime Intraocular Pressure Erhan O¨zyol, MD and Pelin O¨zyol, MD
Purpose: To evaluate the effect of a latanoprost/timolol fixed combination (LTFC) versus a latanoprost and timolol gel-forming solution unfixed combination (LTuFC) on daytime intraocular pressure (IOP) levels and fluctuations. Methods: This was an 8-week, randomized, parallel-group study. Ninety eyes of 90 patients diagnosed with primary open-angle glaucoma or ocular hypertension that were insufficiently controlled with latanoprost monotherapy were enrolled. Randomized patients received either a single evening dose of LTFC or unfixed combination of latanoprost administered once daily in the evening and timolol gel-forming solution administered once daily in the morning without a washout period. IOP measurements were taken at 8 AM, 11 AM, 2 PM, and 5 PM. The mean IOP, daytime IOP measurements, and fluctuation in IOP were assessed at weeks 4 and 8. Results: The mean IOP reduction from baseline to each visit was significant in both groups (P < 0.01). There was a significant difference in the mean IOP between groups at week 4 (P = 0.0021). At week 8, the mean IOP reduction was 3.2 ± 2.1 and 5.7 ± 3.2 mm Hg in LTFC and LTuFC groups, respectively, and the difference was significant (P = 0.001). A decrease in the daytime IOP fluctuation was observed in both groups over time, but the decrease in each group was not significant. At week 8, the mean IOP measurements at 8 AM, 11 AM, 2 PM, and 5 PM in LTuFC group were significantly lower than in the LTFC group (P = 0.024, 0.0001, 0.0008, and 0.0011, respectively). Conclusions: The concomitant use of latanoprost and timolol gelforming solution leads to a larger additional IOP reduction and lower daytime IOP levels as compared with the fixed combination. Key Words: intraocular pressure, latanoprost, timolol maleate, primary open-angle glaucoma, ocular hypertension
(J Glaucoma 2016;25:135–139)
T
he reduction of intraocular pressure (IOP) has been demonstrated to prevent both the development1 and the progression2 of glaucoma. Combined drug therapy is used to treat glaucoma when monotherapy is not effective or sufficient, and b-blockers, such as timolol 0.5%, are commonly used as adjunctive therapy to prostaglandin analogues in patients requiring a multidrug regimen. Several studies have demonstrated that fixed or concomitant combinations of latanoprost and timolol are more effective than latanoprost or timolol monotherapy.3–6 The Received for publication August 14, 2013; accepted August 26, 2014. From the Department of Ophthalmology, U¨nye State Hospital, Ordu, Turkey. Disclosure: The authors declare no conflict of interest. Reprints: Erhan O¨zyol, MD, Department of Ophthalmology, U¨nte State Hospital, 52300 Ordu, Turkey (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/IJG.0000000000000170
J Glaucoma
Volume 25, Number 2, February 2016
administration frequency for the latanoprost/timolol fixed combination (LTFC) is once daily, but the original administration frequency for timolol is twice daily, so there is a concern that there could be a reduction in the efficiency of the fixed combination. Latanoprost prevents nocturnal hypertension.7 The timing of timolol administration in combined therapy cannot be ignored for daytime IOP levels. However, there has not yet been any report comparing a single evening dose of timolol in the fixed combination with a single morning dose of gel-forming solution in the unfixed combination as adjunctive therapy to latanoprost 0.005%. The purpose of the current study was to evaluate the effect of a single evening dose of LTFC versus an unfixed combination of latanoprost administered once daily in the evening and timolol gel-forming solution administered once daily in the morning on daytime IOP levels and fluctuations.
MATERIALS AND METHODS Study Design and Subjects This was an 8-week, randomized, parallel-group study conducted between January 2012 and April 2013. This study conducted in accordance with the tenets of Declaration of Helsinki. All patients signed an informed consent agreement approved by an institutional review board before any procedure was performed. Patients older than 30 years and diagnosed with primary open-angle glaucoma or ocular hypertension were eligible for the study. Patients were informed in detail about the appropriate time and correct technique of eye drop instillation (1 single drop into the lower conjunctival sac and nasolacrimal occlusion for at least 1 min), and thereafter, they were treated for at least 4 weeks immediately before screening with latanoprost monotherapy. Patients were excluded if they met any of the following criteria: (1) closed/barely open anterior chamber angle or a history of acute angle-closure glaucoma; (2) ocular surgery in 1 or both eyes before the baseline visit; (3) argon laser trabeculoplasty or selective laser trabeculoplasty 3 months before the baseline visit; (4) any condition in 1 or both eyes that could prevent reliable applanation tonometry; (5) ocular inflammation/infection occurring within 1 month before baseline visit; (6) use, or planned use, of any topical or systemic medication known to affect IOP; (7) known hypersensitivity to benzalkonium chloride or to any component of the study drug solutions; (8) any ocular or medical condition in which treatment with b-blocking or prostaglandin agents is contraindicated; (9) any acute or uncontrolled medical or psychiatric illness; and (10) treatment noncompliance. Pregnant or lactating women or women of childbearing potential not using an acceptable method of contraception were also excluded. Patients with an www.glaucomajournal.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
135
¨ zyol and O ¨ zyol O
J Glaucoma
IOP decrease 3 times a week or had not administered the drops at the right time and using correct instillation technique, the patient was excluded before switching to dual therapy. Only 1 patient had forgotten instillation of drops >3 times a week, and therefore this patient was excluded from the study. Similar questioning was also repeated at each visit. The patients whose IOP was not sufficiently controlled with latanoprost monotherapy (IOP of 19 through 25 mm Hg) were assigned to treatment by computer-generated randomization (1:1 ratio) performed for 2 groups of consecutive patients. At the baseline visit, ophthalmic and systemic history was recorded. Visual acuity, slit-lamp biomicroscopy, dilated ophthalmoscopy, and corneal pachymetry were performed. IOP measurements were taken at 8 AM, 11 AM, 2 PM, and 5 PM at baseline and all consecutive visits. In the latanoprost and timolol gel-forming solution unfixed combination (LTuFC) group, the 8 AM IOP measurement was taken immediately before administration of timolol gelforming solution 0.5%. At each measurement timepoint, 2 assessments were performed for each eye, and the IOP for a given timepoint was defined as the average of 2 measurements. For each patient, the IOP assessments were performed by the same examiner using the same calibrated Goldmann applanation tonometer at each visit. After baseline measurements, the randomized patients received either 1 drop of LTFC (Xalacom; Pfizer Inc., New York, NY) at approximately 8 PM or 1 drop of latanoprost 0.005% (Xalatan; Pfizer Inc.) at approximately 8 PM and 1 drop of timolol gel-forming solution 0.5% (Timoptic XE; Merck Sharp & Dohme, France) at approximately 8 AM with no washout period. IOP measurements were obtained at baseline, week 4, and week 8. The mean IOP was recorded as the mean of 8 AM, 11 AM, 2 PM, and 5 PM IOPs. Fluctuation in IOP was calculated as the “highest daily IOP lowest daily IOP” for each visit.
Volume 25, Number 2, February 2016
TABLE 1. Characteristics of Patients in Groups Mean age (y) Sex (female/male) Diagnosis (POAG/OH) Baseline IOP before LT monotherapy (mm Hg) IOP with LT monotherapy (mm Hg) Corneal pachymetry (mm)
LTFC
LTuFC
P
61.5 ± 7.2 27/20 31/14 27.4 ± 2.3
60.2 ± 5.3 24/19 35/10 27.8 ± 1.9
0.865* 0.561w 0.254w 0.67a*
21.5 ± 3.2
21.7 ± 2.9
0.763*
542.3 ± 21.3 539.7 ± 23.4 0.561*
*Unpaired Student t test. ww2 test. IOP indicates intraocular pressure; LT, latanoprost; LTFC, latanoprost/ timolol fixed combination; LTuFC, latanoprost and timolol gel-forming solution unfixed combination; OH, ocular hypertension; POAG, primary open-angle glaucoma.
ocular hypertension. The baseline demographic characteristics of patients are shown in Table 1. The mean IOP with latanoprost monotherapy was 21.5 ± 3.2 mm Hg in the LTFC group and 21.7 ± 2.9 mm Hg in the LTuFC group. No significant difference was observed between the groups according to demographic characteristics or mean IOP values before switching to fixed or unfixed combinations (P > 0.05, for all). After switching to fixed or unfixed combinations, there was no patient incompatible with the treatment during follow-up. At week 8, the mean IOP was 18.3 ± 2.2 and 16.4 ± 1.7 mm Hg in the LTFC and LTuFC groups, respectively, and the difference in the mean IOP between baseline and week 8 was significant (P = 0.00022 and 0.00001, respectively). At weeks 4 and 8, the difference in the mean IOP was significant between groups (P = 0.0021 and 0.001, respectively) (Fig. 1). At week 8, the mean IOP reduction was 3.2 ± 2.1 and 5.7 ± 3.2 mm Hg in the LTFC and LTuFC groups, respectively, and the difference was significant between the groups (P = 0.001). There was a decrease in daytime IOP fluctuation in both groups over time, but the decrease in each group was not significant, and no significant difference was observed between groups at any visit (P > 0.05) (Fig. 2). The decrease in the mean IOP at 8 AM, 11 AM, 2 PM, and 5 PM was significant in both groups during follow-up
Statistical Analysis Analysis of variance for repeated measures with the Bonferroni test was used to analyze the differences between IOP at individual timepoints before and after treatment in both groups. Differences in the mean IOP between 2 treatment groups were evaluated using an unpaired Student t test. The sample size was calculated before initiation of the study. Assuming a SD of 2.8 mm Hg and an a-level of 0.05, this study provided an 85% power to detect a difference of 1.5 mm Hg between the fixed and unfixed combinations of latanoprost and timolol groups with 42 evaluable subjects per group. The values for patient characteristics were statistically analyzed with the w2 test and the unpaired Student t test. A P-value
The Efficacy of a Latanoprost/Timolol Fixed Combination Versus Latanoprost and Timolol Gel-forming Solution Unfixed Combination on Daytime Intraocular Pressure Erhan O¨zyol, MD and Pelin O¨zyol, MD
Purpose: To evaluate the effect of a latanoprost/timolol fixed combination (LTFC) versus a latanoprost and timolol gel-forming solution unfixed combination (LTuFC) on daytime intraocular pressure (IOP) levels and fluctuations. Methods: This was an 8-week, randomized, parallel-group study. Ninety eyes of 90 patients diagnosed with primary open-angle glaucoma or ocular hypertension that were insufficiently controlled with latanoprost monotherapy were enrolled. Randomized patients received either a single evening dose of LTFC or unfixed combination of latanoprost administered once daily in the evening and timolol gel-forming solution administered once daily in the morning without a washout period. IOP measurements were taken at 8 AM, 11 AM, 2 PM, and 5 PM. The mean IOP, daytime IOP measurements, and fluctuation in IOP were assessed at weeks 4 and 8. Results: The mean IOP reduction from baseline to each visit was significant in both groups (P < 0.01). There was a significant difference in the mean IOP between groups at week 4 (P = 0.0021). At week 8, the mean IOP reduction was 3.2 ± 2.1 and 5.7 ± 3.2 mm Hg in LTFC and LTuFC groups, respectively, and the difference was significant (P = 0.001). A decrease in the daytime IOP fluctuation was observed in both groups over time, but the decrease in each group was not significant. At week 8, the mean IOP measurements at 8 AM, 11 AM, 2 PM, and 5 PM in LTuFC group were significantly lower than in the LTFC group (P = 0.024, 0.0001, 0.0008, and 0.0011, respectively). Conclusions: The concomitant use of latanoprost and timolol gelforming solution leads to a larger additional IOP reduction and lower daytime IOP levels as compared with the fixed combination. Key Words: intraocular pressure, latanoprost, timolol maleate, primary open-angle glaucoma, ocular hypertension
(J Glaucoma 2016;25:135–139)
T
he reduction of intraocular pressure (IOP) has been demonstrated to prevent both the development1 and the progression2 of glaucoma. Combined drug therapy is used to treat glaucoma when monotherapy is not effective or sufficient, and b-blockers, such as timolol 0.5%, are commonly used as adjunctive therapy to prostaglandin analogues in patients requiring a multidrug regimen. Several studies have demonstrated that fixed or concomitant combinations of latanoprost and timolol are more effective than latanoprost or timolol monotherapy.3–6 The Received for publication August 14, 2013; accepted August 26, 2014. From the Department of Ophthalmology, U¨nye State Hospital, Ordu, Turkey. Disclosure: The authors declare no conflict of interest. Reprints: Erhan O¨zyol, MD, Department of Ophthalmology, U¨nte State Hospital, 52300 Ordu, Turkey (e-mail: [email protected]). Copyright r 2014 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/IJG.0000000000000170
J Glaucoma
Volume 25, Number 2, February 2016
administration frequency for the latanoprost/timolol fixed combination (LTFC) is once daily, but the original administration frequency for timolol is twice daily, so there is a concern that there could be a reduction in the efficiency of the fixed combination. Latanoprost prevents nocturnal hypertension.7 The timing of timolol administration in combined therapy cannot be ignored for daytime IOP levels. However, there has not yet been any report comparing a single evening dose of timolol in the fixed combination with a single morning dose of gel-forming solution in the unfixed combination as adjunctive therapy to latanoprost 0.005%. The purpose of the current study was to evaluate the effect of a single evening dose of LTFC versus an unfixed combination of latanoprost administered once daily in the evening and timolol gel-forming solution administered once daily in the morning on daytime IOP levels and fluctuations.
MATERIALS AND METHODS Study Design and Subjects This was an 8-week, randomized, parallel-group study conducted between January 2012 and April 2013. This study conducted in accordance with the tenets of Declaration of Helsinki. All patients signed an informed consent agreement approved by an institutional review board before any procedure was performed. Patients older than 30 years and diagnosed with primary open-angle glaucoma or ocular hypertension were eligible for the study. Patients were informed in detail about the appropriate time and correct technique of eye drop instillation (1 single drop into the lower conjunctival sac and nasolacrimal occlusion for at least 1 min), and thereafter, they were treated for at least 4 weeks immediately before screening with latanoprost monotherapy. Patients were excluded if they met any of the following criteria: (1) closed/barely open anterior chamber angle or a history of acute angle-closure glaucoma; (2) ocular surgery in 1 or both eyes before the baseline visit; (3) argon laser trabeculoplasty or selective laser trabeculoplasty 3 months before the baseline visit; (4) any condition in 1 or both eyes that could prevent reliable applanation tonometry; (5) ocular inflammation/infection occurring within 1 month before baseline visit; (6) use, or planned use, of any topical or systemic medication known to affect IOP; (7) known hypersensitivity to benzalkonium chloride or to any component of the study drug solutions; (8) any ocular or medical condition in which treatment with b-blocking or prostaglandin agents is contraindicated; (9) any acute or uncontrolled medical or psychiatric illness; and (10) treatment noncompliance. Pregnant or lactating women or women of childbearing potential not using an acceptable method of contraception were also excluded. Patients with an www.glaucomajournal.com |
Copyright r 2016 Wolters Kluwer Health, Inc. All rights reserved.
135
¨ zyol and O ¨ zyol O
J Glaucoma
IOP decrease 3 times a week or had not administered the drops at the right time and using correct instillation technique, the patient was excluded before switching to dual therapy. Only 1 patient had forgotten instillation of drops >3 times a week, and therefore this patient was excluded from the study. Similar questioning was also repeated at each visit. The patients whose IOP was not sufficiently controlled with latanoprost monotherapy (IOP of 19 through 25 mm Hg) were assigned to treatment by computer-generated randomization (1:1 ratio) performed for 2 groups of consecutive patients. At the baseline visit, ophthalmic and systemic history was recorded. Visual acuity, slit-lamp biomicroscopy, dilated ophthalmoscopy, and corneal pachymetry were performed. IOP measurements were taken at 8 AM, 11 AM, 2 PM, and 5 PM at baseline and all consecutive visits. In the latanoprost and timolol gel-forming solution unfixed combination (LTuFC) group, the 8 AM IOP measurement was taken immediately before administration of timolol gelforming solution 0.5%. At each measurement timepoint, 2 assessments were performed for each eye, and the IOP for a given timepoint was defined as the average of 2 measurements. For each patient, the IOP assessments were performed by the same examiner using the same calibrated Goldmann applanation tonometer at each visit. After baseline measurements, the randomized patients received either 1 drop of LTFC (Xalacom; Pfizer Inc., New York, NY) at approximately 8 PM or 1 drop of latanoprost 0.005% (Xalatan; Pfizer Inc.) at approximately 8 PM and 1 drop of timolol gel-forming solution 0.5% (Timoptic XE; Merck Sharp & Dohme, France) at approximately 8 AM with no washout period. IOP measurements were obtained at baseline, week 4, and week 8. The mean IOP was recorded as the mean of 8 AM, 11 AM, 2 PM, and 5 PM IOPs. Fluctuation in IOP was calculated as the “highest daily IOP lowest daily IOP” for each visit.
Volume 25, Number 2, February 2016
TABLE 1. Characteristics of Patients in Groups Mean age (y) Sex (female/male) Diagnosis (POAG/OH) Baseline IOP before LT monotherapy (mm Hg) IOP with LT monotherapy (mm Hg) Corneal pachymetry (mm)
LTFC
LTuFC
P
61.5 ± 7.2 27/20 31/14 27.4 ± 2.3
60.2 ± 5.3 24/19 35/10 27.8 ± 1.9
0.865* 0.561w 0.254w 0.67a*
21.5 ± 3.2
21.7 ± 2.9
0.763*
542.3 ± 21.3 539.7 ± 23.4 0.561*
*Unpaired Student t test. ww2 test. IOP indicates intraocular pressure; LT, latanoprost; LTFC, latanoprost/ timolol fixed combination; LTuFC, latanoprost and timolol gel-forming solution unfixed combination; OH, ocular hypertension; POAG, primary open-angle glaucoma.
ocular hypertension. The baseline demographic characteristics of patients are shown in Table 1. The mean IOP with latanoprost monotherapy was 21.5 ± 3.2 mm Hg in the LTFC group and 21.7 ± 2.9 mm Hg in the LTuFC group. No significant difference was observed between the groups according to demographic characteristics or mean IOP values before switching to fixed or unfixed combinations (P > 0.05, for all). After switching to fixed or unfixed combinations, there was no patient incompatible with the treatment during follow-up. At week 8, the mean IOP was 18.3 ± 2.2 and 16.4 ± 1.7 mm Hg in the LTFC and LTuFC groups, respectively, and the difference in the mean IOP between baseline and week 8 was significant (P = 0.00022 and 0.00001, respectively). At weeks 4 and 8, the difference in the mean IOP was significant between groups (P = 0.0021 and 0.001, respectively) (Fig. 1). At week 8, the mean IOP reduction was 3.2 ± 2.1 and 5.7 ± 3.2 mm Hg in the LTFC and LTuFC groups, respectively, and the difference was significant between the groups (P = 0.001). There was a decrease in daytime IOP fluctuation in both groups over time, but the decrease in each group was not significant, and no significant difference was observed between groups at any visit (P > 0.05) (Fig. 2). The decrease in the mean IOP at 8 AM, 11 AM, 2 PM, and 5 PM was significant in both groups during follow-up
Statistical Analysis Analysis of variance for repeated measures with the Bonferroni test was used to analyze the differences between IOP at individual timepoints before and after treatment in both groups. Differences in the mean IOP between 2 treatment groups were evaluated using an unpaired Student t test. The sample size was calculated before initiation of the study. Assuming a SD of 2.8 mm Hg and an a-level of 0.05, this study provided an 85% power to detect a difference of 1.5 mm Hg between the fixed and unfixed combinations of latanoprost and timolol groups with 42 evaluable subjects per group. The values for patient characteristics were statistically analyzed with the w2 test and the unpaired Student t test. A P-value
