The Open Ophthalmology Journal




ISSN: 1874-3641 ― Volume 13, 2019
RESEARCH ARTICLE

Efficacy and Safety of Switching from Tafluprost to a Tafluprost/Timolol Fixed Combination in Patients With Primary Open-Angle Glaucoma



Kenji Inoue1, *, Takeaki Ueda1, Kyoko Ishida2, Goji Tomita2
1 Inouye Eye Hospital, Tokyo, Japan
2 Department of Ophthalmology, Toho University Ohashi Medical Center, Tokyo, Japan

Abstract

Background:

The Tafluprost/Timolol Fixed Combination (TTFC) has demonstrated efficacy and safety in reducing Intraocular Pressure (IOP). However, direct comparisons of switching from tafluprost to TTFC are limited.

Objective:

To investigate the efficacy and safety of switching from tafluprost to TTFC in patients with Primary Open-Angle Glaucoma (POAG).

Methods:

Thirty-four eyes (34 patients) with POAG that did not achieve adequate IOP reduction on tafluprost were switched to TTFC with no washout period. IOP, systolic/diastolic blood pressure and pulse rate were measured 1 and 3 months later and compared with baseline values. All participants were asked about specific adverse reactions after 1 and 3 months of treatment. Patients also completed a questionnaire about preference and adherence after 1 month of treatment.

Results:

Mean IOP after 1 and 3 months was significantly lower than at baseline (14.2 ± 2.1 mmHg and 14.1 ± 2.3 mmHg, respectively, vs 16.0 ± 2.0 mmHg, P < 0.0001). Systolic/diastolic blood pressure and pulse rate were not significantly different from baseline after 1 and 3 months. The questionnaire indicated that the frequency of missing a dose was not different before (27.3%) or after (18.2%) switching to TTFC (P = 0.2371). There were five reports of adverse reactions (14.7%), including a corneal epithelium disorder, ocular irritation, skin irritation at the wrist, and chest pain. Two patients (5.9%) withdrew because of adverse reactions.

Conclusion:

Switching from tafluprost to TTFC achieved IOP control safely and was well accepted by patients.

Keywords: Tafluprost, Tafluprost/timolol fixed combination, Primary open-angle glaucoma, Intraocular pressure, Safety, Efficacy.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 121
Last Page: 126
Publisher Id: TOOPHTJ-12-121
DOI: 10.2174/1874364101812010121

Article History:

Received Date: 27/12/2017
Revision Received Date: 20/4/2018
Acceptance Date: 24/5/2018
Electronic publication date: 29/6/2018
Collection year: 2018

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© 2018 Inoue et al.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at Inouye Eye Hospital, 4-3 Kanda-Surugadai, Chiyoda-ku, Tokyo, 101-0062, Japan; Tel: 03-3295-0911; Fax: 03-3295-0917; E-mail: inoue-k@inouye-eye.or.jp




1. INTRODUCTION

Glaucoma is often initially treated with a single medication that lowers Intraocular Pressure (IOP). However, when a single medication has inadequate IOP-lowering efficacy, it is necessary to change the therapy or add other eye drops [1The Japan Glaucoma Society Guidelines for Glaucoma (4th Edition) 2018.]. Multiple medications increase the number of eye drops that need to be instilled, which can lead to poor patient adherence [2Djafari F, Lesk MR, Harasymowycz PJ, Desjardins D, Lachaine J. Determinants of adherence to glaucoma medical therapy in a long-term patient population. J Glaucoma 2009; 18(3): 238-43.[http://dx.doi.org/10.1097/IJG.0b013e3181815421] [PMID: 19295380] ]. Therefore, a fixed-combination eye drop that contains two medications is recommended.

Prostaglandin (PG) analogs are generally the first choice for treatment of glaucoma because they are effective in reducing IOP, have few systemic adverse effects, and allow a convenient once-daily administration protocol [3Li T, Lindsley K, Rouse B, et al. Comparative effectiveness of first-line medications for primary open-angle glaucoma: A systematic review and network meta-analysis. Ophthalmology 2016; 123(1): 129-40.[http://dx.doi.org/10.1016/j.ophtha.2015.09.005] [PMID: 26526633] ]. A switch from a PG analog to a PG/timolol fixed combination eye drop is common when more aggressive therapy is required [4Schmier JK, Hulme-Lowe CK, Covert DW. Adjunctive therapy patterns in glaucoma patients using prostaglandin analogs. Clin Ophthalmol 2014; 8: 1097-104.[http://dx.doi.org/10.2147/OPTH.S63760] [PMID: 24959067] ] because of the high patient compliance and ability to continue on a once-daily administration protocol.

The preservative-containing Tafluprost/Timolol Fixed Combination (TTFC) was approved for use in Japan in 2014 and the preservative-free agent is used in many other parts of the world. TTFC has demonstrated efficacy and safety in reducing IOP in some studies [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.-11Holló G, Ropo A. Intraocular pressure decrease with preservative-free fixed and unfixed combination of tafluprost and timolol in pseudoexfoliative glaucoma. Curr Med Res Opin 2015; 31(1): 13-6.[http://dx.doi.org/10.1185/03007995.2014.972500] [PMID: 25275411] ]. However, with the exception of some studies in Japan [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94., 6Kuwayama Y. DE-111 Collaborative Trial Group. A long-term, open-label study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) in patients with open-angle glaucoma or ocular hypertension. Atarashii Ganka 2015; 32: 133-43., 8Takagi Y, Osaki H, Yamashita T, Kai Y. Prospective observational post-marketing study of tafluprost 0.0015%/timolol 0.5% combination ophthalmic solution for glaucoma and ocular hypertension: short-term efficacy and safety. Ophthalmol Ther 2016; 5(2): 191-206.[http://dx.doi.org/10.1007/s40123-016-0057-3] [PMID: 27492380] ] and one study in Germany [7Pillunat LE, Erb C, Ropo A, Kimmich F, Pfeiffer N. Preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% in patients with open-angle glaucoma and ocular hypertension: Results of an open-label observational study. Clin Ophthalmol 2017; 11: 1051-64.[http://dx.doi.org/10.2147/OPTH.S128453] [PMID: 28652689] ], direct comparisons of switching from tafluprost to TTFC are limited. The efficacy and safety of TTFC have been investigated in patients with all types of glaucoma and Ocular Hypertension (OH) [7Pillunat LE, Erb C, Ropo A, Kimmich F, Pfeiffer N. Preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% in patients with open-angle glaucoma and ocular hypertension: Results of an open-label observational study. Clin Ophthalmol 2017; 11: 1051-64.[http://dx.doi.org/10.2147/OPTH.S128453] [PMID: 28652689] , 8Takagi Y, Osaki H, Yamashita T, Kai Y. Prospective observational post-marketing study of tafluprost 0.0015%/timolol 0.5% combination ophthalmic solution for glaucoma and ocular hypertension: short-term efficacy and safety. Ophthalmol Ther 2016; 5(2): 191-206.[http://dx.doi.org/10.1007/s40123-016-0057-3] [PMID: 27492380] ], but there are no reports on the efficacy and safety of TTFC in Japanese patients with primary open-angle glaucoma (POAG). Furthermore, the previous studies of TTFC in Japan [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94., 6Kuwayama Y. DE-111 Collaborative Trial Group. A long-term, open-label study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) in patients with open-angle glaucoma or ocular hypertension. Atarashii Ganka 2015; 32: 133-43.] were conducted as clinical trials, and there have been no direct comparisons of the efficacy and safety of tafluprost and TTFC in patients with POAG and OH in routine clinical practice.

In this prospective study, we investigated the efficacy and safety of IOP reduction and patient adherence in routine clinical practice in Japanese patients with POAG who were switched from tafluprost to TTFC.

2. MATERIALS AND METHODS

The study protocol was approved by the ethical committee at our hospital and all participants provided written informed consent before any study procedure or examination was performed. The study conduct adhered to the tenets of the Declaration of Helsinki.

Fig. (1)
Questionnaire on patient preference, adherence, and specific adverse reactions.


The study was conducted between July 2015 and May 2017 at Inouye Eye Hospital (Tokyo, Japan) and included 34 eyes of 34 patients with POAG who had had an inadequate decrease in IOP after more than 3 months of treatment with tafluprost 0.0015% (Tapros®; Santen Pharmaceutical Co. Ltd., Osaka, Japan), necessitating a change in IOP-lowering medication. In cases where both eyes qualified for inclusion in the study, the eye with the higher IOP was selected as the study eye. If both eyes had the same IOP, the right eye was selected as the study eye.

The study participants discontinued using tafluprost once daily at night and switched to TTFC (Tapcom®; Santen Pharmaceutical Co. Ltd.) once daily at night with no washout period in between.

All eyes underwent ophthalmic examination, including IOP measurement (Goldmann tonometry), before and after using the study medication for 1 month and 3 months. Systolic/diastolic Blood Pressure (BP) and pulse rate were measured using an Udex super type pulsometer, Elquest Inc., (Chiba, Japan) at each time point. The width and rate of IOP reduction from baseline values were assessed after 1 and 3 months of treatment. The study participants were asked about specific adverse reactions after 1 and 3 months of treatment. Preference and adherence were investigated using a questionnaire after 1 month of treatment (Fig. 1).

Analysis of variance and Bonferroni/Dunn analyses were used to compare the IOP, systolic/diastolic BP, and pulse rate values obtained before and after administration of TTFC. The width and rate of IOP reduction from baseline at 1 and 3 months were compared using the Wilcoxon signed-rank test. We calculated that a target sample size [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.] of 26 would be required to allow detection of a 2-mmHg difference in IOP after switching to TTFC, with an expected standard deviation of 3.5 mmHg at a power of 0.80. A p-value <0.05 was considered statistically significant.

3. RESULTS

The patients comprised 14 men and 20 women with a mean age at baseline of 66.6 ± 11.4 (range 27–82) years. The mean deviation on the Humphrey visual field test program 30-2 SITA Standard was -6.63 ± 5.59 (range -19.33 ~ 0.02) dB. Six eyes had POAG and 28 had normal-tension glaucoma. The IOP was significantly lower after 1 (14.2 ± 2.1 mmHg) and 3 (14.1 ± 2.3 mmHg) months of using the study medication when compared with baseline (16.0 ± 2.0 mmHg, both P < 0.0001; Fig. 2). There was no statistically significant difference in width or rate of IOP reduction after 1 and 3 months of treatment with the study medication.

Fig. (2)
Changes in mean intraocular pressure before and after switching to the fixed combination of tafluprost/timolol. *p < 0.0001.


There were also no statistically significant differences in pulse rate or systolic/diastolic BP between baseline and 1 and 3 months after switching medication (pulse rate, p = 0.3433; systolic BP, p = 0.5367; diastolic BP, p = 0.7645, Table 1).

Table 1
Differences in pulse rate or systolic/diastolic BP between baseline and 1 and 3 months after switching medication (pulse rate, p = 0.3433; systolic BP, p = 0.5367; diastolic BP, p = 0.7645).


One patient dropped out of the study because of an adverse effect after 5 days of using the study medication, leaving 33 patients available to complete the questionnaire after 1 month of treatment. Six patients (18.2%) answered ‘yes’ and 27 (81.8%) answered ‘no’ when asked if they had ever forgotten to use their medication during the first week after switching to the study medication. The 6 patients who answered ‘yes’ to the above question reported missing one dose. When asked if they had ever forgotten to use their medication in the week before switching to the trial medication, 9 patients (27.3%) answered ‘yes’ and 22 (66.7%) answered ‘no’ (2 [6.0%] did not answer this question); 7 (77.8%) of the 9 patients who answered ‘yes’ missed one dose, 1 (11.1%) missed two doses, and 1 (11.1%) did not answer this question.

Six patients (18.2%) reported a preference for the trial medication, 21 (63.6%) had no preference, and 6 (18.2%) preferred tafluprost alone. Two of the 6 patients who preferred the trial medication reported that they did so because there was ‘no blurred vision’, 1 because of the ‘lower dosing frequency’, and 1 because of ‘feeling refreshed’. Four of the 6 patients who preferred to use tafluprost alone did so because of ‘no ocular irritation’ and 1 because of ‘no discomfort’.

Five patients (14.7%) experienced adverse reactions, included irritation of the skin at the wrist after 5 days, ocular irritation at 1 month, chest pain at 1 month, a corneal epithelium disorder at 1 and 3 months, and a corneal epithelium disorder at 3 months (all in 1 patient each). Two patients (5.9%) discontinued using the TTFC because of irritation of skin at the wrist (n = 1) and chest pain (n = 1).

4. DISCUSSION

In this study, the width and rate of IOP reduction from baseline values was significant 3 months after the patients switched from tafluprost alone to the TTFC (1.8 ± 1.8 mmHg and 11.2 ± 10.3%, respectively). In a previous study in which timolol was added to tafluprost, the width and rate of IOP reduction were 2.2 ± 1.8 mmHg and 11.4%, respectively [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.]. There was no significant difference in the efficacy of IOP reduction between switching from tafluprost to TTFC in our present study and the previous study in which timolol was added to tafluprost [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.].

The IOP-lowering effect of a prostaglandin/timolol fixed combination eye drop formulation has been of concern because of the need to decrease the frequency of instillation of timolol from twice daily to once daily. Several studies have reported that penetration of timolol increases with increasing pH, so in the present study we used a pH-adjusted formulation to increase the penetration of timolol to the level that would be achieved by once-daily administration [12Ueda K, Tonouchi A, Fukano Y. Tafluprost 0.0015%/timolol 0.5% combination ophthalmic solution (DE-111 Ophthalmic solution) formulation design and intraocular penetration in rats. J Eye 2013; 30: 1761-6.]. Our findings are very similar to those of another study in which timolol was added to tafluprost [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.].

When switching from tafluprost to a fixed combination of tafluprost/timolol in patients with POAG, decreases in IOP width of 2.6 ± 1.8 mmHg [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.] and 1.7 mmHg [6Kuwayama Y. DE-111 Collaborative Trial Group. A long-term, open-label study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) in patients with open-angle glaucoma or ocular hypertension. Atarashii Ganka 2015; 32: 133-43.] during 4 weeks of follow-up have been reported, as well as a decrease of 2.2 mmHg during 52 weeks of follow-up [6Kuwayama Y. DE-111 Collaborative Trial Group. A long-term, open-label study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) in patients with open-angle glaucoma or ocular hypertension. Atarashii Ganka 2015; 32: 133-43.].There have been reports of IOP reduction rates of 10.0% [6Kuwayama Y. DE-111 Collaborative Trial Group. A long-term, open-label study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) in patients with open-angle glaucoma or ocular hypertension. Atarashii Ganka 2015; 32: 133-43.] and 13.5% [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.] during 4 weeks of follow-up, and 12.9% during 52 weeks of follow-up [6Kuwayama Y. DE-111 Collaborative Trial Group. A long-term, open-label study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) in patients with open-angle glaucoma or ocular hypertension. Atarashii Ganka 2015; 32: 133-43.]. Again, there was no significant difference between our findings and those of the above-mentioned studies [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94., 6Kuwayama Y. DE-111 Collaborative Trial Group. A long-term, open-label study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) in patients with open-angle glaucoma or ocular hypertension. Atarashii Ganka 2015; 32: 133-43.]. However, the previous studies that investigated in patients with glaucoma and OH reported that the width and rate of IOP reduction were 3.6–5.1 mmHg and 18.0–24.0% during 4–16 weeks of follow-up [7Pillunat LE, Erb C, Ropo A, Kimmich F, Pfeiffer N. Preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% in patients with open-angle glaucoma and ocular hypertension: Results of an open-label observational study. Clin Ophthalmol 2017; 11: 1051-64.[http://dx.doi.org/10.2147/OPTH.S128453] [PMID: 28652689] ] and 2.5 mmHg and 15.0% during 3 months of follow-up [8Takagi Y, Osaki H, Yamashita T, Kai Y. Prospective observational post-marketing study of tafluprost 0.0015%/timolol 0.5% combination ophthalmic solution for glaucoma and ocular hypertension: short-term efficacy and safety. Ophthalmol Ther 2016; 5(2): 191-206.[http://dx.doi.org/10.1007/s40123-016-0057-3] [PMID: 27492380] ].

When switching from latanoprost to a fixed combination of latanoprost/timolol, the width of IOP reduction was 2.4 ± 2.2 mmHg after 3 months and 2.1 ± 2.3 mmHg after 6 months, with respective IOP reduction rates of 13.1 ± 10.9% and 11.2 ± 11.8% [13Inoue K, Fujimoto T, Higa R, et al. Efficacy and safety of a switch to latanoprost 0.005% + timolol maleate 0.5% fixed combination eyedrops from latanoprost 0.005% monotherapy. Clin Ophthalmol 2012; 6: 771-5.[http://dx.doi.org/10.2147/OPTH.S31085] [PMID: 22693419] ]. When switching from travoprost to a fixed combination of travoprost/timolol, the respective width and rate of IOP reduction were 1.9 ± 1.7 mmHg and 10.5 ± 9.9% after 1 month and 2.1 ± 1.7 mmHg and 11.9 ± 9.6% after 3 months [14Aoki Y, Nagumo H, Inoue K, Tomita G. Ocular hypotensive effect and safety of travoprost 0.004%/timolol maleate 0.5% fixed combination, switched from travoprost 0.004% alone for 3 months. Atarashii Ganka 2012; 29: 1559-62.]. The findings in those two studies are not significantly different from those in our present study.

In our study, neither systolic/diastolic BP nor pulse rate values were significantly different after 1 and 3 months of treatment from those at baseline, which is consistent with earlier studies reporting no significant difference in systolic/diastolic BP from baseline after 2 and 4 weeks of treatment [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94., 6Kuwayama Y. DE-111 Collaborative Trial Group. A long-term, open-label study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) in patients with open-angle glaucoma or ocular hypertension. Atarashii Ganka 2015; 32: 133-43.]. In one of the previous studies, the pulse rate values after 2 and 4 weeks were significantly lower than the pulse rate at baseline [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.]; however, in the other study, the difference detected at 2 weeks was no longer present at 4 weeks [6Kuwayama Y. DE-111 Collaborative Trial Group. A long-term, open-label study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) in patients with open-angle glaucoma or ocular hypertension. Atarashii Ganka 2015; 32: 133-43.]. The reduction in pulse rate width after 2 and 4 weeks was -2.0 ± 7.5/min and -1.3 ± 7.9/min, respectively, but these values were within normal limits [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.]. These reports also suggested that TTFC had no adverse effects on the circulatory system.

Adverse reactions occurred in 5 patients (14.7%) and included a corneal epithelium disorder, ocular irritation, irritation of the skin at the wrist, and chest pain. These adverse reactions were the same as those reported in the previous studies [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.-8Takagi Y, Osaki H, Yamashita T, Kai Y. Prospective observational post-marketing study of tafluprost 0.0015%/timolol 0.5% combination ophthalmic solution for glaucoma and ocular hypertension: short-term efficacy and safety. Ophthalmol Ther 2016; 5(2): 191-206.[http://dx.doi.org/10.1007/s40123-016-0057-3] [PMID: 27492380] ]. Adverse reactions occurred in 10.5% [5Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.] and 8.3% [6Kuwayama Y. DE-111 Collaborative Trial Group. A long-term, open-label study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) in patients with open-angle glaucoma or ocular hypertension. Atarashii Ganka 2015; 32: 133-43.] in the previous studies, which is similar to the frequency in our present study.

A previous study reported a dropout rate of 6.5% (2 cases) because of adverse reactions (itch and bradycardia) when patients were switched from latanoprost to a fixed combination of latanoprost/timolol [13Inoue K, Fujimoto T, Higa R, et al. Efficacy and safety of a switch to latanoprost 0.005% + timolol maleate 0.5% fixed combination eyedrops from latanoprost 0.005% monotherapy. Clin Ophthalmol 2012; 6: 771-5.[http://dx.doi.org/10.2147/OPTH.S31085] [PMID: 22693419] ]. In another study, 1 patient (3.3%) dropped out because of blurred vision after switching from travoprost to a fixed combination of travoprost/timolol [14Aoki Y, Nagumo H, Inoue K, Tomita G. Ocular hypotensive effect and safety of travoprost 0.004%/timolol maleate 0.5% fixed combination, switched from travoprost 0.004% alone for 3 months. Atarashii Ganka 2012; 29: 1559-62.]. In our study, 2 patients (5.9%) dropped out because of irritation of the skin at the wrist and chest pain. The dropout rate in our study is similar to that in the previously reported studies [13Inoue K, Fujimoto T, Higa R, et al. Efficacy and safety of a switch to latanoprost 0.005% + timolol maleate 0.5% fixed combination eyedrops from latanoprost 0.005% monotherapy. Clin Ophthalmol 2012; 6: 771-5.[http://dx.doi.org/10.2147/OPTH.S31085] [PMID: 22693419] , 14Aoki Y, Nagumo H, Inoue K, Tomita G. Ocular hypotensive effect and safety of travoprost 0.004%/timolol maleate 0.5% fixed combination, switched from travoprost 0.004% alone for 3 months. Atarashii Ganka 2012; 29: 1559-62.]. Therefore, we consider that the safety of TTFC is similar to that of other fixed combinations.

In this study, we investigated patient preference and adherence by questionnaire, which has not been undertaken in previous studies. Adherence to medication did not change after switching to TTFC because the dosing frequency was the same as that for tafluprost used alone. Moreover, more than 80% of patients in our present study had a favorable or unchanged impression of TTFC after switching, suggesting that both fewer adverse reactions and improved adherence can be expected with this medication.

The main limitation of this study is that it only evaluated the short-term safety and efficacy of IOP reduction. Future studies should include larger sample sizes and long-term follow-up to confirm the utility of switching from tafluprost to TTFC in patients with POAG.

CONCLUSION

In this study, we prospectively investigated the efficacy and safety of switching from tafluprost to a TTFC in Japanese patients with POAG in routine clinical practice. Switching to the TTFC was safe and effective for IOP reduction with no decrease in patient adherence. The TTFC is an acceptable treatment option for patients with POAG.

ETHICS APPROVAL AND CONSENT TO PARTICIPATE

The study protocol was approved by the Ethical committee at Inouye Eye Hospital.

HUMAN AND ANIMAL RIGHTS

No Animals were used in this research. All human research procedures followed were in accordance with the ethical standards of the committee responsible for human experimentation (institutional and national), and with the Helsinki Declaration of 1975, as revised in 2013.

CONSENT OF PUBLICATION

All participants provided written informed consent before any study procedure or examination was performed.

CONFLICT OF INTERESTS

The authors declare no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] The Japan Glaucoma Society Guidelines for Glaucoma (4th Edition) 2018.
[2] Djafari F, Lesk MR, Harasymowycz PJ, Desjardins D, Lachaine J. Determinants of adherence to glaucoma medical therapy in a long-term patient population. J Glaucoma 2009; 18(3): 238-43.[http://dx.doi.org/10.1097/IJG.0b013e3181815421] [PMID: 19295380]
[3] Li T, Lindsley K, Rouse B, et al. Comparative effectiveness of first-line medications for primary open-angle glaucoma: A systematic review and network meta-analysis. Ophthalmology 2016; 123(1): 129-40.[http://dx.doi.org/10.1016/j.ophtha.2015.09.005] [PMID: 26526633]
[4] Schmier JK, Hulme-Lowe CK, Covert DW. Adjunctive therapy patterns in glaucoma patients using prostaglandin analogs. Clin Ophthalmol 2014; 8: 1097-104.[http://dx.doi.org/10.2147/OPTH.S63760] [PMID: 24959067]
[5] Kuwayama Y. DE-111 Collaborative Trial Group. Phase III double-masked study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) versus tafluprost 0.0015% alone or given concomitantly with timolol 0.5% in primary open angle glaucoma and ocular hypertension Atarashii Ganka 2013; 30: 1185-94.
[6] Kuwayama Y. DE-111 Collaborative Trial Group. A long-term, open-label study of fixed combination tafluprost 0.0015%/timolol 0.5% (DE-111) in patients with open-angle glaucoma or ocular hypertension. Atarashii Ganka 2015; 32: 133-43.
[7] Pillunat LE, Erb C, Ropo A, Kimmich F, Pfeiffer N. Preservative-free fixed combination of tafluprost 0.0015% and timolol 0.5% in patients with open-angle glaucoma and ocular hypertension: Results of an open-label observational study. Clin Ophthalmol 2017; 11: 1051-64.[http://dx.doi.org/10.2147/OPTH.S128453] [PMID: 28652689]
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Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


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