Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 03/15/15 For personal use only.
Original Research
1.
Background
2.
Methods
3.
Results
4.
Discussion
5.
Conclusion
From benzalkonium chloridepreserved Latanoprost to Polyquad-preserved Travoprost: a 6-month study on ocular surface safety and tolerability Gemma Caterina Maria Rossi†, Luigia Scudeller, Teresa Rolle, Gian Maria Pasinetti & Paolo Emilio Bianchi †
University Eye Clinic of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
Background: To evaluate the safety and tolerability of Polyquad-preserved Travoprost (PQ-Travoprost) in patients previously treated with benzalkonium chloride (BAK)-preserved Latanoprost. Methods: Cohort 6-month study on open-angle glaucoma or ocular hypertension patients. Complete ophthalmic examination, intraocular pressure (IOP) measurement and ocular surface status (tear film break-up time [TF-BUT], corneal staining and ocular surface disease index [OSDI]) were evaluated at baseline and 6 months later. Results: A total of 44 patients were enrolled. Median (interquartile range [IQR]) baseline IOP was 18 (15.5 -- 21) and 16 (14 -- 17) mmHg (p < 0.0001) after 6 months. At baseline, 18 (40.9%) patients presented an IOP of < 18 mmHg, 11 (25%) < 16 mmHg, 2 (4.3%) < 14 mmHg and 1 (2.3%) < 12 mmHg; 6 months later the proportions were 36 (81.8%) (p < 0.0001), 21 (47.7%) (p = 0.00075), 8 (18.2%) (p = 0.0143) and 6 (13.6%) (p = 0.0253). Concerning safety, TF-BUT improved from 8 [IQR 6 -- 10] to 10 [IQR 8 -- 12] s (p < 0.0001). No eye developed corneal staining; punctate keratitis was absent in 13 (29.5%) patients at baseline and in 31 (70.4%) after 6 months (p < 0.001). OSDI changed from 16 (10 -- 30) to 9 (2 -- 20). Conclusions: No patient treated with PQ-Travoprost developed ocular surface disease after 6 months of monotherapy, whereas many patients reached a good IOP control with lower IOP values. Ocular surface status statistically improved when examined by TF-BUT and corneal staining. Keywords: efficacy, glaucoma, ocular surface disease, Polyquad-preserved, quality of life, tolerability, Travoprost Expert Opin. Drug Saf. [Early Online]
1.
Background
Glaucoma is a chronic disease of the optic nerve, often associated with elevated intraocular pressure (IOP), that can cause an irreversible loss of vision [1]. IOP still remains the most clinically important risk factor for developing and/or progressing glaucoma. In fact, international Randomized Clinical Trials have demonstrated that reducing IOP can slow the progression of disease in patients with glaucoma (AGIS in 2000 [1], EMGT in 2003 [2]), and can delay or even prevent the development of open-angle glaucoma in patients with ocular hypertension ([OH] OHTS in 2002 [3], EGPS in 2005 [4]). Topical ocular hypotensive medications are the most used therapeutic option to lower IOP in patients with glaucoma or OH. Prostaglandin analogues have been 10.1517/14740338.2015.1017467 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
1
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 03/15/15 For personal use only.
G. C. M. Rossi et al.
proved to be effective in lowering IOP without causing systemic side effects, and this class of drugs is thus recommended as first-choice therapy for lowering IOP in glaucoma by the European Glaucoma Society Guidelines [5]. As glaucoma is a chronic disease, the long-term safety of prostaglandin analogues is of paramount importance. The safety of a drug is not only related to the active drug itself but also to its preservative [6]. The most common preservative in IOP-lowering medications is benzalkonium chloride (BAK), a quaternary ammonium compound that causes bacterial cell death by lysing cytoplasmic membranes; however, it has been demonstrated to be toxic to the eye [6-9]. Recently, in Italy, most patients treated with Latanoprost 0.005% had to be switched to the nonbrand formulation for regulatory reasons; however, Latanoprost 0.005% contains 0.02% BAK, one of the highest BAK concentrations found in ophthalmic preparations and many clinicians opted for a switch to a less toxic formulation. One of these is the new formulation of Travoprost 0.004% preserved with polyquaternium (PQ, Polyquad). PQ, a preservative recently introduced in some anti-glaucoma medications, is a polymeric quaternary ammonium with cationic antimicrobial properties that has shown significantly lower cytotoxicity than BAK, both in in vitro and in in vivo studies [10-12]. A multi-center clinical study comparing BAK-preserved and PQ-preserved Travoprost has demonstrated the noninferiority of the PQ-preserved drug: the authors concluded that the formulation resulted safe and effective while avoiding BAK exposure [13]. However, few long-term clinical studies are available. The primary objective of our study was to evaluate safety and tolerability of the new PQ-preserved Travoprost 0.004% in patients previously treated with BAK-preserved Latanoprost 0.005%; the secondary objective was to confirm drug’s efficacy in lowering IOP after 6 months of treatment. 2.
Methods
This was a 6-month, clinician blind (the ophthalmologist who measured the IOP and evaluated the ocular surface status was blinded to patient’s therapy), observational study involving glaucoma patients. The study was carried out in accordance with the Declaration of Helsinki and according to the Local Ethical Committee. The study was not supported by any industry neither received any other form of financial grant or sponsorship. Patients with open angle glaucoma (OAG) or OH needing a change in the topical monotherapy from branded (Xalatan, Pfizer) to non-branded Latanoprost 0.005% and asking a switch to a branded drug were selected. PQ-preserved Travoprost (one drop in each eye at 9 pm) was prescribed. Inclusion criteria were as follows: age 18 years or older, diagnosis of OAG or OHOH, ongoing BAK-Latanoprost monotherapy since at least one year. Exclusion criteria were filtering or other ocular surgery in the preceding 6 months and a previous diagnosis of dry eye 2
or any inflammatory disease (ocular and/or systemic). The diagnosis of OAG required the presence of glaucomatous optic nerve head (ONH), confirmed by a fundus examination by an experienced ophthalmologist; and at least two reliable Humphrey 24-2 full threshold visual field tests performed on different days with glaucoma hemifield test (GHT) outside normal limits, independently of IOP value [5]. The diagnosis of OH required IOP > 21 mmHg and < 32 mmHg on at least two visits; normal ONH, confirmed by an expert fundus examination; and at least two reliable Humphrey 24-2 full threshold visual field tests performed on different days with GHT within normal limits [5]. Gender and age were collected as demographic parameters. Patients were assessed twice: at baseline and at the 6-month follow-up visit. All patients, at each occasion, underwent a complete ophthalmic examination with the evaluation of IOP (for efficacy) and fluorescein corneal staining/keratitis, tear film break-up time (TF-BUT), central corneal thickness (CCT) and ocular surface disease index (OSDI) questionnaire (for safety/tolerability) [14,15]. The ophthalmic examination was comprehensive of the visual acuity evaluation (decimals) and the optic nerve examination with fundoscopy (subjective) and optical coherence tomography (objective). Conjunctival hyperemia was graded by using a validated scale with descriptive and photographic anchors [14]. IOP (the mean of three consecutive measurements) was recorded with the Goldmann tonometer for each eye at time of therapy’s change and after 6 months; all IOP values were recorded in the morning (between 9 am and 12 noon) at each visit, last dose having being administered the previous evening at 9 pm. The right eye of each patient was chosen for IOP analysis; however, both eyes were treated, if needed. TF-BUT analysis was performed before instillation of any anaesthetic drops for IOP measurement at both visits. A strip of fluorescein was used and the patient asked to blink several times. The time required for the first area of tear film break-up to appear after a complete blink was determined using the cobalt blue filter on the slit lamp biomicroscope. The lower (worse) score of the average of two readings of both eyes for each individual was used for analysis. TF-BUT values greater than or equal to 10 s were classified as normal and TF-BUT values less than 10 s as abnormal [14]. The presence of corneal surface damage was determined by staining the cornea with fluorescein. The presence of corneal staining was defined as more than one dot of fluorescein staining over the corneal surface. Superficial punctate keratitis was graded in according to a four degree staining scale by determining the area and density of the lesion [14] on a 0 -- 3 scale, where 0 is absence of keratitis punctate, 1 = mild (a few punctate of staining but less than 10% coverage of the corneal surface); 2 = moderate (10 -- 50% coverage of the corneal surface) and 3 = severe (more than 50% coverage of the corneal surface).
Expert Opin. Drug Saf. (2015) 14(5)
Ocular surface status switching from BAK-Latanoprost to Polyquad-Travoprost
The OSDI is a disease-specific questionnaire used to quantify the specific impact of dry eye on vision-related quality of life. It includes three subscales: ocular discomfort (OSDI symptoms), functioning (OSDI function) and environmental triggers (OSDI triggers) [15]. The questions refer to a oneweek recall period, possible responses refer to the frequency of the disturbance. OSDI subscale scores can range from 0 to 100, with higher scores indicating more problems or symptoms.
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 03/15/15 For personal use only.
2.1.
4.
Statistical analysis
Descriptive statistics were produced for demographic and clinical characteristics of cases. Mean and standard deviations (SDs) are presented for normally distributed variables; median and interquartile range (IQR) for non-normally distributed variables; numbers and percentages for categorical variables. 95% confidence intervals were also calculated when relevant. For group comparison, parametric or non-parametric tests (according to data distribution) were used for quantitative variables, and Pearson’s chi-2 test (Fisher exact test where appropriate) for categorical variables; test for paired data and test for trend were used when relevant. All analysis refers to right eye; left eye’s data are similar. The mean IOP reduction and the percentage of patients with IOP £ 18 mmHg were calculated to judge effectiveness. 3.
(p < 0.0001). The mean reduction from baseline at month 6 was s -3.45 (95%CI -4.92 to o -1.98, p < 0.001). At baseline, 18 (40.9%) patients had an IOP < 18 mmHg, 11 (25%) < 16 mmHg, 2 (4.3%) < 14 mmHg and 1 (2.3%) < 12 mmHg; 6 months later patients reached statistically lower IOP measurements: 36 (81.8%) (p < 0.001), 21 (47.7%) (p = 0.0075), 8 (18.2%) (p = 0.0143) and 6 (13.6%) (p = 0.0253), respectively (Table 2).
Results
A total of 44 patients were enrolled, and all completed the study. All were Caucasian; 25 (56.8%) were males; the median [IQR] age was 71 [62.3 -- 78.9] years. The mean (± SD) basal MD value was s -3.2 ± 6.4 dB; the median [IQR] CCT was 555.5 545 -- 566 micron. Most patients were OH (24 subjects, 54.6%); 20 were OAG (45.4%). No significant difference was noted in mean ocular hyperemia, visual acuity or optic nerve from baseline to the 6-month visit. Median TF-BUT changed from 8 [IQR 6 -- 10] s at baseline to 10 [IQR 8 -- 12] s at 6 months (p < 0.0001). Median change in TF-BUT was s -1 (95%CI -1.6 to o -0.6, p < 0.001). Punctate keratitis was present in 31 (70.5%) patients at baseline and in 13 (29.5%) after 6 months. No eye developed new corneal staining; conversely, in those patients with keratitis at baseline staining grading improved (Table 1): at baseline, 11 (25%) patients presented a grade 2 keratitis and four (6.8%) a grade 3 keratitis, these percentages decreased to 1 (2.3%) and 0 (0%) after 6 months, respectively, and overall, 29 patients (65.9%, 95%CI 50 -- 79.5%) improved (p < 0.001). OSDI (median [IQR]) was 16 (10 -- 30) at baseline and 9 (2 -- 20) at 6 months, and mean change was -7 (95% CI -11.1 to o -3.2) (p = 0.0027). The median [IQR] baseline IOP was 18 (15.5 -- 21) mmHg: it decreased to 16 (14 -- 17) mmHg after 6 months
Discussion
Most patients treated with an IOP-lowering medication are under a prostaglandin analogue accordingly to the European Glaucoma Society [5]. The once-a-day dosing makes prostaglandin analogues an attractive therapeutic option due to their good IOP-lowering efficacy, expected better adherence (once a day instillation instead of more instillations) and lack of systemic side effects. Several studies have pointed out that, frequently, patients chronically treated with IOP-lowering medications are more exposed to ocular surface alterations [6-9]. In a recent paper investigating ocular surface disease, we have considered a number of potential risk factors: class of previous and current IOP-lowering drugs, number of drugs, number of drops/day, total and current BAK exposition [9]. We found that ocular surface disease was independently associated with the number of medications used, the prolonged use of preserved medications and the total BAK exposure, confirming previously reported data [9]. Unfortunately, prostaglandin analogues are generally BAK preserved and Latanoprost contains one of the highest BAK concentrations among marketed drugs. Baudouin and coworkers in a paper about preservatives in eye drops [6] strongly suggest avoiding long-term use of preservatives, and the use of a less toxic alternative to BAK. In the EU, a new formulation of Travoprost BAK-free is now available, preserved with Polyquaternium-1, that is as safe and as efficient as the BAK-preserved formulation [13] while avoiding the toxic exposition to BAK. Based on these data, we selected patients on BAK-preserved Latanoprost who needed to change their therapy to the nonbrand formulation for economical reasons, and were switched to the BAK-free therapy with PQ-Travoprost. All patients showed a favorable effect on ocular surface status with an increase of about 2 s in TF-BUT after 6 months of PQ-Travoprost monotherapy: this change, even if small, is clinically relevant and favorably perceived by patients. A possible explanation for this significant improvement might be the loss in conjunctival goblet cells, which has been observed with BAK-preserved Latanoprost but not with BAK-free Travoprost [16]. Goblet cells facilitate ocular surface wettability and tear film stability through the secretion of mucin: a loss of these cells may destabilize the tear film leading to decreased break-up time [16].
Expert Opin. Drug Saf. (2015) 14(5)
3
G. C. M. Rossi et al.
Table 1. Grading of fluorescein corneal staining. Fluorescein corneal staining
Baseline n (%)
6 months n (%)
Overall p-value
Grade Grade Grade Grade
13 (29.5) 17 (38.6) 11 (25) 4 (6.8)
31 (70.5) 12 (27.3) 1 (2.3) 0 (0)
< 0.001
0 1 2 3
n: Number of patients.
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 03/15/15 For personal use only.
Table 2. Intraocular pressure values change over the time.
IOP value < < <
Original Research
1.
Background
2.
Methods
3.
Results
4.
Discussion
5.
Conclusion
From benzalkonium chloridepreserved Latanoprost to Polyquad-preserved Travoprost: a 6-month study on ocular surface safety and tolerability Gemma Caterina Maria Rossi†, Luigia Scudeller, Teresa Rolle, Gian Maria Pasinetti & Paolo Emilio Bianchi †
University Eye Clinic of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy
Background: To evaluate the safety and tolerability of Polyquad-preserved Travoprost (PQ-Travoprost) in patients previously treated with benzalkonium chloride (BAK)-preserved Latanoprost. Methods: Cohort 6-month study on open-angle glaucoma or ocular hypertension patients. Complete ophthalmic examination, intraocular pressure (IOP) measurement and ocular surface status (tear film break-up time [TF-BUT], corneal staining and ocular surface disease index [OSDI]) were evaluated at baseline and 6 months later. Results: A total of 44 patients were enrolled. Median (interquartile range [IQR]) baseline IOP was 18 (15.5 -- 21) and 16 (14 -- 17) mmHg (p < 0.0001) after 6 months. At baseline, 18 (40.9%) patients presented an IOP of < 18 mmHg, 11 (25%) < 16 mmHg, 2 (4.3%) < 14 mmHg and 1 (2.3%) < 12 mmHg; 6 months later the proportions were 36 (81.8%) (p < 0.0001), 21 (47.7%) (p = 0.00075), 8 (18.2%) (p = 0.0143) and 6 (13.6%) (p = 0.0253). Concerning safety, TF-BUT improved from 8 [IQR 6 -- 10] to 10 [IQR 8 -- 12] s (p < 0.0001). No eye developed corneal staining; punctate keratitis was absent in 13 (29.5%) patients at baseline and in 31 (70.4%) after 6 months (p < 0.001). OSDI changed from 16 (10 -- 30) to 9 (2 -- 20). Conclusions: No patient treated with PQ-Travoprost developed ocular surface disease after 6 months of monotherapy, whereas many patients reached a good IOP control with lower IOP values. Ocular surface status statistically improved when examined by TF-BUT and corneal staining. Keywords: efficacy, glaucoma, ocular surface disease, Polyquad-preserved, quality of life, tolerability, Travoprost Expert Opin. Drug Saf. [Early Online]
1.
Background
Glaucoma is a chronic disease of the optic nerve, often associated with elevated intraocular pressure (IOP), that can cause an irreversible loss of vision [1]. IOP still remains the most clinically important risk factor for developing and/or progressing glaucoma. In fact, international Randomized Clinical Trials have demonstrated that reducing IOP can slow the progression of disease in patients with glaucoma (AGIS in 2000 [1], EMGT in 2003 [2]), and can delay or even prevent the development of open-angle glaucoma in patients with ocular hypertension ([OH] OHTS in 2002 [3], EGPS in 2005 [4]). Topical ocular hypotensive medications are the most used therapeutic option to lower IOP in patients with glaucoma or OH. Prostaglandin analogues have been 10.1517/14740338.2015.1017467 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted
1
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 03/15/15 For personal use only.
G. C. M. Rossi et al.
proved to be effective in lowering IOP without causing systemic side effects, and this class of drugs is thus recommended as first-choice therapy for lowering IOP in glaucoma by the European Glaucoma Society Guidelines [5]. As glaucoma is a chronic disease, the long-term safety of prostaglandin analogues is of paramount importance. The safety of a drug is not only related to the active drug itself but also to its preservative [6]. The most common preservative in IOP-lowering medications is benzalkonium chloride (BAK), a quaternary ammonium compound that causes bacterial cell death by lysing cytoplasmic membranes; however, it has been demonstrated to be toxic to the eye [6-9]. Recently, in Italy, most patients treated with Latanoprost 0.005% had to be switched to the nonbrand formulation for regulatory reasons; however, Latanoprost 0.005% contains 0.02% BAK, one of the highest BAK concentrations found in ophthalmic preparations and many clinicians opted for a switch to a less toxic formulation. One of these is the new formulation of Travoprost 0.004% preserved with polyquaternium (PQ, Polyquad). PQ, a preservative recently introduced in some anti-glaucoma medications, is a polymeric quaternary ammonium with cationic antimicrobial properties that has shown significantly lower cytotoxicity than BAK, both in in vitro and in in vivo studies [10-12]. A multi-center clinical study comparing BAK-preserved and PQ-preserved Travoprost has demonstrated the noninferiority of the PQ-preserved drug: the authors concluded that the formulation resulted safe and effective while avoiding BAK exposure [13]. However, few long-term clinical studies are available. The primary objective of our study was to evaluate safety and tolerability of the new PQ-preserved Travoprost 0.004% in patients previously treated with BAK-preserved Latanoprost 0.005%; the secondary objective was to confirm drug’s efficacy in lowering IOP after 6 months of treatment. 2.
Methods
This was a 6-month, clinician blind (the ophthalmologist who measured the IOP and evaluated the ocular surface status was blinded to patient’s therapy), observational study involving glaucoma patients. The study was carried out in accordance with the Declaration of Helsinki and according to the Local Ethical Committee. The study was not supported by any industry neither received any other form of financial grant or sponsorship. Patients with open angle glaucoma (OAG) or OH needing a change in the topical monotherapy from branded (Xalatan, Pfizer) to non-branded Latanoprost 0.005% and asking a switch to a branded drug were selected. PQ-preserved Travoprost (one drop in each eye at 9 pm) was prescribed. Inclusion criteria were as follows: age 18 years or older, diagnosis of OAG or OHOH, ongoing BAK-Latanoprost monotherapy since at least one year. Exclusion criteria were filtering or other ocular surgery in the preceding 6 months and a previous diagnosis of dry eye 2
or any inflammatory disease (ocular and/or systemic). The diagnosis of OAG required the presence of glaucomatous optic nerve head (ONH), confirmed by a fundus examination by an experienced ophthalmologist; and at least two reliable Humphrey 24-2 full threshold visual field tests performed on different days with glaucoma hemifield test (GHT) outside normal limits, independently of IOP value [5]. The diagnosis of OH required IOP > 21 mmHg and < 32 mmHg on at least two visits; normal ONH, confirmed by an expert fundus examination; and at least two reliable Humphrey 24-2 full threshold visual field tests performed on different days with GHT within normal limits [5]. Gender and age were collected as demographic parameters. Patients were assessed twice: at baseline and at the 6-month follow-up visit. All patients, at each occasion, underwent a complete ophthalmic examination with the evaluation of IOP (for efficacy) and fluorescein corneal staining/keratitis, tear film break-up time (TF-BUT), central corneal thickness (CCT) and ocular surface disease index (OSDI) questionnaire (for safety/tolerability) [14,15]. The ophthalmic examination was comprehensive of the visual acuity evaluation (decimals) and the optic nerve examination with fundoscopy (subjective) and optical coherence tomography (objective). Conjunctival hyperemia was graded by using a validated scale with descriptive and photographic anchors [14]. IOP (the mean of three consecutive measurements) was recorded with the Goldmann tonometer for each eye at time of therapy’s change and after 6 months; all IOP values were recorded in the morning (between 9 am and 12 noon) at each visit, last dose having being administered the previous evening at 9 pm. The right eye of each patient was chosen for IOP analysis; however, both eyes were treated, if needed. TF-BUT analysis was performed before instillation of any anaesthetic drops for IOP measurement at both visits. A strip of fluorescein was used and the patient asked to blink several times. The time required for the first area of tear film break-up to appear after a complete blink was determined using the cobalt blue filter on the slit lamp biomicroscope. The lower (worse) score of the average of two readings of both eyes for each individual was used for analysis. TF-BUT values greater than or equal to 10 s were classified as normal and TF-BUT values less than 10 s as abnormal [14]. The presence of corneal surface damage was determined by staining the cornea with fluorescein. The presence of corneal staining was defined as more than one dot of fluorescein staining over the corneal surface. Superficial punctate keratitis was graded in according to a four degree staining scale by determining the area and density of the lesion [14] on a 0 -- 3 scale, where 0 is absence of keratitis punctate, 1 = mild (a few punctate of staining but less than 10% coverage of the corneal surface); 2 = moderate (10 -- 50% coverage of the corneal surface) and 3 = severe (more than 50% coverage of the corneal surface).
Expert Opin. Drug Saf. (2015) 14(5)
Ocular surface status switching from BAK-Latanoprost to Polyquad-Travoprost
The OSDI is a disease-specific questionnaire used to quantify the specific impact of dry eye on vision-related quality of life. It includes three subscales: ocular discomfort (OSDI symptoms), functioning (OSDI function) and environmental triggers (OSDI triggers) [15]. The questions refer to a oneweek recall period, possible responses refer to the frequency of the disturbance. OSDI subscale scores can range from 0 to 100, with higher scores indicating more problems or symptoms.
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 03/15/15 For personal use only.
2.1.
4.
Statistical analysis
Descriptive statistics were produced for demographic and clinical characteristics of cases. Mean and standard deviations (SDs) are presented for normally distributed variables; median and interquartile range (IQR) for non-normally distributed variables; numbers and percentages for categorical variables. 95% confidence intervals were also calculated when relevant. For group comparison, parametric or non-parametric tests (according to data distribution) were used for quantitative variables, and Pearson’s chi-2 test (Fisher exact test where appropriate) for categorical variables; test for paired data and test for trend were used when relevant. All analysis refers to right eye; left eye’s data are similar. The mean IOP reduction and the percentage of patients with IOP £ 18 mmHg were calculated to judge effectiveness. 3.
(p < 0.0001). The mean reduction from baseline at month 6 was s -3.45 (95%CI -4.92 to o -1.98, p < 0.001). At baseline, 18 (40.9%) patients had an IOP < 18 mmHg, 11 (25%) < 16 mmHg, 2 (4.3%) < 14 mmHg and 1 (2.3%) < 12 mmHg; 6 months later patients reached statistically lower IOP measurements: 36 (81.8%) (p < 0.001), 21 (47.7%) (p = 0.0075), 8 (18.2%) (p = 0.0143) and 6 (13.6%) (p = 0.0253), respectively (Table 2).
Results
A total of 44 patients were enrolled, and all completed the study. All were Caucasian; 25 (56.8%) were males; the median [IQR] age was 71 [62.3 -- 78.9] years. The mean (± SD) basal MD value was s -3.2 ± 6.4 dB; the median [IQR] CCT was 555.5 545 -- 566 micron. Most patients were OH (24 subjects, 54.6%); 20 were OAG (45.4%). No significant difference was noted in mean ocular hyperemia, visual acuity or optic nerve from baseline to the 6-month visit. Median TF-BUT changed from 8 [IQR 6 -- 10] s at baseline to 10 [IQR 8 -- 12] s at 6 months (p < 0.0001). Median change in TF-BUT was s -1 (95%CI -1.6 to o -0.6, p < 0.001). Punctate keratitis was present in 31 (70.5%) patients at baseline and in 13 (29.5%) after 6 months. No eye developed new corneal staining; conversely, in those patients with keratitis at baseline staining grading improved (Table 1): at baseline, 11 (25%) patients presented a grade 2 keratitis and four (6.8%) a grade 3 keratitis, these percentages decreased to 1 (2.3%) and 0 (0%) after 6 months, respectively, and overall, 29 patients (65.9%, 95%CI 50 -- 79.5%) improved (p < 0.001). OSDI (median [IQR]) was 16 (10 -- 30) at baseline and 9 (2 -- 20) at 6 months, and mean change was -7 (95% CI -11.1 to o -3.2) (p = 0.0027). The median [IQR] baseline IOP was 18 (15.5 -- 21) mmHg: it decreased to 16 (14 -- 17) mmHg after 6 months
Discussion
Most patients treated with an IOP-lowering medication are under a prostaglandin analogue accordingly to the European Glaucoma Society [5]. The once-a-day dosing makes prostaglandin analogues an attractive therapeutic option due to their good IOP-lowering efficacy, expected better adherence (once a day instillation instead of more instillations) and lack of systemic side effects. Several studies have pointed out that, frequently, patients chronically treated with IOP-lowering medications are more exposed to ocular surface alterations [6-9]. In a recent paper investigating ocular surface disease, we have considered a number of potential risk factors: class of previous and current IOP-lowering drugs, number of drugs, number of drops/day, total and current BAK exposition [9]. We found that ocular surface disease was independently associated with the number of medications used, the prolonged use of preserved medications and the total BAK exposure, confirming previously reported data [9]. Unfortunately, prostaglandin analogues are generally BAK preserved and Latanoprost contains one of the highest BAK concentrations among marketed drugs. Baudouin and coworkers in a paper about preservatives in eye drops [6] strongly suggest avoiding long-term use of preservatives, and the use of a less toxic alternative to BAK. In the EU, a new formulation of Travoprost BAK-free is now available, preserved with Polyquaternium-1, that is as safe and as efficient as the BAK-preserved formulation [13] while avoiding the toxic exposition to BAK. Based on these data, we selected patients on BAK-preserved Latanoprost who needed to change their therapy to the nonbrand formulation for economical reasons, and were switched to the BAK-free therapy with PQ-Travoprost. All patients showed a favorable effect on ocular surface status with an increase of about 2 s in TF-BUT after 6 months of PQ-Travoprost monotherapy: this change, even if small, is clinically relevant and favorably perceived by patients. A possible explanation for this significant improvement might be the loss in conjunctival goblet cells, which has been observed with BAK-preserved Latanoprost but not with BAK-free Travoprost [16]. Goblet cells facilitate ocular surface wettability and tear film stability through the secretion of mucin: a loss of these cells may destabilize the tear film leading to decreased break-up time [16].
Expert Opin. Drug Saf. (2015) 14(5)
3
G. C. M. Rossi et al.
Table 1. Grading of fluorescein corneal staining. Fluorescein corneal staining
Baseline n (%)
6 months n (%)
Overall p-value
Grade Grade Grade Grade
13 (29.5) 17 (38.6) 11 (25) 4 (6.8)
31 (70.5) 12 (27.3) 1 (2.3) 0 (0)
< 0.001
0 1 2 3
n: Number of patients.
Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 03/15/15 For personal use only.
Table 2. Intraocular pressure values change over the time.
IOP value < < <
