Efficacy and safety of benzalkonium chloride-free fixed-dose combination of latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension

Abstract

Background: Benzalkonium chloride (BAK) is a common preservative in topical ocular preparations; however, prolonged use may lead to deleterious effects on the ocular surface, affecting quality of life and reducing adherence to treatment and overall outcomes. This study compared the intraocular pressure (IOP)-lowering efficacy and safety of a novel once-daily, BAK-free, fixed-dose combination of latanoprost plus timolol with latanoprost or timolol administered as monotherapy or concomitantly.

Methods: This was a 6-week, randomized, open-label, parallel-group, active-controlled study in patients aged ≥18 years with open-angle glaucoma or ocular hypertension. A total of 227 patients were randomized to either a once-daily, BAK-free, fixed-dose combination of latanoprost 0.005%/timolol 0.5% ophthalmic solution or concomitant administration of once-daily latanoprost 0.005% plus twice-daily timolol 0.5% or once-daily latanoprost 0.005% monotherapy, or twice-daily timolol 0.5% monotherapy. Efficacy end points were assessed at three time points on visits at weeks 1, 2, 4, and 6 versus baseline.

Results: The IOP-lowering efficacy of the fixed-dose combination of latanoprost/timolol was similar to that of latanoprost plus timolol administered concomitantly at all time points (mean IOP difference and 95% confidence interval within ±1.5 mmHg; P=0.4223 to P=0.9981). The fixed-dose combination of latanoprost/timolol demonstrated significantly better IOP-lowering efficacy than timolol monotherapy at all time points (P=0.001 to P<0.0001) and significantly better IOP-lowering efficacy than latanoprost monotherapy at all time points. Responder rates on at least one time point and on at least two time points with fixed-dose combination latanoprost/timolol were similar to those with concomitant latanoprost plus timolol (85.5% versus 82.1%, P=0.6360; 78.2% versus 75%, P=0.6923), but significantly better than either latanoprost or timolol monotherapy (68.5%, P=0.0355; 55.4%, P=0.0005; 57.4%, P=0.0202; and 46.4%, P=0.0006, respectively). No significant differences in ocular and nonocular treatment-emergent adverse events were found between the treatment groups.

Conclusion: A BAK-free, fixed-dose combination of latanoprost 0.005%/timolol 0.5% was as effective and well tolerated as concomitant latanoprost and timolol for treatment of elevated IOP in patients with open-angle glaucoma or ocular hypertension.

Keywords: benzalkonium chloride; latanoprost; ocular hypertension; open-angle glaucoma; pharmaceutical preservatives; timolol.

Figure 1

Patient disposition. Notes: ^aThe 227 randomized patients represented the safety population, which included all patients who received at least one dose of study medication. ^bITT population (efficacy analysis population) included all patients with baseline visit assessment who received at least one dose of study medication and at least one on-therapy efficacy assessment. Missing data were treated by last observation carried forward. ^cPP population included patients with at least one on-therapy efficacy assessment and no major protocol violation. Abbreviations: ITT, intent to treat; PP, per protocol; N/n, number.

Figure 2

Mean IOP at each time point by visit. Notes: Mean IOP is the mean per treatment group at each time point at each visit (day 7±1, 14±2, 28±2, and 42±2) during the 6-week treatment period. Data shown are from the efficacy analysis (ITT) population. P-value was calculated using a paired Student’s t-test for comparing mean value from baseline (day 0) to mean value for week 1 (day 0 to day 7±1), week 2 (day 0 to day 14±2), week 4 (day 0 to day 28±2), and week 6 (day 0 to day 42±2) for each treatment group. Abbreviations: IOP, intraocular pressure; ITT, intent to treat.

Figure 3

Responder rates (defined as patients having IOP ≤18 mmHg for at least two time points at each follow-up visit) for the four treatment groups. Notes: P-values were calculated using chi-square test for comparing treatment groups (each treatment group versus latanoprost/timolol fixed-dose combination group). Data shown are from the efficacy analysis (ITT) population. *indicates a statistically significant P-value. Abbreviations: IOP, intraocular pressure; ITT, intent to treat.