Amy L. Batoosingh

Bimatoprost/timolol fixed combination: a 3-month double-masked, randomized parallel comparison to its individual components in patients with glaucoma or ocular hypertension.

PurposeTo evaluate the safety and efficacy of a fixed combination (FC) of bimatoprost (BIM) and timolol (TIM) compared with each of the active components for 3 months. Patients and MethodsTwo double-masked, randomized, multicenter parallel studies of FC (once-daily, mornings), BIM (once-daily, evenings), or TIM (twice-daily) were conducted in 1061 patients with glaucoma or ocular hypertension. ResultsMean diurnal decreases from baseline intraocular pressure (IOP) at month 3 were 8.1, 7.9, and 6.4 mm Hg for the FC, BIM, and TIM groups, respectively. The proportion of patients with a mean diurnal percent reduction from baseline in IOP of more than 20% across all visits was 81.8% (436/533), 72.1% (191/265), and 49.8% (131/263) for the FC, BIM, and TIM groups, respectively (P<0.001 for FC vs. BIM and FC vs. TIM). The proportion of patients achieving an IOP of less than 18 mm Hg at all time points was 39.2% (209/533), 28.7% (76/265), and 12.2% (32/263) for the FC, BIM, and TIM groups, respectively (P=0.003 for FC vs. BIM, and P<0.001 for FC vs. TIM). The most commonly reported treatment-related adverse event was conjunctival hyperemia, with the greatest incidence in BIM (38.5%, 102/265), followed by FC (22.7%, 121/533, P<0.0001 vs. BIM) and TIM (6.8%, 18/263; P<0.001 vs. FC). ConclusionsFC was statistically significantly more effective than BIM or TIM for most comparisons, and safer than BIM with respect to common ocular adverse events. FC represents a convenient, therapeutic advantage over separate bottles.

Twelve-Month, Randomized, Controlled Trial of Bimatoprost 0.01%, 0.0125%, and 0.03% in Patients with Glaucoma or Ocular Hypertension

PURPOSE To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of ophthalmic formulations of bimatoprost 0.01% and 0.0125% compared with bimatoprost 0.03%. DESIGN Prospective, randomized, double-masked, multicenter clinical trial. METHODS Patients with glaucoma or ocular hypertension were randomized to receive once-daily bimatoprost 0.01% (n = 186), bimatoprost 0.0125% (n = 188), or bimatoprost 0.03% (n = 187) for 12 months. The primary efficacy measure was IOP. Safety measures included adverse events and an objective assessment of conjunctival hyperemia. RESULTS Baseline mean IOPs were similar among treatment groups. Differences in mean IOP between the bimatoprost 0.01% or 0.0125% groups and the bimatoprost 0.03% group were less than 0.9 mm Hg throughout follow-up. Bimatoprost 0.01%, but not bimatoprost 0.0125%, was equivalent in efficacy to bimatoprost 0.03% based on predetermined criteria (limits of the 95% confidence interval of the between-group difference in mean IOP within +/- 1.5 mm Hg at all time points and within +/- 1 mm Hg at most time points). The overall incidence of treatment-related adverse events was reduced significantly in the bimatoprost 0.01% and bimatoprost 0.0125% groups compared with the bimatoprost 0.03% group (P < or = .034). The percentage of patients with a moderate to severe increase from the baseline macroscopic hyperemia score was: bimatoprost 0.01%, 3.2%; bimatoprost 0.0125%, 9.0%; bimatoprost 0.03%, 9.1% (P = .019 for bimatoprost 0.01% vs 0.03%). CONCLUSIONS Bimatoprost 0.01% was equivalent to bimatoprost 0.03% in lowering IOP throughout 12 months of treatment and demonstrated improved tolerability, including less frequent and severe conjunctival hyperemia. Bimatoprost 0.01% demonstrated a better benefit-to-risk ratio than bimatoprost 0.0125%.

The safety and efficacy of bimatoprost/timolol fixed combination: a 1-year double-masked, randomized parallel comparison to its individual components in patients with glaucoma or ocular hypertension.

In 2, identical, double-masked, parallel studies of 3 month duration, the safety and efficacy of the fixed combination (FC) of 0.03% bimatoprost (BIM) and 0.5% timolol (TIM, Ganfort, Allergan, Inc) was clinically and statistically significantly more effective than BIM and TIM for most comparisons, a

A randomized, controlled comparison of macroscopic conjunctival hyperemia in patients treated with bimatoprost 0.01% or vehicle who were previously controlled on latanoprost

Purpose To evaluate conjunctival hyperemia associated with bimatoprost 0.01% treatment in patients who replace latanoprost 0.005% with bimatoprost 0.01%. Methods Randomized, double-masked, vehicle-controlled, multicenter study of patients with ocular hypertension or glaucoma whose intraocular pressure (IOP) was adequately controlled on latanoprost monotherapy. At baseline, patients discontinued latanoprost and were randomized to treatment with once-daily bimatoprost 0.01% (n = 151) or vehicle (n = 71). The primary endpoint was the peak change in macroscopic hyperemia (conjunctival hyperemia evaluated by gross visual inspection) from baseline to month 1. Results Bimatoprost 0.01% was noninferior to vehicle in the mean [standard deviation] peak change from baseline macroscopic hyperemia at month 1 (0.18 [0.46] in the bimatoprost 0.01% group vs 0.02 [0.32] in the vehicle group, P = 0.009). The between-group difference was 0.15 (95% confidence interval [CI]: 0.04, 0.26), which was within the predefined margin for noninferiority of 0.5 on a hyperemia grading scale of 0 to +3. There were no statistically significant between-group differences in the percentage of patients with a ≥1-grade increase in macroscopic hyperemia from baseline. Mean IOP was decreased from baseline (−0.7 to −1.3 mm Hg) in the bimatoprost 0.01% group (P ≤ 0.002) and was increased from baseline (+3.3 to +3.6 mm Hg) in the vehicle group (P < 0.001) at month 1. There were no statistically significant between-group differences in adverse events. Conclusions Bimatoprost 0.01% was noninferior to vehicle with respect to conjunctival hyperemia in this study population. Replacement of latanoprost with bimatoprost 0.01% in patients with ocular hypertension or glaucoma can result in additional IOP reduction without clinically important hyperemia.

Brimonidine-purite 0.1% versus brimonidine-purite 0.15% twice daily in glaucoma or ocular hypertension : a 12-month randomized trial

ABSTRACT Objective: To compare the safety and intraocular pressure (IOP)-lowering effects of brimonidine-purite‡ 0.1% with the marketed formulation of brimonidine-purite 0.15% (Alphagan P§ 0.15%) when used twice daily (BID) by patients with glaucoma or ocular hypertension previously treated with brimonidine-purite 0.15% for at least 6 weeks. Methods: In a 12-month, randomized, double-masked, multicenter, parallel group, non-inferiority study, patients with glaucoma or ocular hypertension who were treated with brimonidine-purite 0.15% BID were randomly assigned to continue brimonidine-purite 0.15% (n = 102) or to administer brimonidine-purite 0.1% (n = 105) BID for 12 months. IOP was measured at approximately 8 a.m. (hour 0) and 10 a.m. (hour 2). Main outcome measures: Mean change from baseline IOP and adverse events. Results: Demographics and baseline characteristics were similar between treatment groups. Treated-baseline mean IOPs at both timepoints were similar between groups (p ≥ 0.606). Brimonidine-purite 0.1% provided IOP-lowering that was non-inferior to brimonidine-purite 0.15% at each of the 12 follow-up timepoints, and there were no statistically significant between-group differences at any timepoint. The most commonly reported adverse event was conjunctival hyperemia (13.5% for brimonidine-purite 0.1%; 10.8% for brimonidine-purite 0.15%). No significant differences in the incidence of adverse events were noted between the two formulations. Conclusions: Brimonidine-purite 0.1% BID is as effective as brimonidine-purite 0.15% BID in lowering IOP in patients with glaucoma or ocular hypertension who were previously treated with brimonidine-purite 0.15%, and both formulations are well tolerated. Limitations of the study include enrollment of only patients who were already on treatment with brimonidine-purite 0.15%. The 0.1% formulation of brimonidine-purite allows for decreased exposure to brimonidine while providing an IOP-lowering effect comparable to that of the 0.15% formulation. Clinical trial registered at clinicaltrials.gov; identifier: NCT00168363.

Safety and tolerability of brimonidine purite 0.1% and brimonidine purite 0.15%: a meta-analysis of two phase 3 studies

ABSTRACT Objective: To compare the safety and tolerability of two formulations of brimonidine ophthalmic solution, brimonidine Purite* (P) 0.1% and brimonidine P 0.15%, for reducing intraocular pressure in patients with glaucoma or ocular hypertension (OHT). * Purite is a registered trademark of Allergan, Inc., Irvine, CA, USA Study design and methods: Meta-analysis of safety and tolerability results from two previously reported prospective, randomized, 12-month, double-masked, multicenter, parallel-group clinical studies with similar entry criteria and protocols. In study 1 (two clinical trials), after washout of previous medications, patients with glaucoma or OHT were randomized to thrice-daily treatment with brimonidine P 0.15% (n = 381), brimonidine P 0.2% (n = 383), or brimonidine 0.2% (n = 383). In study 2 (one clinical trial), the treatment arms were thrice-daily brimonidine P 0.1% (n = 215) and brimonidine 0.2% (n = 218). Main outcome measure: Treatment-related adverse events (AEs) and discontinuations due to AEs. Results: Treatment-related AEs were significantly reduced with brimonidine P 0.15% compared with brimonidine 0.2% in study 1 (p < 0.001). Treatment-related AEs and discontinuations due to AEs were significantly reduced with brimonidine P 0.1% compared with brimonidine 0.2% in study 2 (p ≤ 0.014). In the meta-analysis of study 1 and study 2, the overall incidence of treatment-related AEs was lower with brimonidine P 0.1% than with brimonidine P 0.15% (41.4 vs. 49.7%; p = 0.050). Although the incidence of treatment-related ocular AEs was similar with brimonidine P 0.1% and 0.15% (p = 0.461), treatment-related systemic AEs were less frequent with brimonidine P 0.1% than with brimonidine P 0.15% (4.7 vs. 14.2%; p < 0.001), and there were fewer discontinuations due to systemic AEs with brimonidine P 0.1% than with brimonidine P 0.15% (p = 0.025). Conclusions: Brimonidine P 0.1% has improved systemic safety and tolerability compared with brimonidine P 0.15%. The ocular safety and tolerability of the formulations are similar. The present meta-analysis is based on only two clinical studies, and additional studies further evaluating the safety and tolerability of these medications are warranted.

Aqueous humor penetration of topical bimatoprost 0.01% and bimatoprost 0.03% in rabbits: response to authors

We read with great interest the recent article by Ogundele and Jasek,1 in which the authors concluded that bimatoprost ophthalmic solution 0.01% (Lumigan®; Allergan, Inc, Irvine, CA) produced lower bimatoprost acid concentration than bimatoprost ophthalmic solution 0.03% (Lumigan; Allergan, Inc) in the aqueous humor of rabbits. This conclusion was made based on two treatment time points (30 and 90 minutes) with a small sample size (n = 4) at each time point and with large variability. In comparing pharmacokinetic profiles of two formulations, it is a general practice that the study design would support assessment of the speed of onset (ie, time to maximum exposure [Tmax]), and the extent of absorption (ie, maximum concentration and area under the concentration-time curve). Therefore, a more complete temporal profile would be necessary. An erroneous conclusion could be drawn based on two seemingly arbitrary time points. For example, it is unclear whether these two time points reside in the ascending or descending portion of the temporal profile or if they reside one in each portion and the Tmax is missing. Based on two data points, Ogundele and Jasek1 hypothesized that bimatoprost 0.01% might have compromised the intraocular pressure (IOP)-lowering effect. Not only is there no reported correlation of animal pharmacokinetic and/or metabolism results to clinical efficacy, this hypothesis directly contradicts existing evidence. A multicenter, 12-month, randomized, controlled trial demonstrated equivalent efficacy of bimatoprost 0.01% and bimatoprost 0.03% based on predetermined IOP criteria (limits of the 95% confidence interval of the between-group difference in mean IOP within ±1.5 mmHg at all time points and within ±1 mmHg at most time points).2 In addition, Ogundele and Jasek1 speculated that bimatoprost 0.01% might have increased the risk of ocular toxicity, based on prior publications of in vitro and animal studies that may not be relevant to patients, case series, or open-label clinical studies. This evidence is considered lower level compared with randomized, controlled trials. Katz et al2 conducted a randomized, controlled trial and reported bimatoprost 0.01% had (a) significantly lower overall incidence of treatment-related adverse events (P < 0.03); (b) significantly reduced conjunctival hyperemia (P < 0.044), skin pigmentation (P < 0.02), and eye pruritus (P < 0.035); and (c) significantly lower discontinuation rates than bimatoprost 0.03% (P = 0.043). Based on clinical trial evidence, the claims of ocular toxicity are unfounded for at least 12 months of administration as monotherapy.2 In addition, a recent clinical study comparing ocular surface tolerability of topical prostaglandin analogs demonstrated no statistical differences following 3 months of treatment in either corneal staining or conjunctival hyperemia between latanoprost, which has 200 ppm benzalkonium chloride (BAK), similar to bimatoprost 0.01%, and travoprost ophthalmic solution 0.004% (Travatan Z®; Alcon Laboratories, Inc, Fort Worth, TX) (BAK free, preserved with sofZia® [Alcon Laboratories, Inc]).3 Bimatoprost 0.01%, which offers improved ocular tolerability while maintaining the established efficacy of bimatoprost 0.03%, recently gained approval by the European Medicines Evaluation Agency (2009) and the US Food and Drug Administration (2010) as first-line therapy in patients with open-angle glaucoma or ocular hypertension. Any ophthalmologist or patient concerns raised by the incomplete and potentially misleading conclusion published by Ogundele and Jasek1 can be addressed with a carefully constructed pharmacokinetic study with a complete time-concentration profile. We are currently preparing a manuscript that reports the findings of such a study design.