THERAPEUTIC INSIGHTS

One-Stop Drop

Glaucoma drop offers IOP-lowering efficacy and may improve medication adherence.

Ian Benjamin Gaddie, O.D., Louisville, Ky.

Several glaucoma patients require a regimen of at least two or more different drops, each taken multiple times a day, to meet their target intraocular pressure (IOP). As a result, some of these patients have drug compliance issues, and anecdotal evidence suggests that a haphazard pattern of usage is as ineffective as none at all.

The recent Food and Drug Administration (FDA) approval of a combination glaucoma drop, however, may soon make glaucoma-medication compliance for these patients less of an issue. The drop is called Combigan (brimonidine tartrate/timolol maleate ophthalmic solution 0.2%/0.5%, Allergan). Its combination of an alpha-adrenergic receptor agonist with a beta-adrenic receptor antagonist facilitates a dual mechanism of action to lower IOP by reducing aqueous-humor production and enhancing aqueous-humor drainage or outflow.

The FDA-approved dosing schedule for the concomitant use of brimonidine and timolol is five times a day, although clinical-practice patterns generally reflect a more conservative dosing schedule. Combigan, however, requires b.i.d. dosing. So, it may reduce the dosing complexity for glaucoma patients who require multiple medications to manage their elevated IOP.

Here, I discuss the research behind Combigan, its efficacy, adverse effects and how it will fit into my glaucoma-treatment arsenal.

Combigan is a combination of alpha-adrenic receptor agonist with a beta-receptor antagonist, giving it a dual mechanism to lower IOP.

Clinical trial

Researchers conducted two identical, 12-month, randomized, double-masked multicenter trials to evaluate the IOP-lowering efficacy and safety of Combigan vs. monotherapy with either brimonidine tartrate or timolol maleate.¹ A total of 385 ocular-hypertension patients received Combigan b.i.d., while 382 received 0.2% brimonidine tartrate q.i.d., and 392 patients received 0.5% timolol maleate b.i.d.

Results revealed that the mean decrease from baseline IOP was 4.4 mm Hg to 7.6 mm Hg with fixed brimonidine-timolol, 2.7 mm Hg to 5.5 mm Hg with brimonidine tartrate and 3.9 mm Hg to 6.3 mm Hg with timolol. Further, when compared with timolol at all 22 follow-up measurements and brimonidine at 8:00 a.m., 10:00 a.m. and 3:00 p.m., but not 5:00 p.m. (designated times of IOP measurement), mean IOP decreases were significantly greater with Combigan.¹

Also, a significantly greater percentage of patients in the Combigan group than in either monotherapy group maintained a mean IOP throughout the day (IOP averaged across all diurnal measurements at a given visit) of less than 18 mm Hg throughout the study. Mean daytime IOP was consistently below 18 mm Hg in 40% of those in the Combigan group; in 15% of those in the brimonidine group; and in 22% of those in the timolol group.¹

These findings were similar when the researchers analyzed data from left or right eyes only instead of mean data from both eyes. In the Combigan, brimonidine and timolol groups, the percentage of left eyes with a mean-daytime IOP consistently less than 18 mm Hg was 40%, 15% and 22% respectively, while this data for right eyes was 38%, 15% and 20% respectively. This reveals that systemic absorption helps to control for crossover effects of the drugs and controls for asymmetric fluctuations of IOP between right and left eyes.

Also, a significantly greater percentage of patients in the Combigan group than in either monotherapy group achieved a mean-daytime decrease from baseline IOP of greater than 20% at every follow-up visit. The daytime mean decrease from baseline IOP was greater than 20% in 42% of Combigan patients, 13% in the brimonidine patients; and 27% in the timolol patients.¹ These results suggest long-term benefits of Combigan. As for treatment-related adverse events, such as conjunctival folliculosis, incidence was lower in the Combigan group than in the brimonidine group, though higher than in the timolol group. Further, the rate of discontinuation for adverse effects was 14% with Combigan vs. 30.6% with brimonidine and 5.1% with timolol. Something else to note: The rate of allergic conjunctivitis in patients in the Combigan group was 5.2% compared with 9.4% in the bri-monidine group and 0.3% in the timolol group.

Treatment stepladder

I generally start glaucoma patients on a prostaglandin analogue to lower IOP. If I don't achieve the desired results, I switch the patient to another drug within this class. When a prostaglandin alone is not proven sufficient, I generally add one of the adjunctive IOP-lowering drops.

Based on the efficacy data available and the convenience of two proven agents in one drop, Combigan will likely become one of the adjunctive therapies I prescribe for the patient in need of additional IOP lowering. Keep in mind, however, that Combigan is contraindicated in patients who have a history of bronchial asthma; sinus bradycardia; severe chronic obstructive pulmonary disease; overt cardiac failure; cardiogenic shock; second- or third-degree atrioventricular block; and hypersensitivity to any component of the drug. This is mostly due to the beta-blocker component of the combination drug. As with all beta-blocker use, appropriate precautions and medical history are important prior to prescribing the drop.

Multiple factors, such as the number of agents a patient takes and the overall tolerability of the drug, ultimately affects adherence to IOP-lowering medications. While it's impossible to know for certain whether our patients are following their prescribed treatment plans, the odds of compliance rise when you lower dosing frequency.^2,3,4 With that in mind, Combigan has the potential to help patients avoid non-compliant behavior, which in addition to effective IOP lowering, should be our goal in glaucoma treatment. OM

1. Sherwood MB, Craven ER, Chou C, et al. Twice-daily 0.2% brimonidine-0.5% timolol fixed-combination therapy vs. monotherapy with timolol or bri-monidine in patients with glaucoma and ocular hypertension: a 12-month randomized trial. Arch Ophthalmol Sep 2006; 124(9):1230-1238.

2. Robin AL, Covert, D. Does adjunctive glaucoma therapy affect adherence to the initial primary therapy? 2005 May;112(5):863-8.

3. Olthoff CM, Schouten JS, Van de Borne BW, et al. Noncompliance with ocular hypotensive treatment in patients with glaucoma or ocular hypertension. Ophthalmology. 2005. Jun;112(6):953-61.

4. Stewart WC, Konstas AG, Pfeiffer N. Patient and ophthalmologist attitudes concerning compliance and dosing in glaucoma treatment. J Ocul Pharmacol Ther. 2004. Dec;20(6):461-9

Dr. Gaddie is in private practice in Louisville, KY, where he specializes in glaucoma. He is also an adjunct assistant professor of Optometry at Northeastern State University College of Optometry and a consultant to and speaker for Allergan. E-mail him at ibgaddie@bellsouth.net.