Studies such as the Early Manifest Glaucoma Trial demonstrated that lowering the IOP by even one additional millimeter of mercury effectively reduced patients' risk of glaucomatous progression by 10%.1 More than 60% of my glaucoma patients have fairly advanced disease, however, and slowing its progression and sight-threatening consequences typically requires more than one drug.
The FDA approved Combigan (brimonidine tartrate timolol maleate ophthalmic solution 0.2%/0.5%; Allergan, Inc., Irvine, CA) in October 2007. This article shares key information from the drug's pivotal clinical trial, for which I served as a lead investigator, as well as my own clinical observations. I have found that Combigan is particularly useful for patients who are unable to reach their target IOP on monotherapy.
EFFICACY
Combigan combines an alpha adrenergic receptor agonist with a beta adrenergic receptor antagonist. The drug lowers IOP by reducing the production of aqueous humor and boosting the drainage of aqueous humor via the uveoscleral pathway.2 As a clinician, I consistently find that Combigan is an effective adjunctive therapy for patients who are taking a prostaglandin analog and require a further decrease in IOP as well as for those whose IOP is insufficiently reduced by a beta blocker alone.
In the prospective, randomized, double-masked trial of 1,159 subjects, my co-investigators and I found that Combigan reduced the mean IOP by up to 33% (7.6 mm Hg) from baseline and that the mean daytime IOP was consistently below 18 mm Hg in approximately 40% of the subjects taking Combigan twice a day.3 The latter observation is particularly significant given that the Advanced Glaucoma Intervention Study determined that IOP below 18 mm Hg correlates to reduced progression of visual field defects.
In the clinical trial, we compared Combigan administered twice a day with either brimonidine or timolol used alone. We found that Combigan lowered IOP more than brimonidine or timolol used alone, decreased IOP by 1 to 3 mm Hg more than brimonidine dosed three times a day, and lowered IOP by 1 to 2 mm Hg more than timolol dosed twice a day. On average, the decreases in IOP were significantly greater with Combigan compared with timolol at all timepoints and with brimonidine at 8 AM, 10 AM, and 3 PM but not at 5 PM.3
TOLERABILITY
Pooled data from two randomized, masked studies presented at the AAO Annual Meeting in 2007 demonstrated that subjects taking Combigan reported significantly less burning and stinging than those taking Cosopt (Merck & Co. Inc., Whitehouse Station, NJ).4 Ninety-one percent of the subjects in the Combigan group rated the drug as comfortable or very comfortable. In the studies, Combigan reduced mean IOP to 15.6 mm Hg versus 17.2 mm Hg with Cosopt at 3 months.
Greater comfort may lead to better compliance with prescribed therapy. Data from the clinical trial showed that Combigan was well tolerated with a low ocular allergy rate of 5.2%. My clinical experience has closely paralleled the results of the clinical trial in that my patients using this fixed combination rarely report discomfort or an incidence of ocular allergy.
CONVENIENCE
Patients whose IOPs are uncontrolled on a prostaglandin analog or beta blocker usually end up on a regimen of three different drugs in three different bottles administered at three times of day. Such a complicated regimen can decrease some patients' adherence to prescribed therapy. A fixed combination simplifies these individuals' drug regimens.
CONCLUSION
My experience in Combigan's clinical trial and in the clinic indicate that the drug is an ideal adjunct for patients who need lower IOPs than achieved with a prostaglandin analog alone. Efficacy, comfort, and convenience indicate that the fixed combination may improve patients' compliance with prescribed therapy and thus more effectively slow glaucomatous progression than three agents dosed separately. In addition, although Combigan is approved as an adjunctive therapy, I have also found that it can be useful as a first-line treatment in certain instances. For example, a patient in whom a prostaglandin analog is contraindicated may require a greater decrease in IOP than typically achieved with timolol.
E. Randy Craven, MD, is Director of Glaucoma Consultants of Colorado in Littleton. He is a speaker for Allergan, Inc., and participated in the clinical trials of Combigan. Dr. Craven may be reached at (303) 797-1900; ercraven@glaucdocs.com.
