For better or worse, there are far fewer fixed-combination glaucoma medications. This article reviews the drugs that are currently available. In addition, I share my thoughts on the role of combination products in modern glaucoma care and on how to decide if combination products are right for your patients. Finally, I look ahead to potential future fixed-combination glaucoma medications.
A BRIEF HISTORY OF COMBINATION PRODUCTS
The first approved fixed-combination product for glaucoma management was a mixture of pilocarpine and epinephrine, and it was developed at a time when these two drugs composed nearly the entire arsenal of topical glaucoma medications. Many glaucoma patients received both of these agents in separate bottles, so combining them into one bottle offered dosing convenience. Dosing convenience was the only benefit of using the combination product in place of concomitant therapy with the two agents in separate bottles. In fact, some patients may have been better off with the latter option; to reach maximal pilocarpine efficacy, the combination was approved for use q.i.d., so patients received a significant overdosage of the epinephrine component.
The pilocarpine-epinephrine combination is all but extinct in clinical glaucoma management, but there is a more modern fixed-combination product available in the US that contains timolol 0.5% and dorzolamide 2%. COSOPT (Merck & Co., Inc., West Point, PA) debuted in 1998. In the mid-1990s, beta-blockers were the preferred drugs for first-line IOP reduction, and the choices for beta-blocker adjuncts included pilocarpine, dipivefrin, and the new topical carbonic anhydrase inhibitor (CAI), dorzolamide. Because of its safety, efficacy, and convenient dosing, dorzolamide quickly became the second-line drug of choice. Developing the timolol-dorzolamide fixed-combination product reflected common clinical usage and offered the convenience of two medications in one bottle.
As with the pilocarpine-epinephrine combination, however, some dosing incompatibility became evident. Timolol is taken b.i.d. by most patients (although some achieve excellent IOP reduction on one drop daily), and dorzolamide is approved for t.i.d. use. As a compromise, the fixed combination is prescribed b.i.d. When compared with concomitant therapy with timolol b.i.d. and dorzolamide t.i.d., the fixed combination provides slightly less IOP control at the end of each 12-hour dosing period. Nevertheless, the difference is less than 1 mm Hg and is a reasonable trade-off for the improved convenience and therefore potentially better patient compliance.
IS ONE BOTTLE BETTER THAN TWO?
Dosing
Obviously, patients find fixed-combination therapy more convenient than concomitant therapy. Using a fixed combination reduces the number of bottles that patients must keep track of and drops they must instill each day. Unless the dosing frequency is also reduced, however, fixed-combination therapy does not always significantly improve a patient's quality of life. If he uses timolol q.d. and dorzolamide b.i.d. (an off-label but common clinical practice), then switching to the fixed combination may reduce the number of drops administered per eye from three to two, but morning and evening instillations of the medication are still required.
Cost
Patients also potentially benefit from the pricing of fixed-combinations. For individuals with prescription drug benefits who make a copayment on each prescription filled, using a fixed combination can eliminate one of those payments. For patients without prescription drug benefits, however, combination therapy is often more expensive than concomitant therapy, because prescribed combination products invariably contain at least one brand-name ingredient. If one or more of the ingredients in a fixed combination is available in generic form, patients can often save money by remaining on generic concomitant therapy and foregoing convenience for a cost savings.
Safety
Combination products may increase patients' safety by reducing the amount of preservative to which treated eyes are exposed. Preservative-related issues such as chronic hyperemia, low-grade conjunctival inflammation, and frank allergy have all been reported. Some ophthalmologists have speculated that these ocular surface processes may ultimately reduce the success rate of filtration surgery in patients requiring surgery for IOP control.1 Reducing the number of drops—and therefore the absolute amount of preservative—applied to the ocular surface each day may in turn lead to better long-term outcomes for patients.
ISSUES TO CONSIDER WHEN PRESCRIBING FIXED-COMBINATION IOP PRODUCTS
When contemplating fixed-combination therapy for patients, first consider whether the patient needs two IOP-lowering medications. COSOPT, for instance, is not approved for first-line therapy. It is indicated for use when beta-blocker monotherapy alone insufficiently reduces the IOP. Initiating therapy with a combination product as a first-line agent should be avoided in most cases, because it may overmedicate the patient.
Also determine whether all the ingredients in the combination are appropriate for the patient. If a CAI is contraindicated, then so is a combination product containing a CAI. In the past 5 years, we have seen tremendous growth in the number and classes of agents available for glaucoma management. As we refine our treatment algorithms in accordance with the concept of individualized medical regimens for each glaucoma patient, we can construct optimal treatment plans by using only the medications that are best for each patient. Those taking multiple drugs may benefit from the convenience of fixed-combination therapy, but the combination should be used only if their ideal treatment regimen would include the constituent drugs separately.
THE FUTURE OF COMBINATION PRODUCTS
Several potential combinations of existing IOP-lowering drugs are currently undergoing regulatory testing. Among them are several prostaglandin–beta-blocker combinations and an adrenergic agonist–beta-blocker combination. In general, these fixed combinations reflect the common clinical usage of medications. As such, they are designed to provide convenience to patients on multi-drug regimens.
At first glance, the combinations under investigation appear to hold great promise. For instance, the combination of a beta-blocker and a prostaglandin would contain the two most effective drugs we have to lower IOP. As I discussed in an article for an earlier edition of Glaucoma Today,2 however, monotherapy efficacy is not always additive. In several studies, the combined IOP-lowering effect of prostaglandins and beta-blockers is little better than that of prostaglandins alone.3-5 As a result, some of these new combination candidates have been in regulatory limbo for several years, and their future as viable commercial products remains uncertain.
CLINICAL APPLICATIONS
Fixed combination products can improve patients' quality of life by reducing the number of bottles and drops they must use, as well as the amount of preservative to which they are exposed. Greater convenience and better tolerability may, in turn, lead to superior compliance by patients with medical therapy. Physicians may safely prescribe fixed combinations for any patient in whom they would deem the constituent drugs safe. Nevertheless, these combinations should be avoided as first-line agents so as to avoid overmedicating patients whose IOPs might be adequately controlled by a single medication.
Tony Realini, MD, is Director of the Glaucoma Service at the University of Arkansas for Medical Sciences. Dr. Realini participates in the Speakers' Bureaus for Merck & Co., Inc., Alcon Laboratories, Inc., Allergan, Inc., Pharmacia Corporation, and Novartis Ophthalmics. He is also a paid consultant for Merck & Co., Inc. Dr. Realini may be reached at (501) 686-5150; realinianthonyd@uams.edu.
1. Broadway DC, Grierson I, O'Brien C, Hitchings RA. Adverse effects of topical antiglaucoma medication. II. The outcome of filtration surgery. Arch Ophthalmol. 1994;112:1446-1454.
2. Realini T. Selecting Adjunctive Therapy in Glaucoma. Glaucoma Today [serial online]. February 2003;1(1).
3. Bucci MG. Intraocular pressure-lowering effects of latanoprost monotherapy versus latanoprost or pilocarpine in combination with timolol: a randomized, observer-masked multicenter study in patients with open-angle glaucoma. Italian Latanoprost Study Group. J Glaucoma. 1999;8:24-30.
4. Pfeiffer N. A comparison of the fixed combination of latanoprost and timolol with its individual components. Graefes Arch Clin Exp Ophthalmol. 2002;11:893-899.
5. Higginbotham EJ, Feldman R, Stiles M, Dubiner H. Latanoprost and timolol combination therapy vs monotherapy: one-year randomized trial. Arch Ophthalmol. 2002;120:915-922.
