Article Date: 7/1/2005

Combine for Optimum Treatment
With these new drugs on the horizon, the future of glaucoma treatment looks bright.

In many countries, clinicians can manage glaucoma with combination products of fixed proportions of different medications. In the United States, however, many of these combination products have not yet been approved by the FDA. Following is a run-down of what we can use now, and what could be available to us soon.


Why combine?

The chief advantage of combination products is that you can increase the amount of medication a patient is receiving without increasing the complexity of the regimen. This usually leads to increased compliance, which can keep your patient away from the operating table longer. Even though new laser procedures, such as selective laser trabeculoplasty (SLT), look promising, many clinicians (including myself) prefer to have

patients on maximal medications before referring for surgery. In the past this would have meant that a patient administer several different medications and a complicated schedule with instillation of eyedrops three or four times a day. By combining medications into one agent, we can deliver two different medications without making it any more complicated for the patient.

Other advantages of combination products include the patient's only having one medication bottle, which means less chance of a wash-out effect. Many patients do not have the patience to wait five or 10 minutes when instilling different medications, and this sometimes negates the efficacy of one of the agents. In addition, these combination medications should exhibit less ocular side effects because less preservatives are used in concomitant therapy.

What's out there

The one notable exception to the lack of combination glaucoma products available in this country is the drug Cosopt (Merck), which is a fixed-combination product of dorzolamide 2% (10 mg/ml) and timolol 0.5% (5 mg/ml). It was created after many years of research and concerns about the shelf life. There were also some initial concerns about the stability of the two components together, as well as the possibility of a deleterious effect on metabolism by cytochrome enzymes.

In terms of efficacy, clinical studies indicate that the peak effect of the combination product produced a 33% reduction in IOP that was 14% greater than using timolol alone. When comparing the Cosopt with dorzolamide alone, there was a 13% greater reduction in IOP at three months with the combination product. Cosopt is generally used when beta-blocker therapy alone does not achieve the target IOP.

With the emergence of the prostaglandins in recent years, Cosopt has generally been delegated to a third-line agent in our arsenal. One of the most common protocols would involve using a prostaglandin as first line, then adding a beta-blocker if additional therapy is needed. If further lowering is still necessary, then switch from the beta-blocker to Cosopt.

The adverse reactions to this is agent are basically the summations of what one would see with each individual agent and include taste perversion (bitter, sour and unusual), ocular burning and/or stinging, conjunctival hyperemia, blurred vision, punctate keratitis and itching. One of the minor issues with Cosopt is that it's only available with 0.5% timolol maleate. Since research has indicated that many patients do just as well with the 0.25% timolol, this fixed combination increases the potential adverse effects of beta-blockers.

Dream Teams
Cosopt Merck Approved
Extravan Alcon "Approvable" letter
Xalcom Pfizer Approved in European Union
Combigan Allergan Phase III clinical trials

What's in the works

There are several combination glaucoma medications that are in various stages of FDA clinical trials. The first two of them combine a prostaglandin with a beta blocker, timolol. This agent is a traditional first line therapeutic agent with a 20-year track record for successfully treating glaucoma. As a non-selective beta blocker, timolol works to reduce IOP through the inhibition of aqueous formation by blocking beta-2 receptors on nonpigmented ciliary body epithelium. The most common dosage, 0.5% b.i.d., provides a 25% reduction in IOP.

Extravan (travoprost 0.004%/timolol 0.5%, Alcon). In a company-sponsored study, once-daily Extravan demonstrated comparable efficacy to taking both agents separately (i.e., timolol taken in the morning plus travoprost taken at night). In September 2004, Alcon Inc. announced that the FDA had issued an approvable letter for Extravan ophthalmic solution for the management of glaucoma. Based on this announcement, it seemed that the approval for Extravan in the United States would come quickly thereafter. However, nine months later the drug still has not been approved for use.

Xalcom (latanoprost 0.005%/timolol 0.5%, Pfizer). This combination was approved in Europe three years ago and has quickly been incorporated into the management protocol for glaucoma. Xalcom combines latanoprost and timolol in a single bottle for once-daily dosing. Studies have shown that Xalcom provided greater efficacy in lowering IOP when compared with latanoprost used in adjunctive therapy with any combination of a carbonic anhydrase inhibitor, an alpha agonist or a beta-blocker. Xalcom has also been shown to be as effective as latanoprost used adjunctively with Cosopt. Once again the side effects of this combination agent are similar to those of the individual agents.

Combigan (brimonidine 0.2%/timolol 0.5%, Allergan). This drug has already been approved in Canada for the management of open-angle glaucoma. Combigan is indicated for the reduction of IOP in patients with chronic open-angle glaucoma who are not achieving target IOP with topical beta blockers. The recommended dose is one drop in the affected eye twice daily.

Studies have demonstrated that Combigan lowered IOP more effectively than either brimonidine or timolol used as monotherapy. Mean diurnal IOP was reduced to less than 18mm Hg in 40% of patients in the combination group, compared with 15% in the brimonidine group and 26% in the timolol group.

As with other combination drops that include beta blockers, clinicians should be aware of the safety profile. Beta blockers have been known to cause bradycardia, hypotension, atrial tachycardia and fibrillations, and altered lipid profiles after chronic use. Combigan is contraindicated in children and patients

with chronic obstructive pulmonary disease, sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure or cardiogenic shock. The product is also not recommended in patients who take MAOIs, tricyclic antidepressants or mianserin, or those with hepatic or renal impairment.

In the United States, Combigan is currently undergoing Phase III clinical trials to evaluate the IOP-lowering effects of concomitant brimonidine and timolol administration. One study by Arici, et al., examined patients who showed inadequate IOP lowering on timolol alone and found a significant reduction in IOP of 5.1 to 5.9 mmHg in the timolol-plus-brimonidine group.

Better together

Individually, many of the combination products are nothing new, but as a combination agent they may enhance patient convenience when more than one medication is required to reach the target IOP. If the FDA approves a combination product such as Extravan or Xalcom, it would be a nice choice for first-line defense for appropriate patients. Because we are now more aggressive in IOP lowering, why not give a patient a single agent with the combined benefits of both beta blockers and prostaglandins? The more options we have, the greater the probability that we can successfully control a patient's IOP through medical agents instead of surgical means.

References available upon request.

Dr. Gupta is author of the textbook Glaucoma Diagnosis and Management. He practices full scope optometry. Contact him at


Optometric Management, Issue: July 2005