Coordinated by Bobby Christensen, O.D., F.A.A.O.

therapeutic insights
Glaucoma Med Review
Fixed combination glaucoma medications
by John M. Spalding, O.D., F.A.A.O. & Patrick S. Till, O.D., Orlando, Fla.

In glaucoma management, clinicians often face the therapeutic dilemma of what to do when a patient's IOP isn't low enough to prevent additional optic nerve damage or visual field loss. The question becomes, "Do you add a medication to an existing therapeutic regimen, switch to a different medication altogether or recommend surgical or laser intervention?" In such a case, you may want to consider using a fixed-combination glaucoma medication.

Fixed-combination glaucoma medications have been in existence for almost 30 years, but only one is currently available to clinicians practicing in the United States. With this in mind, pharmaceutical companies, clinicians and patients remain interested in the development of newer formulations because of their potential to reduce costs while improving patient convenience, compliance and safety. This article explores the past, present and future of fixed-combination IOP-lowering medications.

A merger made in heaven

Scientists developed the first fixed-combination glaucoma medication in the early 1970s, when scientists combined pilocarpine with epinephrine (E-Pilo) after they found that the combination reduced IOP more than either of the components used alone. Although it's available from at least one Internet pharmacy (Drugstore.com) in a variety of concentrations, it's not approved for use in the United States. Dosing incompatibilities and the potential for side effects may have hampered FDA approval.

In 1978, topical timolol received FDA approval after it was found to reduce IOP as much as pilocarpine without the bothersome ocular side effects associated with cholinergic agents. With this new and effective agent now available, it was only a matter of time before scientists combined the two "big guns." They found the fixed combination of timolol and pilocarpine (Timpilo) to consistently lower IOP greater than either of its individual components. This particular formulation has even proven as effective as latanoprost (Xalatan) or dorzolamide/timolol maleate (Cosopt) in the treatment of open-angle glaucoma or ocular hypertension. Timolol/pilocarpine is available around the world (except in the United States) in two concentrations. Once again, dosing incompatibilities may have prevented FDA approval.

New kids in town

During the 1980s and early 1990s many new agents, including a variety of beta blockers, became available. Attempts to create new fixed combinations followed soon after. Scientists added dipivefrin (Propine) and carteolol (Ocupress) separately to pilocarpine in the hopes of finding a viable fixed combination. Both proved effective in reducing IOP, but neither is available for clinical use. It wasn't until 1997 that a fixed-combination with pilocarpine gained FDA approval.

Allergan introduced a combination of pilocarpine and betaxolol (Betoptic Pilo). Research showed that it was clinically effective and relatively safe, but as newer agents became available, it never achieved widespread clinical use and production was discontinued.

Onward and upward

A number of new individual medications with varying mechanisms of action were introduced in the mid to late 1990s. The first topical carbonic anhydrase inhibitor was approved in 1994. Dorzolamide HCl (Trusopt) effectively lowered IOP without significant systemic or ocular side effects in those patients who were not allergic to sulfa. In 1996 the FDA approved two more medications, the prostaglandin analog latanoprost and the alpha-agonist brimonidine (Alphagan). They're both now approved for first-line therapy and often exert excellent therapeutic control as monotherapy agents.

Over the years, all three of these have become valuable components in the fight against glaucoma. Their approval, clinical success and widespread use subsequently opened the door for the development of newer fixed combinations.

In 1998, the FDA approved the fixed combination of dorzolamide and timolol (Cosopt). Patients and clinicians appreciated the reduction in ocular toxicity that went along with a reduction of number of bottles of medicine. Dorzolamide/timolol displayed greater efficacy than either of its components used individually or when the components were used concomitantly. Six years later, dorzolamide/timolol is as effective as some of the newer agents used alone or in combination. Today, it remains the only fixed combination with FDA approval.

Wanted: Prostaglandins

Researchers have sought to include a prostaglandin in a fixed-combination ever since their inception. The first is a combination of latanoprost and timolol (Xalcom). In comparison studies, latanoprost/timolol reduced the mean daytime diurnal IOP more than concomitant usage of brimonidine and timolol b.i.d. and slightly more than that of dorzolamide/timolol.

Even though it's been found to be safe, with similar side effects as its components, it's currently only available in Canada and in the European Union. While it shows promise, some believe that latanoprost/timolol hasn't been approved in the United States because the additional reduction in IOP with the fixed combination was minimal relative to latanoprost alone in FDA trials.

In 2001, two more prostaglandin analogs gained FDA approval. Bimatoprost (Lumigan) and travoprost (Travatan) have both proven as effective in the reduction of IOP as latanoprost but are more prone to cause significant hyperemia. However, because of their therapeutic effectiveness and absence of systemic side effects, this class of medications has become the favorite of many clinicians. In comparison studies, these agents in monotherapy have improved patient compliance and demonstrated equal or better IOP effect than other agents used alone, in combination or in fixed combination.

More on the horizon

Not surprisingly, while latanoprost/timolol languishes in FDA limbo, newer fixed combinations are undergoing trials. The first of these is the fixed-combination of brimonidine and timolol (Combigan); it's already approved for use in Canada and other countries. Studies have shown the IOP lowering effect of timolol and brimonidine are additive when used concomitantly but the combination agent is still undergoing clinical trials here in the United States.

Another proposed agent combines travoprost and timolol (Extravan). It was recently reported that when patients who have ocular hypertension or open-angle glaucoma were given this fixed combination, it was well tolerated and reduced IOP more than when its components were used alone. It's still undergoing studies here in the United States, but the company filed a new drug application with the FDA.

Keep your fingers crossed

The fixed combinations that are currently under review show signs of promise. However, as we know from past experiences, their approval in the United States isn't guaranteed. Dosing incompatibilities, pH differences and solubility issues may ultimately lead to their demise.

Fortunately, with the encouragement of both clinicians and patients, pharmaceutical companies continue to seek other options for effective IOP reduction. While we wait for the possible FDA approval of some of these agents, we must not lose sight of the potential benefits that these fixed combinations have to offer when patients are not controlled on monotherapy.

For example, dorzolamide/ timolol is clinically effective and has been found cheaper than the combined purchase of its components. Its b.i.d. dosing is more convenient than the b.i.d. or t.i.d. dosing of its individual components. It stands to reason that this convenience may increase patient compliance. However, before making this assumption, remember that one bottle versus two isn't a substitute for the improved compliance gained by good doctor-patient communication.

Finally, dorzolamide/timolol improves patient safety and comfort by reducing exposure to preservatives and decreasing the actual number of drops required. Hopefully, the newer fixed combinations will do the same.

In the meantime . . .

Because currently the only option to manage glaucoma is to reduce IOP, fixed-combination agents remain a viable therapeutic option when monotherapy proves inadequate. As we support the research on creating new fixed-combination agents, we must remember their potential benefits but also realize their limitations. The future of glaucoma management remains uncertain. We as clinicians can only hope that there will be another pharmaceutical breakthrough or clinical procedure that surpasses our current abilities. With this in mind, it will be interesting to see what the FDA approves in the years to come.

References available on request.

Dr. Spalding and Dr. Till are in practice at the VA Healthcare Center in Orlando, Fla.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.