Role of fixed-combination therapeutics in glaucoma evolving

Research to date indicates that fixed-combination therapeutics for glaucoma improve patient compliance, but experts said the role of these therapeutics is evolving, and additional studies are warranted to directly compare the combinations.

“There have been some pretty significant advances on the surgical side for glaucoma in the last decade, but we are due for new improvements on the medical management side,” OSN Glaucoma Section Editor Thomas W. Samuelson, MD, said. “It would be terrific to see a new agent emerge with a novel mechanism of action or perhaps additional fixed combinations with a substantial benefit.”

First-line treatment to reduce IOP is glaucoma drugs. The most frequently used medical therapies are ophthalmic beta-blockers, carbonic anhydrase inhibitors, alpha-agonists, miotics and prostaglandin analogues.

However, it has been established that glaucoma drugs have a host of problems due to patient compliance and adherence. Simplifying therapy and enhancing safety with fixed combinations provide an advantage for patients because complex dosing regimens tend to result in poorer adherence to therapy.

Available fixed-combination therapies

Fixed-combination drugs enhance quality of life for glaucoma patients by offering simplified daily administration and providing better adherence, according to Gábor Holló, MD, PhD, DSc, professor and head of the Glaucoma and Perimetry Unit in the Department of Ophthalmology at Semmelweis University, Budapest. Data have shown that fixed-combination treatments reduce long-term exposure to benzalkonium chloride (BAK), commonly found in topical eye drops and toxic to the ocular surface.

In October 2007, the U.S. Food and Drug Administration approved Combigan (Allergan), a fixed-combination eye drop used to decrease elevated pressure within the eye.

Combigan contains two active ingredients: the alpha-agonist brimonidine tartrate and the beta-blocker timolol maleate. These two ingredients work in different ways to produce a greater effect when combined than they can produce individually.

Additionally, a number of other fixed-combination therapies for glaucoma are currently available but not FDA-approved.

Specifically, three prostaglandin fixed combinations are approved in some markets: Ganfort (bimatoprost 0.03% and timolol 0.5%, Allergan), Xalcom/Xalacom (latanoprost 0.005% and timolol 0.5%, Pfizer) and DuoTrav (travoprost 0.004% and timolol 0.5%, Alcon). For the past decade or so, these fixed combinations have been the drugs of choice for glaucoma treatment because of their once-daily dosing and efficacy in lowering IOP.

Dr. Holló and colleagues published a prospective, observer-masked, crossover comparison study in the British Journal of Ophthalmology that compared 24-hour IOP control of bimatoprost and timolol with bimatoprost alone. Sixty patients with exfoliative glaucoma were randomized to morning or evening therapy, and bimatoprost and timolol were administered for 3 months before regimens were switched. Results showed that both regimens significantly reduced 24-hour IOP compared with bimatoprost monotherapy (P = .006). Furthermore, the evening dose of bimatoprost and timolol led to better control.

Benefits and popularity of use

“There are strict guidelines from the FDA to show benefit of use in combination rather than separately,” OSN Glaucoma Board Member Douglas J. Rhee, MD, said.

“Once you start adding more bottles, you have a decrease in compliance, so the benefit of combination treatments is that they could enhance compliance. Compliance is a major issue with medical management and it is not just something we see in ophthalmology. This occurs throughout the medical arena,” he said.

Controlling IOP with a once-daily dose of a single agent through a fixed combination could potentially provide many benefits such as compliance by simplifying the patient’s medical regimen. Improved compliance would result in better control of IOP and prevent a washout effect.

Furthermore, fixed combinations are increasingly used in the management of chronic disease. According to results of a study published in the European Journal of Ophthalmology, fixed combinations are a potentially popular method to reduce IOP and are most commonly prescribed as second- or third-choice therapy.

Researchers at the PRN Pharmaceutical Research Network in Dallas randomly distributed multiple choice surveys to ophthalmologists in the European Union. Overall, 98% of those surveyed (n = 50) believed fixed-combination therapies improved patient care. More ophthalmologists prescribed fixed-combination therapies as a second-choice (n = 80%) and third-choice (n = 64%) line of therapy than as a first-choice therapy (n = 30%).

“Fixed combinations are useful,” Dr. Samuelson said. “I think tolerability and compliance is the Achilles’ heel of aggressive medical therapy, which these therapeutics show to improve.”

Future of fixed combinations

Generic latanoprost is slated to be available next year in several countries, which may have an impact on the price of fixed-combination products containing latanoprost. This addition of a generic form raises several efficacy and safety issues as well.

“The fact that latanoprost is going generic raises several important issues,” Dr. Samuelson said. “While it may be significantly more affordable, that is not always the case. Also, it remains to be seen how well-tolerated the generic preparations are. If tolerability and adherence are not as good, this move could potentially be a step backward because drug benefit plans may require the generic form, yet if not well tolerated, it may lessen compliance. Hopefully the generic versions will be of similar efficacy and tolerability.”

Generic latanoprost also presents the need for direct comparison studies that evaluate the drug’s clinical effects and interchangeability in formulations.

“Since there will be several generic latanoprost products, these various products may vary in their clinical characteristics. BAK content may influence penetration, stabilizers, pH, heat/light stability, adhesion of the different ingredients to the drop-tainer material and the size of the opening of the drop-tainer,” Dr. Holló said.

While fixed combinations offer patients the benefits of convenience, cost and compliance, they limit individualization of personalized dosing. The researchers stressed that it is important to balance the efficacy, tolerability and adverse events of glaucoma drugs on a patient-by-patient basis. Treatment should be individualized and may need to change over time because of adverse events.

The key to better understanding the advantages and disadvantages of fixed-combination therapeutics for glaucoma is dependent upon research, which will ultimately facilitate the success of these therapies, the researchers said.

Regulatory hurdles may present a challenge for the approval of some combination therapeutics, but even so, Dr. Rhee stressed that more research is needed to directly compare fixed-combination glaucoma therapies in the pipeline vs. those that are currently available in order to establish the combinations’ efficacy and safety. – by Tara Grassia

References:

• Goldberg I, Crowston JG, Jasek MC, Stewart JA, Stewart WC. Intraocular pressure-lowering efficacy of brinzolamide when added to travoprost/timolol fixed combination as adjunctive therapy [published online ahead of print Nov. 2, 2010]. J Glaucoma. doi: 10.1097/IJG.0b013e3181fc8142.
• Konstas AG, Holló G, Mikropoulos D, et al. Twenty-four-hour intraocular pressure control with bimatoprost and the bimatoprost/timolol fixed combinations administered in the morning or evening in exfoliative glaucoma. Br J Ophthalmol. 2010;94(2):209-213.
• Nordstrom BL, Friedman DS, Mozaffari E, Quigley HA, Walker AM. Persistence and adherence with topical glaucoma therapy. Am J Ophthalmol. 2005;140(4):598-606.
• Stewart WC, Kruft B, Nelson LA, Stewart JA. Ophthalmologist attitudes regarding fixed combination treatment for glaucoma in the European Union. Eur J Ophthalmol. 2009;19(4):588-593.

• Gábor Holló, MD, PhD, DSc, can be reached at the Department of Ophthalmology, Semmelweis University, 1083 Budapest, Tömö u. 25-29, Hungary; email: hg@szem1.sote.hu.Dr. Holló is a consultant to Alcon, Allergan, Merck Sharp and Dohme, Pfizer, and Santen.
• Douglas J. Rhee, MD, can be reached at Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02144; 617-573-3670; fax: 617-573-3707; e-mail: dougrhee@aol.com. Dr. Rhee is a consultant to Alcon, Allergan and Santen.
• Thomas W. Samuelson, MD, can be reached at Minnesota Eye Consultants, 701 E. 24th St., Suite 100, Minneapolis, MN 55404; 612-813-3628; fax: 612-813-2656; email: twsamuelson@mneye.com.Dr. Samuelson is a consultant for Alcon, Allergan and Pfizer