Role of fixed-combination therapeutics in glaucoma evolving

Clinicians may consider this avenue when one agent alone cannot control IOP.

Research indicates that the use of fixed-combination glaucoma agents improves patient compliance, but experts say additional studies are warranted to directly compare this approach to traditional single-agent treatment.

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 in Budapest.

Combigan (brimonidine tartrate 0.2% and timolol maleate 0.5%, Allergan) and Cosopt (dorzolamide 2% and timolol maleate 0.5%, Merck) are two combination treatments approved by the U.S. Food and Drug Administration.

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

According to Weber and colleagues, concomitant use of latanoprost and timolol results in a large additional IOP reduction when compared to the fixed combination. Researchers conducted a systematic review and meta-analysis to evaluate the IOP-lowering effect of the prostaglandins when added to a topical beta-blocker.

Ron Melton

“An interesting finding in the analysis is that the greatest IOP decrease was seen with evening dosing of the combination product,” Primary Care Optometry News Editorial Board member and private practitioner Ron Melton, OD, FAAO, told PCON. “Published reviews like this will continue to make it difficult for the prostaglandin/beta-blocker combination to be approved in the United States, although this combination is used successfully in many other parts of the world.”

Another study published by Dr. Holló and colleagues in the British Journal of Ophthalmology compared 24-hour IOP control of bimatoprost and timolol with bimatoprost alone. In this prospective, observer-masked, crossover comparison study, 60 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,” said Douglas J. Rhee, MD, member of the Glaucoma Section of Ocular Surgery News, a sister publication to Primary Care Optometry News.

Douglas J. Rhee

“Once you start adding more bottles, you have a decrease in compliance, so the benefit of combination treatments is that they could enhance compliance,” said Dr. Rhee, assistant professor of ophthalmology at the Massachusetts Eye and Ear Infirmary at Harvard Medical School in Boston.

A clinician may be unable to reach a target IOP for the patient with one medication, in which case the next step is to try a different class of medication to see if it achieves target pressure, according to Dr. Melton.

“When neither of the drugs allows the patient to achieve target IOP, trying a combination agent would be a next logical sequence to follow in an attempt to reach your goal,” he said.

It would be rare to initiate therapy with a combination drug on a new glaucoma patient unless the patient presents with an IOP of 45 mm Hg and 0.8 glaucomatous-appearing cupping, according to Dr. Melton.

“Here one might want to initiate treatment with a prostaglandin and a combination product such as Combigan, realizing that achieving an IOP low enough for this patient will take more than one medication.”

If a patient is taking two different eye drops to control IOP, a washout effect is a risk, especially if the patient is taking the drops within a few minutes of each other, Dr. Melton said. This disadvantage can be reduced by using fixed combinations.

Randall K. Thomas

Randall K. Thomas, OD, MPH, FAAO, a PCON Editorial Board member and private practitioner from Concord, N.C., told PCON when it comes to combination glaucoma eye drops, physicians must remember that the constituent medicines are generic and only resurrect into an expensive, brand name-protected drug when packaged in combination form.

Fixed-combination glaucoma therapeutics should only be prescribed if there is a clinical need for both medicines, if the patient is struggling to use both medicines as prescribed or if the increased cost is not prohibitive, he added. Therefore, combination products should play a limited role in glaucoma patient care.

Future of fixed combinations

As for the future of fixed-combination glaucoma therapeutics, generic latanoprost is slated to be available in several countries, which may have an impact on the price of fixed-combination products containing latanoprost. This addition of a generic form may raise several efficacy and safety issues.

Thomas W. Samuelson

“While it may be significantly more affordable, that is not always the case,” Thomas W. Samuelson, MD, OSN Glaucoma Section Editor, said. “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.

“Because there will be several generic latanoprost products, they 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 and compliance, they limit individualization of personalized dosing. The doctors 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.

Dr. Melton said that cost is an issue that continually seems to be a big factor in prescribing habits, and that combination products can end up being more expensive than two individual drugs if there are generic versions available.

“This is true of both Cosopt and Combigan, where the individual components of the combination drugs have generic equivalents, making it less expensive to purchase and use the two drugs rather than the more expensive combination product,” he said. – 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.
• Weber CAB, Beckers HJM, Zeegers MP, et al. The intraocular pressure-lowering effect of prostaglandin analogs combined with topical B-blocker therapy. Ophthalmol. 2010;117(11):2067-2074.

• Gábor Holló, MD, PhD, DSc, can be reached at the Department of Ophthalmology, Semmelweis University, 1083 Budapest, Tömö u. 25-29, Hungary; hg@szem1.sote.hu.
• Ron Melton, OD, FAAO, can be reached at 865 Linda Lane, Charlotte, NC 28211; (704) 944-4848; meltonepec@aol.com.
• Douglas J. Rhee, MD, can be reached at Massachusetts Eye and Ear Infirmary, 243 Charles St., Boston, MA 02144; (617) 573-3670; dougrhee@aol.com.
• Thomas W. Samuelson, MD, can be reached at Minnesota Eye Consultants, 701 E. 24th St., Suite 100, Minneapolis, MN 55404; (612) 813-3628; twsamuelson@mneye.com.
• Randall Thomas, OD, FAAO, can be reached at 6017 Havencrest Ct, Concord, NC 28027; (704) 7782-1127; thomasepec@carolina.rr.com.
• Disclosures: Dr. Holló is a consultant to Alcon, Allergan, Merck, Pfizer and Santen. Dr. Rhee is a consultant to Alcon, Allergan, Merck and Santen and does research for Alcon. Dr. Samuelson is a consultant for Alcon, Allergan and Pfizer. Dr. Thomas and Dr. Melton have no direct financial interest in the products mentioned in this article, nor are they paid consultants for any companies mentioned.