Reducing IOP with fixed-combination regimen

Evening dosing of fixed-combination travoprost/timolol appears most efficacious in treating open-angle glaucoma.

ByAnastasios G.P. Konstas, MD, PhD

Anastasios G.P. Konstas

It is estimated that approximately half of patients take their medications improperly. In the United States alone, adherence problems result in estimated costs of up to $100 billion annually. This is due to the higher rate of health problems, disease progression, and complications. Non-adherence can lead to more intensive medical care, including extra hospital admissions. Noncompliance can have serious consequences, including increased risk for blindness, for patients undergoing treatment for glaucoma.¹

Frequent dosing and the complexity of the therapeutic regimem are just two factors consistently associated with poor adherence in the management of chronic diseases. Medicinal therapeutic regimens that require a higher pill burden can lead to worse health outcomes than combination regimens.^2,3 This dilemma has led researchers and the pharmaceutical industry to fuse medications into fixed-combination regimens that allow for once- or twice-daily dosing. The success of this strategy has been confirmed in studies on the treatment of many chronic diseases and conditions. Fixed-dose combination pills simplify adjunctive medication regimens and significantly reduce daily dosing and non adherence.⁴

Dosing studies on arterial hypertension and diabetes show that fixed combinations significantly improve adherence to treatment regimens and improve health outcomes. ^4-5 It has recently been shown that in glaucoma patients, adherence is also less likely when a greater number of medications are required.⁵ As a result, the benefit of using fixed combinations in the management of chronic asymptomatic diseases has been confirmed.

Consequently, there is now a trend for physicians to prescribe fixed combinations earlier and more often, especially in the management of arterial hypertension and diabetes. Further, fixed combinations are increasingly used as first-choice therapy in the management of chronic diseases.

Fixed combinations in glaucoma treatment

Simplifying therapy and enhancing safety with fixed combinations are important and enhance the quality of life for the elderly glaucoma patient.

—Anastasios G.P. Konstas, MD, PhD

An overview of how these fixed-combination regimens potentially improve on the treatment of glaucoma by reducing 24-hour IOP was presented in March 2007 at the International Glaucoma Symposium in Athens, Greece. It was highlighted that in the treatment of glaucoma, if more than one medication is required, there is the potential for wash-out, confusion about when to instill each medication, and decreased adherence. Simplifying therapy and enhancing safety with fixed combinations are important and enhance the quality of life for the elderly glaucoma patient, who often requires more medications than a younger patient.

Importantly, fixed-combination treatments are also useful in reducing long-term exposure to benzalkonium chloride (BAK) and other preservatives commonly found in topical eye drops that are known to be toxic to the ocular surface. Preservative exposure may also impair the long-term success of glaucoma surgery.

DuoTrav

DuoTrav (travoprost 0.004%/timolol 0.5%; Alcon) is one such fixed-combination formulation that has shown promising results in the treatment of glaucoma (Figure).^6-8 This once-daily eye drop solution is currently indicated for the treatment of patients with open-angle glaucoma or ocular hypertension that proved unresponsive to previous treatment with topical beta-adrenoceptor antagonists or prostaglandin analogs.

In early clinical testing, the travoprost/timolol fixed combination produced greater reductions in IOP compared with Travatan (travoprost ophthalmic solution 0.004%; Alcon) or timolol monotherapy. The tolerability of this new fixed combination was similar to that of travoprost plus timolol, travoprost, and timolol alone. Interestingly, hyperemia was less common with the fixed combination than with the unfixed concomitant therapy.⁹

Figure. Comparison of 24-hour IOP reduction with morning vs. evening dosing of the travoprost/timolol fixed combination (DuoTrav).

Best dosing for DuoTrav

Data from a recent crossover study of 32 patients with open-angle glaucoma comparing 24-hour IOP control with both morning and evening dosages of the travoprost/timolol fixed combination were presented at the International Glaucoma Symposium. Patients were randomized after a 4- to 6-week period during which they did not receive treatment. After undergoing 8 weeks of treatment with the travoprost/timolol fixed combination administered in the morning or the evening, patients were monitored for IOP beginning at 6 a.m. and every 4 hours thereafter. Patients then crossed over to the other arm of the study to receive the opposite dosing for 8 weeks and underwent another 24-hour IOP curve. Evening dosing of the travoprost/timolol fixed combination was found to be more effective than morning dosing, resulting in significantly better 24-hour IOP control, lower IOP measurements at four of the six time points, lower 24-hour pressure fluctuation, and lower peak pressure.

Glaucoma treatment goals are to significantly reduce baseline IOP and 24-hour fluctuation. The hallmark of a successful fixed combination may be a 30% mean 24-hour IOP reduction from untreated baseline values. Both dosing regimens effectively controlled 24-hour pressure. The morning dosing of the travoprost/timolol fixed combination produced a 31% IOP reduction, whereas the evening dosing obtained a 34% mean 24-hour IOP reduction from untreated baseline and provided a narrow 24-hour IOP fluctuation.

Safety profile

Conjunctival hyperemia was the most common (7.2%) adverse event in both treatment arms. There were no differences in safety between the two regimens.

These safety results are similar to data reported in other clinical studies.^6-8

Overall, through regulatory studies with the new fixed combinations, there is clear evidence that fixed-combinations therapies cause fewer side effects compared with unfixed concomitant therapy. Use of fixed combinations significantly reduces the amount of preservative and active medication. For example, the travoprost/timolol fixed combination produced significantly less hyperemia than the unfixed combination of travoprost and timolol.

Improved methods of analysis are still needed to properly gauge the long-term efficacy of this and other fixed combinations, as well as their ability to improve adherence in the long term. Hopefully in the future, fixed combinations will eventually become standard in glaucoma treatment.

In many healthcare systems and glaucoma management teams, there is often less than optimal follow-up of patients with glaucoma. It is conceivable that ophthalmologists could provide improved visual outcomes if fixed combinations were used to treat glaucoma more often and earlier. This requires, however, evidence from controlled clinical trials. The use of fixed combinations will likely increase in the future glaucoma treatment.

References

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Neutel JM, Smith DH. Improving patient compliance: major goal in the management of hypertension. J Clin Hypertens (Greenwich). 2003;5:127-132.
Connor J, Rafter N, Rodgers A. Do fixed-dose combination pills or unit-of-use packaging improve adherence? A systematic review. Bull World Health. 2004;82:935–939.
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Barnebey HS, Orengo-Nania S, Flowers BE, et al. The safety and efficacy of travoprost 0.004%/timolol 0.5% fixed combination ophthalmic solution. Am J Ophthalmol. 2005;140:1-7.
Schuman JS, Katz GJ, Lewis RA, et al. Efficacy and safety of a fixed combination of travoprost 0.004%/timolol 0.5% ophthalmic solution once daily for open-angle glaucoma or ocular hypertension. Am J Ophthalmol. 2005;140:242-250.
Hughes BA, Bacharach J, Craven ER, et al. A three-month, multicenter, double-masked study of the safety and efficacy of travoprost 0.004%/timolol 0.5% ophthalmic solution compared to travoprost 0.004% ophthalmic solution and timolol 0.5% dosed concomitantly in subjects with open angle glaucoma or ocular hypertension. J Glaucoma. 2005;14:392-399.
Committee for Medicinal Products for Human Use. European Public Assessment Report (EPAR): Travatan. Committee for Medicinal Products for Human Use, European Medicines Agency; 2001.

Dr. Konstas is an associate professor of ophthalmology and head of the Glaucoma Unit at the 1st University Department of Ophthalmology, AHEPA Hospital, Thessaloniki, Greece.