In 1998, the fixed-combination agent COSOPT (timolol 0.5% and dorzolamide; Merck & Co., Inc., West Point, PA) became available. Despite concern that b.i.d. dosing of the medication compromises the effectiveness of the topical carbonic anhydrase inhibitor, which requires t.i.d. dosing, COSOPT has been commercially successful. The agent is often used as an adjunct or second tier to the prostaglandin analogues.
Why is there not a greater number of fixed combinations for treating glaucoma, especially when such a large percentage of glaucoma patients take more than one IOP-lowering medication? Among patients with primary open-angle glaucoma, almost half use more than one eye drop; the most common combination is a prostaglandin and a beta-blocker. In the Ocular Hypertension Treatment Study,1 40% of subjects in the treatment group took two or more medications at 60 months to achieve the targeted 20% reduction in IOP. In light of the potential severity of glaucoma and patients' known problems using their medications, a fixed-combination agent used q.d. could be helpful. What determines the success of a fixed combination? The answers to these questions are complex and depend on issues of patient compliance, regulatory requirements, and drug efficacy and safety.
COMPLIANCE AND EFFICACY
Assuming patients' compliance with prescribed therapy increases when they are asked to take a medication once versus multiple times daily, it seems logical that a fixed-combination eye drop prescribed q.d. would be successful if it proved to be more effective at IOP-lowering than both its individual components and other competing therapies.2 In the case of COSOPT, the fixed combination was shown in clinical trials to lower pressure to a greater extent than either timolol or dorzolamide alone. All fixed-combination medication are required to fulfill this FDA requirement. COSOPT was approved for b.i.d. dosing, however, which is not optimal for enhancing compliance. Moreover, the agent is not as efficacious as the prostaglandin analogues.
RECENT DEVELOPMENTS
It is challenging to develop a fixed-combination agent that enhances patient compliance, effectively lowers IOP, and achieves regulatory approval, but it is also an opportunity in glaucoma therapy. Pfizer Inc. (New York, NY), Allergan, Inc. (Irvine, CA), and Alcon Laboratories, Inc. (Fort Worth, TX), have each conducted multiple clinical trials to develop a fixed combination of a prostaglandin analogue and timolol for q.d. application. Although Pfizer Inc. received approval in the European Union for Xalcom (latanoprost and timolol), the company was unsuccessful in obtaining FDA approval for the medication. Pfizer Inc. did not satisfy the FDA requirement that its combination product be more effective than its individual components. Allergan, Inc., is awaiting FDA review of its fixed combination of Lumigan (Allergan, Inc.) and timolol as well as of COMBIGAN (brimonidine 0.2% and timolol 0.5%), which is currently available in Canada.
The FDA should decide whether to approve Extravan (Alcon Laboratories, Inc.) by the end of this year. This fixed-combination agent is composed of Travatan 0.004% (Alcon Laboratories, Inc.) and timolol 0.5%. In a pivotal phase III clinical study, Extravan administered q.d. produced a statistically significant and clinically relevant reduction in IOP from baseline. Specifically, the agent decreased patients' (N=155) pressure by 6.8 to 8.6 mm Hg versus 7.3 to 8.4 mm Hg in subjects (N=151) concomitantly receiving Travatan and timolol as separate agents and 4.6 to 7.0 mm Hg in patients (N=81) taking timolol alone. At every 8-AM time point, Extravan delivered therapeutically equivalent pressure reductions to those achieved in the Travatan-plus-timolol concomitant administration group.
Another study compared the safety and efficacy of three treatment groups: (1) Extravan q.a.m. (N=82); (2) Travatan 0.004% q.p.m. (N=84); and (3) timolol 0.5% b.i.d. (N=92). Extravan produced statistically significant and clinically relevant reductions in IOP from baseline, with mean decreases of up to 12 mm Hg or 38%. The agent produced statistically significantly lower mean IOP at all visits compared with timolol. When dosed in the morning, the agent exerted maximum IOP-lowering efficacy at the 8-AM time point (the peak of the diurnal IOP curve). At that time point, it lowered IOP by 2 mm Hg more than Travatan alone. Whether the FDA will consider this amount to be a sufficient pressure reduction remains to be determined.
CONCLUSION
As practitioners raise the pressure-lowering goals of glaucoma treatment in terms of providing maximum compliance, safety, and efficacy, fixed-combination medications will likely gain in popularity. In all probability, such agents will once again become first-line therapy.
Richard A. Lewis, MD, is in private practice in Sacramento, California. He disclosed that he is a clinical investigator and is on the Speakers Bureau for Alcon Laboratories, Inc., Allergan, Inc., and Pfizer Inc. Dr. Lewis may be reached at (916) 455-9938; rlewismd@pacbell.net.
1. Kass MA, Heuer DK, Higginbotham EJ, et al. The Ocular Hypertension Treatment Study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701-713.
2. Winfield AJ, Jessiman D, Williams A, Esakowitz L. A study of the causes of non-compliance by patients prescribed eyedrops. Br J Ophthalmol. 1990;74:477-480.
