E DITORIALS Modern Alchemy: Fixed Combinations of Glaucoma Drugs L. JAY KATZ, MD B ARNEBEY AND ASSOCIATES 1 REPORTED A STUDY that compared the efficacy and safety of travaprost and timololcombined in onebottlewith the efficacy and safety of the same medications when used separately. This report reflects the current surge of interest in partnering glaucoma medications in a single bottle. In the medieval era,alchemists tried to make the rare and precious metal gold by combining common elements such aslead and sulfur. In somewhatsimilarfashion, variousmixturesofcommonly used glaucoma drugs are now combined into a single bottle in hopes that the combined drop will work better than the individual com- ponents alone. This effort raises several questions: 1. Is there a need for fixed combinations of glaucoma medications? 2. Which drugs are pharmacologically complementary through different mechanisms of action and similar dosing schedules? 3. Is the intraocular pressure (IOP)–lowering effect of the fixed combinations sufficiently superior to that of the individual drugs to justify the more frequent side effects that will likely occur? Recent randomized, prospective multicenter trials, such as the Normal Tension Glaucoma Treatment Study, the Collaborative Initial Glaucoma Treatment Study, and the Ocular Hypertension Treatment Study, demonstrate that to reach a desired target IOP, it is often necessary to use multiple drugs. 2– 4 There have been a number of concerns voiced abouthe useof multiplebottlesof glaucoma medications: compliance, washout effect, preservative tox- icity, and cost. Complex dosing regimens have been clearly associated with nonadherence to medical therapy. Patients who useonly one bottleare morelikely to use the medication as ordered than if they are required to use two or more bottles. 5 Furthermore, when more than one bottle isused,patientsdo notalwaysallow adequate time for ocularabsorption oftheir first medication before the second drug is administered. Preservatives, specifically benzalkonium chloride, are toxic to the eye in a variety ways: conjunctival inflammation (possibly jeopardizing t success of future glaucoma surgery), punctate keratopathy and keratitis sicca, cataract progression, and cystoid mac- ular edema after cataract surgery. 6 –10 When two individual bottles are dispensed by certain formularies, the copaym is likely to be morethan the copayment for a fixed combination of the same two drugs. These concerns hav spurred the search for glaucoma drugs that will work we when put together in one bottle. The only fixed-combination products approved by the Federal Drug Administration for use in the United States are epinephrine-pilocarpine and timolol-dorzolamide. Th former combination is rarely used today, because neither drug is particularly well tolerated, because epinephrine is relatively ineffective in lowering IOP, and because the ideal dosing regimen is different for the two medication twice a day forepinephrine and four timesa day for pilocarpine. Conversely, timolol-dorzolamide has attaine widespread favor as a fixed-combination product. Both timololand dorzolamide are effective when used twice daily.Therefore, a twice-daily regimen with the fixed combination of these two drugs provides maximal or ne maximal efficacy. 11 The two drugsare additive in their effect in lowering IOP, despite both being aqueous sup- pressants. At first blush, however, the ideal match would seem to be ␤-blockers and prostaglandin analogs; they are the tw most effective drug classes in lowering IOP, they both a used once a day, and theirmechanisms of action are different, the ␤-blockers suppressing the production of, the prostaglandin analogs enhancing outflow of aqueous. However, the studies of a fixed combination of timolol with a prostaglandin analog have not yet yielded data compelling enough to warrant the endorsement of the Food and Drug Administration. The first reports investi- gated the combination of timolol-latanoprost dosed onc day in the morning. Higginbotham and associates pub- lished their results after 1 year of therapy. 12 All patients were initially placed on timolol and then placed in one o three treatment arms:a fixed combination of timolol- Accepted for publication Mar 10, 2005. From the Glaucoma Service, Wills Eye Hospital, Philadelphia, Penn- sylvania. Inquiries to L. Jay Katz, MD, Glaucoma Service, Wills Eye Hospital, 840 Walnut Street, Philadelphia, PA 19107; fax: (215)928-0166; e-mail: ljk22222@aol.com ©2005 BY E LSEVIER INC. ALL RIGHTS RESERVED . 0002-9394/05/$30.00 125 doi:10.1016/j.ajo.2005.03.034