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March 2012 EW NEWS & OPINION Fixed-combination drugs useful tool to reduce the number of medications by David Laber EyeWorld Contributing Editor cheaper than the FC. This is the case despite the fact that patients would have to make two separate co-payments for the in- dividual drugs, he said. Still, Dr. Cantor cautioned against taking too much stock in the price differential. "Sometimes the cost of the bot- tle is less important," Dr. Cantor said. "If patients are using their drugs—and studies have shown that when there are more bottles there is less compliance—then the extra cost for one bottle is worth it." Consequently, if reducing a patient down to a single bottle in- creases the likelihood of the patient using the drug, then in the long run, the FC drug would be cheaper, Dr. Cantor said. Source: Medioimages/Photodisc/Getty Images With patient compliance handicapping medical therapy success, reducing the number of bottles a patient uses can be important in some glaucoma cases "N o medications work well if the patient doesn't take them," said Douglas J. Rhee, M.D., assistant professor, Massachu- setts Eye and Ear Infirmary, Harvard Medical School, Boston. This is the challenge physicians face when put- ting a glaucoma patient on medical therapy—patient compliance. But it is not a battle unique to this spe- cialty. "It doesn't matter what you are treating," Dr. Rhee said. "Those is- sues cut across all specialties." One potential solution physi- cians have at their disposal is fixed- combination (FC) medications. In the United States, two have FDA ap- proval: Combigan (brimonidine and timolol, Allergan, Irvine, Calif.) and Cosopt (dorzolamide and timolol, Merck, Whitehouse Station, N.J.). For drug approval by the FDA, a fixed combination must have better efficacy than each of the component medications used as monotherapy. Outside of the United States, there are various other FC drugs that do not include the beta-blocker tim- olol, but they have not met the FDA's efficacy requirements thus far, said Louis B. Cantor, M.D., Jay C. and Lucile L. Kahn Professor of Glaucoma Research and Education, and vice chairman of education, ophthalmology department, Indiana University School of Medicine, Indianapolis. FC drugs vs. monotherapy The major advantage of FC drugs is that they simplify medical therapy, Dr. Cantor said. The drugs taken sep- arately provide essentially the same medical benefits as when combined. By simplifying the medical therapy, it increases the likelihood of patient compliance. But a complicating factor, espe- cially for patients, is that FC drugs tend to be more expensive, he said. Combigan and Cosopt are both brand name drugs, while their com- ponents can be bought in generic form, making the separate drugs Treatment regimen evolution For the average glaucoma patient, Dr. Cantor said he starts with a prostaglandin analog monotherapy. If the goal for the patient is to get the IOP under control and the monotherapy is getting the patient to within 5 mm Hg, then he might add a single agent to the mix. But if the monotherapy is not getting the patient within 5 mm Hg, he said he would consider switching to an FC drug. If the patient is a referral pa- tient, this person is usually already on multiple drugs, so Dr. Cantor will start the patient on an FC. This tends to improve the IOP and can even reduce the number of medica- tions the patient is already taking. Dr. Rhee said he starts average glaucoma patients on prostaglandin analogs, then will move them to beta-blockers if he is not getting the results he wants. After gauging the results with the beta-blockers, Dr. Rhee will try the fixed-combination drugs. More variety of FCs abroad As noted, there are two FDA-ap- proved FC drugs in the United States. The lack of availability of FC drugs containing pilocarpine in the United States can probably be ex- plained by the poor tolerability profile of pilocarpine, Eve J. Higginbotham, M.D., Morehouse School of Medicine, Atlanta, said in a 2010 issue of Clinical Ophthalmology. In addition to the obvious goal of controlling a patient's IOP and improving compliance, as FC drugs have evolved, they are becoming more tolerable for patients. This means that patients experience less burning and stinging, Dr. Cantor said. The FC of brinzolamide and timolol (Azarga, Alcon, Fort Worth, Texas) received regulatory approval by the European Medicines Agency in December 2008. In a study in a 2011 issue of Clinical Ophthalmology, Ines Lanzl, M.D., Technical University, Munich, Germany, reported better IOP con- trol than all previous therapies analyzed and favorable tolerability, resulting in a strong patient prefer- ence for brinzolamide/timolol over other therapies. Although Dr. Cantor said the study supports the efficacy and tol- erability of the newer drug, it is im- portant to put open-label, post- market studies into context because these kinds of studies do not take into account that the reason many patients were switched to the alter- native drug is because the previous drug was not working for them. Therefore, such a study cannot be used to make any claims to this drug's superiority over other FC drugs. Dr. Higginbotham also noted that prostaglandin/timolol FCs have not been approved for use in the United States because it is not clear that the improvement in efficacy with the FC relative to monotherapy is clinically significant. "However, given the approval of these fixed combinations in other countries, it may be that subsets of patients are responsive to this ther- apy," she concluded. EW Editors' note: Drs. Cantor and Rhee have financial interests with Alcon, Allergan, and Merck. Contact information Cantor: 317-274-8485, lcantor@iupui.edu Rhee: 617-573-3670, dougrhee@aol.com 33