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Monotherapy is usually the first step in glaucoma therapy, but when IOP is not sufficiently lowered with a single agent, a fixed combination can be considered. The advantages, limitations, and features of fixed combinations of IOP-lowering agents available worldwide are reviewed.
Milan, Italy-Consistent with guidelines of the European Glaucoma Society, fixed-combination therapies may have a role in glaucoma management when monotherapy reduces IOP but not sufficiently to reach the target level, according to Luca Rossetti, MD.
"Most clinicians would agree that monotherapy is ideal, but results of clinical trials and clinical experience show it is often not enough. After 2 years in the Collaborative Initial Glaucoma Treatment Study, more than 75% of patients required two or more medications to reach target IOP, and even in the Ocular Hypertension Treatment Study, 49% of patients at month 60 required two or more medications to reach a 20% IOP reduction," noted Dr. Rossetti, professor of ophthalmology, University of Milan, Italy.
Fixed-combination therapy has several potential benefits compared with treatment with two separate medications, including improved convenience that can lead to better compliance, better safety from reduced lifetime exposure to preservatives, and possible decrease in drug washout if the second drop is applied too soon after the first. If combination therapy is indicated, it seems rational to consider medications with complementary mechanisms of action and with favorable safety and tolerability profiles, recognizing that glaucoma is a chronic disease that requires long-term therapy, Dr. Rossetti said.
Dr. Rossetti said that both dorzolamide and timolol act to reduce IOP by reducing aqueous humor production. However, the fixed combination of those two agents has been shown in a number of studies to be more effective than the individual ingredients and as effective as concomitantly administered timolol and dorzolamide.
"There is also one study that showed the fixed combination might be more effective than concomitantly administered dorzolamide and timolol," Dr. Rossetti noted.
Stability of reduction
Stable reduction of IOP also is an important feature of antiglaucoma therapy, and in one study taking diurnal measurements, the fixed combination of dorzolamide and timolol significantly reduced IOP and achieved a fairly uniform reduction over 24 hours.
Dr. Rossetti noted the fixed combination has been very well tolerated in clinical trials and found to have a safety profile similar to that of concomitant administration of the two medications.
In various countries outside the United States, three fixed combinations of timolol with a prostaglandin analogue are available: latanoprost-timolol (Xalacom, Pfizer), travoprost-timolol (DuoTrav, Alcon), and bimatoprost-timolol (Ganfort, Allergan). The agents composing those combinations have complementary mechanisms of action, providing both reduced aqueous production and increased uveoscleral outflow. In clinical studies, they all have been reported to achieve an IOP reduction of about 30% to 40% and have a peak effect at 8 to 12 hours.
Regarding the fixed combination of latanoprost and timolol, it was shown in phase III clinical trials and other recent studies to be superior to latanoprost alone. Trials comparing the fixed combination with concomitant administration of its two components have yielded conflicting results, with some showing similar efficacy and another where treatment with the separate agents was more effective.
Fewer clinical trials have been conducted of the fixed combination of travoprost and timolol. Available data demonstrate the fixed combination was well-tolerated and superior to the individual components, and generally comparable to their concomitant administration in its IOP-lowering efficacy.
"At the 8 a.m. measurement time, which is important because IOP tends to be higher then, the fixed and unfixed regimens performed similarly. However, at later measurement times during the day, the concomitantly administered drugs did slightly better in lowering IOP," Dr. Rossetti said.
A recent study evaluating the fixed combination of bimatoprost and timolol reported it to be more effective than bimatoprost alone and less effective than concomitant administration of the two separate ingredients.
"More interesting here are the safety data because conjunctival hyperemia occurred at a rate that was about 30% lower with fixed-combination therapy compared with bimatoprost alone," noted Dr. Rossetti.
The fixed combination of brimonidine and timolol (Combigan, Allergan) also is available outside the United States. It too has been investigated in few published studies, but in a 1-year trial, it was found to be more effective than either of its components at all follow-up visits.
"Again, interestingly, the rate of adverse events, including hyperemia, pruritus, and ocular allergy, was significantly less in patients taking the fixed combination compared with brimonidine alone," Dr. Rossetti said.
A few caveats should be considered when prescribing a fixed-combination agent for IOP lowering. All combinations available worldwide contain timolol and so have the potential for serious side effects. In addition, for fixed combinations with timolol and a prostaglandin analogue, there is controversy about the best time for administration (morning or evening) because of the different timing of each agent's peak effect. That phenomenon may also explain why some comparative studies show the fixed combination had limited benefit compared with monotherapy using a potent IOP-lowering agent, said Dr. Rossetti.
He also noted that economic analyses of treatment costs for the various fixed-combination agents available outside of the United States show there is a significant cost difference between the most expensive and least expensive of those products.