Despite being less than ideal, topical medications continue to be a mainstay in the treatment of glaucoma. The main issue with topical glaucoma medications is patient noncompliance. Some patients simply forget to instill the drops, while others are noncompliant because they cannot afford the medications.

“More than half of patients require more than one medication, so the biggest issue is compliance,” says Michael Stiles, MD, who is in private practice in Overland Park, Kan. One way that drug companies have tried to address this issue is by developing combination medications. Unfortunately, combination medications also have downsides.

“There are pluses and minuses to the new combination medications that are coming out these days,” says Mildred M.G. Olivier, MD, who is in private practice in Hoffman Estates, Ill. “They can help to facilitate patient compliance. However, when new medications are released, the cost needs to be factored into the equation, and that’s a struggle for a lot of patients. The drugs may be on the market, but out of reach for many. Individuals with low income, or who have lost their jobs in this economy, may not always be able to afford the newest medication on the market due to increasingly high co-pays, being on fixed incomes, being a Medicare patient who has reached the ‘donut hole,’ or tiers established by the insurance companies.”

A recent study conducted at the University of Toronto found that low-income patients are less likely to be compliant when using eye drops (Leung V, et al. To Investigate the Relationship between Socio-demographic Factors and Non-persistence with Topical Glaucoma Medications. Abstract #99. Presented at the 23rd Annual Meeting of the American Glaucoma Society, 2013). In this study, 61 patients completed a questionnaire about socioeconomic status. They answered questions about income and whether or not their basic needs for food, shelter and transportation were being met on a monthly basis. Pharmacy records were used to assess medication compliance. The researchers found that 54 percent of the glaucoma patients in the study were noncompliant, and those who reported not having their basic needs met were less likely to refill and take their medications.

Patients are driving the call for less expensive glaucoma drugs, and many are requesting generics. Unfortunately, generics often do not stand up well against their brand-name counterparts. “Often, patients have multiple chronic conditions, such as diabetes and high blood pressure, that also require ongoing medication,” says Dr. Olivier. “With rising co-payment costs, patients are obliged to request generics whenever possible in order to try to be compliant. I have a number of patients getting their medications from Canada because the prices are more affordable. Not all generics go through the rigorous testing that brand-name drugs do. We run into situations where a number of different companies offer formulations of a certain generic, and one will do a much better job of controlling pressure than the others.”

Steven Vold, MD, in private practice in Fayetteville, Ark., agrees, noting that the use of generic glaucoma medication has grown dramatically in recent years with the availability of generic latanoprost. “However, the efficacy of generic beta-blockers does not seem to be quite as good as the branded beta-blockers,” he says. “The reduced costs associated with generic medication are often the driving force for many clinicians in their selection of these drugs for their patients.”

Dr. Stiles agrees that generics may not be as efficacious as their brand-name counterparts. “There is concern about equal bioavailability of the active ingredient and equal clinical efficacy in generic medications,” he says. “For instance, generic latanoprost is produced by several companies, and comparative studies between Xalatan and latanoprost have shown reduced clinical efficacy with the generic version. In addition to not always being as efficacious, in some cases, these drugs have a higher side effect profile. Cost is the only reason to consider a generic medication.”

Another reason for non-compliance among patients is confusion about the medications, Dr. Olivier explains: “Glaucoma patients can find it confusing to comply with their medication regimens for a variety of reasons. The names of the drops are often complicated and hard for patients to remember. One way pharmaceutical companies are helping is by standardizing the colors of the tops of their dropper bottles to differentiate the various classes of drugs. Now, when a patient comes to the doctor and talks about taking the ‘colored top’ drops, we know which class of medication it is. But even this is not perfect and may still confuse many patients.”

New Medications

A variety of new medications are in various stages of development. Rescula (unoprostone, Sucampo Pharmaceuticals) has been re-released. “It may have a slightly different mechanism of action than other prostaglandins and may improve ocular blood flow,” Dr. Vold says. “However, Rescula requires twice-a-day dosing and doesn’t lower pressure as well as other prostaglandins, making it a tough sell to many clinicians.”

Dr. Olivier notes that the growing availability of preservative-free glaucoma medications is an encouraging development. “They tend to be friendlier to a patient’s ocular surface,” she says. “Such medications appeal to physicians because they offer us a new dimension for treating patients with low tolerance to preservatives, and they may be more appealing to younger patients with this chronic disease. Timoptic Ocudose, Cosopt PF and Zioptan are examples of these medications. Reformulations or decreased drug concentrations have also hit the market. Our ultimate goal would be a drug that has a low side effect profile, minimal dosing and high efficacy.”

Newly approved Simbrinza (Alcon) pairs brinzolamide 1% and brimonidine 0.2%. It is the only combination drug on the U.S. market that does not contain timolol, a beta-blocker.
A new product that was just approved by the Food and Drug Administration is Simbrinza (Alcon), which is a combination medication composed of brinzolamide 1% and brimonidine 0.2%. “This drug lowers intraocular pressure 22 percent to 35 percent depending on the time of day,” Dr. Vold says. “It clearly works better than each of these drugs used individually. This is the only combination drug on the market that does not have timolol, a beta-blocker. Patients with chronic obstructive pulmonary disease or cardiac arrhythmia will almost certainly benefit from this new glaucoma treatment option.”

A recent double-masked, randomized study compared the efficacy and safety of the combination drug with each agent alone in 650 patients with open-angle glaucoma or ocular hypertension. (Whitson J, et al. Phase 3 Randomized 3-month Trial with an Ongoing 3-month Safety Extension of Fixed Combination Brinzolamide 1%/brimonidine 0.2%. Abstract #91. Presented at the 23rd Annual Meeting of the American Glaucoma Society, 2013).

After the initiation of treatment, patients were evaluated at two weeks, six weeks and three months. During each visit, their IOPs were checked at four times: 8 a.m., 10 a.m., 3 p.m. and 5 p.m. The study found that the combination medication was significantly more effective for lowering IOP than either of the medications alone. All patients experienced significant reductions in IOP at three months, and those in the combination group benefited most. Because Simbrinza doesn’t contain a beta-blocker, it may be a good alternative for patients with asthma or depression.

Bausch + Lomb is also studying a new medication (BOL 303259-X). Phase II results were presented at the AGS meeting. (Weinreb R, et al. A Prospective Randomized, Multicenter, Single-masked, Parallel, Dose Ranging (VOYAGER) Study to Compare the Safety and Efficacy of BOL-303259-X to Latanoprost in Subjects with Open Angle Glaucoma or Ocular Hypertension. Presented at the 23rd Annual Meeting of the American Glaucoma Society, 2013). The study included 413 patients with open-angle glaucoma or ocular hypertension who were assigned to one of five treatment groups: once-daily BOL 303259-X 0.006%, 0.012%, 0.024% or 0.040%, or once-daily latanoprost. All patients were evaluated at seven visits over the 28 days of treatment and on the day after treatment ended.

On day 28 (the last day of treatment), the mean diurnal IOP reduction was 9 mmHg with BOL 303259-X 0.024% and 7.8 mmHg with latanoprost, and there were no significant differences in adverse effects between the two groups. On the day after treatment ended, the mean diurnal IOP reduction was still greater in the BOL 303259-X 0.024% group than in the latanoprost group (7.2 vs. 6.25 mmHg).

Additionally, a new class of glaucoma medications with a unique approach to lowering IOP is being developed. Rho kinase inhibitors will act specifically on the trabecular meshwork to enhance aqueous humor outflow. Rho kinase inhibitors have been shown to reduce cellular stiffness and enhance outflow through the trabecular meshwork, thereby reducing IOP.

New Drug Delivery Systems

Because the biggest issue with topical medications is compliance, companies are investigating new ways to deliver the drugs that could improve compliance. “Punctal plugs that slowly release medication into the tear film are under investigation, eliminating compliance issues,” Dr. Stiles explains. “Biodegradable implants could be placed under the conjunctiva and slowly release medication.”

Dr. Vold notes that both Ocular Therapeutix and ForSight Labs Vision 5 are developing promising new drug delivery systems. “Allergan is currently evaluating a novel method of drug delivery as well,” he says. “All of these developments potentially will make a big difference in how glaucoma patients are cared for in the future. The glaucoma treatment paradigm is definitely in rapid evolution, and I do think new innovative surgical interventions are being utilized earlier in the glaucomatous disease process by many physicians. Yet despite these surgical advances, most doctors will still start with medication for the foreseeable future.”

Drugs or Surgery?

Because of the downsides associated with topical glaucoma medications, debate continues about whether medication or surgery is better for patient care. The iStent, approved in June 2012, is the first ab interno microstent available for clinical use in the United States. “The big question is how does this device impact when ophthalmologists intervene surgically?” Dr. Vold says. “In the past, we would always use medication and laser therapy first, and surgery was more of a last resort. Now, we are thinking about intervening much earlier with surgery. In my mind, more than three or four glaucoma eye drops a day is probably not going to happen with the vast majority of patients. For me, this has become the new maximal medical therapy, and then we are talking about surgery or laser therapy. In some patients, laser trabeculoplasty is actually indicated as first-line therapy because people can’t afford medications or don’t like the side effects of drops. Currently available ab interno microstents and next-generation microstents currently in FDA-approved clinical trials may also potentially evolve to replace medication or laser procedures as first-line therapy.”

Dr. Olivier says that she always offers laser surgery in addition to topical anti-glaucoma medications as a first-line therapy option. “A prostaglandin is usually my preferred class of medications if I initiate medical therapy and is still what most patients prefer,” she says. “Doctors would love to have something to give patients that would alleviate the problem of compliance or forgetfulness. Individuals are working on other options since being challenged by our retinal colleagues. We are also more aware of the effects of medications on the ocular surface and problems with dry eyes. Finding a system that can allow us to deliver a drug that can last for six months to a year and has very few side effects would be phenomenal. Combining techniques that can be delivered with cataract surgery could be an option for many individuals. I look forward to when these ideas reach prime time.”  REVIEW