Using Fixed-combination Medications to Achieve Treatment Goals

Learn how this therapy can provide effective and individualized lowering of IOP.

By Desiree´ Ifft, Contributing Editor

As any ophthalmologist who treats glaucoma will attest, one topical medication often isn’t enough to maintain IOP at the target level. Many, if not most, patients require two or more medications. While therapy with multiple medications can be very effective, it tends to be inconvenient and confusing for patients, making them less likely to comply with treatment recommendations. When a second or third medication is needed to lower IOP, a fixed-combination treatment can be used to add the efficacy of two drugs while adding only one bottle to the patient’s treatment regimen. The potential side effects of two different medications must then be taken into account, although a fixed combination decreases exposure to preservatives and therefore may reduce the effects on the ocular surface. It may also help to prevent a wash-out effect, which occurs when patients instill one eye drop and don’t wait long enough before instilling the next.

Three fixed-combination glaucoma medications are approved by the FDA:

■ dorzolamide hydrochloride 2% and timolol maleate 0.5% (Cosopt, Merck; also available in generic form)

■ brimonidine tartrate 0.2% and timolol maleate 0.5% (Combigan, Allergan)

■ brinzolamide 1% and brimonidine tartrate 0.2% (Simbrinza, Alcon).

“Fixed combinations are formulations of two ocular hypotensive medications selected based on the rationale that their IOP-lowering efficacy is additive to some degree,” explains Angelo P. Tanna, MD, vice chairman of the Department of Ophthalmology and director of the Glaucoma Service at the Northwestern University Feinberg School of Medicine in Chicago. “Any two of the commonly utilized classes of ocular hypotensive medications are at least somewhat additive to one another.”¹

“That said, you cannot necessarily combine any two in one bottle. The molecules have to be compatible with respect to their chemical stability when formulated with the same incipients. A second requirement is dosing compatibility. If one drop needs to be taken three times per day and the other once per day, such as brimonidine and a prostaglandin analog (PGA), for obvious practical reasons they cannot be formulated together.”

Helping Patients Achieve Better Compliance

No drug is efficacious if it’s not used as directed, which is the primary impetus behind the development of fixed-combination glaucoma medications: to foster good patient compliance by simplifying treatment. How well the fixed combinations accomplish this goal has been studied in various ways, mainly by tracking compliance (use of a drug as directed with regard to timing and dosage), persistence (continuation of treatment, i.e., continued refilling of a prescription) or adherence (compliance plus persistence). “Study after study^2-4 has shown that compliance is markedly better when dosing is simpler and fewer bottles are involved,” says L. Jay Katz, MD, director of the Wills Eye Institute Glaucoma Service and professor of Ophthalmology at Jefferson Medical College in Philadelphia. Dr. Katz described one study involving patients who first received a prescription for latanoprost. While 3,146 of the patients remained on monotherapy, 1,784 were prescribed a second medication. When a second medication was added, persistency suffered for not only the first medication but also the second.⁵

According to Joseph Panarelli, MD, a glaucoma specialist at the New York Eye and Ear Infirmary of Mount Sinai, it’s easy to see how difficult it can be for patients to use their glaucoma medications consistently and how a fixed combination can help. For example, he describes the experience of an 81-year-old patient with advanced primary open-angle glaucoma who had undergone selective laser trabeculoplasty in both eyes 5 years ago with little benefit. Her visual field had been stable and her IOP was controlled with timolol 0.5% bid, brimonidine 0.2% tid and dorzolamide tid OU. However, at several recent visits, the patient was noted to have increased IOP and was referred to Dr. Panarelli for possible glaucoma surgery. At that time, her IOP as measured via applanation was 26 mmHg OU. C/D was 0.75 OD and 0.8 OS, and visual field testing showed a moderate superior arcuate scotoma in each eye. “After a lengthy discussion with the patient, it became clear that she was having increasing difficulty administering her medications because of her rheumatoid arthritis,” Dr. Panarelli says. “She had severe ulnar deviation with progressive small joint disease, and her regimen required 16 drops a day.” The patient was switched to Cosopt (dorzolamide hydrochloride 2% and timolol maleate 0.5%) bid OU. “For the past year and a half, her pressures have remained stable at 14 mmHg. The simplified regimen has resulted in better compliance and hence better IOP control,” says Dr. Panarelli.

Efficacy of the Fixed-combination Meds

In clinical trials, all three of the fixed-combination medications approved by the FDA lowered IOP significantly more than each of their components used as monotherapy and exhibited an IOP-lowering effect similar to their individual components used concomitantly. Also, “We have evidence that the amount of pressure lowering is along the same lines as the prostaglandin analogs,⁶ which is accepted to be 25-30% from an untreated baseline, so these are very powerful medications,” says Nathan Radcliffe, MD, director of the Glaucoma Service and clinical assistant professor at New York University Langone Ophthalmology Associates.

For ophthalmologists reviewing the results of studies evaluating fixed combinations, Dr. Tanna offers a few caveat: “Other than the pivotal trials, many studies lack a control arm, which allows the regression-to-the-mean phenomenon to occur unchecked and potentially skew the IOP results.”

Using Fixed Combinations in Practice

In the majority of cases, a fixed-combination medication is considered as an option when a PGA or another agent hasn’t lowered pressure sufficiently. That fits with the approach Dr. Tanna uses, although he prescribes a fixed-combination for long-term use only after he confirms the IOP-lowering efficacy of each of its components sequentially. “If it turns out both components are beneficial, well-tolerated and needed in an individual patient, that’s the perfect time to prescribe a fixed combination,” he says.

The usual protocol for Dr. Panarelli is similar to Dr. Tanna’s. He uses a PGA as first-line treatment and, if necessary, adds a topical carbonic anhydrase inhibitor or a beta-blocker. If he needs to add a third medication, he tends toward fixed-combination medications. Dr. Panarelli says one drawback to jumping to a fixed-combination drop right away is the inability to know what the true IOP-lowering effect is for each component. In addition, if the patient has a reaction to the medication, it may not be clear which component is responsible. “I prefer to take a step-wise approach,” he adds “and as a result, I shift to a combination drop a little later in my treatment regimen.”

Dr. Radcliffe prescribes a fixed combination most often for patients who have achieved significant pressure reduction with a PGA but need significantly more. For example, he says, “If a patient comes in with an IOP of 28 mmHg, we set a target pressure of 13 mmHg, and a PGA gets us to 19 mmHg, we’re halfway there but have a long way to go. That’s the type of situation in which keeping the PGA and adding a fixed combination can make a big difference.” He cites several reasons he believes more ophthalmologists will be adopting that strategy. “There is, without question, an evolution in the treatment paradigm such that today we’re more likely than we were 10 years ago to use a fixed-combination medication as the first add to a prostaglandin analog,” he says. “We have an appreciation of how important IOP-lowering efficacy is in treating glaucoma. We have an appreciation of how a single medication added to a prostaglandin analog doesn’t always give us the pressure lowering that we want. And efficiency, patient convenience and compliance are important to us. I have no doubt this trend will continue until adding a fixed combination is much more common than adding just a single agent.”

Dr. Katz offers another potential reason the trend may continue: “We may be inclined to add a fixed combination to the PGA instead of adding only one medication because we’re increasingly evaluated and compensated based on outcomes and we know we’re not likely to achieve the IOP goal with just one additional drug. The PGA plus the fixed combination can take us to maximum medical therapy, the point from which we can consider surgery if necessary, with less office time spent on pressure checks that won’t be as low as desired and are inconvenient for patients.”

A fixed combination can be a sensible choice in several other scenarios as well:

■ when IOP is dangerously high and needs to be lowered as quickly as possible (such as ≥40 mmHg in an eye that already has mild glaucomatous damage, or around 30 mmHg in an eye with severe damage — as Dr. Katz notes, “We really can’t go too low with IOP. It’s not like systemic hypertension, where pressure that’s too low can lead to dizziness or fainting. Once the IOP is back under control, the combination medication can be withdrawn, especially if it’s causing issues with ocular surface side effects or costs for the patient.”

■ as replacement therapy for a patient who doesn’t tolerate a PGA

■ for patients who need treatment in only one eye and would like to avoid the cosmetic side effects of a PGA, e.g., redness and eyelash growth, which might be more noticeable in that situation

■ to treat acute IOP crises that are expected to be transient such as may occur with uveitis or following cataract or drainage implant surgery

■ whenever a fixed combination can safely and effectively replace two medication bottles with one.

Dr. Radcliffe’s next step when a PGA and a fixed combination are already on board? “For my next agent, I usually add pilocarpine,” he says. “It’s unlike any of the other agents in that it increases trabecular outflow while PGAs tend to increase uveoscleral outflow and the fixed combinations suppress aqueous production with the exception of Combigan and Simbrinza (brimonidine-containing fixed-combination agents), which also increase outflow. I find that for patients who are already using a drop in those medication classes, pilocarpine can be quite additive.”

In deciding which of the three available fixed combinations to prescribe, potential systemic and ocular side effects are considerations. According to Dr. Tanna, “All the pivotal trials did a good job of disclosing side effects. The bottom line is there were no surprises. The side effects were what would be expected with each agent separately.” The best approach, Dr. Radcliffe says, “is a thorough history and conversation with the patient to understand their underlying health conditions. Obviously, we would avoid a fixed combination if a patient is allergic or sensitive to one of its components. Common sensitivities are allergic conjunctivitis associated with brimonidine and stinging caused by the acidic pH of dorzolamide. And, as is well-known, topical beta blockers should be avoided in patients who have asthma or cardiopulmonary problems.” Dr. Tanna prefers to avoid use of topical beta blockers at bedtime, especially in patients with normal-tension glaucoma. “To minimize adverse effects, optimal dosing for a beta blocker is once per day in the morning,” he explains.

Dr. Katz adds two additional considerations. He avoids dorzolamide for patients with a history of sulfa allergy. He also provides this reminder: “If a patient is taking an oral beta blocker, it may already be having an effect on IOP. Therefore, a topical beta blocker may be less robust in lowering IOP.”

Interestingly, many ophthalmologists report that it seems some patients using a fixed combination drop don’t experience the ocular surface side effects the individual components could be expected to cause. In fact, according to a recent literature review of all prospective clinical trials of timolol-containing fixed-combination medications, timolol seems to make the allergy and hyperemia associated with other medications less frequent.⁷ “In several studies, the rate of allergy was significantly lower with the fixed combination than with brimonidine 0.2% individually,” says Dr. Radcliffe, who conducted the review. “And studies in Europe, where PGA/beta blocker combinations are available, showed timolol can lessen hyperemia seen with bimatoprost and latanoprost. So it’s not always the case that with a fixed combination we’ll have double the side effects.” Although it doesn’t contain timolol, Dr. Panarelli comments that he has been pleasantly surprised by the tolerability of Simbrinza for his patients. “I’ve definitely seen less irritation than I was seeing with the separate components. I wasn’t expecting that based on my experience with the medications individually,” he says.

An Important Role in Safeguarding Sight

In Dr. Radcliffe’s view, fixed-combination medications are a very positive development for glaucoma patients. “Having several of these drops available to us brings us into the current era of individualizing therapy to meet the needs of diverse patients, and all of our available options have a welcomed place,” he says. “Furthermore, even among intelligent individuals, a lack of health literacy can be a problem. Once we arrive at prescribing three medications, confusion is universal among glaucoma patients. Any chance we have to simplify things for them is very important, and the fixed combinations fill that need very well.” ■

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