Rx Perspective

Combination Drug Delivers Lower IOPs

Today's lower-target IOPs often require strong, tolerable adjunctive therapy.

By Thomas Bournias, M.D.

The consensus among ophthalmologists is that the simplicity and safety profile of monotherapy makes it the ideal treatment for glaucoma patients. The benefits of monotherapy are clear:

• Prostaglandin analogues (PGAs) can provide more than 30% IOP lowering while keeping compliance simple

• Monotherapy may reduce the risk of adverse events, drug interactions and exposure to preservatives

• Monotherapy is often a less expensive option for patients.

However, it's also clear that monotherapy can be inadequate for some patients. The Ocular Hypertension Study showed that 50% of medically treated ocular hypertension patients required two or more medications to reach 20% IOP reduction after 5 years.¹ As we see in our own practices, it is not uncommon for patients to juggle regimens of three and even four glaucoma agents with the ultimate goal of reaching target pressure. There are several reasons why so many patients are on multiple medications. Target IOPs are set lower today than they were in the past.

For example, prior to the publication of the Advanced Glaucoma Intervention Study in 1998, many clinicians felt that an IOP less than 21 mm Hg was adequate for many glaucoma patients. With recent data, it has become clear that many patients, especially those with advanced or aggressive forms of glaucoma, require an IOP consistently in the mid-to-low teens. Because so many of our patients have baseline IOPs of 25 mm Hg or higher, there is great need to reduce the IOP by 40% or more — which requires multiple modalities of therapy. As the disease progresses, patients may need even lower pressures, and even the most effective IOP-lowering medications — the PGAs — do not achieve low target IOPs for all patients. Of course, all medications have the potential of having a different therapeutic effect when used as an adjunctive therapy as opposed to being used as monotherapy. Therefore, physicians should consider multiple factors when choosing an adjunctive therapy such as:

► the drug's efficacy when it is used with the first-line medication

► IOP reduction of at least an additional 15%²

► complementary mechanisms of action

► favorable safety and tolerability profiles.

Allergan's Combigan was approved for the U.S. market in October 2007.

Alpha-agonists, beta-blockers, carbonic anhydrase inhibitors (CAIs) and fixed combinations are among the adjunctive therapy options to consider when a PGA does not enable the patient to achieve target pressure. Administration of a fixed combination has several advantages. Dosing one drop vs. two drops affords convenience that may help with patient compliance and there is no risk of washout from the second drug.³ In this article, I will examine the additional benefits of a fixed-combination therapy.

New Combination on the Market

In October 2007, the FDA approved brimonidine tartrate/timolol maleate ophthalmic solution (Combigan, Allergan) 0.2%/0.5%. Prior to Combigan's approval, Cosopt (dorzalamide hydrochloride/timolol maleate ophthalmic solution, Merck) was the only fixed combination therapy on the market. I believe that Combigan has the potential for widespread use and appeal because it provides clinically significant IOP reduction as well as a favorable tolerability profile.

Indicated for the reduction of elevated IOP in patients with glaucoma or ocular hypertension who require adjunctive or replacement therapy due to inadequately controlled IOP, Combigan is an alpha adrenergic receptor agonist with a beta-blocker. Timolol, the beta-blocker in Combigan, is commonly used in combination therapy because it is a well-established IOP-lowering medication. Brimonidine, the alpha-agonist in Combigan, has a dual mechanism of action, increasing uveoscleral outflow and reducing aqueous humor production. With Combigan's approval, ophthalmologists now have the opportunity to choose between fixed combination adjunctive therapies for their glaucoma patients who require additional IOP lowering.

Combigan Stats

Studies have shown the percentage of Combigan patients reporting moderate to severe stinging, burning and/or unusual taste was 8.2%, 7.1% and 4.7% respectively.^4,5

In Combigan's prospective, randomized, double-masked FDA clinical trials, it was shown in a cohort of 1,159 subjects that Combigan reduced mean IOP up to 33% or 7.6 mm Hg from baseline. And mean daytime IOP was consistently below 18 mm Hg in approximately 40% of the subjects taking Combigan twice a day.⁴ The Advanced Glaucoma Intervention Study determined that IOP <18 Hg mm correlates to reduction of visual field defect progression.

Allergy Issues

In addition to significant IOP reduction, the final phase of Combigan's clinical trials exhibited favorable tolerability and allergy outcomes. In the 12-month, phase 3 clinical study comparing Combigan with its individual component medications, the incidence of ocular allergy was 5.2% in the fixed-combination group and 9.4% in the brimonidine group.⁴ The number of patients discontinuing Combigan in the study was about 14% vs. 30% for brimonidine. Thus far, I have had only one patient discontinue Combigan because of tolerability issues. Its allergy rate certainly appears much lower than brimonidine 0.2%.

Because brimonidine 0.2% as a monotherapy historically has been associated with high ocular allergy rates, Combigan's favorable tolerability profile and low allergy rates may at first seem surprising. However, theories regarding Combigan's low allergy/high tolerability profile revolve around its mechanism of action and the interplay between brimonidine and timolol. For instance, one theory explains that adrenergic agents such as brimonidine reduce epithelial cell size, thereby allowing "pro-inflammatory mediators" to pass through to the subconjunctival tissues. The beta-blocker timolol blocks this effect, thereby reducing the risk of allergic reaction.⁶

Summing up the Advantages

Clinical studies, as well as my own anecdotal experience, have shown that Combigan is a powerful adjunctive therapy, reducing mean IOP up to 6.9 mm Hg, or 29% from baseline when used with a PGA. It is also an effective next step for beta-blocker patients who require additional IOP reduction, lowering mean IOP up to 5.7 mm Hg or 25% from baseline. Patients tolerate Combigan well and it has a proven low allergy rate. The drug's efficacy coupled with its patient-friendly side-effect profile makes it a valuable addition to an ophthalmologist's medical treatment of glaucoma and ocular hypertension. OM

References

1. Kass MA, Heuer DK, Higginbotham EJ, et al; for Ocular Hypertension Treatment Study Group. The ocular hypertension treatment study: a randomized trial determines that topical ocular hypotensive medication delays or prevents the onset of primary open-angle glaucoma. Arch Ophthalmol. 2002;120:701-713.
2. Coleman AL, Baerveldt G, Bournias TE. Evidence-based management of glaucoma: recommendations of an expert panel. In: Managing Glaucoma: The Current Clinical Strategies. 1st ed. Montvale, NJ: Thomas PDR; 2003:212.
3. Choudhri S, Wand M, Shields MB. A comparison of dorzolamide-timolol combination versus the concomitant drugs. Am J Ophthalmol. 2000;130:832-833.
4. Sherwood MB, Craven ER, Chou C, et al; for Combigan Study Groups I and II. Twice-daily 0.2% brimonidine-0.5% timolol fixed-combination therapy vs. monotherapy with timolol or brimonidine in patients with glaucoma or ocular hypertension: a 12-month randomized trial. Arch Ophthalmol. 2006;124:1230-1238.
5. Nixon DR, Hollander DA. Comparison of the efficacy and tolerability of twice-daily Combigan vs. Cosopt fixed-combination therapies. Poster presented at: 111th Annual Meeting of the American Academy of Ophthalmology; November 10-13, 2007; New Orleans.
6. Alvarado JA, Franse-Carman L, McHolm G, Murphy C. Epinephrine effects on major cell types of the aqueous outflow pathway: in vitro studies/clinical implications. Trans Am Ophthalmol Soc. 1990;88:267-288.