therapeutic insights
Two Is Better Than One
Combigan broadens the scope of combination glaucoma medications.
By Megan Hunter, O.D., Miami, Fla.

Glaucoma patients often require two or three topical medications in order to reach ideal intraocular pressure (IOP) ranges. Dosages of popular glaucoma drops range from once a day to three times a day. The result is often a complex dosage schedule that reduces patient compliance. Combination drops, if effective, reduce the burden of medical therapy.

Cosopt (dorzolamide 2% and timolol maleate 0.5%) remains the only combination drop since pilocarpine/ epinephrine. When used alone, Trusopt (dorzola-mide 2%) reduces IOP about 15% to 20%; Cosopt provides an additional 2 mg to 3 mg of IOP reduction in patients using timolol maleate 0.5% and is welcomed by practitioners and patients alike.

Combigan is on the horizon

But another combination drug is on the way: Combigan (brimonidine tartrate 0.2% and timolol maleate 0.5%) is currently undergoing Phase III clinical trials. While the results of the trials haven't been published, several studies have evaluated the IOP-lowering effects of concomitant brimonidine and timolol administration.

Arici, et al., studied patients who showed inadequate IOP lowering on timolol alone and found a significant reduction in IOP of 5.1 to 5.9 in the timolol-plus-brimonidine group. The timolol-plus-placebo group had no significant IOP-lowering effect.

It's estimated that Combigan will perform favorably in comparison with Cosopt; Sall, et al., found no clinically significant difference in IOP reduction with Cosopt versus the concomitant administration of brimonidine and timolol.

Building a good defense

Timolol malaete is a tradi-tional first line drug with a 20-year track record for successfully treating glaucoma. As a non-selective beta blocker, timolol blocks both beta-1 and beta-2 receptors. Beta-1 receptors are predominant in cardiac tissues; beta-2 receptors in pulmonary tissues and the ciliary body.

Timolol maleate is effective in reducing IOP through the inhibition of aqueous formation by blocking beta-2 receptors on nonpigment-ed ciliary body epithelium. The most common dosage, 0.5% b.i.d., provides a 25% reduction in IOP.

Brimonidine has a star role

Alphagan (brimonidine 0.2%), although effective as a first-line agent, is commonly used as a second-line drug in managing glaucoma. Not surprisingly, Alphagan has shown a significant additive effect when used in combination with all other popular glaucoma drug classes: prostaglandin analogs, beta blockers and carbonic anhydrase inhibitors. Alphagan is an alpha-2 agonist; when post-synaptic alpha-2 receptors located in the ciliary body are stimulated, they start a cellular cascade that leads to the reduction of aqueous formation.

Alphagan has been shown to possess a neuroprotective component in animal and in vitro studies, but we don't yet know if neuroprotective properties effectively halt visual field loss in glaucoma patients. Although approved for t.i.d. dosing, b.i.d. dosing is most common; it provides a 20% to 25% reduction in IOP in most patients.

The side effects

As with other combination drops that include beta blockers, eyecare practitioners must be aware of Combigan's side effects. Beta blockers can cause bradycardia, hypotension, atrial tachycardia and fibrillations, and altered lipid profiles after chronic use, so they're contraindicated in people who have serious heart disease.

Beta-2 receptors are responsible for pulmonary bronchodilation, so beta blockers are also contraindicated in asthmatics because they cause broncho-spasm. Use them with caution in insulin-dependent diabetics because they block the beta-receptor mediated hypoglycemic response. Also, beta blockers depress the central nervous system and can cause depression even in patients who have no prior history of the problem.

Alphagan has a significantly safer clinical profile. Side effects may include fatigue, headache, dry mouth and drowsiness. Most common is an allergic conjunctivitis characterized by a red, irritated eye with a mixed follicular/ papillary response. The reported incidence of allergic reactions ranges from 15% to 20%.

Consider the choices

In addition to Combigan, optometrists will soon have another combination drop to consider. Pharmacia's Xalcom combines latanoprost 0.005% and timolol 0.5% in a single bottle for once- daily dosing. Although still in clinical trials in the United States, Xalcom is approved for use in other parts of the world.

We can count on efficacy

While patient contraindications and side effects will remain a consideration, it's safe to assume that Combigan will be effective in providing an additional reduction of IOP in patients already successfully treated with one of its components because of the IOP-lowering capabilities of both timolol maleate 0.5% and brimonidine 0.2% when used alone.

Dr. Hunter is a graduate of the Illinois College of Optometry. She has just completed a one- year residency in ocular disease at the Bascom Palmer Eye Institute in Miami and has joined the Miami Veteran Affair's Hospital.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.