Two new medications continue 'bonus' trend in glaucoma management

Issue: July 1998

In April, the Food and Drug Administration (FDA) approved two new medications for treating ocular hypertension and open-angle glaucoma: Azopt (brinzolamide 1%, Alcon) and Cosopt (dorzolamide HCl and timolol maleate, Merck). These third-generation medications are the latest in the trend towards more cost effective, more convenient and more comfortable glaucoma management.

Azopt: three times a day

Azopt is a carbonic anhydrase inhibitor (CAI) and was approved for three times daily dosing. It is expected to reduce intraocular pressure (IOP) by between 4 mm Hg and 5.65 mm Hg, according to the product labeling. Alan L. Robin, MD, one of the core clinical investigators and an Editorial Advisory Board member of Primary Care Optometry News, said the medication also works well with a twice-daily schedule, even though the labeling specifies three times a day.

"I suspect it will quickly become a twice-daily therapy," added Jimmy D. Bartlett, OD, FAAO, a professor of optometry and pharmacology at the University of Alabama at Birmingham who worked on the adjunctive study with timolol. "Most patients are going to have a good diurnal effect, in terms of pressure control, using it on a twice-daily basis," he said.

The drug burns less than dorzolamide upon instillation because it has a pH of 7.5, similar to the pH of tear film, compared with the 5.6 pH of dorzolamide, Dr. Robin said. In the clinical trials, patients were asked to rank the burning sensation between 0 (for comfortable) and 4 (for burning). Brinzolamide was rated at an average of 0.4, while dorzolamide received an average of 1.7.

"If you look at the distribution of how comfortable this drug is, 75% of the brinzolamide patients found it to be totally comfortable, compared with more than half of the dorzolamide patients who found [dorzolamide] severely uncomfortable," Dr. Robin said.

"If you have a more comfortable medication that is just as effective, that represents a major advantage. Patients are going to comply better because it doesn't really sting," Dr. Bartlett said.

Like dorzolamide, Azopt is a sulfonamide and should not be administered to patients who are allergic to sulfa medications, he said. "This is a suspension glaucoma drug formulation that needs to be shaken before it is put in the eye," Dr. Bartlett added.

Azopt also could provide a systemic exposure bonus because it does not last as long in red blood cells, according to Dr. Robin. The most frequent ad- verse events re- ported were blurred vision in 5.8% of patients and a bitter, sour or unusual taste in 5.7%.

According to Robert Allen, MD, a professor of ophthalmology and pharmacology at the Medical College of Virginia and Virginia Commonwealth University in Richmond and chairman of the department of ophthalmology at the Medical College of Virginia, "Azopt as 'monotherapy' will offer another good option to patients and physicians."

Cosopt: CAI/beta-blocker

Cosopt is the first topical glaucoma agent to combine a CAI with a beta-blocker. Merck markets the active ingredients that make up Cosopt individually as Trusopt (dorzolamide HCl), a CAI introduced in 1995, and Timoptic (timolol maleate), available since 1978.

Cosopt, indicated for the reduction of elevated IOP in patients with open-angle glaucoma or ocular hypertension who fail to respond to beta-blockers alone, is administered twice daily - once in the morning and once before bedtime.

According to Merck, more than half of glaucoma patients being treated for the disease are currently taking more than one medication to achieve control of IOP. Simplifying multiple drug regimens is important, Merck officials say, because glaucoma patients tend to remain on therapy for years.

The concept of combining two drugs that work independently makes sense from the perspective of increasing patient compliance, said Jerome Sherman, OD, a Distinguished Teaching Professor at the State University of New York College of Optometry and an Editorial Advisory Board member of Primary Care Optometry News.

"Cosopt will reduce IOP more than either Timoptic or Trusopt individually, though the resultant pressure drop is not completely additive," Dr. Sherman said. Like Trusopt, the agent also will increase blood flow to the optic nerve, retina and choroid, he added.

Dr. Allen noted another potential advantage of Cosopt: because the drug combines a CAI and a beta-blocker into one drop, it could allow patients with particularly high IOP to take a variety of different medications with fewer daily administrations.

"If, for example, Cosopt is partnered with a prostaglandin drug such as Xalatan (latanoprost, Pharmacia & Upjohn), a patient could be taking three pressure control medications daily with only three drops. In the past, such a combination would have required five drops daily," Dr. Allen said. "A high number of patients are taking two medications, and I am excited about having Cosopt around."

While the product is likely to enhance convenience, a 15-month long clinical study of Cosopt revealed that the combination product is actually slightly less effective than its active ingredients when they are administered concomitantly.

Studies were conducted to compare the daily IOP-lowering of Cosopt twice a day to individually and concomitantly administered 0.5% timolol twice a day and 2.0% dorzolamide three times a day. Results consistently showed that the IOP-lowering effect of Cosopt twice a day was about 1 mm Hg less than that of its two ingredients administered concomitantly. Dr. Allen believes the difference can be attributed to the administration of the afternoon dose of Trusopt in those receiving the concomitant regimen. This research involving more than 300 patients was submitted for publication in the journal Ophthalmology.

Dr. Allen said that the slightly de- creased IOP-lowering power of Cosopt in the quoted study presumably results from the fact that the "concomitant group" was getting an extra dose of dorzolamide at midday (that is, three times daily dosage), which was 2 hours before the trough IOP measurement that found the small (less than 1 mm Hg) difference.

Dr. Allen also predicted that Cosopt would be proven to be more effective than latanoprost.

"We know, from phase 3 studies, that Cosopt is more effective than its component ingredients timolol and dorzolamide," Dr. Allen said. "We also carefully evaluated studies comparing timolol with Xalatan and found that they are interchangeable in terms of efficacy at peak IOP time. By inference, comparing Xalatan to the combination product, we are expecting that Cosopt will be more efficacious in terms of pressure than Xalatan. The downside, of course, is that Cosopt also has to be given twice a day."

According to Dr. Robin, "There are also some disadvantages to Cosopt. It takes a comfortable drug like Timoptic and makes it uncomfortable. Also, in most, Timoptic can be used daily. Now, Cosopt needs to be used twice daily."

Azopt and Cosopt, together with Allergan's alpha agonist Alphagan (brimonidine tartrate) and Xalatan, make up the so-called third generation of glaucoma drugs. First-generation beta-blockers, such as timolol, and second-generation drugs, such as carteolol and metipranolol, still form the foundation of glaucoma therapy, experts say.

Partnering the new therapies with one another is likely to become a trend, especially among physicians whose patients' pressures are poorly controlled.

In addition to the new treatment options introduced recently, glaucoma therapy remains a growing pharmaceutical category. Pharmacia & Upjohn is reported to be investigating a timolol/Xalatan combination, while Ciba Vision, Allergan and Alcon are all developing new prostaglandin analogs.

A fourth generation emerges

Current glaucoma medications focus on lowering pressure, but the future of glaucoma research is moving toward preventing visual field loss, Dr. Robin said.

Real advances could come not from known glaucoma drugs, but from drugs used to treat nervous system diseases such as stroke or degenerative conditions, Dr. Robin said. Memantine and riluzole are now undergoing investigations.

Memantine is an N-methyl-D-aspartate glutamate receptor blocker being investigated by Allergan Specialty Therapeutics. Phase 3 trials were expected to begin this month for two indications: open-angle glaucoma and ocular hypertension. Riluzole is a glutamate antagonist being investigated for other neurological conditions.

For Your Information:
Alan L. Robin, MD, can be reached at 6115 Falls Rd., Baltimore, MD 21209-2226; (410) 377-2422; fax: (410) 377-7960. Dr. Robin has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.
Jimmy D. Bartlett, OD, FAAO, can be reached at 1716 University Blvd., Birmingham, AL 35294; (205) 934-3036; fax: (205) 934-6758. Dr. Bartlett has no direct financial interest in the products mentioned in this article. He is a paid consultant for Alcon Laboratories.
Robert Allen, MD, can be reached at Box 980262 MCV, Richmond, VA 23298; (804) 828-9680; fax: (804) 828-6543. Dr. Allen has no direct financial interest in the products mentioned in this article. He is a paid consultant for Pharmacia, Alcon and Merck.
Jerome Sherman, OD, can be reached at 100 East 24th St., New York, NY 10010; (212) 780-5004; fax: (212) 780-5207. Dr. Sherman has no direct financial interest in the products mentioned in this article, nor is he a paid consultant for any companies mentioned.

Azopt is available from Alcon Laboratories, Inc., 6201 South Freeway, Fort Worth, TX 76134-2099; (817) 293-0450.
Cosopt is available from Merck, P.O. Box 4, West Point, PA 19486; (215) 652-5000.