Fixed combination glaucoma medications await U.S. approvals

One fixed glaucoma drug, Cosopt, has had FDA approval since 1998. Several others have “approvable” letters but are awaiting final word.

Issue: November 1, 2005

ByDaniele Cruz

Several fixed combination glaucoma medications have established popularity in Europe, but the Food and Drug Administration is still examining those same drugs for the U.S. market, according to Prof. Carlo E. Traverso, MD, of the University of Genoa, Italy.

During a presentation at the annual American Academy of Ophthalmology meeting’s Glaucoma Subspecialty Day, he presented a review of the European experience with combination agents for reduction of IOP.

Prof. Traverso said that according to available sales data, some of the combined preparations available and commonly used in Europe are not yet FDA approved.

“I found it interesting that one of the most trusted drugs in combination in Europe is not yet available in the States,” Prof. Traverso said. “For new patients that start medications either as a switch patient or a new patient, monotherapy is of course prevalent, but fixed combinations are quite relevant in all new patient categories.”

“Our working hypothesis is that the treatment pattern of clinicians can be, to a large extent, inferred from data on drug sales,” he said. “Worldwide, in the past 10 years, the impact of new molecules has caused a reduction of the use of beta-blockers. Similarly, the use of fixed combinations has increased due to the availability of new preparations.”

A justified need

“Unfortunately, many patients cannot be managed sufficiently well with monotherapy, so they need more than one active agent in their medications,” Prof. Traverso said. “In recent years, the availability of new molecules has widened the treatment choices.”

When a first-choice monotherapy is not effective in lowering IOP, a switch to another topical agent can often be effective, he said.

“The justification for adding a second drug is only if the first one showed to be tolerated and somewhat effective on the IOP, outlining the concept of switching rather than adding drugs at random,” he said. “The effective drug combinations can be measured today only in terms of IOP reduction. Assuming equal IOP effects, no drug combination is yet known to be preferable in terms of optic nerve head or visual field preservation, so there is not a magic formula.”

Prof. Traverso noted that guidelines issued by the European Glaucoma Society recommend switching to another monotherapy before adding a drug to an unresponsive patient’s treatment regimen.

Available combinations

Combination fixed formulations currently available in Europe include timolol with pilocarpine and timolol with dorzolamide, which has been around for a number of years, and the more recent additions timolol with latanoprost and timolol with brimonidine, Prof. Traverso said.

All of these drugs are indicated for the lowering of IOP in patients with open-angle glaucoma or ocular hypertension who do not respond sufficiently to timolol alone.

The timolol-brimonidine fixed combo only recently became available in parts of Europe, he said. The drug, marketed as Combigan by Allergan, was approved by regulators in the United Kingdom in September, and reciprocal positive opinions were received from regulators in other European Union countries, meaning the drug will be available across Europe.

In the United States, Cosopt (dorzolamide HCL, timolol maleate, Merck) is the only fixed combination glaucoma ophthalmic solution on the market. Cosopt received approval in the United States in 1998.

Combinations under investigation

Fixed-combination glaucoma drugs that still await FDA approval include Extravan (timolol maleate 0.5%, travoprost 0.004%, Alcon), Xalcom (timolol maleate 0.5%, latanoprost 0.005%, Pfizer), Combigan (timolol maleate 0.5%, brimonidine tartrate 0.2%, Allergan) and an as-yet unbranded combination of bimatoprost and timolol, also from Allergan.

Xalcom is marketed by Pfizer in Europe under the brand name Xalacom. Pharmacia, the original developer of Xalcom/Xalacom, received an “approvable” letter for the combination drug from the FDA as early as 2000, but the drug, which was since sold to Pfizer, is still awaiting final approval in the United States.

Alcon’s Extravan received an approvable letter in September 2004.

The bimatoprost-timolol combination from Allergan received an approvable letter in August 2004.

Allergan’s Combigan received an approvable letter in April 2005, which the FDA issues as part of what conditions need to be met in order for the drug to receive approval.

Susan Cruzan, a media relations representative for the FDA, said she could not disclose details of any ongoing clinical trials or discussions regarding the drug combinations.

European popularity

Despite their status in the United States, combination drugs have become popular in Europe, Dr. Traverso said.

“Whenever indicated and available, combined drugs are preferable because they improve compliance and they have a positive influence on dosing and quality of life,” he said. “According to available commercial data, the percentage of sales for fixed combinations in Europe is increasing at a faster pace than in the United States.”

For Your Information:

Prof. Carlo E. Traverso, MD, can be reached at Glaucoma Service, Clinica Oculistica DiNOG, Azienda Ospedale Universita San Martino, 16132 Genova, Italy;. Prof. Traverso has been a clinical investigator and advisor for many drug companies in the field of glaucoma. He received no support or consultation fee for this presentation.

Alcon, maker of Extravan, can be reached at 6201 S. Freeway, Fort Worth, TX 76134-2099; 817-293-0450; fax: 817-551-4615.

Allergan, maker of Combigan and the fixed combination of bimatoprost and timolol, can be reached at P.O. Box 19534, Irvine, CA 92623; 714-246-4500; fax: 714-246-4971.

Merck, maker of Cosopt, can be reached at One Merck Drive, P.O. Box 100, Whitehouse Station, NJ 08889-0100; 908-423-1000.

Pfizer, maker of Xalcom, can be reached at 235 East 42nd St., New York, NY 10017; 212-733-2323.

Daniele Cruz is an OSN Staff Writer who covers all aspects of ophthalmology.