New glaucoma agents hit the market

Issue: April 2001

As pharmaceutical companies strive to broaden the options for glaucoma treatment, three new agents have recently hit the market and another is undergoing the Food and Drug Administration (FDA) approval process. Rescula (unoprostone isopropyl), now available from Novartis, is a docosanoid, which is a new class of drugs in the prostaglandin family. The drug was approved by the FDA on Aug. 3, 2000, and launched by Novartis in October 2000.

Travatan (travoprost, Alcon) and Lumigan (AGN 192024, Allergan) both received FDA approval on March 16 of this year. Xalcom (latanoprost/timolol maleate, Pharmacia) has completed its clinical studies and has been submitted to the FDA.

Jimmy D. Bartlett, OD, who gave a presentation at the SnowVision meeting in Colorado recently about these new glaucoma medications, discussed the products with Primary Care Optometry News.

Rescula

“Rescula is in the prostaglandin family of agents, but it’s further down on the food chain,” said Dr. Bartlett. “It’s a derivative of a prostaglandin metabolite. By configuring it that way, the drug is working very much like other prostaglandins work — to increase aqueous outflow from the eye; but we know there’s no effect on the production of aqueous and probably no effect on uveoscleral outflow. So the drug probably works by enhancing conventional outflow.”

Since the drug is a docosanoid and not a prostaglandin, it can be used in conjunction with prostaglandins such as Xalatan, said Dr. Bartlett.

The 0.15% concentration has effects similar to those of Timoptic, he said, but appears to be less effective than latanoprost. In terms of clinical practice, he said, it is expected to have effects the same as beta-blockers, although not the same as Xalatan. There may be other effects of the drug in addition to lowering IOP, he said.

“Although Rescula may not be as effective as Xalatan, a number of studies now show that it increases blood flow in the optic nerve head and it increases blood flow in the retina and choroid,” Dr. Bartlett said. “So it may increase tissue perfusion there, which may offset some of the perceived deficiencies of intraocular pressure (IOP) reduction. Time will tell, and other studies will suggest whether that is a real advantage or not in terms of increasing blood flow and providing neuroprotection to preserve visual fields.”

While clinically used to treat primary open-angle glaucoma and ocular hypertension, Rescula may be useful in lowering pressure in normal tension glaucoma, Dr. Bartlett noted.

Side effects are similar to those seen with other prostaglandins, Dr. Bartlett said, such as a low incidence of iris color darkening and a slightly higher incidence of hypertrichosis, or the increased lengthening and darkening of eyelashes. “The most important side effect is corneal toxicity,” he said. “This drug, more than any other, can cause superficial keratitis or persistent epithelial defects with the cornea — so we have to be a little more aware of what’s going on with the cornea with these patients.”

Otherwise, Dr. Bartlett said, there have been no other problems in terms of systemic safety, such as cardiac or pulmonary problems or cases of cystoid macular edema or uveitis. Dosage is one drop twice a day.

Travatan

Alcon’s new prostaglandin analog, Travatan, is also being compared to Xalatan in terms of its pharmacology, said Dr. Bartlett.

The dosage that yields the best therapeutic effect with the fewest side effects is the 0.004% formulation, he said. Also, researchers have compared morning vs. evening dosing as well as once-a-day vs. twice-a-day dosing, and have recommended once-daily dosing in the evening for maximum efficacy, according to the manufacturer.

In addition to the medication providing an additive effect to beta-blockers such as Timoptic, he said, travoprost can be used in conjunction with Alphagan (brimonidine, Allergan), he noted.

“You have to show the FDA that your drug works better than, or equal to, Timoptic. That’s still pretty much the gold standard in glaucoma therapy,” he said. “Secondly, you have to do a study convincing the FDA that your drug can be used with a beta-blocker. Alcon has gone one step further and has shown that the drug can be used with Alphagan. The drug appears to be very safe. The side effects seem to be pretty mild, and most resolve without treatment.” While there is always a concern with redness with prostaglandins, this side effect seems to be fairly insignificant with Travatan, Dr. Bartlett said.

According to the manufacturer, Travatan has demonstrated greater effectiveness in black patients.

Lumigan

Allergan’s new drug, Lumigan, falls into a new class of glaucoma drugs, the ocular hypotensive lipids (HTLs), also referred to as “prostamides” by Allergan, said Dr. Bartlett. “Prostamides are naturally occurring in the eye, and they are felt to play a role in the regulation of IOP,” he said. “If you can develop a synthetic prostamide that lowers pressure similar to what the eye will do, that may represent a new way to treat glaucoma.”

There is some controversy about whether this class of drugs is actually new or whether they are just prostaglandins, he said. While they are related chemically to prostaglandins, there are some technical differences that may keep them from being classified as prostaglandins, Dr. Bartlett said. “The reason Allergan will argue that these are not prostaglandins is that, in all of their studies, they have failed to find any receptor that any of these drugs are binding to that would classify them as prostaglandins,” he said. “The classic prostanoid receptors are activated by prostaglandins — for instance, Xalatan would activate the FP receptor. They’re not able to determine that the prostamides, the ocular HTLs, will occupy any of those classic receptor sites. Therefore, they can’t technically be classified as prostaglandins.”

A phase 3 study was conducted comparing Lumigan to Timoptic, said Dr. Bartlett, with Lumigan 0.03% formulation administered once or twice a day and Timoptic administered twice a day to nearly 600 test patients with glaucoma or ocular hypotension. The results showed Lumigan once a day with a 35% ocular hypertensive effect, twice a day with 30% ocular hypotensive effect and Timoptic at 26% ocular hypotensive effective. “There is a really phenomenal reduction of IOP when used with Timoptic once a day,” he said. “There are studies ongoing comparing it with Xalatan, but we don’t yet have those results.”

Some adverse effects include conjunctival hyperemia, eyelash growth and ocular itching, he said.

Xalcom

The new glaucoma drug by Pharmacia, Xalcom, is a combination of 0.005% latanoprost and 0.5% timolol maleate. This combination drop presents the opportunity to improve compliance with patients as well as keep costs down, said Dr. Bartlett.

“There’s the possibility of an additive effect when the two medications are used in combination, so it would simplify therapy for the patient and probably be less expensive,” he said. “For patients who haven’t done as well on either drug alone, they have the opportunity to combine them in a single bottle.”

Because all clinical studies are complete, a new drug application has been submitted to the FDA. While none of the studies on Xalcom thus far have been published, he said that any side effects are expected to be the same as with either drug used alone.

“They’re the usual side effects we’re concerned with with Xalatan, in terms of iris color darkening, increased lengthening or darkening of the eyelashes, sometimes a little redness of the eye,” he said. “With the beta-blocker timolol, all of the usual side effects from beta-blockers — respiratory depression, cardiac depression, decreased pulse rate — can occur. So the same precautions that apply to each of the individual drugs apply to Xalcom.”

Dosage is one drop per day, but because the medication contains a beta-blocker, it should not be taken immediately before bedtime but rather an hour or two before, Dr. Bartlett said. He suggested that a morning dose may be preferable.

Also on the horizon

At press time, a new glaucoma agent, Alphagan P (brimonidine tartrate, Allergan), preserved with Purite, was approved by the FDA. The alpha2 agonist, a new formulation containing the same active ingredient as Alphagan, is indicated for lowering IOP in patients with open-angle glaucoma and ocular hypertension.

Also, topical calcium channel blockers such as verapamil are being used in combination with very low concentrations of pilocarpine to see if a synergistic effect is achieved in reducing IOP. Early results show pressure reduction with relatively few side effects, with one remarkable effect being a reduced pulse rate. “We’re going to be looking into that a little more carefully,” Dr. Bartlett said.

For Your Information:

Jimmy D. Bartlett, OD, is the interim chair of the Dept. of Optometry at the School of Optometry and a professor of pharmacology in the School of Medicine at the University of Alabama at Birmingham. He can be reached at 1716 University Blvd., Birmingham, AL 35294-0010; (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.