these new drugs on the horizon, the future of glaucoma treatment looks bright.
many countries, clinicians can manage glaucoma with combination products of fixed
proportions of different medications. In the United States, however, many of these
combination products have not yet been approved by the FDA. Following is a run-down
of what we can use now, and what could be available to us soon.
BY JOHN SCHREINER
The chief advantage of combination
products is that you can increase the amount of medication a patient is receiving
without increasing the complexity of the regimen. This usually leads to increased
compliance, which can keep your patient away from the operating table longer. Even
though new laser procedures, such as selective laser trabeculoplasty (SLT), look
promising, many clinicians (including myself) prefer to have
patients on maximal medications before
referring for surgery. In the past this would have meant that a patient administer
several different medications and a complicated schedule with instillation of eyedrops
three or four times a day. By combining medications into one agent, we can deliver
two different medications without making it any more complicated for the patient.
Other advantages of combination products
include the patient's only having one medication bottle, which means less chance
of a wash-out effect. Many patients do not have the patience to wait five or 10
minutes when instilling different medications, and this sometimes negates the efficacy
of one of the agents. In addition, these
combination medications should exhibit less ocular side effects because less preservatives
are used in concomitant therapy.
What's out there
The one notable exception to the
lack of combination glaucoma products available in this country is the drug Cosopt
(Merck), which is a fixed-combination product of dorzolamide 2% (10 mg/ml) and timolol
0.5% (5 mg/ml). It was created after many years of research and concerns about the
shelf life. There were also some initial concerns about the stability of the two
components together, as well as the possibility of a deleterious effect on metabolism
by cytochrome enzymes.
In terms of efficacy, clinical studies
indicate that the peak effect of the combination product produced a 33% reduction
in IOP that was 14% greater than using timolol alone. When comparing the Cosopt
with dorzolamide alone, there was a 13% greater reduction in IOP at three months
with the combination product. Cosopt is generally used when beta-blocker therapy
alone does not achieve the target IOP.
With the emergence of the prostaglandins
in recent years, Cosopt has generally been delegated to a third-line agent in our
arsenal. One of the most common protocols would involve using a prostaglandin as
first line, then adding a beta-blocker if additional therapy is needed. If further
lowering is still necessary, then switch from the beta-blocker to Cosopt.
The adverse reactions to this is
agent are basically the summations of what one would see with each individual agent
and include taste perversion (bitter, sour
and unusual), ocular burning and/or stinging, conjunctival hyperemia, blurred vision,
punctate keratitis and itching. One of the minor issues with Cosopt is that it's
only available with 0.5% timolol maleate. Since research has indicated that many
patients do just as well with the 0.25% timolol, this fixed combination increases
the potential adverse effects of beta-blockers.
What's in the works
There are several combination glaucoma
medications that are in various stages of FDA clinical trials. The first two of
them combine a prostaglandin with a beta blocker, timolol. This agent is a traditional
first line therapeutic agent with a 20-year track record for successfully treating
glaucoma. As a non-selective beta blocker, timolol works to reduce IOP through the
inhibition of aqueous formation by blocking beta-2 receptors on nonpigmented ciliary
body epithelium. The most common dosage, 0.5% b.i.d., provides a 25% reduction in
(travoprost 0.004%/timolol 0.5%, Alcon). In a company-sponsored study, once-daily
Extravan demonstrated comparable efficacy to taking both agents separately (i.e.,
timolol taken in the morning plus travoprost taken at night). In September 2004,
Alcon Inc. announced that the FDA had issued
an approvable letter for Extravan ophthalmic solution for the management of glaucoma.
Based on this announcement, it seemed that the approval for Extravan in the United
States would come quickly thereafter. However, nine months later the drug still
has not been approved for use.
(latanoprost 0.005%/timolol 0.5%, Pfizer). This combination was approved in Europe
three years ago and has quickly been incorporated into the management protocol for
glaucoma. Xalcom combines latanoprost and timolol in a single bottle for once-daily
dosing. Studies have shown that Xalcom provided greater efficacy in lowering IOP
when compared with latanoprost used in adjunctive therapy with any combination of
a carbonic anhydrase inhibitor, an alpha agonist or a beta-blocker. Xalcom has also
been shown to be as effective as latanoprost used adjunctively with Cosopt. Once
again the side effects of this combination agent are similar to those of the individual
(brimonidine 0.2%/timolol 0.5%, Allergan). This drug has already been approved in
Canada for the management of open-angle glaucoma. Combigan is indicated for the
reduction of IOP in patients with chronic open-angle glaucoma
who are not achieving target IOP with topical beta blockers. The recommended dose
is one drop in the affected eye twice daily.
Studies have demonstrated that Combigan
lowered IOP more effectively than either brimonidine or timolol used as
Mean diurnal IOP was reduced to less than 18mm Hg in 40% of patients in the combination
group, compared with 15% in the brimonidine group and 26% in the timolol group.
As with other combination drops that
include beta blockers, clinicians should be aware of the safety profile. Beta blockers
have been known to cause bradycardia, hypotension, atrial tachycardia and fibrillations,
and altered lipid profiles after chronic use. Combigan is contraindicated in children
chronic obstructive pulmonary disease, sinus bradycardia, second or third degree
atrioventricular block, overt cardiac failure or cardiogenic shock. The product
is also not recommended in patients who take MAOIs, tricyclic antidepressants or
mianserin, or those with hepatic or renal impairment.
In the United States, Combigan is
currently undergoing Phase III clinical trials to evaluate the IOP-lowering effects
of concomitant brimonidine and timolol administration. One study by Arici, et al.,
examined patients who showed inadequate IOP lowering on timolol alone and found
a significant reduction in IOP of 5.1 to 5.9 mmHg in the timolol-plus-brimonidine
Individually, many of the combination
products are nothing new,
but as a combination agent they may enhance patient convenience when more than one
medication is required to reach the target IOP. If the FDA approves a combination
product such as Extravan or Xalcom, it would be a nice choice for first-line defense
for appropriate patients. Because we are now more aggressive in IOP lowering, why
not give a patient a single agent with the combined benefits of both beta blockers
and prostaglandins? The more options we have, the greater the probability that we
can successfully control a patient's IOP through medical agents instead of
is author of the textbook Glaucoma Diagnosis and Management. He
practices full scope optometry. Contact him at firstname.lastname@example.org.
Optometric Management, Issue: July 2005