With the U.S. Food and Drug Administration’s approval of Alcon’s Travatan and Allergan’s Lumigan in March 2001, ophthalmologists found a family of drugs where Pharmacia’s Xalatan had long stood alone. The consensus on the phospholipids, which comprise both prostaglandin analogs and prostamide compounds, is that they’re not associated with many of the systemic side effects that beta-blockers are. This boon, combined with these drugs’ efficacy at lowering intraocular pressure, has led many ophthalmologists to foresee a future in which the phospholipids become their first-line drug choice.
Much remains unknown about these drugs, however, particularly the new additions, and even the savviest practitioner may find it difficult to differentiate one from another. This article will take a look at how the three drugs compare so far and how some ophthalmologists are using them in clinical practice.
Efficacy
Sifting through the labeling for the three drugs on the FDA’s website (http://www.fda.gov/) indicates that the IOP-lowering capabilities of the three drugs are similar. In the clinical studies that their labels cite, Xalatan reduced IOP by 6-8 mmHg from a baseline pressure of 24-25 mmHg, Travatan by 7-8 mmHg from a baseline IOP of 24-26 mmHg, and Lumigan by 7-8 mmHg from a baseline IOP of 26 mmHg.
Nevertheless, some surgeons aver that they’ve observed a small but noticeable difference in the overall performance of the drugs. Says Robert Noecker, MD, of Tucson, Ariz., “There’s initial data that Lumigan is probably a little bit stronger than the other two, and we’re talking on an average 1 mmHg.”
“If you had to rank them, I’d probably rank them Lumigan, Travatan, Xalatan, with Travatan and Xalatan about equal,” he adds.
Boston surgeon Joel Schuman, too, ranks the IOP response as higher for Lumigan than Travatan and for Travatan than Xalatan.
Rick Halprin, senior product manager for Alcon, states that a recent study showed Travatan to deliver either equal or greater IOP lowering than Xalatan, with the difference’s being statistically significant at the 4 p.m. visit.1 Gerald Bean, product manager for Global Pharmaceutical Ophthalmology at Pharmacia, counters, “You don’t pick specific time points, which is what both of the companies [Alcon and Allergan] have tried to do. When you go back and when you objectively look at the trials in terms of their primary endpoint, you’ll find there are no differences, and that’s what the FDA pretty much concludes.”
Another issue raised by practitioners and company spokespeople is that of the drugs’ onset of action.
“Lumigan appears to have probably the fastest onset of action, because it has this bi-modal way of working,”2 says Dr. Noecker (See “Prostaglandin or Prostamide?” on p. 55). “It increases outflow from the trabecular meshwork [and uveoscleral pathway], which … changes the pressure very quickly, vs. uveoscleral outflow only, which is probably what’s going on in Xalatan and Travatan. If you need quicker IOP reduction, you’re probably more likely to get it with Lumigan. … With Xalatan, the common thought is that you wait six weeks to see the full effect of the drug.”
Mr. Halprin remarks that Travatan’s been shown to reach peak pressure reduction within two weeks, though he notes that a reduction in IOP occurs quickly upon the first installation of the drug. Mr. Bean says that the initial administration of Xalatan begins to reduce IOP within a few hours, but he also emphasizes that “if you’re talking about chronic disease, it’s kind of a moot point about how soon a drug goes to work.” He hesitates to discuss any possible difference between when the three drugs reach peak efficacy, because “what we’d be doing is comparing different trials, and that gets extremely risky, because, when you do that, you are not able to truly control for the same inclusion criteria.”
Another hot-button topic has been a study that, among its findings, reported that travoprost lowered IOP in black patients more so than in non-blacks.1 (See “The Racial Divide”).
Side Effects
Though the side-effect profile of these drugs is lesser than that of other glaucoma medications, it isn’t nonexistent.
• Hyperemia. Ocular injection can be a cause for concern among patients, and its incidence as a side effect varies between the phospholipids. Lumigan’s package insert lists an incidence of 15-45 percent, Travatan’s 35-50 percent and Xalatan’s 5-15 percent.
Mr. Halprin, however, notes that the degree of hyperemia in patients taking travoprost was mild. He adds that “less than 3 percent of patients discontinued use of Travatan due to hyperemia. With Xalatan, it was just under 1 percent discontinued. … That discontinuation rate, by the way, is the same as identified under Lumigan, about 3 percent.”
Alexander Kent, MD, of Charleston, S.C., also stipulates that the hyperemia is transient and that educating patients before they begin their drops can head off their concerns.
“Most of that goes away with both of the new medications within the month,” he says. “The key to that is to make sure that the patients are aware that it [the eye] will be red, and that way they will not stop it [the drug] automatically or they will resist their spouse, family member or friend telling them their eye is red, what kind of medicine are they on? Then they stop because of peer pressure.”
Dr. Schuman, however, takes ocular injection into account when prescribing a phospholipid.
“I usually start with Lumigan, because it’s the most potent of the three,” he says. “If they have the conjunctival hyperemia side effect, I’ll usually back off to Xalatan, … either if they’re bothered by it or if I am. It depends on how much hyperemia they have.”
• Change in iris pigment. These changes seem mainly to be cosmetic ones and, according to the drugs’ respective labels, occurred in 5-15 percent of Xalatan patients, 1-4 percent of Travatan patients and 1-3 percent of Lumigan patients.
Mr. Bean again questions the fairness of comparing drugs across trials and also notes that certain irides (those of mixed color) are more prone to these changes. Amanda VanDenburgh, PhD, MS, MBA, manager of ophthalmology clinical research for Allergan, meanwhile, points out that “glaucoma patients tend to be elderly, 70s and higher, so they don’t really care about iris color if it means that they’re not going to go blind.”
• Cystoid macular edema. Dr. Noecker has found inflammation to be an issue with this class of drugs. He’s personally seen CME and uveitis associated with Xalatan but not with the other two drugs, though he notes that Xalatan has a longer track record than Travatan and Lumigan. Mr. Halprin comments that CME was reported during the clinical trials for Lumigan but not those for Travatan, while Mr. Bean points out that the incidence of CME and iritis with Xalatan is rare.
• Other. Eyelash changes (increased growth, thickness or number and changes in pigmentation) are reported in the labels for all three phospholipids. Another side effect noted with these drugs is that of pruritis. Referring to the package inserts, Mr. Halprin notes an incidence of 5-15 percent with latanoprost, 5-10 percent with travoprost and 15 percent with bimatoprost. He also describes a 1-4 percent incidence of ocular dryness with travoprost and latanoprost vs. 10 percent with bimatoprost, as well as a 1-5 percent incidence of hirsutism with bimatoprost vs. no reports with latanoprost or travoprost.
Dr. Schuman says that only a minority of patients must discontinue one of the phospholipids due to side effects. He describes the occurrence as rare, specifically with latanoprost, which he finds to be extremely well-tolerated.
Stability
Of concern for all physicians is the continuing efficacy of their patients’ medications, which can lose their potency during storage or simply lose effect in an individual. The former can occur due to light exposure or to inappropriate or fluctuating temperature conditions.
Xalatan’s labeling states that the drug should be refrigerated (2-8 degrees Celsius) until it’s opened and should be protected from light. Once opened, it should be kept at room temperature (up to 25 C). According to their labeling, Travatan should be stored at 2-25 C and Lumigan at 15-25 C.
Recently, Dr. Noecker completed a study of latanoprost’s stability when exposed to controlled amounts of light and heat,3 and he is currently planning a comparative study of how these elements affect all three of the phospholipids. In the former, Dr. Noecker and his fellow investigators found that latanoprost remained stable at 4 C and 25 C for 30 days but underwent a 10-percent degradation in 8.25 days at 50 C and 1.32 days and 70 C. They concluded that ideal storage for the drug would be at below room temperature in the dark, and Dr. Noecker remarks that patients’ living conditions (such as a lack of air conditioning in a warm clime) should be taken into account when physicians prescribe medications.
Mr. Bean emphasizes that the study was not a comparative trial and that all information on the storage and handling of latanoprost was submitted to the FDA years ago, as per its requirements. He also contends that latanoprost may be left out at over 100 F for eight days and at room temperature for a year without suffering any degradation. Mr. Halprin, meanwhile, comments that travoprost has “the widest approved temperature storage range.”
Accessibility
As Eve Higginbotham, MD, of Baltimore points out, all of the phospholipids may be a financial burden for patients without prescription drug coverage. The three drugs seem to be comparably priced, however. Travoprost may cost a bit less than the other two, as Mr. Halprin states that the drug has the lowest wholesale price.
Another part of the equation depends on the number of drops in the bottle. Xalatan comes in a 2.5-mL container; 2.5 mL of Travatan is packaged in a 3.5-mL bottle; and Lumigan comes as both a 2.5-mL and 5-mL fill of an 8-mL container. Dr. Noecker has found more drops per 2.5 mL with bimatoprost and travoprost than with latanoprost, and he notes that bimatoprost’s larger bottle may be a factor, depending on the patient’s co-pay plan. If that person can get the 5-mL fill for the same price as the 2.5-mL fill, for instance, the difference can be significant, he observes.
Mr. Halprin, meanwhile, asserts that “Travatan is the cheapest product by anywhere from 5 to 15 percent” when the price paid at the pharmacy and the number of days of therapy from one bottle are factored together.
For his part, Thomas A. Perkins, one of the U.S. product managers for Xalatan, says that the availability of the drugs also plays a role.
“Really, it depends on which plans you look at,” he says. “Xalatan is widely available on most, if not all, the major managed-care plans, whereas there’s limited availability on these newer products. You’re seeing that trend along all the major, as well as regional, managed-care plans.”
In the Clinic
The major marketing efforts and above comparisons raise the question of how these drugs are being used in the clinic. Here’s how several ophthalmologists are choosing between the phospholipids for their patients, a tough decision according to Dr. Kent.
“If a patient cannot deal with the redness or he’s had allergy problems before, I tend, if I have a choice, I’ll go with Xalatan,” he says. “Sometimes, you might get a super lowering of the pressure with Lumigan in ways that you don’t see with Xalatan, but that’s maybe 10-15 percent of the time, if that. If I need to get a tremendous drop, I will try Lumigan. Sometimes, I’ll find that’s true with travoprost.”
Neither is Dr. Kent sure that switching between the phospholipids is effective. He says he hasn’t observed a tremendous difference when doing so but also questions whether a single private practitioner could accrue enough data on the subject to be meaningful.
Dr. Higginbotham echoes that thought and essentially uses the drugs interchangeably. Nonetheless, if a patient fails on one of the phospholipids, she will try that person on another. As for her first choice, she goes with her experience.
“I usually will prescribe Xalatan as a first choice, just because I’ve worked with Xalatan for so many years,” she says. “… It’s a well-researched drug, so I know what to expect.”
Dr. Noecker, by contrast, sees his drug choice changing.
“Of the three, I probably have the most patients on Xalatan, but Lumigan is probably the one [for which] I’m increasing my rate of use fastest, because I have patients for whom maybe Xalatan worked well at first and now it’s not working well for some reason, lost effect or whatever,” he says. “By switching them to Lumigan, I find that I can get a couple of points of IOP reduction.”
He adds that he’s increasing his use of travoprost, as well, “because of managed-care issues. It tends to be the cheapest, and you don’t have these storage issues, as with Xalatan. I’m pretty comfortable switching out Travatan for Xalatan, as well.”
“We’re really talking about fine-tuning here, in general, because all of these drugs work similarly in terms of pressure lowering,” Dr Schuman points out.
M. Roy Wilson, MD, MS, of Omaha, Neb., comes at the decision from a slightly different angle.
“For each patient, I really think it’s best to try to get the pressure down to what you think is best for that patient, using whatever medications are available to you,” he says. “I’m not sure, in most cases, from a clinical standpoint, that 1 mmHg makes much of a difference.”
|
Prostaglandin or Prostamide? |
|
The identification of latanoprost (Xalatan, Pharmacia), travoprost (Travatan, Alcon) and bimatoprost (Lumigan, Allergan) as a prostaglandin or prostamide and the delineation of how they work is an issue surrounded by the contentious fireworks between their manufacturers. Both latanoprost and travoprost are classified as prostaglandin analogs, and their main means of action is the enhancement of uveoscleral aqueous outflow. Bimatoprost, by contrast, is classified as a prostamide compound. According to Amanda VanDenburgh, PhD, MS, MBA, manager of ophthalmology clinical research for Allergan, bimatoprost has a dual effect.1
“It increases [aqueous outflow via] the pressure-insensitive or uveoscleral [pathway] by 50 percent and the trabecular, classical or pressure-sensitive [pathway] … by 35 percent,” she says.
The hot buttons of debate between the companies are that of the receptor that the drugs affect in order to effect a reduction in IOP, whether or not they’re all prodrugs and if being or not being a prodrug has a positive, negative or no impact on efficacy and safety. Touching on these points in order, both latanoprost and travoprost are F2 alpha compounds that affect the FP receptor. By contrast, Lumigan is prostaglandin F2 alpha 1-ethanolamide, which works on a different receptor, according to Dr. VanDenburgh.
“We don’t have that receptor yet, but that’s not unusual,” she says. “Within the scientific community, it can take years in order to find the receptor, but we do know what it’s not hitting.”
“We have pharmacological evidence that the prostamide-sensitive receptor exists,” agrees Achim Krauss, PhD, principal scientist at Allergan. “Currently, we’re trying to clone that gene, but we have not cloned it at this point.”
Rick Halprin, senior product manager for Alcon, however, disputes the idea that bimatoprost doesn’t work as an FP receptor agonist. He and Gerald Bean, product manager for Global Pharmaceutical Ophthalmology at Pharmacia, also argue that bimatoprost is a prodrug, as are latanoprost and travoprost, despite Allergan’s claims to the contrary.
“What happens is, both Travatan and Xalatan, when they’re put into the cornea, there is an additional ring, if you will, that has to be cleaved off as it goes through the cornea,” explains Mr. Halprin. “That cleaving is known as hydrolyzation. That kind of drug is known as a prodrug. In other words, it becomes active as a free acid after it becomes this hydrolyzed or cleaved molecule. Is there a pro or con to that? No, that just happens to be the nature of the mechanism.”
The potential “con” cited by Dr. Krauss is that conversion in the eye depends on an enzyme that may not be present in certain eyes, may not be sufficiently expressed or may have a mutation that renders it less effective. Such cases, he says, could account for non-responder rates to a prodrug.
Mr. Halprin, however, argues that, upon instillation, bimatoprost “also turns into a prodrug, goes to the FP receptor and does the same thing that the other products do. The difference is that it’s not an efficiently done job, and that’s why Lumigan has eight times as much active ingredient as does Travatan and six times as much active ingredient as does Xalatan. … I would also submit that there well may be a side effect penalty associated with that heavier concentration.”
Mr. Bean, meanwhile, remarks that Pharmacia’s creation of the prodrug, latanoprost, actually resulted in less hyperemia than did the application of the active form of the drug.
Dr. Krauss, however, states that they “have identified systems or tissue that respond to bimatoprost directly. … It does not need to be converted. Our data very strongly suggests that bimatoprost is acting as bimatoprost in the human eye.” He adds that, as part of the study submitted to the FDA, they found “bimatoprost in systemic circulation and, again, not the free acid. So, the data that we have strongly indicates that bimatoprost is not acting as a prodrug but directly in the eye.”
While Mr. Bean questions the methodology of this study, Boston surgeon Joel Schuman relies on his clinical experience.
“There may be real differences between the families of these prostaglandin/prostamide products, and there may be differences between the receptors that they act at,” he says, “but they seem to have a similar side effect profile and to work, in the end, in a similar way.”
1. Brubaker RF, Schoff EO, Nau CB, Carpenter SP, Chen K, VanDenburgh AM. Effects of AGN 192024, a new ocular hypotensive agent, on aqueous dynamics. Am J Ophthalmol 2001;131:1:19-24.
|
|
The Racial Divide |
|
Among its conclusions, a multicenter, randomized, double-masked, one-year clinical study comparing the efficacy of travoprost with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension found that travoprost lowered IOP in black patients more so than in non-blacks.1
“That’s a very different kind of response than we’ve seen in other drugs, like timolol and pilocarpine, which have had less of a response in black patients,” notes lead author Peter Netland, MD, PhD. “It makes us optimistic that this [travoprost] will be a useful drug for the black patients.”
One charge leveled against the study is that it didn’t take the change from baseline into account, which Gerald Bean, product manager for Global Pharmaceutical Ophthalmology at Pharmacia, says would mean that there would be no statistically significant difference in efficacy in black patients. Dr. Netland responds that the baselines were significantly different only in the comparison of latanoprost and travoprost in black patients vs. the general population and that, while a good suggestion, a change from baseline analysis would affect the conclusions regarding only that group
“The FDA asked them to look at this population, and they did it prospectively, so it was something they planned in advance, and it turns out that, for some reason, the African American group did better,” comments Robert Noecker, MD, of Tucson, Ariz. “… The question is: Was the sample size big enough, or was this a statistical fluke? Even though they did find a true statistical difference, there’s a 5 percent chance it was just chance.”
According to the study, there were at least 40 black subjects in each of the subgroups. This number, contends Dr. Netland, “appeared to give adequate statistical power.” Nevertheless, he agrees that there’s a need for a larger study, the protocol of which is “specifically designed to address the racial differences in the response to the drug.”
For Philadelphia surgeon Marlene Moster, the study’s sample size actually made its findings more convincing.
“If a small group of patients shows a significant drop in pressure, it’s actually even more significant than a large group, because, in a large group, small differences get washed out and you need a big difference over time, over a lot of patients, to show a small difference between the groups,” she says.
While she’d like to see a broader-based prospective study, Dr. Moster notes that the literature has shown racial differences in disease progression and response to various drugs.
“Why do black people go blind faster with glaucoma?” she asks. “We don’t know, but we think there’s something different genetically about their optic nerve that may make them more susceptible to changes in pressure.”
Along those lines, both Eve Higginbotham, MD, of Baltimore and M. Roy Wilson, MD, MS, of Omaha, Neb., comment that the study lacks a theory for why such a difference in response might exist.
“Until someone says … there’s greater pigment binding of Travatan compared to the other drugs or there’s something mechanistic as the basis of this, I guess I’m just a little bit hesitant to totally buy into that [finding],” says Dr. Higginbotham.
Dr. Wilson, noting the inherent difficulties in defining race, asserts that the lack of a hypothesis further muddies the waters and could result in misleading findings.
“I think it’s really important to not just present differences but to come up with some kind of hypothesis that can be tested,” he avers. “Otherwise, I think that we’re not really getting at whether the difference is due to some sort of biologic reason or genetic reason vs. something more sociological.”
As an example, Dr. Wilson points to a hypothesis developed to explain why certain classes of anti-hypertensives work differently in black vs. non-black patients.
“The hypothesis is a plausible one having to do with the so-called slave deficit, which has to do with the fact that slaves, when they were coming over to this country, were put in these ships with very close quarters and they had to preserve their salt and their fluids, …” he explains. “A lot of the slaves actually died. Those who survived were actually those who did that the best, so there was natural selection. The hypothesis, in terms of why certain classes of drugs, anti-hypertensives, work better than others, has to do with your ability to retain salt.”
Currently, Dr. Wilson is looking forward to a completed paper by the study’s authors that he believes will take baseline pressures into account and offer a hypothesis for the mechanism behind any racial difference. As to whether the recent findings will impact his drug choices in the future, he remarks that, “just on the basis of the paper, I don’t think I would change. I would really just individualize it. I have started using travoprost a lot more, and I’m sure I will continue, because it does a good job at lowering the pressure and not because this paper tells me that there’s 1 mmHg difference between blacks and non-blacks.”
1. Netland PA, Landry T, Sullivan EK, Andrew R, Silver L, Weiner A, Mallick S, Dickerson J, Bergamini MVW, Robertson SM, Davis AA, the Travoprost Study Group. Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol 2001;132:4:472-84.
|
1. Netland PA, Landry T, Sullivan EK, et al. Travoprost compared with latanoprost and timolol in patients with open-angle glaucoma or ocular hypertension. Am J Ophthalmol 2001;132:4:472-84.
2. Brubaker RF, et al. Effects of AGN 192024, a new ocular hypotensive agent, on aqueous dynamics. Am J Ophthalmol 2001;131:1:19-24.
3. Morgan PV, et al. Effect of temperature and light on the stability of latanoprost and its clinical relevance. J Glaucoma 2001;10:5:401-5.
|
