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The patent for the most widely prescribed glaucoma medication in the United States has just expired, and as many as eight companies are said to be lined up to bring generic formulations to market.

The drug is latanoprost, a prostaglandin F_2a analog developed in the 1990s as Xalatan by Pharmacia & Upjohn, which since became an arm of Pfizer. Though Xalatan has enjoyed the largest sales of any drug in the ophthalmic industry, economic forces will certainly draw patients over to less expensive generic formulations.

This raises questions for future glaucoma management but also shines a spotlight on the broader issue of generic vs. branded drugs. “Everybody’s anticipating that since Xalatan is the market leader in glaucoma, there’s going to be a sizable change in the market and in what our patients are using,” said Louis B. Cantor, MD, professor and chairman of ophthalmology and director of the glaucoma service at Indiana University in Indianapolis.

Does it matter if patients get the originally developed agent or a generic? The answer is uncertain. Yet anecdotal reports suggest that it may matter. Such reports raise concerns about the consistency of generic formulations and their therapeutic equivalence.

Danger in Discrepancies

Dr. Cantor noted that for most patients, generics work. “But there are exceptions,” he said. Robert J. Noecker, MD, MBA, agreed. “We use generics every day. And many people seem to do OK. But some people don’t do well.” Dr. Noecker is professor of ophthalmology and vice chairman of UPMC Eye Center in Pittsburgh.

For example, one of Dr. Cantor’s patients was doing well on Cosopt, a combination of dorzolamide and timolol, but after his insurance plan switched him to a generic alternative, his pressure rose 10 points. A return to the branded product yielded a 10-point drop in pressure. “For him, the switch to the generic made a huge, huge difference,” Dr. Cantor said.

Mass melting. One of the most dramatic stories concerning generics involved the 1999 voluntary withdrawal of a reformulation of diclofenac ophthalmic solution after at least 200 cases of corneal toxicity were reported. “That product was a disaster,” said Richard G. Fiscella, MPH, PharmD, clinical professor of pharmacy practice at the University of Illinois in Chicago. “It caused corneal melts, some requiring corneal transplants in normal patients after cataract surgery.”

Delivery without a drug. Problems also occurred with prednisolone acetate, a drug that required shaking before each use to prevent clumping. Sometimes patients received only the top fluid, or supernatant, Dr. Fiscella said. “So you’re getting the vehicle without all the active ingredients. Ask uveitis specialists; for years, they would not allow patients to use generic Pred Forte.”

What Are the Discrepancies?

Generic drug manufacturers are generally required by the FDA to demonstrate equivalence, which means their product must contain the same concentration of active ingredient as the formulation that earned FDA approval. Most ophthalmic solutions, however, are not required to prove therapeutic equivalence, said Dr. Cantor, who has written about the generic drug approval process.¹

Inactive constituents. Then there’s the matter of excipients, like preservatives, pH adjusters, antioxidants, thickening agents, buffers and substances to adjust tonicity. The excipients can mean the difference between a drug clumping or staying in solution, or causing more redness or less. “There’s a balancing act that manufacturers are doing when formulating ocular preparations,” Dr. Noecker said.

In the case of Xalatan 0.005 percent solution, excipients make up 99.995 percent of what’s in the bottle. And while the excipients are listed on the package insert, their individual concentrations are not, which means generic manufacturers don’t have the exact recipe.

“The ingredients should meet the same quality specifications. But how equal is equal?” said Gary D. Novack, PhD. “How important are minor differences?” Dr. Novack, who is president of PharmaLogic, a company that consults to the pharmaceutical industry, said that a small difference between generic and branded latanoprost could result in more redness. Pharmacologically, latanoprost causes vasodilation, which shows up clinically as conjunctival hyperemia, so Xalatan was designed to generate the greatest IOP reduction with the least redness.

When Generics Are OK

Disparities in formulation are not always problematic.

Short-course therapies. A generic antibiotic is probably okay for a short-term condition such as conjunctivitis, said Dr. Noecker. The intraocular penetration is not that critical because you’re treating the ocular surface. “You want to kill the bacteria, and once it’s gone you come off of it.”

Easy-to-make? Dr. Noecker added that some glaucoma drugs are easy to formulate. Timolol, for example, “is very stable, very happy in aqueous formation, very easy to work with.” In one study, he found small differences between the generic and original formulation. The biggest problem with generic timolol wasn’t efficacy but side effects, often due to pH differences and drop size.²

On the other hand, prostaglandins, like latanoprost, are more challenging to formulate. “Latanoprost is lipophilic. It doesn’t like water. It doesn’t go easily into solution,” Dr. Noecker said, adding that the developer worked hard to adjust the preservative so more of the drug went into solution.

Other Concerns

Dr. Noecker listed concerns for generic latanoprost formulations that might easily be extended to other drugs:

Heat and light. Latanoprost is sensitive to extreme heat and UVB light, raising worries during shipping.

Containers. Before an eyedrop comes to market, much attention is paid to packaging, Dr. Noecker said. Alcon, for example, made a special bottle for Travatan (travoprost). But generics can go into any bottle, he said. Some drugs may bind to plastic, or the dropper may not release enough of the active ingredient, Dr. Fiscella explained. The bottle tip for Xalatan was modified after patients wasted too much medication. The Xalatan bottle is, in fact, unique, he said. “It’s a blown plastic form, totally different from any ophthalmic product out there.”

Consistency and Compliance

Dr. Cantor weighs the obvious advantage of generics against potential disadvantages. “Generics can save money. That’s the only reason for them, and most of the time they’re fine,” he said. But a generic that feels different or blurs vision—“things we might consider small”—could affect compliance, Dr. Cantor said.

Drs. Cantor and Noecker added that many patients and, by extension, the health care system as a whole, cannot afford to fill all prescriptions with brand names only. Otherwise, they said, patients may not be adherent due to financial constraints, and the health care system would essentially be subsidizing brand name products long after their patents have expired.

With this, Hester Ho Lee, MD, agrees. She pointed out that the options physicians face when prescribing drugs are complicated by the fact that benefit managers will sometimes stipulate that only generics, when available, should be chosen. That stipulation can often be overcome with an appeal, but appeals are time-consuming. Dr. Lee is a refractive surgeon in practice at Kaiser Permanente Medical Center in Richmond, Calif.

But for many physicians, generics are preferable to begin with, in most situations, said Dr. Lee, adding that her patients deserve the best therapies—but also the best costs. “All things being equal, Kaiser physicians are strongly encouraged to prescribe the best-priced equivalent of any drug. It’s a policy I personally support as long as the quality of treatment remains the same because I want to keep the overall cost of health care reasonable. Both patients and physicians need to be mindful of prescription costs.”
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1 Cantor, L. B. J Glaucoma 1997;6(5):344–349.
2 Le, A. Q. and R. J. Noecker. Poster presentation at the Annual Meeting of the American Academy of Ophthalmology, 1998.
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Dr. Cantor is a consultant for Allergan and has received research support from Pfizer and Alcon. Dr. Fiscella is a consultant and speaker for Allergan. Drs. Harbin, Lieberman and Lee report no related financial interests. Dr. Noecker has been a consultant for Allergan and Alcon. Dr. Novack is a stockholder in Inspire and consults for numerous ophthalmic pharmaceutical and medical device firms.

Generics Have Their Place (and Their Champions)

The sky didn’t fall with the advent of generic timolol, and Marc F. Lieberman, MD, isn’t worried that it will cave in as latanoprost does the same. “When timolol went generic, people were doing the same Chicken Little number that they’re doing now, and the generic is fine,” said Dr. Lieberman, who is clinical professor of ophthalmology at the University of California, San Francisco, and director of glaucoma services at California Pacific Medical Center. While acknowledging the differences between generic and branded products, he said either can cause problems, and the concerns that people raise about generics—such as tolerability—may apply equally to the brand. For example, Lumigan 0.003 percent was so poorly tolerated by many patients that doctors avoided it. Eventually, Lumigan was reformulated to reduce the incidence of conjunctival hyperemia, Dr. Lieberman said. “The fact that it’s generic or nongeneric does not eliminate this issue of tolerability. It’s a red herring.” Dr. Lieberman called for “some very basic studies” that compare drops. “Let’s have a Consumer Reports of these drugs.” Until then, at least for glaucoma medications, generics are just another variable alongside adherence, persistence and affordability, he said. “Generic is another issue, but we don’t know how important it is.” In the meantime, Dr. Lieberman welcomes the introduction of generic Xalatan. “I have patients who cannot afford the nongeneric medication.” Thomas S. Harbin Jr., MD, MBA, a clinical professor emeritus of ophthalmology at Emory University and in private practice in Atlanta, concurred. While he prescribes Xalatan “all the time,” he has no qualms about switching patients to an off-brand drop, especially timolol. “If a patient has mild glaucoma and was controlled by Xalatan or Lumigan, I’ve taken him off that and put him on the cheaper drug, and the gratitude has been unbelievable,” said Dr. Harbin. “Now, if I want to use a prostaglandin, I have to prescribe a brand name drop. But I’m looking forward to anything that lowers the cost to my patients. Paying out of pocket for drugs has been a terrible burden on their life.” Does he worry about problems with generics? “You see these people every three, four, six months. If there’s a problem, you take them off the drop and try something different. So I don’t have any fear. I’m looking forward to anything that’s going to save my patients money, as long as it works. If it doesn’t work, you’ll find that out the next time you see them, and you’ll put them on something different.”