Generic Latanoprost: One Year After Approval
Generic Latanoprost: One Year After Approval
Experts in glaucoma management issue their 12-month report card.
Robert J. Murphy contributing editor
Pharmacia & Upjohn’s 1996 introduction of latanoprost (Xalatan) shook the landscape of glaucoma management with a seismic force that upended long-standing treatment practices. Thanks to its IOP-lowering efficacy and gentle safety profile, several eyecare practitioners turned to topical Xalatan and later other prostaglandin analogues.
The March 2011 approval of generic latanoprost by the U.S. Food and Drug Administration (FDA) likewise has altered clinicians’ approach to glaucoma treatment almost like a long-anticipated aftershock. Practitioners who, for years, had their glaucoma patients distributed among branded prostaglandin analogues Xalatan (now Pfizer Inc.), travoprost (Travatan Z, Alcon Laboratories) and bimatoprost (Lumigan, Allergan) are now considering the generic prostaglandin option, according to the doctors interviewed for this article.
Following an initial wariness that prompted more frequent monitoring of patients newly switched to generic latanoprost, practitioners say they are gaining confidence in the effectiveness and tolerability of the generic formulation. Insurers, meanwhile, are likely to see a modest uptick to their bottom lines thanks to the lower cost of the generic drug, and pharmacists stand to profit, owing to incentives to encourage the sales of generic latanoprost, as is the case with any generic product.
Now that it has been a year since generic latanoprost hit the ophthalmic market, we felt it was a good time to issue a report card on its performance. So, we asked several glaucoma specialists how they would grade generic latanoprost. Here, they discuss where they think it makes the grade and where it may fall short.
Clinicians found they could count on branded prostaglandin analogs to bring about IOP reductions of roughly 30% on average. 1 This compares favorably with the topical beta-blockers, which effect roughly a 25% pressure drop.1 Beta-blockers, however, have been known to cause numerous side effects — some serious (low blood pressure), others less so (fatigue) — and are contraindicated in patients who have lung disease, such as bronchial asthma, and heart conditions, such as second or third degree atrioventricular block.2
Practitioners say they find that generic latanoprost lowers IOP by just about the same 30% as that of its branded counterpart.
“To clinicians, the main concern about the use of generic latanoprost is whether or not its efficacy is equivalent to branded latanoprost,” says Kathy Yang-Williams, O.D., who specializes in glaucoma management at Seattle, Washington’s Roosevelt Vision. “The majority of my patients who have switched to the generic drug are maintaining pressure readings equivalent to those achieved with their branded medication.”
Glaucoma specialist Murray Fingeret, O.D., of the North Harbor Veterans Affairs Hospital in Brooklyn, N.Y., says, “I have had no problems at all” with the patients who have switched to the generic formulation. That means not only good pressure control, but also little incidence of side effects, such as photophobia.
Dr. Fingeret says he initially followed up with patients one month after switching. “We found no difference in IOP or side effects [compared with branded latanoprost],” he says. After multiple similar positive outcomes, Dr. Fingeret says he returned to a three-month recall schedule for patients who were switched to the generic drug, advising them to call him if they experienced any problems in the interim.
Few generic vs. branded studies
Formal studies comparing generic latanoprost with its branded counterpart are lacking in the United States, but a randomized, crossover study in India did just that, looking at 29 patients who have primary openangle glaucoma or ocular hypertension. 3 The specific details of the study:
► Distribution of Xalatan and generic latanoprost: A total of 11 patients received Xalatan for weeks one through 12 and then were switched to generic latanoprost for weeks 13 through 24; 18 patients received generic latanoprost for the first 12 weeks and were then switched to Xalatan for weeks 13 through 24.
► IOP reduction findings after week 12: The Xalatan-first group had average IOP reductions from 23.64mmHg to 14.29mmHg (a drop of 9.35mmHg or 38%).
The generic latanoprost-first group had average IOP reductions from 22.74mmHg to 16.98mmHg (a drop of 5.76mmHg or 25%).
► IOP reduction findings after the crossover (at week 24): Patients who switched from generic latanoprost to Xalatan had further IOP reductions from an average of 16.98mmHg to 16.09mmHg at week 24.
The pressures of those switching from Xalatan to generic latanoprost rose an average of 14.29mmHg to 15.36mmHg.
► Patients experiencing adverse events by week 12: Eight of the 11 Xalatan-first patients experienced ophthalmic adverse events, such as conjunctival hyperemia, while 16 of the 18 generic latanoprost-first patients experienced such events.
► Patients experiencing adverse events after the crossover (week 24): At this time, a further 11 adverse events were reported in the 11 patients who had been switched to generic latanoprost, while six such events were noted in the 18 patients switched to Xalatan. None of the Xalatanfirst patients experienced ocular irritation from baseline to week 12, while five of the 18 generic latanoprost-first patients complained of such irritation.
Remember that this was a pilot study completed with a relatively small population. Also note that the generic latanoprost formulation used in the study came from India’s Sun Pharmaceuticals, whose manufacturing standards and practices may differ from those of U.S. manufacturers that produce generic latanoprost.
Impact of manufacturing and packaging
Fairfield, Conn., practitioner J. James Thimons, O.D., says many of the incidences of toxicity and IOP drift he has seen in patients using generic latanoprost resulted from the use of formulations made in China and India.
“I started doing some research because numerous patients were coming back with levels of response that were inconsistent with what they’d experienced with the branded drug,” Dr. Thimons explains, noting some of these cases involved severe toxicity. “In each instance, a generic from either China or India was involved.”
Currently, at least five U.S. companies manufacture generic latanoprost: Apotex Inc., Bausch + Lomb Inc., Falcon Pharmaceuticals Ltd. (an affiliate of Alcon Laboratories Inc.), Greenstone LLC and Mylan Pharmaceuticals.4
“Are they all the exact same thing?” wonders glaucoma specialist L. Jay Katz, M.D., in Eye-World’s December 2011 edition.4 “I don’t think we know that yet.
We’re waiting to see some papers come out that are an independent analysis of the composition of each of the bottles, assuring us they are all pretty much the same.”
The composition and design of the bottles from which generic latanoprost is dispensed is not a trivial matter. Different bottle designs may prove difficult for elderly glaucoma patients to handle, with the risk that too much or too little of the drug will be dispensed. There is also the possibility that drug components will absorb the bottle material or, conversely, that elements of the bottle will infiltrate the drug.
Wiley Chambers, M.D., FDA deputy director for the Division of Transplant and Ophthalmology Products, addressed the latter concern in a March 2011 Q&A with the American Glaucoma Society’s Cynthia Mattox, M.D.5
“We set specifications for both the innovators and the generics to catch migrating materials from the bottles into the solutions and vice versa,” Dr. Chambers says. “Most innovator products have several known impurities that come either from the bottles, degradation of one of the components in the product, inks on the box, glue on the box or an interaction between these
At least one batch per year is expected to be placed in an ongoing stability program, and if it falls out of its specifications at any time, the failure can subject the entire lot to be recalled.”
Another concern among clinicians is bioequivalence. Does enough of the generic drug penetrate to the ciliary body level, the production center for aqueous humor?
“Since the product is a solution and has the same active and inactive ingredients in the same concentrations [as those found in Xalatan], there would be no difference in performance,” says Lisa Kubaska, L.C.D.R., of the FDA’s U.S. Public Health Service.4
Despite this assurance, some practitioners still wonder about relative bioequivalence, not just between Xalatan and generic latanoprost, but also among other various generic formulations. According to Dr. Thimons, given the expense and complexity of testing ophthalmic medications for bioequivalence, the FDA chooses not to do so.
“With ophthalmics, you have to measure aqueous levels, corneal penetration levels, and then you have to measure metabolic levels at the ciliary body level,” Dr. Thimons says. “And at some point in the past, from the research that I have done, the FDA decided that was just too onerous.”
Whether variations in ophthalmic bioequivalence among generic latanoprost formulations reach the threshold of clinical significance remains an open question. For his part, Dr. Thimons now has upwards of 225 glaucoma patients who have switched to generic latanoprost, and he says the majority are doing quite well.
Switching? Preparation is key to success
Perhaps the first step in assuring that a switch from Xalatan to generic latanoprost goes well is to discuss with the patient why you are recommending the change and what the patient can expect from the new drug.
“Educate patients about the medications you’re prescribing for them, and let them know that you wish to switch them from a branded to a generic product,” says Michael Chaglasian, O.D., of the Illinois Eye Institute and the Illinois College of Optometry in Chicago. “Explain that generic drugs are made to the same equivalence as branded drugs, but there may be differences in the bottle or the drop. Schedule a follow-up appointment to evaluate efficacy, but if the patient’s IOP rises, don’t immediately assume the medication isn’t working because it’s generic.”
That’s important, Dr. Chaglasian says, because elevated IOP may signal a worsening of the disease, stemming from variables other than an ineffective medication.
Finally, some clinicians may feel more comfortable scheduling a follow-up appointment within a month or so after switching a patient from branded to generic latanoprost to check for efficacy and tolerability. If your patients are doing well with the generic product, you may ultimately decide this is not mandatory. According to the doctors we interviewed, this is a matter for each practitioner to decide based on his or her comfort level with the generic formulation.
Overall, a strong grade
Although some clinicians retain reservations, owing to sporadic instances of toxicity and IOP drift, most give generic latanoprost strong marks.
“We’ve been waiting on this since 1996,” says Concord, N.C., clinician and well-known lecturer Randall K. Thomas, O.D., M.P.H. “The thing you always look for is, number one, clinical efficacy. As long as your pressure control is maintained, that is the Holy Grail of glaucoma drug efficacy.” Generic latanoprost appears to have met this test while possessing a relatively benign safety profile.
Naturally, the shift to generic latanoprost also benefits patients financially. “Ninety-nine percent of the time, in my experience, which is fairly extensive, patients are loving the reduced cost,” Dr. Thomas says.
Xalatan is just the first of the prostaglandin analogues to go generic. Travatan Z and Lumigan will follow suit in March 2014. OM
1. Personal communication, Randall K. Thomas, O.D., and others, 2011.
2. Merck & Co., Inc. Sterile Ophthalmic Solution: Timoptic 0.25% and 0.5% (timolol maleate ophthalmic solution) www.merck.com/product/usa/pi_circulars/t/timoptic/timoptic_optsol_p i.pdf (Accessed 2/29/12)
3. Narayanaswamy A, Neog A, Baskaran M, et al. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan in comparison with generic Latanoprost (Latanoprost) in subjects with primary open angle glaucoma or ocular hypertension. Indian J Ophthalmol. 2007 Mar- Apr;55(2):127-131.
4. EyeWorld: The Newsmagazine of the American Society of Cataract & Refractive surgery. Glaucoma editor’s corner of the world. Does generic latanoprost measure up to branded Xalatan? eyeworld.org/article.php?sid=6151 (Accessed 2/29/12’)
5. Mattox C. Questions about generic ophthalmic medications from AGS members, answered by Wiley Chambers, M.D., FDA Deputy Director for the Division of Transplant and Ophthalmology Products. American Glaucoma Society (white paper), Sept. 2011.
|Mr. Murphy is a freelance journalist based in Philadelphia.|
Optometric Management, Volume: 47 , Issue: March 2012, page(s): 50 - 54