4/24/2018
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`Clinicians: prostaglandins are the clear choice for first-line glaucoma therapy
`
`Clinicians: prostaglandins are the clear
`choice for first-line glaucoma therapy
`
`Primary Care Optometry News, April 2004
`Jennifer Byrne
`
`NEW YORK — Boasting once-a-day dosing, minimal side effects, persistence and
`efficacy, some practitioners feel prostaglandins are a clear choice as first-line
`treatment for glaucoma. Although only one prostaglandin — Xalatan (latanoprost
`ophthalmic solution, Pfizer Inc., New York) — is currently FDA approved as first-line
`therapy, many clinicians strongly recommend this indication for all available
`prostaglandins.
`
`“These are all great medications, and they all work very well,” said Bruce E. Onofrey,
`OD, RPh, a Primary Care Optometry News Editorial Board member based in
`Albuquerque, N.M. “They are a godsend to the treatment of glaucoma. There has
`been a huge drop in the number of patients who have needed to go forward and have
`surgery, and there has been a drop in the use of other glaucoma medications since
`these drugs came along.”
`
`Dr. Onofrey lectured on prostaglandins at last year’s Primary Care Optometry News
`New York Symposium.
`
`Efficacy debate
`While Xalatan is the only one of the three that
`has a first-line indication in the United States,
`the European Commission approved Lumigan
`(bimatoprost ophthalmic solution, Allergan,
`Irvine, Calif.) and Travatan (travoprost
`ophthalmic solution, Alcon, Fort Worth, Texas)
`as first-line therapy for the reduction of
`elevated intraocular pressure in chronic open-
`angle glaucoma and ocular hypertension
`patients.
`
`According to Dr. Onofrey, clinical comparisons
`between Xalatan, Lumigan and Travatan have
`escalated into an all-out efficacy “war.”
`
`Take-home pearls
`
`The effects of prostaglandins are
`consistent over time.
`Minimal absorption of the drug
`occurs outside the eye
`In patients who experience
`hyperemia, the goal is to get them
`past the first 2 weeks, when the
`redness will decrease.
`Beta-blockers are still a viable
`option for some patients.
`
`Exhibit 1058
`ARGENTUM
`IPR2017-01053
`https://www.healio.com/optometry/glaucoma/news/print/primary-care-optometry-news/%7Be241beec-4d3f-45e6-9a24-e715f594371c%7D/clinicians-prostaglandins-are
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`4/24/2018
`Clinicians: prostaglandins are the clear choice for first-line glaucoma therapy
`“Although these are all excellent drugs, there is a lot of pressure on the companies
`right now to differentiate their products in some way,” he told the audience.
`
`Dr. Onofrey cited one of the most recent studies conducted on this topic, by Robert J.
`Noecker, MD, and sponsored by Allergan.
`
`This 6-month, multicenter, randomized, masked, prospective, parallel-group clinical
`comparison found that mean changes from baseline IOP were 0.9 mm Hg to 2.2 mm
`Hg greater with Lumigan than with Xalatan. The greater IOP-lowering efficacy of
`Lumigan relative to Xalatan was also confirmed by the mean IOP, which was
`“statistically significantly lower in the Lumigan group at all timepoints on all follow-up
`visits,” Dr. Onofrey said.
`
`Dr. Onofrey also discussed a Pfizer-sponsored study by Richard K. Parrish, II, MD, of
`Bascom Palmer Eye Institute, University of Miami. This study determined that all three
`prostaglandin analogs have similar effectiveness.
`
`This 12-week, randomized, parallel-group, masked-evaluator study was conducted at
`45 U.S. sites. The study compared the IOP-lowering efficacy of the three drugs, as
`well as ocular tolerability and systemic adverse events.
`
`The determination was that the three medications had comparable IOP-lowering
`effectiveness in patients with open-angle glaucoma or ocular hypertension. Study
`participants reported a greater tolerability for latanoprost.
`
`Shortcomings of the studies
`Dr. Onofrey said that although both of these studies were well done, the International
`Glaucoma Review was concerned with some of the flaws of each study.
`
`“Anne Coleman, MD, PhD, editor of the International Glaucoma Review, stated that
`‘the fact that manuscripts or clinical studies come to different conclusions despite
`similar study designs has caused a lot of consternation and confusion among
`clinicians,’” Dr. Onofrey said.
`
`Some of the study differences cited were the fact that Dr. Parrish’s subjects were
`older, fewer of them were Caucasian, more were brown-eyed and more were open-
`angle glaucoma patients vs. Dr. Noecker’s slightly higher percentage of ocular
`hypertensives.
`
`In addition, Dr. Onofrey stated that there was a higher baseline IOP in Dr. Parrish’s
`patients, although not clinically significant.
`
`https://www.healio.com/optometry/glaucoma/news/print/primary-care-optometry-news/%7Be241beec-4d3f-45e6-9a24-e715f594371c%7D/clinicians-prostaglandins-are
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`4/24/2018
`Clinicians: prostaglandins are the clear choice for first-line glaucoma therapy
`Dr. Onofrey said that another major shortcoming of both studies is that they do not
`include central corneal thickness data. “You can see the variability and adjusted
`pressures that can occur by including that particular data,” he said.
`
`Dr. Onofrey said that, at this point, there is no clear evidence of superiority among the
`prostaglandins. “If this is true, then the deciding factor should be side effects,” he said.
`
`Side effects of prostaglandins
`According to J. James Thimons, OD, a lecturer and Primary Care Optometry News
`Editorial Board member based in Fairfield, Conn., the topic of side effects and
`contraindications of prostaglandins is thankfully not a very broad one. “We all know the
`side effects are fairly superficial,” he said. “No evidence exists of any serious side
`effects of these drugs.”
`
`Dr. Thimons also addressed the PCON New York Symposium crowd.
`
`Hyperemia is one noted side effect of prostaglandins, especially in the first 2 weeks of
`treatment, Dr. Thimons told the audience. Lumigan tends to have the highest
`incidence of hyperemia, he added.
`
`“So your goal as a clinician is to get the patient past that 2-week zone where
`hyperemia decreases and be able to maintain the use of the drug, even though you
`are going to get a little bit of red eye,” he said. “One way around this is to instruct
`patients that the drug will make their eye a little red for the first few days, and we
`expect that to happen. I ask them to please call me if they don’t get a red eye.”
`
`According to Allergan, data presented at the recent American Glaucoma Society
`meeting by June Chen showed that vasodilation — not inflammation — appears to be
`the cause of hyperemia following Lumigan instillation.
`
`Iris pigmentation tends to be quite variable in terms of its prominence in a particular
`practice. “My patients are probably 35% to 40% Irish, English, Scottish or Northern-
`European Caucasians with glaucoma,” he said. “The vast majority do not have brown
`eyes, and there is a large population of high-risk irises in our practice that we feel
`compelled to identify and follow.”
`
`Dr. Thimons said iris pigmentation is the major irreversible complication and needs to
`be explained to patients. “The actual complication is not a problem medically for
`patients. It is simply cosmetic,” he said. “There is no indication that the change of the
`size of the melanocytes will affect outcome. However, I do refrain from first-line use of
`this therapy in pigmentary dispersion patients.”
`
`https://www.healio.com/optometry/glaucoma/news/print/primary-care-optometry-news/%7Be241beec-4d3f-45e6-9a24-e715f594371c%7D/clinicians-prostaglandins-are
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`4/24/2018
`Clinicians: prostaglandins are the clear choice for first-line glaucoma therapy
`Not all prostaglandins are “created equal” in this area, Dr. Thimons said. “There is a
`difference in the drugs in this category. Both Travatan and Lumigan have significantly
`lower rates of iris pigmentation, somewhere between 1.5% and 3%, whereas Xalatan
`has a significantly higher rate at 16% at 12 months,” he said.
`
`Dr. Thimons said in patients with high-risk irises, he would adjust his prescribing habits
`based on this information. “I also think it is important to discuss this issue with patients
`at risk before starting them on therapy,” he added.
`
`Hypertrichosis is another side effect that is rather benign and, in some cases,
`desirable, Dr. Thimons said. “The increased number, density and pigmentation of
`eyelashes is interesting,” he said. “It is not necessarily a negative effect. It is also an
`interesting indirect monitor of compliance.”
`
`Periorbital pigmentation is a much less cosmetically appealing side effect of
`prostaglandins, Dr. Thimons said. This side effect, which occurs in fewer than one out
`of every 500 patients, appears as a deepening of the coloration in the immediate
`periorbital area. However, this side effect is reversible, he said. “It takes about 2 to 3
`months to come on, and once the medication is stopped, the reversal takes about the
`same amount of time,” he said.
`
`The incidence of cystoid macular edema is an infrequent side effect of prostaglandin
`use, Dr. Thimons said. “It does occur,” he said. “But if you have an uncomplicated
`cataract surgery, you can use this drug afterwards, and, in all probability, it will be a
`safe drug for you.”
`
`Dr. Thimons did advise against the first-line use of prostaglandins for patients with a
`history of herpes simplex keratitis or herpes zoster keratitis. “I would also put into this
`category patients with chronic uveitis, because the drug does activate an inflammatory
`cycle as part of its mechanism of action,” he said.
`
`Chemical structure of prostaglandins
`Dr. Onofrey discussed the chemical structure of prostaglandins. He said that all three
`of the main prostaglandin drugs start with the same basic nucleus, to which side
`chains have been attached.
`
`“They all have an important factor, and that is their ability to bind to receptors. These
`are receptor-based medications,” he said.
`
`https://www.healio.com/optometry/glaucoma/news/print/primary-care-optometry-news/%7Be241beec-4d3f-45e6-9a24-e715f594371c%7D/clinicians-prostaglandins-are
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`4/24/2018
`Clinicians: prostaglandins are the clear choice for first-line glaucoma therapy
`“When we combine these drugs, we try to produce synergism. Prostaglandins are one
`of the few medications that work by increasing outflow, so we try to combine a drug
`that increases outflow with one that decreases aqueous production, he continued.”
`
`A word about beta-blockers
`Dr. Thimons emphasized that the emergence of prostaglandins as first-line therapy
`has not eliminated other options, such as beta-blockers, the previous first-line choice.
`“Prostaglandins have just supplanted a broad portion of the selection process and
`made themselves the first-line choice,” he said. “The selection has not been reduced.”
`
`Dr. Thimons added that beta-blockers are still a viable option for glaucoma treatment
`and, in some cases, are the best therapy for some patients. “There has been a lot of
`beta-blocker bashing going on, but they are very good drugs,” he said. “They have
`been around a long time, and there have been only 38 recorded deaths out of millions
`of patients.”
`
`He added that many glaucoma patients will still end up using a beta-blocker at some
`point in their treatment. “If you have a patient on two drugs, one of the drugs will be a
`beta-blocker in 90% of patients,” he said. “So don’t give up on beta-blockers. They are
`really good drugs. They are just not the drug we are using as first-line therapy
`anymore.”
`
`Prostaglandins: the drugs of the future?
`According to Dr. Thimons, there is little question that prostaglandins have arrived at
`the forefront of glaucoma treatment.
`
`He said prostaglandins feature a once-a-day dosing, which is quite effective. In
`addition, he said, prostaglandins show persisitence and endurance over time.
`
`https://www.healio.com/optometry/glaucoma/news/print/primary-care-optometry-news/%7Be241beec-4d3f-45e6-9a24-e715f594371c%7D/clinicians-prostaglandins-are
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`4/24/2018
`Clinicians: prostaglandins are the clear choice for first-line glaucoma therapy
`“One really nice thing about these drugs is that once you get an initial effect and
`establish efficacy with the agent, you will have a long-term commitment with that
`patient, and that drug is going to be really consistent,” he said. “You don’t see drift at 6
`months or 12 months, as you do with all other categories of drugs.”
`
`Prostaglandins are also very rapidly metabolized and very ocular-specific, with
`minimal absorption outside the eye. They have also been shown to be quite
`efficacious on normal-tension patients, Dr. Thimons said.
`
`According to Murray Fingeret, OD, a Primary Care Optometry News Editorial Board
`member who practices in New York, the side effects of prostaglandins are quite
`minimal when measured against the tremendous efficacy of the drugs. Dr. Fingeret
`joined Drs. Onofrey and Thimons to lecture on prostaglandins at the PCON New York
`Symposium.
`
`“Both in this country and around the world, there have been no problems with
`prostaglandins other than topical, cosmetic side effects,” he told attendees. “The
`benefits far outweigh these minimal side effects.”
`
`Dr. Fingeret said he is confident that prostaglandins will soon become the established
`first-line treatment glaucoma. “When you look at the efficacy, minimal side effects,
`once-a-day dosing, reduction of the diurnal curve, long duration of action and
`persistence, it really paints prostaglandins as being our first-line therapy,” he said.
`“They are way ahead of everything else in the game.”
`
`For Your Information:
`
`Bruce E. Onofrey, OD, RPh, can be reached at 5150 Journal Center Blvd.,
`NE, Albuquerque, NM 87109; (505) 275-4226; fax: (505) 262-3366; e-mail:
`Eyedoc3@aol.com.
`J. James Thimons, OD, can be reached at 75 Kings Highway Cutoff,
`Fairfield, CT 06430; (203) 366-8000; fax; (203) 334-2401; e-mail:
`jim.thimons@tlcvision.com.
`Murray Fingeret, OD, can be reached at St. Albans VA Hospital, Linden
`Blvd. and 179th Street, St. Albans, NY 11425; (718) 526-1000 ext. 2435;
`fax: (516) 569-3566; e-mail: murrayf@optonline.net.
`
`Neither Dr. Onofrey, Dr. Thimons nor Dr. Fingeret has a direct financial
`interest in the products mentioned in this article, nor is either a paid
`consultant to any companies mentioned.
`
`https://www.healio.com/optometry/glaucoma/news/print/primary-care-optometry-news/%7Be241beec-4d3f-45e6-9a24-e715f594371c%7D/clinicians-prostaglandins-are
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`4/24/2018
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`Clinicians: prostaglandins are the clear choice for first-line glaucoma therapy
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`https://www.healio.com/optometry/glaucoma/news/print/primary-care-optometry-news/%7Be241beec-4d3f-45e6-9a24-e715f594371c%7D/clinicians-prostaglandins-are
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