At Press Time

Does Flomax Deserve a "Black Box" Warning?

The Initiative Moves Ahead — But Slowly.

By Leslie Goldberg, Associate Editor

■ A large Canadian study recently published in the Journal of the American Medical Association showed that men dispensed Flomax (tamsulosin) in the weeks prior to cataract surgery were at 2.3 times greater risk for postoperative complications than those who were not. These new results add to previous studies showing an association between tamsulosin and intraoperative floppy iris syndrome (IFIS), which was first reported by David Chang, MD, and John Campbell, MD, in 2004.

Accompanying the JAMA article was an editorial suggesting that the risk of cataract surgery complications associated with tamsulosin had been proven high enough to warrant a "black box" warning on the product's label.

Dr. Chang does not think that the risks are so great as to warrant a black box warning. "In the 2008 ASCRS member survey about IFIS, approximately three-quarters of respondents felt that tamsulosin increased the risk of cataract surgery, meaning that onequarter did not," he says.

Dr. Chang notes that the largest prospective study of cataract surgery in tamsulosin patients, published in Ophthalmology in 2007, also showed that good outcomes were achieved if highly experienced surgeons were forewarned by the drug history and used appropriate methods to combat the syndrome. He says that what frustrates many ophthalmologists is that the multimillion dollar advertising of Flomax is further increasing market dominance of the one alpha blocker most likely to cause severe IFIS.

As shown in a paper published in the 2007 Journal of Cataract and Refractive Surgery (JCRS), Marie- Claude Blouin, MD, of Montreal and colleagues found that "around 86% of patients taking Flomax will have IFIS during cataract surgery, making the surgery more difficult, more time consuming (because we have to use iris-retracting devices) and above all more risky, with a higher rate of complications."

A new study links cataract surgery complications with Flomax.

She says that UroXatral (alfuzosin) is equally effective in treating benign prostatic hypertrophy symptoms, has an equivalent systemic safety profile and the same cost but causes much less IFIS (only 15% in this paper) than Flomax.

Dr. Blouin supports adding a black box warning for Flomax. "I maintain my position regarding Flomax and UroXatral as stated in the conclusion of my article: 'Considering that the two agents have comparable efficacy in the treatment of benign prostatic hypertrophy (BPH), clinicians should consider alfuzosin as a first-choice therapy in patients who have not yet had cataract surgery to reduce surgical risk. Tamsulosin should therefore be reserved for patients who do not tolerate alfuzosin therapy because of vasodilatory adverse effects or those whose cataracts have already been removed.'"

She says that colleagues agree with her on the topic. "We have warned all the urologists and general practitioners in our hospital and prompted them to use UroXatral instead of Flomax as a first-line therapy of BPH, with a good collaboration."

Dr. Chang agrees with Dr. Blouin, saying that for cataract patients, alfuzosin would be his personal recommendation as a first-line alpha blocker.

Both ASCRS and the AAO have collaborated in efforts to increase awareness about IFIS among prescribing doctors, advocating that they involve the ophthalmologist prior to initiating tamsulosin in patients who already have cataracts or consider alternative medications for this group.

Dr. Chang says that while ASCRS does not have an official position on this topic, a white paper by the ASCRS Cataract Clinical Committee, published in the December 2008 JCRS, addresses clinical questions based on a thorough review of the peer-reviewed literature.

Boehringer Ingelheim, the manufacturer of Flomax, asserts that patient safety is the company's first concern. "Flomax has a well-established profile of efficacy, safety and tolerability that has been built over the course of more than a decade and we do not believe a boxed warning should be required," says Susan Holz, senior public relations specialist at the drug company.

The current Flomax prescribing information and patient guidance states that patients considering cataract surgery should tell their eye surgeon if they are taking or have taken Flomax. The Flomax prescribing information also states that the patient's eye surgeon should be prepared for possible modifications to the surgical technique for any patient who has taken Flomax.

IN THE NEWS…

■ Patent expirations on key drugs. An emerging issue for ophthalmologists to watch for in coming months will be possible attempts to introduce generic versions of such key ophthalmic drugs as Alcon's eye allergy treatment Patanol and Allergan's dry eye drug Restasis. Both of these widely used drugs have annual sales in the $500 million range. One Restasis patent for "method of use" has just expired but a critical "formulation" patent is effective until 2014. In the case of Patanol, one patent expires in December of next year but another remains in effect until 2015. Patanol patents have already been challenged by Apotex and Barr Labs, which produce generic versions of market-leading drugs. Alcon has vigorously defended the patents. ■ Crystalens HD range expands. Bausch & Lomb said it has received approval from the FDA to market the Crystalens HD in quarter-diopter steps in the United States. Quarter diopters will first be available for the Crystalens HD for the models HD500 and HD520 in the ranges of 18-22. Bausch & Lomb expects to have the diopters available in a wider range by the end of the year. ■ B&L opens global pharma HQ. Bucking the trend toward employee layoffs and business consolidation, one iconic American company has been able to expand despite the persistent economic downturn. New Jersey Gov. Jon Corzine officially welcomed Bausch & Lomb to its new global pharmaceutical headquarters in Madison, NJ, on July 20, citing it as evidence that "the state remains an attractive location for major pharmaceutical companies to grow and thrive." Indeed, New Jersey's existing pharmaceutical and biotech industries were a key factor in Bausch & Lomb's decision to establish its pharmaceutical headquarters in Madison: 15 of the world's top 25 drug companies have either world or North American headquarters or significant operations in the state, according to the Healthcare Institute of New Jersey. B&L CEO Gerald Ostrov and Gov. Jon Corzine at the ribbon-cutting ceremonies for B&L's new global pharmaceutical headquarters in Madison, NJ. The move "opens up opportunities to partner with other pharmaceutical companies and to drive commercialization of new products," said Bausch & Lomb CEO Gerald M. Ostrov, who cited the company's recent co-promotion agreement with Pfizer as an example. "We're looking forward to growing our presence here, which in turn will help us bring the best possible eye health products and services to people around the world." B&L expects to create 70 new highpaying full-time jobs at the 30,000- square-foot facility. ■ FDA panel supports Bepreve. Ista Pharmaceuticals said the Dermatologic and Ophthalmic Drugs Advisory Committee appointed by the FDA unanimously recommended the approval of Bepreve (bepotastine besilate ophthalmic solution) 1.5% as a topical treatment for ocular itching associated with allergic conjunctivitis. The panel's recommendation does not ensure FDA approval of a drug but it does count heavily in the final decision. At the same meeting, the Advisory Committee voted six to one against recommending approval of Rejena, a proposed treatment for dry eye developed by privately held River Plate Biotechnology. The panel found flaws and statistical issues in the two clinical studies conducted on Rejena. Ista has also announced positive results from a proof-of-concept phase 2 clinical study in subjects with dry eye disease using a new, proprietary, low-dose formulation of bromfenac, the active ingredient in Xibrom. The study achieved statistical significance in conjunctival staining, corneal staining, subjective symptoms and bothersome symptoms. ■ Anecortave acetate fails glaucoma trial. Alcon said it has discontinued development of anecortave acetate for the reduction of IOP associated with glaucoma after reviewing interim efficacy and safety data from more than 200 patients in a large, controlled phase 2 trial. These data confirmed previous pilot clinical results that anecortave acetate, a corticosteroid applied through a single anterior juxtascleral injection, measurably reduced IOP for an extended period of time. However, based on a detailed analysis of the data, and after gaining input from a panel of expert clinical advisers, the company determined that the amount of IOP reduction and the responder rate provided by even the highest dose were not sufficient to support this novel approach as a viable way to address the problem of patient compliance with eye drop therapy. Before being studied for glaucoma, anecortave acetate (Retaane) had been in clinical trials as a wet AMD therapy and was approved for that indication in Australia but not in the United States. ■ Innovative glaucoma medication. Inotek Pharmaceuticals has announced positive top-line results from an ascending-dose phase 1/2 clinical trial of the company's lead candidate, INO-8875, in 84 patients with glaucoma. Topical INO-8875 was well tolerated at all doses and resulted in a statistically significant IOP reduction at the two highest dose levels. Inotek says that INO-8875, a highly selective adenosine A1 receptor agonist, represents a new approach to treating glaucoma by increasing outflow of ocular fluid via the trabecular meshwork. ■ Conjunctivitis drug begins phase 2 trial. Alcon and its partner, NovaBay Pharmaceuticals, said that Alcon has begun treating patients in a phase 2 clinical trial of NovaBay's patented lead aganocide compound, NVC-422, for viral conjunctivitis. The study is expected to enroll approximately 250 patients. Developed by NovaBay to mimic the body's defense against infection, aganocides are proprietary synthetic analogs of the same molecules used by white blood cells to destroy harmful microbes in the body. Because of their natural mechanism of action, NovaBay believes that aganocide compounds have a low potential for generating microbial resistance, offering a potential solution to the problem of rising resistance of microbes to traditional antibiotics. The phase 2 study follows a recently completed phase 1 trial in which safety and tolerability were successfully demonstrated in 120 healthy volunteers with no reported serious adverse events. ■ Software monitors glaucoma progression. EyeIC, an innovator of eyecare solutions, said that its MatchedFlicker technology has received FDA 510(k) clearance from the FDA. MatchedFlicker is a device-agnostic, software-only solution that uses time-series retinal photographs to help doctors easily monitor the advent and progress of glaucoma. EyeIC says the technology enables eyecare professionals to compare two retinal images taken at different visits from the same patient — from nearly any source — and see change brought to life as motion. After doctors make their evaluation, they have the ability to mark the changes on the flicker and on the images. The software also translates markings made on any image in a Flicker project to the appropriate location on all other images in the same project. All images and annotations are saved in an electronic format and can be printed. ■ Alcon expands in Asia. Alcon marked the beginning of construction of its first pharmaceutical manufacturing plant in Asia with a groundbreaking ceremony in Singapore's Tuas Biomedical Park. The new 330,000-square-foot plant, to be completed in 2012, will create 150 new jobs. The new plant will primarily manufacture ophthalmic pharmaceutical products for Asian markets. ■ Uncertainty on Medicare Fee Schedule. As in previous years, the preliminary Medicare Physicians Fee Schedule for 2010 will most likely not be the final schedule. That's because the combination of the sustainable growth rate (SGR) formula and previous temporary fee "fixes" passed by Congress call for a 21.5% reduction in Medicare physicians' fees in 2010. However, as an offset to the SGR formula, CMS has also indicated that it is willing to make a large upward revision in hourly practice expense for ophthalmology. The most likely result is further negotiation and possibly legislation that will end the use of SGR as a benchmark for Medicare reimbursement.

Remembering an Eyecare Innovator

Nidek Founder Hideo Ozawa Was a True Visionary.

By René Luthe, Senior Associate Editor

■ In the wake of Nidek-founder Hideo Ozawa's death last month at the age of 79, many in the ophthalmic industry are taking time to reflect on the achievements of the man one called a "lion within the ophthalmic industry."

Mr. Ozawa founded Nidek in 1971, in Gamagori, Japan, and built it into a multinational company that became known for the distinction of being "comprehensive" in offering complete lines of eyecare equipment for medical practices. The achievement wasn't that surprising to those who worked closely with him.

"I found him to be one of the most innovative people I've met in ophthalmology," says Daniel S. Durrie, MD, clinical professor of ophthalmology at the University of Kansas, of his 25-year association with Mr. Ozawa. "I can remember I was with him at an ASCRS meeting in the late '90s and there was a project that I sat down with him and he sketched out on a napkin an intraoperative topography device. I didn't hear much back from him, but by the time we were at the Academy meeting, just a few months later, he had done all the engineering design and produced it. He showed a working model to me several months later."

Dr. Durrie's past experience was that such a thing would normally require the involvement of numerous committees and numerous people, "but he saw the vision and was able to take what was a discussion with some doctors and implement it into equipment faster than anyone I've ever seen."

George O. Waring, MD, FACS, FRCOphth, clinical professor of ophthalmology at Emory University and a consultant for Nidek, agrees that Mr. Ozawa was both innovative and visionary. One night when they were dining together, Mr. Ozawa said that he wanted to show something to Dr. Waring.

"I thought of course it was going to be a new instrument design. He reached into his briefcase and pulled out a scroll. I actually for a moment thought he was going to show me some ancient Japanese document," Dr. Waring laughs. "He said, 'I want to show you my 100-year plan for Nidek.' And he unrolled the scroll, which was quite long. It went back to the beginning of Nidek to the present time, and then forward 100 years. It contained things like tissue engineering and artificial vision implants in the brain for the blind, very advanced things. It showed his farsightedness."

Nidek founder Hideo Ozawa

"I asked him one time how he measured success for Nidek," Dr. Durrie recalls. "And he told me he measures success by the number of Japanese families who can make a living by working at his company. It was remarkable, his perspective that it wasn't about dollars and it wasn't about prestige, it was about growing a local business that supported people."

Joint Commission Accepts "Short-Cycle" Steam Sterilization

But There Are Caveats to its Use.

By René Luthe, Senior Associate Editor

■ The Joint Commission has determined that "flash" (steam) sterilization of instruments is an outdated term. In its place the accrediting organization recommends "short-cycle" steam sterilization, which is acceptable provided it is part of a "complete and effective process" that involves "meticulous cleaning" before sterilization as well as covering sterilized instruments before they are returned to the OR.

The decision comes after a review of procedures by a committee made up of members of the American Society for Cataract and Refractive Surgery, the American Academy of Ophthalmology and the Outpatient Ophthalmic Surgery Society, says William J. Fishkind, MD, FACS, of Fishkind Bakewell Maltzman Eyecare and Surgery Center, Tucson, and clinical professor of ophthalmology at the University of Utah.

Further, the Joint Commission will concentrate its survey efforts on the entire sterilization process rather than a method of sterilization. Surveyors will, among other things: observe instruments from the time they leave one OR until they are delivered to another; require healthcare staff to provide manufacturer's instructions for instrument sterilization and to describe and demonstrate how instruments are being cleaned and decontaminated; observe the cleaning of the instruments; verify that staff are wearing protective equipment; review sterilization logs; observe the return of instruments to the sterile field and verify that they are being protected from recontamination, according to a report from ASCRS.

"Centers will be placed under a microscope as to how they're handling their instruments and equipment," says Dr. Fishkind. "They have to develop new policies and procedures for care of instruments and sterilization techniques. We need to be much more careful about documentation."

He also noted that the Joint Commission's decision means surgery centers will likely need to purchase closed-system sterilization devices. Dr. Fishkind says these are not costly.

"The beauty of this ruling is that the potential expense could have been horrendous and through the work of the three organizations and the Joint Commission, we have a solution that's good for surgeons, good for patients and will maintain the low level of endophthalmitis that surgeons have experienced," he says.

Research Digest

New & Noteworthy Journal Articles

Compiled by Andrew E. Mathis, PhD, Medical Editor

► Drug-releasing contact lens. Innovative drug-releasing contact lenses may have the potential to ensure that glaucoma patients and others get correct and consistent dosages of medication.

A new article in Investigative Ophthalmology & Visual Science asserts that this method of administering drugs could be a significant improvement on traditional eye drops, from which the eye absorbs as little as 1% of the dose.

"Compliance is the biggest issue addressed here," said lead researcher Daniel Kohane, MD, PhD, from Boston's Children's Hospital. "People need to be able to properly and easily give themselves medication at home."

According to the study, several factors counteract the effectiveness of medicine when traditional eye drops are used. Only a minimal amount of the dose is actually absorbed by the eye. The rest either runs down the sides of the pa tient's face, is washed away by reflex tearing or dispersed by blinking.

The prototype drug-releasing contact lens is described as like a jelly doughnut; the lens is the pastry outside and the polymer film is the gooey middle. By constantly "oozing out" medicine, the lens can deliver the proper dosage and increase the effectiveness of treatment.

The lens may be fitted for any dosage of medicine and made compatible with a person's current contact lens prescription. "We expect this prototype to completely change the way people receive ocular medication," said Dr. Kohane.

The researchers are taking steps to begin FDA approval proceedings.

► Phaco problems in developing countries. A study published in the July issue of the British Journal of Ophthalmology addresses the reasons that phacoemulsification has had less than optimal results in developing countries. Doctors studied 346 patients who underwent cataract removal in Kenya, Bangladesh and the Philippines, finding that, of 452 eyes treated, a full quarter had adverse outcomes.

Among the most interesting statistical findings of the study was that poverty level had no statistically significant relationship with outcome. Rather, co-morbid disease was the culprit in 58% of cases in Bangladesh and 26% and 27% of cases in Kenya and the Philippines, respectively. Surgical complications accounted for 21% of negative outcomes in Bangladesh, while the single largest cause of adverse outcome in Kenya and the Philippines was refractive error.

► LASIK for presbyopia. Doctors at the Mercy Center for Corrective Eye Surgery in McHenry, Ill., have published a piece in the June 2009 issue of the Journal of Refractive Surgery on monocular peripheral presbyLASIK.

Of 103 patients undergoing the technique under discussion, 91.3% of all patients were able to go without glasses, with another 7.8% of patients reporting using glasses less than one hour per week. While longer follow-up is needed, the authors believe presbyLASIK can be a valuable option for presbyopic patients considering refractive surgery.

► Mini-strokes and normal-tension glaucoma. A study conducted in Hong Kong of 286 people with normal-tension glaucoma found a positive correlation between more rapid vision loss and silent cerebral infarcts, commonly kno wn as mini-strokes. The rate of mini-strokes in normal-tension glaucoma patients was almost twice as high (29.6% vs. 15.3%) when patients experienced steady vision deterioration.

As with most studies, this study still leaves several questions unanswered. For one, because the Hong Kong study only followed Chinese patients, there remains the possibility that this correlation will not be as pronounced in other ethnic groups. Furthermore, Andrew Iwach, MD, executive director of the Glaucoma Center of San Francisco and an AAO spokesman, reminded readers of HealthDay News, where the report appeared, that, even though a vascular component in normaltension glaucoma may be possible, the first line of treatment is still lowering IOP.

► Stem cells back in the picture. Doctors at Wills Eye Institute in Philadelphia published a literature review in the May 2009 issue of Current Opinions in Ophthalmology suggesting that stem cells hold great promise for the treatment of retinal disorders. The team identified five donor sources, including previously banned embryonic stem cells, and described transplantation methods currently under investigation, with special attention paid to direct transplantation to the retinal pigment epithelium.

► New use for Avastin? A team of retinal physicians at the Bascom Palmer Eye Institute in Miami have completed a trial of Avastin in 65 eyes with either branch retinal or hemiretinal vein occlusions, finding improvements in visual acuity of a mean of 12 letters at month one, 13 letters at months three and six, 14 letters at month 9 and 15 letters at one year. They also found corresponding reductions in retinal thickness as measured on OCT, according to the study published in the July/August issue of Retina.

These results come just as data from the BRAVO and CRUISE trials, which tested Lucentis for retinal vein occlusions, are set to be announced in the early fall. And while Avastin and Lucentis are currently undergoing head-to-head comparison for the treatment of wet AMD in the CATT clinical trial, the Retina study may indicate more areas in which Avastin and Lucentis may compete as treatment options.

Depending on which vein is occluded, effects to vision may vary, although macular edema is a common side effect of the inability of blood to flow properly in and out of the eye. OM