Quick Hits

Treat progressive keratoconus off label?

Not anymore. Hello, Photrexa.

On keratoconus, the MKO Melt, a vitrectomy conversation, and more

Collagen cross-linking has finally been sanctioned on this side of the Atlantic … and Pacific.

The FDA has given its approval to Photrexa, a combination treatment system for progressive keratoconus. Photrexa, comprised of a riboflavin ophthalmic solution and irradiating light system known as KXL, was approved based on the results of three randomized, 12-month trials; 512 eyes belonging to 364 patients received the treatment.¹

Avedro, Photrexa’s developer and manufacturer, said in a release it would begin taking orders immediately and ship product within the next few months. Photrexa is the first cross-linking product approved by the FDA; it received orphan designation in 2011.

Trial results

Photrexa does more than stop progressive keratoconus from advancing, trial results show.

“The trials also showed [cross-linking, or CXL] was effective … in reversing progression in some subjects, as evidenced by a clinically relevant increase in the proportion of CXL-treated subjects who showed improvement via a reduction in Kmax over time vs. baseline,” according to information Avedro presented to an FDA advisory committee last winter.¹ “The proportion of progressive keratoconus subjects in the CXL group with either stabilization or improvement in Kmax over baseline increased over time, reaching over 70% [76% in [[one study,]] 70% in [[a second,]] and 72% pooled) at Month 12.”

Worldwide, more than 100,000 eyes have been treated with Avedro’s cross-linking technology, said Rajesh Rajpal, MD, chief medical officer, Avedro, Inc., based in Waltham, Mass. All told, more than 60 countries have approved this Avedro product, including Japan, China, South Korea, Malaysia, India, Australia and New Zealand.

CXL is a standard of care for keratoconus and corneal ectasia outside the United States, said Dr. Rajpal. “[Before the approval by the FDA] the procedure [was] being performed with devices that are not approved for cross-linking and [with] compounded drug products that are not manufactured according to Good Manufacturing Practices.”

Little wonder. According to a FDA advisory document, the first of numerous investigational new drug applications was filed in 2007 under different ownership. Avedro assumed ownership in 2010. More filings occurred — more requests for information — until Avedro filed a complete response to the final, new drug application in September 2014.²

How it works

Photrexa is a one-time treatment. Once the epithelium is debrided, the riboflavin phosphate solution is applied topically every two minutes for 30 minutes or so.

The surgeon then performs ultrasound pachymetry. The corneal thickness must be 400 microns. It is at this point that the KXL system is used to irradiate the eye for 30 minutes. The riboflavin phosphate also comes in a dextran-containing formulation.

And it does work, says Peter S. Hersh, MD, corneal specialist in Teaneck, NJ, director, cornea and refractive surgery division, University of Medicine and Dentistry of New Jersey and the medical monitor for the Avedro U.S. trials. “Our clinical studies and the years of data overseas show the efficacy of the procedure” and the improved prognosis of those with progressive keratoconus. Internationally, he said, this is a procedure that “has become the standard of care in keratoconus management.”

Contact lens wearers alone should experience a remarkable difference. In his own single study center, Dr. Hersh said 75% of progressive keratoconus patients, who also wore contacts, had to give them up. But after the treatment, “90% were contact-lens tolerant.”

Another happy corneal surgeon was LASIK and refractive specialist Stephen Slade, MD, of Houston, Texas. He said he had been involved with several CXL trials and had spoken at the FDA Panel meeting in February 2015. CXL, he said, was “a quick, easy treatment that typically halts a blinding eye disease.”

He continued. “Even as a corneal surgeon, I am happy to have CXL to avoid grafts for my patients.”

Contraindications

In clinical studies, the most common adverse reactions in a cross-linked eye were related to corneal epithelial debridement. Adverse events include corneal opacity/haze (64%), punctate keratitis (25%), corneal striae (24%), corneal epithelium defect (24%) and blurred vision (16%). Most issues were gone within the first month, while some lasted six months before resolving. Corneal opacity lasted the longest, nearly a year. Development of ulcerative keratitis is a possibility, and surgeons should ensure that any epithelial defects are resolved, Dr. Rajpal said.

At the moment, Photrexa has no Medicare code, but Dr. Hersh doesn’t think that is a situation that will last. “Keratoconus is a known corneal disease. … [Photrexa] will keep people from a corneal transplant, it is a cost-effective management option. Our hope is that it will decrease the need for corneal transplants in the future.” OM

REFERENCES

MKO Melt, a sublingual sedative

New medication makes cataract surgery easier for both doctors and patients.

By René Luthe, Senior Editor

A new sedative option for cataract patients allows them to avoid IV needles and their surgeons to dodge the OR delays that often accompany them, says one of the medication developers, John Berdahl, MD, of Vance Thompson Vision, Sioux Falls, S.D. The midazolam-ketamine-ondansetron conscious sedation sublingual tablet — or the MKO Melt — dissolves over a period of approximately two minutes, peaking about 15 minutes later. It’s composed of 3 mg midazolam, 25 mg ketamine and 2 mg ondansetron.

Catalyst: The IV obstacle

Since cataract surgery has become so advanced, and excellent outcomes more likely, Dr. Berdahl says surgeons now consider starting an IV the fly in the ointment. Some patients dislike or even fear needles, while others’ veins are difficult to access — either way, the result is that surgeries might run over-schedule, causing problems for the whole surgery center. To avoid these problems, Dr. Berdahl tried sublingual midazolam. “It worked pretty well, but it wasn’t quite as much anesthesia as we wanted.”

After consulting with some anesthesiologists he decided to try ketamine, which some surgeons had been using successfully in an IV. “We wondered if we could find a way to make this sublingual. So I talked with our anesthetist and he did a little background work and we started using sublingual midazolam plus sublingual ketamine, and it worked great — except that was an uncomfortable amount of fluid people had to hold under their tongues.”

Partnering with Imprimis

Then Dr. Berdahl approached Imprimis. The compounding company has a strong track record of taking medications, putting them together and delivering them to ophthalmologists at a fair value, he says. His pitch was, “Hey, we have this idea for you of this sublingual melt … it will be a fast-dissolving sublingual tablet and provide a really nice, consistent sedation for patients and make it easy on the patients since they don’t have to have an IV, and easy on doctors and staff.”

“He had an amazing result” with his creation, says Mark J. Baum, Imprimis CEO and founder.

After Dr. Berdahl came to the company with the idea, Imprimis conducted literature searches for proper dosing and then deployed the sedative in the field.

“We gave it to surgeons besides the inventor and they loved it, all continued to buy it,” Mr. Baum says. Ten physicians took part in the test, administering the melt to more than 1,000 patients to get feedback on the right dose.

Multiple advantages

In addition to eliminating the need for an IV, it provides predictable dosing, making life easier for anesthesiologists.

The melt offers two other advantages, according to Dr. Berdahl. First is the small amount of ondansetron the melt contains. It is an antiemetic to help prevent postop nausea.

“The other thing is that we think the ketamine and the Versed are synergistic — because ketamine provides a little bit of analgesia that midazolam doesn’t.” It also provides what Dr. Berdahl refers to as “ketamine stare.” “The light doesn’t seem to bother patients as much. So when you swing the microscope over, people don’t squinch their eyes and fight the light as much as they did without the melt,” Dr. Berdahl explains. “Also, there’s probably a little bit — it’s a very low dose of ketamine — but a whisper of euphoria to it that helps the experience seem really good.”

The advantages aren’t just on the medical side, Dr. Berdahl says: Less time struggling to start IVs means he can perform an extra surgery or two per day. He also believes drastically reducing the number of IVs used has saved his practice money as well.

Mr. Baum says the medication will be sold in a two-pack for $25. “If you don’t have to put an IV in, it’s a cost savings,” estimating the total cost of using an IV line to be $100. Most patients will find the two-pack dose effective, according to Imprimis.

The melt, says Mr. Baum, is “like all formulations we have: an innovation that’s a lot less expensive, resulting in happy patients and lower costs.”

The early returns are good

The MKO Melt has been a hit with other cataract surgeons who have tried it as well. William F. Wiley, MD, medical director, Cleveland Eye Clinic and another developer, is not surprised that the melt seems to deliver.

“In general the sublingual route of the medication allows for a more gentle and more effective sedation,” he explains. “It would be counterintuitive to have improvements in sedation without being more aggressive with dosing; however, the oral route seems to be a more gradual sedation, allowing the patient’s anxiety to decrease before reaching the operating room.”

In his two-plus months of using the MKO Melt, Ralph Chu, MD, of Chu Vision Institute in Bloomington, Minn., finds his patients are much less anxious because they are not getting an IV.

And, most of his patients can avoid that needle.

“About 85% of our patients can go IV-free even in this short time of our early adoption curve,” he says. “I anticipate this will improve as we continue to increase our comfort level with the product.”

Dr. Wiley also finds the decrease in patient anxiety striking. “With IV sedation, it seemed that the patients were entering the OR anxious, and once that anxiety cycle began it was hard to reverse or break. With sublingual sedation, onset begins in the preop area and by the time the patient is being wheeled back to the OR, the patient is feeling good,” he says. “Effectively, you have bypassed the fear response before it sets in and is difficult to control. Even in situations where IV sedation is begun in pre-op, the timing can be difficult and sometimes the effect is waning while the patient is being brought back.”

Dr. Chu also confirms Dr. Berdahl’s claim of improved efficiency with the melt. “IVs do take time and resources on the day of surgery in the ASC. Discharging patients has also been smoother as patients are awake more quickly after the surgery.”

What to watch out for

As for side effects, Dr. Chu says his practice has not encountered anything significant. “All of the medications in the melt are known sedatives, familiar to our CRNA,” he explains.

Dr. Wiley reports that there is a small learning curve to undergo before getting the most out of the melt. It comes packaged in a two-tablet peel, a dosage that Imprimis says is effective for approximately 95% of patients. Still, the anesthesiologist must assess what is correct for the individual patient. “If the patient is too sedated, it may delay his time in postop recovery. So the main side effect that is minimized with experience is over-sedation,” Dr. Wiley says.

And of course, not all patients are good candidates for the melt. As Dr. Chu points out, patients with comorbidities could require an IV for safety during surgery. Additionally, some patients could require more sedation, so that an IV is preferable, says Dr. Wiley, while others might not tolerate sedation medically.

That leaves many patients for whom the MKO Melt is suitable, however, and all three surgeons report more efficient preop in their surgery centers. “If I ever asked my nurses to go back to IVs, they’d revolt,” jokes Dr. Berdahl. OM

Practice makes the perfect vitrectomy

Newer technology also helps make the operation easier.

By Louise Gagnon, Contributing Editor

Performing a vitrectomy does not have to be daunting for anterior segment surgeons, says the director of the Toronto Cataract Course.

Refined skill comes with performing more and more procedures, says Ike Ahmed, MD, FRCPC, assistant professor at the University of Toronto. “I am very fortunate that I perform a vitrectomy a couple of times per week,” says Dr. Ahmed, speaking in late February at the course held in his city. “It can be a challenge if you don’t do it very often.”

A vitrectomy is required for cases such as vitreous prolapse or when there are complications with an intraocular lens, according to Dr. Ahmed.

Different technologies come with different settings that facilitate performing a vitrectomy, and newer technologies, in particular, allow the clinician to turn off the cutter. “You simply turn the cutter off when you do not want to use it and turn it on when you do,” says Dr. Ahmed.

Most anterior surgeons will choose to perform a limbal vitrectomy, notes Dr. Ahmed. In terms of cutting and aspirating, he advises fellow ophthalmologists to ensure to turn on cutting and then to aspirate to remove vitreous.

For the anterior segment surgeon, the objective is to remove vitreous from the anterior chamber, trying to either push vitreous back or pull it back. “It’s important not to pull the vitreous forward,” says Dr. Ahmed.

Stabilizing the anterior chamber and maintaining that stability is a strategy to ensure vitreous does not come forward, says Dr. Ahmed, noting the use of paracentesis ports is helpful in keeping the chamber stable.

Some vitrectomy cases can present with the added challenge of a small pupil, says Dr. Ahmed. In such instances, microforceps could be used to make small incisions.

When asked by an attendee about using triamcinolone when performing vitrectomy, Dr. Ahmed replied that he regularly uses it. “It helps to see vitreous,” he said, but noted there is some toxicity risk with its use. “I think it’s safe overall, and it helps keep the eye quiet.”

Asked by an audience member about using a co-axial approach to vitrectomy, the panelists said they supported the bimanual approach, describing it as efficient.

Panelists touched on similarities and differences in cataract surgery between the United States and Canada. Femtosecond cataract surgery is more common in the United States than in Canada, a difference that can be attributed in part to a more market-driven health-care system south of the border, according to Dr. Ahmed. “Americans tend to be faster adopters [of technology].”

Due to Canada’s single-payer system, most cataract surgeries are performed in hospital while most cataract surgeries in the United States are performed in ASCs. “There are far fewer private centers in Canada than in the United States,” says Dr. Ahmed.

Arsham Sheybani, MD, assistant professor of ophthalmology, advanced anterior segment and glaucoma surgery, Washington University School of Medicine in St. Louis, Mo., agreed that earlier technology adoption in the US is driven by a more competitive practice environment than exists in Canada.

He also noted, though, that Canada is ahead in other respects.

“Canada is sometimes several years ahead of the United States in the approval of IOLs,” said Dr. Sheybani, who did a fellowship in Toronto. Iris prosthetic devices are available in Canada while none have received FDA approval, he added. OM