Article

Pushing forward with perioperative drugs

A look at advances that address dilation, infection, inflammation and pain.

As a resident, did you learn that cataract surgery could involve making an 8-mm incision and expecting months to pass before the patient recovered any kind of visual function?

If so, your experience mirrors that of John A. Hovanesian, MD, FACS, a specialist in cataract, refractive and corneal surgery at Harvard Eye Associates in Laguna Hills, Calif., and spokesperson for the AAO. Thankfully, times changed; given the great leaps in cataract surgery, today’s patients “are disappointed when they don’t have their final vision the day after surgery,” he says.

Despite that progress, one area has not benefited from such notable advances, says Dr. Hovanesian. With the exception of adding an NSAID to the cataract surgery regimen, “we’re still using basically the same drugs we did at the beginning of my career.”

Still, drug development for cataract and other eye surgeries has not stood still. Trends are evolving in antibiotics, NSAIDS and steroids.

In this article, we touch on major advances in perioperative drugs, mainly for cataract surgery.

RETINA EVOLUTION

“There has been an evolution of the perioperative treatment around retina surgery, because retina surgery has evolved so much in the last 15 years,” says Shlomit Schaal, MD, PhD, professor and chair of the Department of Ophthalmology & Visual Sciences at the University of Massachusetts Medical School, Worcester, Mass. “There’s minimal risk for pain and minimal risk for infection.” Dr. Schaal gives no antibiotics preoperatively. Postoperatively, she uses antibiotic drops and steroid drops.

The medication that’s most needed for retinal surgery is an anti-VEGF drop to eliminate the need for anti-VEGF injections, she says.

Dr. Schaal also sounds a cautionary note about using opiates, given the current crisis with those medications. For pain, she instead uses Tylenol.

PREVENTING MIOSIS, REDUCING PAIN

A significant advance in perioperative drug use for cataract surgery involves Omidria (phenylephrine and ketorolac intraocular solution) 1% / 0.3% (Omeros). Omidria, approved by the FDA in 2014, is added to ophthalmic irrigating solution used during cataract surgery or IOL replacement and is indicated for maintaining pupil size by preventing intraoperative miosis and reducing postoperative ocular pain. Omidria is the only FDA-approved drug for intracameral pupillary dilation.

Omidria provides cataract patients various benefits, says George O. Waring IV, MD, FACS, founder and medical director of the Waring Vision Institute in Mount Pleasant, S.C. The medication leads to more predictable pupil mydriasis and greatly reduces the occurrence of intraoperative floppy iris syndrome (IFIS). What’s more, it has limited the need for pupil expansion devices and improves patient anesthesia. He has also observed that the drug may have "a protective role from postoperative cystoid macular edema," Dr. Waring says.1,2

Specifically, phenylephrine stimulates the dilator muscle of the iris and both maximizes and maintains pupil dilatation, notes Robert H. Osher, MD, professor of ophthalmology at the College of Medicine of the University of Cincinnati and medical director emeritus of the Cincinnati Eye Institute. Ketorolac, he says, offers three benefits: it prevents prostaglandin-induced miosis, diminishes inflammation caused by cataract surgery and has an analgesic effect to help control postoperative pain.

Reducing the occurrence of IFIS is particularly important, notes Dr. Osher. “We’re faced with this epidemic of patients who have these very unusual IFIS characteristics,” he says.

A major cause is the increasing use of Flomax (tamsulosin hydrochloride, USP; Sanofi). Dr. Osher has been using Omidria for all Flomax patients and for patients with pupils that don’t dilate well; he might use Epi-Shugarcaine, a previous mainstay for pupil dilation, for a patient with an NSAID allergy.

Another benefit of Omidria, though not yet fully explored, pertains to the longer term delivery of keterolac, according to Dr. Hovanesian. During cataract surgery, he notes, the surgeon soaks the eye for 5 or 10 minutes with ketorolac, which may lead to some retention of the drug in the tissue for several days after surgery and perhaps longer, thus reducing inflammation.

To get the greatest benefit from Omidria, Dr. Osher uses Omidria in the infusion bag to irrigate the eye during surgery and injects a small amount of Omidria before he puts in the ophthalmic viscoelastic device (OVD). If he puts the OVD in before injecting Omidria, the constant infusion of fluid might not get to all portions of the iris because the viscoelastic device can act as a buffer. But, if he puts in Omidria before the OVD, “then I know I’ve drenched the iris,” Dr. Osher says. “Then I can put in my OVD. And then when I start the phacoemulsification, the infusion constantly bathes the intraocular tissue.”

PEARLS

  • When she teaches new surgeons about cataract surgery, Lisa Park, MD, of Columbia University Medical Center, offers this: “Get rid of the inflammation quickly and completely. My strategy is to use the steroids much more often and intensively in the first few days, and get the eye completely quiet before starting to taper.” This helps avoid the scenario of a patient having a prolonged low-level inflammation, because they are not taking enough drops or stopping them too quickly, which leads to a longer recovery.
  • When injecting Dexycu into the ciliary sulcus, John A. Hovanesian, MD, FACS, of Harvard Eye Associates in Laguna Hills, Calif., says a small amount of medication at the end of the injection may go into the anterior chamber. If it does, there is no cause for concern even if it causes some corneal swelling. There will be no corneal edema or long-term loss of endothelial cells.

APPROVED INTRACAMERAL ANTIBIOTIC NEEDED

When it comes to preventing infection through ocular antibiotics, trends involve the use of fewer eyedrops and the need for an intracameral antibiotic.

Infection rates in cataract surgery are extremely low — endophthalmitis rates vary, but it is estimated to affect between 0.012% and 0.2% of patients.3-5 Lisa Park, MD, ophthalmologist at ColumbiaDoctors and associate professor of ophthalmology at Columbia University Medical Center, begins topical antibiotics preoperatively on the day of surgery only. “The surgical preparation of patients performed on the day of surgery is safe for preventing infection,” she says.

A recent area of interest is preventing infection through administration of intracameral antibiotics into the eye at the conclusion of surgery. Multiple international studies have shown this is effective, but currently there is no FDA-approved intracameral antibiotic in the United States. Having such a medication, Dr. Park believes, “should be a matter of time. That would diminish the burden and cost of taking eyedrops postoperatively.”

About half of U.S. surgeons have used or consistently use intracameral antibiotics, according to an ASCRS clinical survey, Dr. Hovanesian says. So, by using an intracameral antibiotic, Omidria and Dexycu (dexamethasone intraocular suspension 9%, EyePoint Pharmaceuticals) or Dextenza (dexamethasone ophthalmic insert 0.4 mg, Ocular Therapeutix), surgeons may be able to completely eliminate postoperative drops, Dr. Hovanesian suggests. “That’s quite a nice accomplishment,” he notes.

The development of an FDA-approved, fully vetted, injectable intracameral antibiotic for use during cataract surgery would be widely welcomed, says Adam H. Kaufman, MD, FACS, vice chairman and associate professor, residency program director, director of cornea and uveitis, department of ophthalmology, University of Cincinnati. “There’s increasing data supporting the use of intracameral antibiotics for cataract surgery, and it is becoming increasingly popular to use compounded agents.”

NSAIDS

As to NSAIDs for cataract surgery, the goal is to control postoperative pain and diminish prolonged inflammation after surgery. Once-daily formulations of bromfenac (Prolensa, Bausch + Lomb) and nepafenac (Ilevro, Alcon/Novartis) reduce the burning and stinging that comes with instilling generic NSAID eyedrops the usual four times a day, notes Dr. Park.

To reduce the number of drops that a patient has to instill postoperatively, Dr. Waring uses compounded smart drops, which is compounded gatifloxacin, prednisolone and bromfenac from Ocular Science. “It’s an all-in-one steroid, nonsteroid and antibiotic in a single drop,” he says. Such a drop is “more likely to ensure that the postoperative medications are being used. And it reduces cost to the patient in most cases,” he says. Another benefit, he notes, is “greener surgery” in that the amount of plastic generated is decreased from three bottles to one.

STRONGER, SUSTAINED STEROIDS

For steroids, trends include increased potency and sustained delivery.

The 2008 FDA approval of Durezol (difluprednate ophthalmic emulsion 0.05%, Novartis) continues to represent “the most important advance in steroid eye drop therapy,” says Dr. Kaufman. “It is an incredibly potent steroid with great penetration.” Durezol is specifically FDA approved, he notes, for the treatment of post-operative ocular inflammation and pain.

Other new arrivals include options for “less drops” following cataract surgery. The recent approval of Inveltys (loteprednol, Kala Pharmaceuticals), indicated at b.i.d. for postop use following ophthalmic surgery, and Lotemax SM (loteprednol, Bausch Pharmaceuticals), indicated at t.i.d. postop surgery, allow for a decreased postoperative drop regimen. Also, Imprimis Pharmaceuticals produces compounded antibiotics as well as antibiotic steroid combinations for intracameral use following cataract surgery.

Along with the advent of Dexycu and Dextenza, surgeons now have new access to sustained delivery of steroid, potentially bringing surgeons closer to the goal of eliminating drops. If a surgeon infuses Omidria at the time of surgery and couples that with either Dexycu or Dextenza, the result is a “whole lot of anti-inflammatory effect to the patient,” says Dr. Hovanesian. Trials indicate that, there is no need for a postoperative steroid drop when using Dexycu or Dextenza, says Dr. Hovanesian. Surgeons may also be able to eliminate the NSAID, he suggests, though no current data supports that.

Coming soon: MicroStat

When it comes to pupil dilation, one pipeline drug promises to make dilation easier and faster, ensuring that you are not waiting on a patient to dilate before surgery. MicroStat (Eyenovia) is a fixed combination microdose formulation of phenylephrine and tropicamide for mydriasis. Phase 3 studies of MicroStat are complete, and Eyenovia anticipates a 2020 NDA filing.

Instead of instilling traditional drops, MicroStat utilizes Eyenovia’s Optejet, which uses piezo-print technology to deliver 6 μL to 8 μL of drug to the eye. This can avoid spilling the drug out of the eye, says David Wirta, MD, founder, Eye Research Foundation, Newport Beach, Calif. The microdose “goes in literally 100% of the time,” he notes. To the patient, it is “barely recognizable” that the medication has been instilled, he says.

In the MicroStat Phase 3 MIST-1 study, 94% of MicroStat-treated eyes reached 6 mm or greater pupil dilation at 35 minutes after administration. Dr. Wirta adds that he has been impressed with the power of the dilation.

LOOKING AHEAD

As surgeons take advantage of the drug developments that improve cataract and other ocular surgeries, they can be mindful that current drugs and methods of administration will continue to evolve.

Perhaps in a few years time, eyedrops will look as antiquated to today’s ophthalmology residents as that 8-mm cataract incision does to surgeons today. OM

REFERENCES

  1. Kauffman L, Walter K, Hess J. Presentation at the ASCRS-ASOA Annual Meeting; May 7-9, 2019; San Diego, CA.
  2. Visco D. et al. Presentation at the 28th ACES, ABES, and the SEE, Caribbean Eye Meeting; February 1-5, 2019; Cancún, Mexico.
  3. Yannuzzi NA, Si N, Relhan N, et al. Endophthalmitis after clear corneal cataract surgery: outcomes over two decades. Am J Ophthalmol. 2017;174:155-159.
  4. Miller JJ, Scott IU, Flynn HW Jr, et al. Acute-onset endophthalmitis after cataract surgery (2000–2004): incidence, clinical settings, and visual acuity outcomes after treatment. Am J Ophthalmol. 2005;139:983-987.
  5. Packer M, Chang DF, Dewey SH, et al. Prevention, diagnosis, and management of acute postoperative bacterial endophthalmitis. J Cataract Refract Surg. 2011;37:1699-1714.