Cornea
Winter 2024

by Ellen Stodola
Editorial Co-Director

Many patients use drops to help with a variety of ophthalmic issues, however, one thing to consider is the formulation of these products, specifically if they have preservatives. Three ophthalmologists discussed the precautions with preservatives and shared the importance of monitoring for toxicity and potentially finding alternative treatment options. 

Anat Galor, MD, MSPH, said finding a preservative-free product is not as easy as you would think. “We’re always jealous because in Europe, they have a ton of preservative-free products,” she said. When talking about chronic medications like for glaucoma, the non-preserved medications are much more expensive.

The best option would be to never use preservatives, but it’s not always feasible, so Dr. Galor tries to identify the patients who have toxicity from preservatives, mostly based on epithelial staining patterns, and tries to switch those that show adverse effects.

Dr. Galor offered several key principles in these scenarios: 1) Don’t have patients on medications they don’t need; carefully consider if they need chronic medications; 2) talk to patients about different types of medications, what they’re buying over the counter, etc., and make sure they’re making good decisions; 3) monitor for toxicity in anyone who uses chronic eye drops with preservatives; in the office, stain with vital dyes, and if you see it, that’s a patient population where you can consider other options. It doesn’t have to be non-preserved drops; it could be options like SLT.

Stephen Pflugfelder, MD, also shared the concern of corneal and conjunctival epithelial toxicity with preservatives. This is most relevant to drops preserved with benzalkonium chloride (BAK), he said, which can cause corneal barrier disruption leading to an irregular and dry corneal surface that can reduce visual function and cause irritation. It can also cause death of conjunctival goblet cells, thus reducing secretion of tear-stabilizing mucin from these cells. Dr. Pflugfelder said that if possible, reducing the frequency of instillation or switching to a preservative-free formulation should be considered to help with the effects of these products. The risk of toxicity is related to the frequency of use and the BAK concentration. Usually, most patients can tolerate one drop with BAK preservative per day.

Dr. Pflugfelder said there aren’t many circumstances where you would need to use a product with preservatives. Theoretically, BAK-preserved antibiotic drops may be more effective for treatment of bacterial keratitis because the preservative can provide added bactericidal activity. However, severe corneal infections are often treated with compounded preservative-free fortified antibiotics.

John Sheppard, MD, noted two sets of concerns to consider with preservatives—short term and long term.

In the short term, normal people will be fine with preservatives, he said. One example is antibiotics. In the past, companies have advertised a synergistic effect between the preservative and antibiotic. In short-term use, they’re fine for a normal surface. “If the patient has ocular surface disease, even the short-term use of a preservative can exacerbate ocular surface disease,” he said, adding that moxifloxacin is a preservative-free option. In a situation where you’re concerned about toxicity, this could be a good option because it has a tremendous track record of safety and efficacy, he said.

“Due to hyper concentration unachievable by oral anti-microbial medications, any antibiotic in the tear film many times supersedes the minimum inhibitory concentration sensitivity threshold. Often, I’ll have a patient treated for an acute ulcer, doing well with infiltrate resolution but delayed epithelialization, and I want to accelerate surface healing but prevent any future infections. I will frequently use a bandage contact lens,” Dr. Sheppard said. It’s important to consider intermediate-term antibiotic prophylaxis, and moxifloxacin is a well-matched partner for the clinician and the patient. Another example, he said, is Eysuvis (loteprednol etabonate 0.25%, Alcon), which is indicated for intermittent treatment of episodic dry eye disease.

Chronic diseases are notoriously age related, recalcitrant, and incurable, but they benefit from long-term therapy, Dr. Sheppard said. The classic examples are glaucoma and dry eye, and many in this cohort also have cataracts. These patients require intervention for long periods of time, and continuous use of preserved glaucoma medications are known to create changes in the ocular surface.

He added that infiltration of inflammatory cells into the conjunctiva can cause a hypersensitivity reaction that can be exacerbated by the preservative themselves. Patients who have sensitivities to the active ingredient may become even more sensitive because the preservative is a well-known way to enhance permeability, so medications with continuous insult to the ocular surface are more efficacious because they enter the corneal or conjunctival tissues more readily. On the other hand, you have to be very cautious in this population because they tend to be older, and therefore more likely at risk for dry eye disease and trabecular meshwork outflow damage.

There are many choices to address this, Dr. Sheppard said. You can use artificial tears for dry eye, and most brands have single-dose dispenser options that allow for preservative-free preparation. There’s also a growing menu of multidose, preservative-free dry eye tear replacements for chronic use.

The tears that patients will most likely choose over the counter are less likely to be preservative-free and more likely to be store brand, which are produced in the most cost-effective manner with the least efficacious but still FDA acceptable ingredients, Dr. Sheppard said. The patient, when ill-advised and self-directed, will most likely pick an inferior product based on store name brand promotion and eye level display. Therefore, it is incumbent upon eyecare practitioners to provide the education to make patients with chronic ocular surface disease aware of the relative disadvantages of over-the-counter medications and the need to have a proper diagnosis from an eyecare professional. Virtually all prescription medications for dry eye are preservative-free, except Eysuvis, he said.

Dr. Pflugfelder said preservative-free formulations are available for certain glaucoma drops (timolol, dorzolamide-timolol, tafluprost, latanoprost). “Typically, the preservative-free formulations are more expensive, and they may not be covered by the patient’s prescription plan,” he said. “Other strategies are to use combination glaucoma drops versus the individual agents. This will decrease the BAK burden.” There are an increasing number of preservative-free options for treatment of glaucoma. Preservative-free steroids are needed, he said.

Dr. Sheppard said there are also strategies for keeping drops out of the eye altogether, like punctal occlusion, where a temporary or permanent punctal plug is inserted to conserve tear film production. There’s also an intranasal stimulant, varenicline (Tyrvaya, Viatris), used twice a day to enhance trigeminal afferent production of the tear film, thereby avoiding drops altogether. “We have a tremendous variety of procedures that can be done in the office that enhance the lipid layer of the eyes and reduce ocular discomfort,” Dr. Sheppard added.

In terms of glaucoma, Dr. Sheppard said there is a revolution in drop-sparing therapy to lower IOP. He said the most recent option is iDose (Glaukos), a 3-year travoprost sustained-release implant placed into the angle. There is a shorter-acting Durysta implant (AbbVie) using bimatoprost that can be placed into the anterior chamber at the slit lamp in the office. By far, the most common intervention has been SLT, which is Dr. Sheppard’s first choice for any glaucoma patient. It’s extremely safe, and treatment effect endures 1–5 years, he said. He added that there are still some glaucoma medications that are available only with preservatives, but companies are producing preservative-free glaucoma medications, like Iyuzeh (Thea), a preservative-free latanoprost.

Another solution to glaucoma and dry eye medications with preservatives is through a compounding pharmacy, Dr. Sheppard said, noting that Imprimis and Ocular Science produce a wide variety of medications. “We use their services for combination glaucoma drops,” he said. The glaucoma drop may be preservative free or preserved and contain three medications. It’s not FDA approved, but more and more patients seem to benefit from this approach.

Dr. Sheppard thinks the advantages of preservative-free therapy for chronic disease far outweigh the inconvenience. Unfortunately, insurance companies and third-party payers generally tier the preservative-free medications despite FDA approval far above the universally preserved generic preparation, and third-party payers never pay for compounded medications, he said.

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About the physicians

Anat Galor, MD, MSPH
Professor of Ophthalmology
Bascom Palmer Eye Institute
Miami, Florida

Stephen Pflugfelder, MD
Director of the Ocular Surface Center
Cullen Eye Institute
Baylor College of Medicine
Houston, Texas

John Sheppard, MD
Senior Founding Partner
Virginia Eye Consultants and EyeCare Partners Practice
Professor of Ophthalmology
Eastern Virginia Medical School
Norfolk, Virginia

Relevant disclosures

Galor: Alcon, Bausch + Lomb, Dompe, Novartis, Oculis, Tarsus
Pflugfelder: None
Sheppard: AbbVie, Alcon, Aldeyra, Bausch + Lomb, Dompe, Glaukos, Imprimis, Kala, Viatris

Contact

Galor: AGalor@med.miami.edu
Pflugfelder: stevenp@bcm.edu
Sheppard: jsheppard@cvphealth.com