This article was originally published in a sponsored newsletter.

Positive outcomes in modern ocular surgery are often achieved rapidly with routine anterior segment procedures. In premium cataract surgery cases (e.g., toric and presbyopia-correcting intraocular lenses, corneal astigmatic correction and other refractive procedures), however, patients’ visual demands can still exceed realistic expectations. Some key factors that can impact postoperative visual outcomes are the efficacy, convenience, tolerability and adverse effects in our choice of topical medications. This is especially important as we face further challenges in insurance coverage for some of our brand-name-only drops and the availability of generic similars.

In a typical postoperative drop regimen, patients are asked to instill a topical antibiotic, steroid and non-steroidal anti-inflammatory medication for variable lengths of time after their surgery. The pH and osmolality (Osm) of formulations, preservative content of each drop and the frequency of dosage can contribute to ocular surface disease (OSD). Typically, less surface toxicity is induced and patients perceive less of a stinging sensation when formulations are close to the natural tear film and use minimal or no preservatives.

Surface toxicity also affects procedure outcomes. The importance of diagnosing and managing perioperative keratitis sicca, or dry eye syndrome, is paramount when considering the downstream implications of delayed visual recovery and patient satisfaction, not to mention worsening of the underlying disease state and further complications from OSD. In 2019, the American Society of Cataract and Refractive Surgery Cornea Clinical Committee published the first presurgical-specific algorithm for diagnosing and managing ocular surface disease before refractive surgery.¹ This tool is helpful for all ocular surgeries when visual results can be affected significantly by even minimal corneal toxicity, for example in the case of presbyopia-correcting intraocular lenses, due to their complex optical properties.

Aside from proactively diagnosing and managing OSD, ensuring that we do not worsen underlying disease or induce keratitis sicca through postoperative medications is a natural extension of patient-focused care. This, along with patient convenience, is the rationale that some surgeons have used to introduce dropless surgical regimens to their operative care. Nevertheless, many surgeons have concerns about the safety of intraocular depots of medications and their potential side effects, along with the need, in most cases, to order these medications from external compounding pharmacies.

Generic prednisolone acetate, dexamethasone, difluprednate, fluorometholone, loteprednol and rimexolone are commonly-used topical steroid eyedrops. Prednisolone acetate 1% is available at a low price point for those with insurance coverage. However, many of these generic and brand-name steroid eyedrops include benzalkonium chloride (BAK), a preservative that is known to be toxic to cell junctions and leads to breakdown of the corneal epithelium.²

Alternatives with lower concentrations of BAK exist, such as loteprednol 0.5% gel and loteprednol 0.35% submicron gel (Lotemax SM, B+L), which have BAK concentrations of 0.003% (vs. other drops that typically have 0.01%). Loteprednol 0.35% submicron gel’s molecule size leads to more rapid penetration into the eye. The gel vehicle and decreased BAK in both gel formulations provides more time on the ocular surface and active ingredient retention, as well as less toxicity. As an alternative to BAK, difluprednate 0.05% (Durezol, Novartis) employs sorbic acid 0.1% as its preservative. For a truly preservative-free steroid, though, there is only loteprednol 0.5% ointment (Lotemax, B+L) or a visit to a compounding pharmacy for a specific formulation.

For topical, nonsteroidal anti-inflammatory agents, ketorolac 0.5% is one of the least expensive, but its lower osmolality, standard BAK concentration of 0.01% and labeled qid dosing regimen contribute to frequent complaints of ocular stinging and its toxicity profile. Alternatives such as bromfenac 0.07% (Prolensa, B+L; BAK 0.005%, pH 7.8, Osm 300) and 0.09% (Bromday, B+L; BAK 0.005%, pH 8.3, Osm 300) as well as nepafenac 0.3% (Ilevro, Harrow; BAK 0.005%, pH 6.8, Osm 300) decrease toxicity to the cornea with approved once-daily dosing. The major difference in these formulations is their pH. As compared to the mean corneal tear film pH of approximately 7.45,^3,4 Prolensa is closest to natural tears with a pH of 7.8, followed by Ilevro at 6.8 and Bromday at 8.3.

Surgeons have reported anecdotes of sudden changes in clinical responses when using standardized generic drop protocols for their patients. These cases remind us that, while generic products must demonstrate equivalence in the concentration of their active ingredient, their inactive ingredients do not need to follow the same guidelines. Because these vehicles are untested, their impact on the ocular surface is unknown and they can lead to significant differences in product tolerability or even the bioavailability of the active ingredient. Nevertheless, a product with an equivalent active ingredient concentration in an unknown solution may be substituted by a pharmacist or a pharmaceutical insurance plan arbitrarily, often without the patient’s knowledge. These changes can make it challenging when a patient fills prescriptions without a complete understanding of why we prefer brand-name agents for their postoperative care, or that advanced formulations such as gels and submicron particle sizes are typically not available as generics.

References:

1. ASCRS. Cornea resources: ASCRS preoperative OSD algorithm. Accessed July 18, 2024. https://ascrs.org/clinical-education/cornea/ascrs-preoperative-osd-algorithm
2. Goldstein MH, Silva FQ, Blender N, Tran T, Vantipalli S. Ocular benzalkonium chloride exposure: problems and solutions. Eye (Lond). 2022 Feb;36(2):361–368. doi:10.1038/s41433-021-01668-x
3. Van Haeringen NJ. Clinical biochemistry of tears. Surv Ophthalmol. 1981 Sep-Oct;26(2):84-96. doi: 10.1016/0039-6257(81)90145-4
4. Yamada M, Mochizuki M, Kawai M, Yoshino M, Mashima Y. Fluorophotometric measurement of pH of human tears in vivo. Cur Eye Res. 1997 May;16(5):482-486. doi:10.1076/ceyr.16.5.482.7050