Article

Drug advances in cataract and refractive surgery

Drug delivery innovations continue to improve these procedures.

Despite advances in surgery, today’s cataract and refractive patients can still struggle with significant challenges. You have no doubt encountered patients who, despite their best efforts, fail to comply with their eyedrop regimen. Others risk cornea toxicity from ocular surface disease due to the preservatives in the drops.

But innovations in drug delivery are helping us to address these concerns and overcome barriers in treating postoperative inflammation and pain. Such advancements as nanotechnology and depot medication delivery are making major inroads. In one case, a medication that was once frequently used and then became poorly accessible is once again available.

In this article, I’ll explain the latest developments for cataract and refractive surgery.

LOTEPREDNOL ETABONATE DELIVERY

Two new drugs leverage advances in nanotechnology and submicron technology to better deliver loteprednol etabonate: Kala Pharmaceuticals’ INVELTYS (loteprednol etabonate ophthalmic suspension) 1% and Bausch + Lomb’s LOTEMAX SM (loteprednol etabonate ophthalmic gel) 0.38%.

Nanotechnology is defined as having a size of 0.5 microns or less; submicron technology is 0.6 microns or less. Oftentimes, however, the terms are used interchangeably. Small particles penetrate into mucus pores more readily. Nanotechnology helps increase the penetration of the medication to the target tissues of the eye.

Loteprednol, an ester steroid, binds well to glucocorticoid receptors and is rapidly metabolized into inactive metabolites. The loteprednol molecule has been used effectively for more than 21 years and is my first choice for patients undergoing any type of ophthalmic surgery, especially if the patient has a history of a steroid response. In contrast to other ketone-based steroids, such as dexamethasone or prednisolone, loteprednol reduces the risk of adverse effects, offering a very low incidence of elevated IOP.1-4

Approved by the FDA in August 2018, INVELTYS is the first and only corticosteroid the agency authorized for twice-daily dosing to treat postop pain and inflammation after ocular surgery (not just cataract surgery). The INVELTYS mucus-penetrating nanoparticle technology results in significant improvement in penetration without compromising safety or efficacy.

Mucus on the ocular surface poses major challenges to topical drug delivery. INVELTYS uses Kala Pharmaceuticals’ AMPPLIFY Mucus-Penetrating Particle drug delivery technology. AMPPLIFY has two proprietary attributes that allow it to penetrate the mucus barrier: its nanoparticle size (selectively sized nanoparticles, 200 to 400 nm) and a proprietary coating to prevent adherence to mucus. These attributes allow drug particles formulated with AMPPLIFY to penetrate into mucus pores, avoid adherence to the mucins and deliver active drug to the target tissues, including the cornea and aqueous humor. Concentrations in the cornea drive pain resolution and, in the aqueous humor, mediate resolution of inflammation.

In two Phase 3 multicenter, randomized, double-masked, vehicle-controlled clinical trials,5,6 INVELTYS met both primary endpoints for complete resolution of pain and inflammation at postop day eight through 15 compared to placebo.

Further, two in-vivo preclinical studies underscore the effectiveness of the AMPPLIFY technology.7 In the first, 48 rabbits received either loteprednol etabonate 0.4% with AMPPLIFY or the traditional suspension 0.5%. In this study, AMPPLIFY achieved more than three times higher ocular exposure at both the cornea and the aqueous humor compared to LOTEMAX suspension without the AMPPLIFY technology. These differences were statistically significant.

In the second preclinical study, 36 rabbits received either INVELTYS 1% with AMPPLIFY compared to the traditional loteprednol etabonate suspension 0.5% without AMPPLIFY.7 Results were similar. Researchers observed a 2.7 times higher concentration in the cornea, and 3.75 times higher in the aqueous humor compared to loteprednol etabonate without AMPPLIFY.

LOTEMAX SM is a corticosteroid that makes use of submicron size technology. The FDA approved the medication in February 2019 for pain and inflammation after ocular surgery.

LOTEMAX SM offers a submicron formulation in which the particles are 80% smaller than LOTEMAX gel. This allows for more efficient penetration of the medication into the eye.8-13 At 0.38%, it contains the lowest concentration of loteprednol on the market for treatment of postop pain and inflammation.

The use of polycarbophil prolongs exposure of the drug on the ocular surface. It has a neutral pH and offers three-times-daily dosing compared to the four-times-daily dosing of LOTEMAX gel. LOTEMAX SM is friendly to the ocular surface with proprietary moisturizers, low BAK (0.003%) concentration and a neutral pH.

In Phase 3 clinical trials, LOTEMAX SM met both primary endpoints for pain and inflammation. Resolution of ocular pain occurred as early as 48 hours. The endpoint of pain was day eight.

DEXTENZA pearls

When inserting the DEXTENZA intracanicular insert, two steps are most critical: proper dilation technique and drying the punctum. Punctal depth is 2 mm in length while DEXTENZA is 3 mm in length.

First, put the eyelid on stretch, temporally, and insert nasally. Then, ensure that you dry the area near the punctum and move expeditiously to administer the insert. This is because DEXTENZA is moisture-activated and any exposure to fluid will expand the insert, making it difficult to pass through the lacrimal punctum into the canaliculus.

If you experience this, Ocular Therapeutix offers support via DEXTENZA360 (www.DEXTENZA360.com ), which offers reimbursement and access programs including unusable product replacement.

DEXAMETHASONE DEPOT DELIVERY

Two other medications that make use of innovative drug delivery systems are DEXTENZA and DEXYCU, which are depot versions of dexamethasone.

DEXTENZA (dexamethasone ophthalmic insert [0.4 mg], Ocular Therapeutix) received FDA approval in November 2018 for pain and inflammation after ocular surgery. The medication is provided as an intracanicular insert, placed into the lacrimal punctum and into the canaliculus, delivering a sustained release of dexamethasone for 30 days after ocular surgery.

Key attributes of DEXTENZA include its ability to reduce compliance concerns and prevent exacerbation of ocular surface disease through occlusion of the punctum; it’s also preservative-free. There are no FDA-approved preservative-free steroids available on the market today.

DEXTENZA’s hydrogel platform offers a tapered release of the medication over 30 days, allowing the patient to use fewer drops. What’s more, there is no need to remove the insert — it reabsorbs during treatment. Should the insert require removal, it can be done by irrigation or expression of the punctum.

Another depot version of dexamethasone, DEXYCU (dexamethasone intraocular suspension 9%, EyePoint Pharmaceuticals) received FDA approval in February 2018 for the treatment of postop inflammation after ocular surgery. It is the only single-dose, sustained-release intracameral steroid FDA-approved for that indication. DEXYCU uses the company’s biodegradable Verisome sustained-release technology and has a clinical effect for up to 30 days.

The drug is injected behind the iris after cataract surgery. Like DEXTENZA, it helps with patient compliance and reduces the risk of corneal toxicity from preservatives.

INTRAOPERATIVE MIOSIS PREVENTION

For cataract patients who are at risk for intraoperative floppy iris syndrome (IFIS), you now can utilize OMIDRIA (phenylephrine and ketorolac intraocular solution) 1% / 0.3% (Omeros). Keep OMIDRIA in mind for your patients who have a history of taking alpha blockers such as Flomax (tamsulosin hydrochloride, USP, Sanofi). It is the only FDA-approved drug for maintaining pupil size by preventing intraoperative miosis and reducing intraoperative pain.

Approved by the FDA in 2014, OMIDRIA is added to irrigating solution used during cataract surgery and is indicated for maintaining pupil size by preventing intraoperative miosis and reducing postoperative ocular pain.

REINVIGORATION

Eye-care practitioners who were disappointed when Alcon de-prioritized the FLAREX (fluorometholone acetate ophthalmic suspension 0.1%) brand will be pleased to learn that FLAREX was recently acquired by Eyevance Pharmaceuticals and is now actively being promoted nationwide.

FLAREX is the first and only corticosteroid containing the acetate derivative of fluorometholone. FLAREX has the broadest indication of any promoted branded steroid. It is indicated for use in the treatment of steroid-responsive inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the eye. With its broad indications, it offers a low incidence of increased IOP.

I currently use FLAREX for ocular surface inflammatory conditions (that is, induction treatment for DED) and corneal surgeries (LASIK, PRK, or keratectomy). It can also be used for corneal cross-linking, DSEK, DMEK and pterygium removal.

COST

Besides these technical advances in drug delivery, manufacturers have been addressing cost concerns. Coupons or copay cards can reduce medication expenses, not only for commercial payers but also for Medicare recipients.

DEXYCU (J1095), DEXTENZA (J1096) and OMIDRIA (J1097) now have permanent reimbursement J-codes.

NEW OPTIONS

All of the medications mentioned in this article offer unique advantages and notable benefits for your patients.

As you treat your cataract and refractive patients, you now have a greater range of powerful, innovative medications to achieve the best possible outcomes. OM

DEXCYU pearls

DEXYCU can occasionally stick to the cannula upon administration. To avoid this, it is best to inject the time-released dexamethasone “pellet” parallel to the edge of the iris with a “quick pull” technique, or paint it into the ciliary space. This will release the depot off the cannula underneath the iris.

Though a rare occurrence, after injecting DEXYCU be aware that the medication can migrate from beneath the iris into the anterior chamber and touch the cornea, which can result in mild corneal edema. However, this resolves when the medication dissolves.

REFERENCES

  1. Comstock TL, Sheppard JD. Loteprednol etabonate for inflammatory conditions of the anterior segment of the eye: twenty years of clinical experience with a retrometabolically designed corticosteroid. Expert Opin Pharmacother. 2018;19:337-353.
  2. Sheppard JD, Comstock TL, Cavet ME. Impact of the topical ophthalmic corticosteroid loteprednol etabonate on intraocular pressure. Adv Ther. 2016;33:532-552.
  3. Druzgala P, Hochhaus G, Bodor N. Soft drugs--10. Blanching activity and receptor binding affinity of a new type of glucocorticoid: loteprednol etabonate. J Steroid Biochem Mol Biol. 1991;38:149-154.
  4. Comstock TL, Decory HH. Advances in corticosteroid therapy for ocular inflammation: loteprednol etabonate. Int J Inflam. Epub 2012 Mar. 28.
  5. Schopf LR, Popov AM, Enlow EM, et al. Topical ocular drug delivery to the back of the eye by mucus-penetrating particles. Trans Vis Sci Tech. 2015;4:11.
  6. Kim T, Sall K, Holland EJ, et al. Safety and efficacy of twice daily administration of KPI-121 1% for ocular inflammation and pain following cataract surgery. Clin Ophthalmol. 2018;13:69-86.
  7. Schopf L, Enlow E, Popov A, Bourassa J, Chen H. Ocular Pharmacokinetics of a Novel Loteprednol Etabonate 0.4% Ophthalmic Formulation. Ophthalmol Ther. 2014;3:63–72.
  8. Ghate D, Edelhauser HF. Ocular drug delivery. Expert Opin Drug Deliv. 2006;3:275-287.
  9. Nakamura T, Yamada M, Teshima M, et al. Electrophysiological characterization of tight junctional pathway of rabbit cornea treated with ophthalmic ingredients. Biol Pharm Bull. 2008;30:2360-2364.
  10. Patel A, Cholkar K, Agrahari V, Mitra AK. Ocular drug delivery systems: an overview. World J Pharmacol. 2013;2:47-64.
  11. Cavet ME, Glogowski S, Lowe ER, Phillips E. Rheological properties, dissolution kinetics, and ocular pharmacokinetics of loteprednol etabonate (submicron) ophthalmic gel 0.38. J Ocul Pharmacol Ther. Epub 2019 Mar 23.
  12. Coffey MJ, DeCory HH, Lane SS. Development of a non-settling gel formulation of 0.5% loteprednol etabonate for anti-inflammatory use as an ophthalmic drop. Clin Ophthalmol. 2013;7:299-312.
  13. Fong R, Silverstein BE, Peace JH, Williams JI, Vittitow JL. Submicron loteprednol etabonate ophthalmic gel 0.38% for the treatment of inflammation and pain after cataract surgery. J Cataract Refract Surg. 2018;44:1220-1229.

About the Author