Simplifying glaucoma medical therapy for our patients

Adherence with lifelong glaucoma therapy demands a great deal from our patients. They must be able to afford and acquire their medications, remember the daily dosing schedule, be able to tolerate the drops well enough not to skip doses, and physically succeed in instilling the drops. That is a lot to ask of patients, especially as they age and begin to have concomitant health problems or cognitive loss.

Numerous studies have shown that adherence declines with more complex regimens of more than 1 or 2 bottles. Leung, Rossi, and others have shown us that, when you add a second or third bottle with preservatives, such as benzalkonium chloride, the incidence of ocular surface disease (OSD) increases^1,2 (Figure 1 ). Then, in a vicious cycle, patients with OSD become even less adherent.³

More than ever, we are now beginning to appreciate the effect of compliance on long-term IOP control in our glaucoma patients. Both the HORIZON study [NCT04566445], looking at implantation of Hydrus Microstents at the time of cataract surgery,⁴ and the LiGHT study, in which first-line selective laser trabeculoplasty (SLT) was compared with medical therapy,⁵ found that patients with the surgical/laser interventions were less likely to progress to incisional glaucoma filtration surgery. Even though we have medications that nominally provide the same IOP-lowering effect as SLT or minimally invasive glaucoma surgery (MIGS), we aren’t getting the full benefit of those medications because patients simply aren’t using them consistently.

More MIGS and SLT is part of the answer, but there will always be patients who need to continue topical therapy instead of or in addition to these options. In my practice, I typically prescribe a branded, commercially available glaucoma drug first, and I may make this choice for the second bottle as well. These drugs have gone through rigorous FDA trials and are marketed accordingly.

However, as the regimens get more complex with 3 to 4 medications, or if there are cost and adherence challenges with even 2 drops, I find that compounded fixed-combination glaucoma drops (Simple Drops; ImprimisRx) nicely address many of the factors that lead to poor adherence. Although we have a few dual-drug combinations in the US, none of them include a ß-blocker with a prostaglandin analogue (PGA), and none include more than 2 agents. Using Simple Drops, as the name implies, allows me to simplify the regimen for the patient to a single bottle once a day or 1 bottle each for morning and evening. These drugs are compounded in a Pharmacy Compounding Accreditation Board-accredited 503A patient-specific pharmacy that follows many of the same high manufacturing standards as its 503B facility. Every batch is tested for potency, sterility, and endotoxins, so I can be confident that my patients get a high-quality product.

IOP fluctuation is the problem

For many of our patients who are still progressing or have poorly controlled IOP on topical medications, the problem is not that the drops aren’t working, it is that their pressure is fluctuating with inconsistent use of the medication. The Advanced Glaucoma Intervention Study (AGIS) demonstrated that long-term IOP fluctuation of greater than 3.0 mm Hg is associated with visual field progression.⁶ Among AGIS patients with low mean IOP—those patients whose pressure looks fine when we see them in the office—fluctuations increase the risk of progression more than 3-fold).⁷ Simplifying the regimen for these patients can boost adherence enough to stabilize them. 

In a study I conducted, switching my patients to a 3-in-1 or 4-in-1 drop resulted in lower IOP across most patient types, particularly among those who were poorly controlled on their prior regimen of 3 bottles or more.8 Four patients in the study were able to avoid planned surgery. 

One of these patients was a 43-year-old African American woman with advanced glaucoma who was still progressing on brimonidine/timolol (Combigan) , brinzolamide (Azopt), and travoprost (Travatan). Her eyes were always red, and she told me she couldn’t keep taking so many drops. We discussed trabeculectomy, and I decided to put her on Tim-Brim-Dor PF (timolol 0.5%, brimonidine 0.15%, dorzolamide 2.0%) and stop the PGA to improve her ocular surface symptoms before surgery. At the next follow-up, her IOP was down to our target of 12 mm Hg, her eyes weren’t red, and she was happy with the reduced drop burden. Four years later, she is still on this regimen and has been able to avoid filtering surgery.

Clarity of cost and ingredients

Another major reason for using compounded combination drops is that I know what to expect and what it will cost the patient. If I prescribe 3 separate medications to a patient, it is very hard for me to answer their very reasonable question, “How much is that going to cost?” in any sort of accurate or transparent way. The cost to the patient could be $15 or $300, depending on their insurance coverage, co-pays, and formulary requirements. 

Moreover, they are highly likely to get generic substitutions from the pharmacy. The pH, viscosity, and other aspects of the inactive vehicle ingredients can vary widely from one generic to another, greatly affecting the bioavailability and efficacy of the active ingredient and the tolerability and safety of the drop overall.^9-12 There can even be considerable variability in the quality of the dropper bottle, causing drops to spill out too fast and the patient to run out of a 30-day supply in a much shorter period of time. 

Finally, compounded drops also give me the ability to prescribe preservative-free formulations so the glaucoma medications are not contributing further to ocular surface toxicity. About half of our glaucoma patients have OSD,¹³ and those with concomitant OSD are more likely to experience adverse effects from topical glaucoma therapy, more likely to be nonadherent, and more likely to progress.¹⁴ If we can minimize the effect on the ocular surface, we also are maximizing the chances of success with later Xen implantation or filtration surgery if required.

If cost, compliance, and generic substitution were not factors at all, I might prefer separate bottles of each branded medication. But we have to recognize that patients aren’t getting what we prescribe and aren’t consistently instilling what they do receive, with resulting IOP fluctuation and disease progression. A simplified regimen of compounded fixed-combination glaucoma therapy is a very welcome solution to these real-world problems. 

Inder Paul Singh, MD

E: ipsingh@amazingeye.com

Singh is in practice at the Eye Centers of Racine and Kenosha in Wisconsin. He is a consultant for many glaucoma companies, including Glaukos, ImprimisRx, and Ivantis, Inc.

References:

1. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17(5):350-355.
2. Rossi GCM, Pasinetti GM, Scudeller L, et al. Risk factors to develop ocular surface disease in treated glaucoma or ocular hypertension patients. Eur J Ophthalmol. 2013;23(3):296-302.
3. Baudouin C, Labbé A, Liang H, et al. Preservatives in eyedrops: The good, the bad and the ugly. Retin Eye Res 2010;29(4):312-334.
4. Ahmed IK, Rhee DJ, Jones J, et al, on behalf of the HORIZON investigators. Three-year findings of the HORIZON Trial: A Schlemm canal microstent for pressure reduction in primary open-angle glaucoma and cataract. Ophthalmology 2021;128(6):857-865.
5. Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selectivelaser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): A multicentre randomised controlled trial. Lancet 2019;393:1505-1516.
6. Nouri-Mahdavi K, Hoffman D, Coleman AL, et al; Advanced Glaucoma Intervention Study. Predictive factors for glaucomatous visual field progression in the Advanced Glaucoma Intervention Study. Ophthalmology 2004;111(9):1627-1635.
7. Caprioli J, Coleman AL. Intraocular pressure fluctuation a risk factor for visual field progression at low intraocular pressures in the advanced glaucoma intervention study. Ophthalmology 2008;115(7):1123-1129.
8. Singh IP. Clinical outcomes after use of new combinations of topical antiocular hypertensive medications to maintain or lower IOP in patients with glaucoma. Poster, 2018 American Society of Cataract and Refractive Surgery Annual Meeting.
9. Kolko M, Jensen PK. The physical properties of generic latanoprost ophthalmic solutions are not identical. Acta Ophthalmol 2017;95(4):370-373.
10. Narayanaswamy A, Neog A, Baskaran M, et al. A randomized, crossover, open label pilot study to evaluate the efficacy and safety of Xalatan in comparison with generic latanoprost (Latoprost) in subjects with primary open angle glaucoma or ocular hypertension. Indian J Ophthalmol 2007;55(2):127-131.
11. Diagourtas A, Kagelaris K, Oikonomakis K, et al. Prospective study comparing Xalatan eye drops and two similar generics as to the efficacy and safety profile. Eur J Ophthalmol 2018;28(4):378-384.
12. Tatham AJ. The use of generic medications for glaucoma. J Ophthalmol 2020:1651265.
13. Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea. 2010;29(6):618-21.
14. Denis P, Lafuma A, Berdeaux G. Medical outcomes of glaucoma therapy from a nationwide representative survey. Clin Drug Invest. 2004; 24(6):343-352.