Adherence to lifelong glaucoma treatment demands a lot 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 be physically successful in instilling the drops. That’s a lot to ask of patients, especially as they age and begin to have co-occurring health conditions or cognitive loss.
Numerous studies have shown that compliance decreases with more complex regimens of more than 1 or 2 vials. 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) increases1.2 (Figure 1 ). Then, in a vicious circle, 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. The HORIZON study [NCT04566445]examining the 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 treatment,5 found that patients who had surgical/laser procedures were less likely to progress to incisional filtration surgery for glaucoma. Even though we have drugs that theoretically offer the same IOP lowering effect as SLT or minimally invasive glaucoma surgery (MIGS), we are not taking full advantage of these drugs because patients simply do not use them. coherently.
More MIGS and SLT are part of the answer, but there will always be patients who will need to continue topical therapy instead of or in addition to these options. In my practice, I usually prescribe a commercially available brand name glaucoma medication first, and I can make that choice for the second bottle as well. These drugs have been rigorously tested by the FDA and are marketed accordingly.
However, as regimens become more complex with 3-4 drugs, or if there are cost and compliance issues with even 2 drops, I find fixed combination glaucoma drops (Simple Drops; ImprimisRx ) deal well with many factors that lead to poor adhesion. Although we have a few two-drug combinations in the United States, none of them include a ß-blocker with a prostaglandin analog (PGA), and none include more than 2 agents. Using Simple Drops, as the name suggests, allows me to simplify the regimen for the patient to just one bottle once a day or 1 bottle each for morning and evening. These medications are compounded in a Pharmacy Compounding Accreditation Board-accredited 503A patient-specific pharmacy that adheres to many of the same high manufacturing standards as its 503B facility. Each batch is tested for potency, sterility and endotoxins, so I can be sure that my patients are getting a high quality product.
IOP fluctuation is the problem
For many of our patients who are still progressing or have poorly controlled IOP with topical medications, the problem is not that the drops don’t work, it’s that their pressure fluctuates with inconsistent use of the medication. The Advanced Glaucoma Intervention Study (AGIS) demonstrated that long-term IOP fluctuation greater than 3.0 mm Hg is associated with visual field progression.6 Among AGIS patients with low mean IOP – those patients whose pressure seems fine when we see them in the office – the fluctuations increase the risk of progression by more than 3 times).seven Simplifying the regimen for these patients may stimulate compliance 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 in most types of patients, especially in those who were poorly controlled during their previous regimen of 3 or more bottles.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 that was still progressing on brimonidine/timolol (Combigan), brinzolamide (Azopt), and travoprost (Travatan). Her eyes were still 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 PGA to improve her symptoms ocular surface before surgery. At the next follow-up, her IOP was down to our 12 mm Hg target, her eyes were not red, and she was happy with the reduced drop load. Four years later, she is still on this diet and has been able to avoid filtering surgery.
Clarity of costs and ingredients
Another major reason to use Compound Combination Drops is to know what to expect and what it will cost the patient. If I prescribe 3 separate drugs to a patient, it is very difficult for me to answer his very reasonable question: “How much is it going to cost?” in a precise or transparent way. The cost to the patient could be $15 or $300, depending on their insurance coverage, co-pay, and form requirements.
Plus, they’re very likely to get generic substitutions from the pharmacy. The pH, viscosity and other aspects of the ingredients of the inactive vehicle can vary widely from generic to generic, significantly affecting the bioavailability and effectiveness of the active ingredient as well as the tolerability and safety of gout in general.9-12 There may even be considerable variability in the quality of the dropper bottle, causing the drops to spread too quickly and the patient to run out of supply for 30 days in a much shorter time frame.
Finally, compound drops also allow me to prescribe preservative-free formulations so that glaucoma medications do not contribute further to ocular surface toxicity. About half of our glaucoma patients suffer from OSD,13 and those with concurrent OSD are more likely to experience adverse effects from topical glaucoma treatment, more likely to be non-adherent, and more likely to progress.14 If we can minimize the effect on the ocular surface, we also maximize the chances of success with subsequent Xen implantation or filtration surgery if needed.
If cost, compliance, and generic substitution weren’t factors at all, I might prefer separate bottles of each brand name drug. But we have to recognize that patients don’t get what we prescribe and don’t consistently instill what they get, leading to IOP fluctuation and disease progression. A simplified fixed-combination glaucoma treatment regimen is a very welcome solution to these real-world problems.
Inder Paul Singh, MD
Email: [email protected]
Singh practices at Racine and Kenosha Eye Centers in Wisconsin. He is a consultant for many glaucoma companies, including Glaukos, ImprimisRx, and Ivantis, Inc.
- Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface diseases in patients with glaucoma. Glaucoma J. 2008;17(5):350-355.
- Rossi GCM, Pasinetti GM, Scudeller L, et al. Risk factors for developing ocular surface disease in patients treated for glaucoma or ocular hypertension. Eur J Ophthalmol. 2013;23(3):296-302.
- Baudouin C, Labbé A, Liang H, et al. Preservatives in eye drops: the good, the bad and the ugly. Retin Eye Res 2010;29(4):312-334.
- Ahmed IK, Rhee DJ, Jones J, et al, on behalf of the HORIZON investigators. Three-Year Results of the HORIZON Trial: A Schlemm Canal Microstent for Pressure Reduction in Primary Open-Angle Glaucoma and Cataract. Ophthalmology 2021;128(6):857-865.
- Gazzard G, Konstantakopoulou E, Garway-Heath D, et al. Selective laser trabeculoplasty versus eye drops for first-line treatment of ocular hypertension and glaucoma (LiGHT): multicenter randomized controlled trial. Lancet 2019;393:1505-1516.
- Nouri-Mahdavi K, Hoffman D, Coleman AL, et al; Glaucoma Advanced Intervention Study. Predictors of glaucomatous visual field progression in the advanced glaucoma intervention study. Ophthalmology 2004;111(9):1627-1635.
- Caprioli J, Coleman AL. Intraocular pressure fluctuation is a risk factor for visual field progression at low intraocular pressures in the Glaucoma Advanced Intervention Study. Ophthalmology 2008;115(7):1123-1129.
- Singh IP. Clinical results after the use of novel combinations of topical antiocular hypertensive drugs to maintain or lower IOP in patients with glaucoma. Poster, 2018 Annual Meeting of the American Society of Cataract and Refractive Surgery.
- Kolko M, Jensen PK. The physical properties of generic latanoprost ophthalmic solutions are not identical. Acta Ophthalmol 2017;95(4):370-373.
- Narayanaswamy A, Neog A, Baskaran M, et al. A randomized, open-label, pilot study to evaluate the efficacy and safety of Xalatan versus generic latanoprost (Latoprost) in subjects with primary open-angle glaucoma or ocular hypertension. Indian J Ophthalmol 2007;55(2):127-131.
- Diagourtas A, Kagelaris K, Oikonomakis K, et al. Prospective study comparing Xalatan eye drops and two similar generics in terms of efficacy and safety profile. Eur J Ophthalmol 2018;28(4):378-384.
- Tatham AJ. The use of generic drugs for glaucoma. J Ophthalmol 2020:1651265.
- Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical medications to reduce intraocular pressure. Cornea. 2010;29(6):618-21.
- Denis P, Lafuma A, Berdeaux G. Medical outcomes of glaucoma treatment from a representative national survey. Clin Drug Invest. 2004 ; 24(6):343-352.