Compounded medications are playing a central role in the process.
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. This is a lot to ask of them, 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 one or two bottles. Various studies have shown 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 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 intraocular pressure (IOP) control in our glaucoma patients. Both the HORIZON study, looking at implantation of Hydrus Microstents (Ivantis) 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 are not getting the full benefit of these medications because patients simply are not 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 United States Food and Drug Administration (FDA) trials and are marketed accordingly. However, as the regimens get more complex with three to four medications, or if there are cost and adherence challenges with even two 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 beta-blocker with a prostaglandin analogue (PGA), and none include more than two 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 one 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.
For many of our patients who are still progressing or have poorly controlled IOP on topical medications, the problem is not that the drops are not working; it is that their IOP 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 clinic—fluctuations increase the risk of progression more than three-fold.7 Simplifying the regimen for these patients can boost adherence enough to stabilise 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 three 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, Allergan), brinzolamide (Azopt, Novartis), and travoprost (Travatan, Alcon Laboratories). Her eyes were always red, and she told me she could not 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%; ImprimisRx) 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 were not 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.
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 three 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 non-adherent and more likely to progress.14 If we can minimise the effect on the ocular surface, we are also maximising 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 recognise that patients are not getting what we prescribe and are not 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.