Glaucoma Medical Therapy Simplified Through Compounded Medications

Glaucoma Medical Therapy Simplified Through Compounded Medications

January 12, 2022

Glaucoma is an optic neuropathy in which damage to the retinal ganglion cells and their axons can result in blindness. It is the second leading cause of blindness worldwide.

The exact etiology of the degenerative damage to the optic nerve seen in glaucoma is multifactorial, and risk factors include older age, increased cup-to-disc ratio of the optic nerve, a thin central cornea, family history, and increased Intraocular Pressure (IOP).

IOP is the only known modifiable risk factor; the greater the IOP, the faster damage progresses. Glaucoma treatment is therefore focused on reducing IOP through surgery, laser, or pharmacological therapy, and medications are generally the first step.

The goal of treatment in glaucoma and ocular hypertension is to reduce intraocular pressure (IOP) to a target pressure sufficiently low to prevent glaucomatous progression.

The most commonly used classes of IOP-lowering medications are the prostaglandin analogs, beta-adrenergic receptor antagonists (beta-blockers), alpha adrenergic receptor agonists (alpha agonists), and carbonic anhydrase inhibitors (CAIs).

For many patients, a single medication is insufficient to reduce IOP to the target pressure, and the treatment regimen includes 2, 3, or more medications from different classes.

While the initial approach to adult glaucoma is often surgical and often involves early cataract extraction to lower IOP and accompanying angle surgery to restore outflow via Schlemm’s canal, some patients refuse or fail surgery and require multiple medications for disease management.

Often, more than one medication is needed to meet and maintain the target IOP, and effectiveness of treatment is limited by treatment adherence. Medications also have the active ingredients and preservatives that can lead to ocular erythema and conjunctivitis, further reducing compliance.

Compounding multiple topical agents into a single solution has several benefits when compared with monotherapy: reduced burden of therapy, cost savings, reduced exposure to preservatives, and easier use.

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.

Then, in a vicious cycle, patients with OSD become even less adherent. More than ever, we are now beginning to appreciate the eff ect of adherence on longterm IOP control in our patients with glaucoma.

Both the HORIZON study (NCT0466445), looking at implantation of Hydrus Microstents at the time of cataract surgery, and the LiGHT study (ISRCTN32038223), in which first-line selective laser trabeculoplasty (SLT) was compared with medical therapy, 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 our practice, we typically prescribe a branded, commercially available glaucoma drug first, and we 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, we 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 confi dent 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 are not 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.

Among AGIS patients with low mean IOP—those patients whose pressure looks fi ne when we see them in the office—fluctuations increase the risk of progression more than 3-fold.

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 fi ltering 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 we 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 aff ecting the bioavailability and effi cacy of the active ingredient and the tolerability and safety of the drop overall.

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.

Preservative-free formulations

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 patients with glaucoma have OSD, and those with concomitant OSD are more likely to experience adverse eff ects from topical glaucoma therapy, more likely to be nonadherent, and more likely to progress.

If we can minimize the effect on the ocular surface, we also are maximizing the chances of success with later Xen implantation or fi ltration 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 are not getting what we prescribe and are not consistently instilling the medications that 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.

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