Predictable, branded steroids offer control over surgery

Achieving the best surgical outcomes means putting as much effort into choosing a consistent and predictable postoperative steroid as surgeons do into every other aspect of eye surgery. 

Special to Ophthalmology Times®

We do so much to standardize surgery and minimize variability. To produce reliably positive outcomes, we focus first on the preoperative assessment and biometry, and then on using surgical tools and techniques that help us achieve micron-level precision. We optimize the ocular surface before surgery and refine our minimally invasive surgical techniques to improve postoperative recovery.

After surgery, we need to apply the same control-focused mindset in prescribing a postoperative steroid. There is enough variability in generic steroids to potentially affect healing and IOP, challenge compliance, and even erode patient satisfaction in the month following surgery. We cannot let that happen to our patients, and we should not diminish all of the careful work we have done up to that point. 

No time for generics
To me, it is certainly not worth taking a chance with a generic steroid after surgery. Older generic drug formulations only needed to match the active ingredient of an original innovator or branded drug, not demonstrate equivalence. This included corticosteroids such as prednisolone acetate.^1,2

Today, generic drops still may not be 100% bioequivalent to their branded counterparts. Manufacturers are only required to prove 80% bioequivalence, matching only in the active molecule while free to differ significantly in where they outsource the vehicle, inactive ingredients and bottle make and construction. 

When good manufacturing processes are followed, the differences between branded and generic medications are minimal in ophthalmic solutions, where all of the active and inactive ingredients are dissolved. However, the common generic ophthalmic corticosteroids used today are formulated as suspensions, not solutions or emulsions. 

Branded drugs rely on advanced vehicles that improve a drug’s therapeutic properties. It is almost impossible to accurately duplicate these important vehicles because they rely heavily on certain milling and other manufacturing processes that affect the particle size, coating, mixing, and other vehicle characteristics.

A different vehicle and variation in the manufacturing process can cause several problems. The active molecule can settle in the new vehicle, so patients do not get the desired effect unless they shake the bottle, and patients have poor compliance with shaking the bottle postoperatively.

In addition, differing pH levels can affect absorption. Buffering agents can be inadequate. The ocular surface problems and other side effects of benzalkonium chloride (BAK) preservative can be greater because some generics may use higher concentrations of BAK than the branded alternative.

In short, a drop’s efficacy, safety and tolerance are affected by the vehicle and other inactive ingredients that make up most of the bottle. This relationship can be used to our advantage, such as when brimonidine tartrate 0.1% (Alphagan P, Allergan) was developed by changing the inactive ingredients in the brimonidine tartrate 0.2% drop. 

The preservative was changed, thereby increasing the pH, giving us half the concentration of active medication with the same efficacy and fewer side effects.

In addition, the concentration of bromfenac (Prolensa, Bausch +Lomb) was changed from 0.09% to 0.07% while maintaining efficacy by changing the pH of the vehicle. With generics, however, we do not consistently know how and from whom the manufacturer sources the inactive ingredients. There is no oversight of the bottle’s contents, so it is no surprise that efficacy and tolerability can vary. 

It should be noted that in many cases, there is little or no savings in purchasing a generic steroid drop. Many generics are very close in price to branded counterparts, and manufacturers of new branded drugs typically offer coupons. Even if there is some small savings, to me it is not worth it to add potential unpredictability to the surgical recovery process. 

We have tried to educate our patients to provide them with enough understanding of the differences between a branded and generic medication so they can make a better decision on their own if it is worth it for them to pay the potentially higher cost. Essentially, we place value on everything we purchase, so providing patients with this knowledge is crucial for them to make an informed decision. 

Avoiding pressure spikes
In addition to sticking to the predictability of branded drops, it is important for me to factor IOP control into the selection of a steroid. I routinely perform not only cataract surgery, but also almost every type of glaucoma procedure. 

I am concerned about pressure spikes in patients with glaucoma who undergo any kind of eye surgery, but I am most worried when they have surgery that does not address glaucoma. For example, in cataract surgery without a concomitant minimally invasive glaucoma surgery (MIGS), patients can get significant pressure spikes postoperatively. 

Many years ago, a study by Armaly showed a significant rise in pressure in 95% of primary open-angle glaucoma (POAG) patients treated with steroids.³ About 50% of POAG patients had an IOP above 40 mm Hg at two weeks. I have seen pressure rise within the first week in glaucoma patients on a certain steroids, such as difluprednate (Durezol, Novartis), an emulsion.

Related: Genetic variants linked with onset, progression of POAG

We also know that almost all low-tension glaucoma patients are steroid responders. We always need to be aware of that risk.³

Loteprednol is a molecule used to minimize that risk. I have long used loteprednol for cataract surgery with or without MIGS, trabeculectomy, canaloplasty, XEN (Allergan), Hydrus (Ivantis), and other MIGS procedures because I am very comfortable with both its efficacy and its comparatively low risk for pressure spikes. There used to be a misconception that because loteprednol did not cause the same rate of pressure spikes as prednisolone, it was not as powerful as other steroids, but now we understand that this is not the case. It delivers the necessary efficacy with lower risk to IOP.^4-6
 

Unique formulation, BID dosing
After years of using loteprednol postoperatively, I was very comfortable trying a new formulation comprised of loteprednol nanoparticles with a mucus-penetrating surface coating (Inveltys, Kala Pharmaceuticals), an ophthalmic suspension, which offers better penetration of the mucin layer and cornea as well as less elimination with tears.

The vehicle keeps the nanoparticles with their proprietary coating equally distributed in solution, playing an important role in ensuring patients get the amount of medication they need.

The drop’s improved bioavailability of active medication in the anterior chamber makes it possible to get the same results with BID dosing I had with other suspension steroid formulations with QID dosing. In my opinion, we cannot underestimate the value of a BID drug versus a QID drug for improving compliance.

As a glaucoma specialist, I always deal with eye drop compliance problems, from physical limitations to forgetfulness to ocular surface discomfort. Any time I can decrease the number of medications on the eye, I take that opportunity. BID dosing is simpler, so there’s less room for patient confusion and compliance errors. 

Patients appreciate the convenience as well. We asked our patients, three months after cataract surgery when everything is healed, if any factor negatively affect their happiness with this experience. Their top problem was taking so many drops every day after surgery. Now they can use fewer drops. And there’s no tapering-just BID dosing until the bottle runs out. 

This makes the regimen is less confusing throughout recovery, and it is an especially welcome change when patients have the fellow eye done and can follow the same schedule for both eyes.

In fact, simplifying the regimen to BID dosing has actually saved us 2 to 3 minutes of staff time normally spent verifying the tapering medications for the first eye and educating patients about the dosing schedule, which, in turn, improved office flow in general. 

Branded versus generic 
Last year, I saw a patient who had used generic prednisolone acetate after cataract surgery. She was happy at one week with 20/25 vision, but unhappy at two weeks with 20/60 vision. Prednisolone was reducing inflammation, but the generic formulation was aggravating the ocular surface and affecting her vision. (See Figure 1)

Inveltys had just been released, so I prescribed it after doing her second eye two weeks later. She was 20/20 and happy at one week, and the ocular surface looked much better compared to the prednisolone acetate eye. 

It is not a direct comparison-these drops have two different active molecules-but the case illustrates just how destructive the generic vehicle can prove to be.

The detrimental effects of some generic formulations are not always so pronounced and may not always be clinically significant, but the possibility is always there.

By carefully choosing a branded steroid, we get an approach that works clinically, improves compliance (which can make our patients happier), and also saves us time-all while delivering the reliable control over postoperative recovery that we all want. And when significant pharmacological advances come along to help our patients, we are not limited to older generic options. 

Inder Paul Singh, MD
E: ipsingh@amazingeye.com
Dr. Singh is president of the Eye Centers of Racine and Kenosha, Racine, WI. 

References:

Roberts CW, Nelson PL. Comparative analysis of prednisolone acetate suspensions. J Ocul Pharmacol Ther. 2007 Apr;23(2):182-7.

Walsman AM, Antes A, Rescigno RJ, Lutz D, Lama PJ. What is in a drop? Brand versus generic prednisolone acetate formulations: A quantitative analysis. Investigative Ophthalmology & Visual Science. ARVO Annual Meeting Abstract. 2007 May;48(13):5825.

Armaly MF. Effect of corticosteroids on intraocular pressure and fluid dynamics. I. The effect of dexamethasone in the normal eye. II. The effect of dexamethasone in the glaucomatous eye. Arch Ophthalmol. 1963 Oct;70:482-99.

Pleyer U, Ursell PG, Rama P. Intraocular pressure effects of common topical steroids for post-cataract inflammation: Are they all the same? Ophthalmol Ther. 2013 Dec; 2(2): 55–72.

Fong R, Leitritz M, Siou-Mermet R, Erb T. Loteprednol etabonate gel 0.5% for postoperative pain and inflammation after cataract surgery: Results of a multicenter trial. Clin Ophthalmol. 2012;6:1113–1124. 

Rajpal RK, Roel L, Siou-Mermet R, Erb T. Efficacy and safety of loteprednol etabonate 0.5% gel in the treatment of ocular inflammation and pain after cataract surgery. J Cataract Refract Surg. 2013;39:158–167.