With the advent of the prostaglandin analogues, a paradigm shift in the treatment of glaucoma and ocular hypertension was realized. Finally, a once-daily, well-tolerated, safe and efficacious medication was introduced into the treatment armamentarium for a potentially blinding optic neuropathy. Today, this description of the prostaglandin class continues to hold true for the vast majority of patients for whom we daily prescribe either latanoprost (Xalatan, Pfizer), bimatoprost products (Lumigan, Allergan) or travaprost products (Travatan, Alcon). The relative drawbacks have been local side effects such as hyperemia, iris and periorbital darkening, and eyelash growth, as well as the cost of the medications.1

The New, The Old, The Reformulated
Because the prostaglandin class is indispensable in the treatment of intraocular pressure, the past 15 years have seen various changes in the respective product lines to try to counteract side effects and cost.

Latanoprost, for example, is now available through multiple generic manufacturers. This substitution opens up access to patients who are self-pay or have high deductibles and/or co-pays for brand name medications. It is important to remember, however, that generic medications for the eye are not required to be tested by the FDA for bioequivalence or therapeutic equivalence, but only require the active ingredient to be identical to the brand.2 Inactive ingredients can alter the pH, the penetration, the viscosity and other characteristics of ophthalmic medications which can change the clinical efficacy and side effect profile of the drug. This fact should be taken into consideration for each individual patient and with each different generic manufacturer.

Bimatoprost is generally regarded as the most efficacious of the prostaglandin analogue ophthalmic class.3 Its original 0.03% formulation, however, also demonstrated increased amounts of hyperemia, which discouraged both physicians and patients from using it. In response, Allergan lowered the strength of Lumigan from 0.03% to 0.01% and changed the preservative concentration, with a resultant 65% less moderate to severe hyperemia and equivalent clinical efficacy.4 The 0.01% formulation allows for the known efficacy of brimatoprost with a much better side effect profile.

The original Travatan 0.004% was reformulated as Travatan Z as an option to agents containing benzalkonium chloride (BAK) as a preservative. The concentration of travaprost remained at 0.004% and the BAK was removed and replaced with sofziatim (SofZia), an ionic buffered preservative system. One study found that travoprost with SofZia was less toxic to corneal and conjunctival cells than those exposed to BAK-containing travoprost.5 The amount of hyperemia between Travatan and Travatan Z was unchanged at 30% to 50%.

Recently, another prostaglandin analogue was approved that will further entrench this medication class as the first-line treatment of glaucoma and ocular hypertension. The latest agent to be approved is called Zioptan (tafluprost 0.0015%, Merck) and offers the advantage of being completely preservative-free with the same clinical advantages we have come to expect from the prostaglandin class.6

Zioptan is packaged in unit-dose vials similar to Restasis (cyclosporine, Allergan) and other preservative-free ocular preparations and is recommended for once-daily administration at bedtime. The package insert recommends each vial be discarded immediately after opening because sterility cannot be maintained without a preservative. There is sufficient quantity in each vial for both eyes.

Typical of the topical prostaglandins, Zioptan’s most common adverse reaction is conjunctival hyperemia, reported to be between 4% and 20%—which is closer to the hyperemia profile of latanoprost.6,7 Multiple clinical trials with preservative-containing tafluprost have illustrated its efficacy, and at least one study shows the preservative-free formulation to be equivalent in IOP-lowering effect.8,9

Why Choose Preservative-Free?
It is important to remember that the hyperemia associated with the prostaglandin class is unrelated to the presence or type of preservative. In fact, the original Xalatan had the highest amount of BAK than any of the original three prostaglandin brands, but the lowest amount of reported conjunctival redness. Hyperemia is a side effect of the prostaglandin chemical structure.10

The reason prescribers should consider a preservative-free option is to avoid the toxicity and ocular surface disease inherent with the use of preservatives in general, especially when used chronically or in excess. Although true allergic reactions are rare, multiple daily applications of BAK and other preservatives have been shown to be toxic to corneal and conjunctival epithelial cells and could compound various ocular surface conditions such as dry eye syndrome.11 Patients who do not have an ocular surface disease and/or use monotherapy to control their intraocular pressure may not need a preservative-free option.

Various statistics indicate that our glaucoma patients have compliance rates as low as 50%.12 The most common causes of non-compliance include forgetfulness, medication cost, side effect profile and lack of understanding regarding this asymptomatic disease state. The aforementioned adjustments in the new prostaglandins class and the new tafluprost has paved the way for more affordable and/or better-tolerated medication, and will give prescribers the ability to use these agents on an even broader range of patients with glaucoma or ocular hypertension. Along with better education on our part, we hope to increase the ease of usage and the compliance of our patients in order to avoid the devastating effects of this optic neuropathy.

1. Alm A, Grierson I, Shields MB. Side effects associated with prostaglandin analog therapy. Surv Ophthalmol. 2008 Nov;53 Suppl1:S93-105.
2. Borgheini G. The bioequivalence and therapeutic efficacy of generic versus brand-name psychoactive drugs. Clin Ther. 2003 Jun;25(6):1578-92.
3. Holmstrom S, Buchholz P, Walt J, et al. Analytic review of bimatoprost, latanoprost and travoprost in primary open angle glaucoma. Curr Med Res Opin. 2005 Nov;21(11):1875-83.
4. Katz LJ, Cohen JS, Batoosingh AL, et al. Twelve-month, randomized, controlled trial of bimatoprost 0.01%, 0.0125%, and 0.03% in patients with glaucoma or ocular hypertension. Am J Ophthalmol. 2010 Apr;149(4):661-71.
5. Ammar DA, Noecker RJ, Kahook MY. Effects of benzalkonium chloride-preserved, polyquad-preserved, and sofZia-preserved topical glaucoma medications on human ocular epithelial cells. Adv Ther. 2010 Nov;27(11):837-45.
6. Zioptan [package insert]. Whitehouse Station, N.J.: Merck & Co, Inc; 2012.
7. Latanoprost [package insert]. Morgantown, W.V.: Mylan Pharmaceuticals Inc; 2010.
8. Aihara M. Clinical appraisal of tafluprost in the reduction of elevated intraocular pressure (IOP) in open-angle glaucoma and ocular hypertension. Clin Ophthalmol. 2010;4:163–70.
9. Hamacher T, Airaksinen J, Saarela V, et al. Efficacy and safety levels of preserved and preservative-free tafluprost are equivalent in patients with glaucoma or ocular hypertension: results from a pharmacodynamics analysis. Acta Ophthalmol Suppl (Oxf ). 2008;242:14-9.
10. Feldman R. Conjunctival hyperemia and the use of topical prostaglandins in gaucoma and ocular hypertension. J Ocul Pharmacol Ther. 2003 Feb;19(1): 23-35.
11. De Saint Jean M, Brignole F, Bringuier AF, et al. Effects of benzalkonium chloride on growth and survival of Chang conjunctival cells. Invest Ophthalmol Vis Sci. 1999 Mar;40(3):619-30.
12. Nordstrom BL, Friedman DS, Mozaffari E, et al. Persistence and adherence with topical glaucoma therapy. Am J Ophthalmol. 2005 Oct;140(4):598-606.