The concerns over preservatives, in particular benzalkonium chloride (BAK), used in ophthalmic solutions have been well documented.^1-7

BAK generally is well tolerated with short-term topical therapies (e.g., an antibiotic for bacterial conjunctivitis or a steroid for episcleritis), but glaucoma patients face long-term challenges. These patients can be maintained on glaucoma medications for several decades and their treatment plan often involves concurrent use of multiple BAK-containing drops. In the end, this translates to significant, cumulative exposure to BAK. What are the implications?

The Research
While most published studies outline the harmful effects of BAK on the ocular surface, some findings are less conclusive and perhaps even contradictory.⁸ Since much of the data available is lab-based or preclinical and uses non-human models, making the application to clinical practice can be challenging.

In 2010, Robert Noecker, MD, and Kimberly Miller, MD, published a summary of the BAK literature and its effects on the ocular surface––in particular as it pertains to glaucoma medications. They found the majority of the literature says BAK has an adverse effect on the ocular surface and recommended that practitioners should consider non–BAK-containing glaucoma medications to avoid these potential reactions.⁹

It has been noted that one shortcoming in many past clinical evaluations is the failure to include a control group. Sudipta Ghosh, DO, and colleagues recently compared the prevalence of symptoms and signs of ocular surface disease (OSD) in glaucoma patients vs. a control group. Symptoms of OSD were found to be common in both populations. However, signs of ocular surface disease, including fluorescein staining of the conjunctiva and cornea, were more prevalent in the glaucoma group (70.3% vs. 33%).¹⁰ Reduced tear film break-up time and the presence of ocular surface staining were more likely with each additional glaucoma medication used.

Commercially Available BAK-Free Topical Ocular Hypertensive Medications
Trade Name	Active Ingredient	Preservative	Contact Lens Wear (Per Drug Labeling)	Packaging
Alphagan P	Brimonidine	Purite	Not addressed	5, 10, or 15 mL
Cosopt PF	Timolol maleate 0.5%/Dorzolamide 2%	None	Not addressed	60 SUV (in foil packs) One pack = 15 SUV (0.2 mL each)
Timoptic in Ocudose	Timolol maleate 0.25% or 0.5%	None	Not addressed	60 SUV One pack = 60 SUV (0.2 mL each)
Timolol GFS	Timolol maleate 0.25% or 0.5%	Benzododecinium bromide	“Has not been studied in patients wearing contact lenses”	2.5 or 5 mL
Timoptic XE	Timolol maleate 0.25% or 0.5%	Benzododecinium bromide	“Has not been studied in patients wearing contact lenses”	5 mL
Travatan Z	Travoprost 0.004%	sofZia	Remove lens before instilling; wait 15 minutes before reinserting lens	2.5 or 5 mL bottle
Zioptan	Tafluprost 0.0015%	None	Not addressed	30 or 90 SUV (in foil packs) One pack = 10 SUV (0.3 mL each)
SUV = single vial unit

While 94.2% of the study used drops containing preservatives, the authors did not compare the effects of different preservatives.¹⁰ However, approximately 78% of ophthalmic pharmaceuticals contain BAK, leading to the conclusion that this preservative could be implicated as a contributing factor to the signs of OSD in the above study.¹¹

In a meta-analysis of seven prospective clinical trials, Stefan Trocme, MD, and colleagues failed to demonstrate significant ocular toxicity in patients treated with latanoprost or timolol, both containing BAK. They concluded that when BAK is used in the concentration available in glaucoma medications (0.004% to 0.02%), patients do not experience corneal toxicity.¹²

Charles Tressler, MD, Richard Beatty, MD, and Michael Lemp, MD, determined that dilution of BAK occurs quickly from a normal tear film; despite a BAK concentration of 0.02% (the highest concentration currently available in a glaucoma medication) upon instillation, it is reduced to 0.0025% in 30 seconds and to 0.00056% in three minutes.¹³

Therefore, corneal exposure time to any clinically significant concentration of BAK is very short-lived. It should be noted that the dilution would be less rapid in patients with dry eye, a common coexisting condition in glaucoma patients.¹³

Glaucoma patients who are also contact lens wearers face an additional challenge: The residence time the ophthalmic drop is in contact with the ocular surface increases. If BAK is irritating, the effects will be exacerbated in contact lens wearers who opt to instill their medications while wearing their lenses, despite warnings from eye care practitioners.

Therapeutic Options
• BAK-free options are now available in all classes of contemporary glaucoma medications (see Table 1), except the topical carbonic anhydrase inhibitors that include Trusopt (dorzolamide 2%, Merck) and Azopt (brinzolamide 1%, Alcon)—preserved with 0.0075% and 0.01% BAK, respectively. It should be noted that pilocarpine and Pilopine gel (pilocarpine hydrochloride, Alcon) contain BAK as well.

• Beta-blockers, although not typically used as initial treatment, still play a significant role in glaucoma management due to their reasonable cost and 20% to 25% efficacy in reducing IOP.¹⁴ Timoptic XE (timolol maleate, Valeant Pharmaceuticals) is formulated as a gel-forming solution; as such, it has a longer residence time than a solution in a once-daily drop. Both the branded and the generic (Timolol GFS, Falcon Pharmaceuticals) are preserved with benzododecinium bromide (BDD), which provides a multiuse container of a non-BAK containing beta-blocker. However, BDD and BAK are both quaternary ammonium surfactants and may have properties too similar to make BDD a feasible alternative for patients intolerant to BAK.

• Timoptic in Ocudose (timolol maleate, Aton Pharma) is available in 0.25% and 0.5% concentrations and is preservative-free. Available in prepackaged individual unit doses contained within a foil pack, the 60 vials are meant to last for one month with BID dosing and the vials are to be used within one month of opening the foil pack.

• Brimonidine, an alpha-agonist, is a well-tolerated medication that is typically prescribed twice daily when used as additive therapy. The branded drug, Alphagan P (brimonidine tartrate ophthalmic solution 0.1% or 0.15%, Allergan) is preserved with Purite, which is an oxychloro complex classified as a “disappearing preservation” that dissociates to water, and sodium and chloride ions once exposed to light. Note that the generic solutions contain either 0.15% of 0.2% of brimonidine and are preserved with BAK.

• Due to a significant incidence of allergic reactions and tachyphylaxis, Iopidine (apraclonidine, Alcon) is typically used only for in-office application. The 1% concentration is packaged only in single-unit vials of 0.1ml each, which contain 0.01% BAK.

• When monotherapy fails to sufficiently lower IOP, combinations are often attractive options. Cosopt (Merck) contains 0.5% timolol maleate and 2% dorzolamide; it is available in a preservative-free formulation. Typically used twice a day, this medication is available in a package of 60 single-unit vials. Each foil pack contains 15 vials. Per the manufacturer, once a foil pack is opened, unused single-unit vials should be discarded within 15 days.

• Due to excellent efficacy and tolerability, prostaglandins are often included in the management of patients with glaucoma and ocular hypertension. Travatan Z (travoprost 0.004%, Alcon) contains sofZia, an ionic-buffered system containing boric acid, propylene glycol, sorbitol and zinc chloride. These compounds break up into non-toxic ingredients when exposed to the ocular surface.

Zioptan (tafluprost 0.0015%, Merck) was approved in February 2012 and is the first preservative-free prostaglandin available in the US. The foil pouches contain 10 single-use vials, used once daily, with labeling that indicates the need to discard any vials within an opened foil pouch after 28 days. Cartons of 30- or 90-unit vials are available.

Should additional preservative-free medications be required, or if a patient needs a specific therapeutic agent not commercially available in a BAK-free formulation, consider a compounding pharmacy.

Remember that not all patients require BAK-free options. However, when patients use multiple drops, they are increasing their daily concentration of BAK—so, for contact lens wearers, patients with existing OSD or those with a known BAK sensitivity, consider avoiding the preservative. Fortunately, within the past year, there have been several new drug approvals to give us many BAK-free glaucoma options to help manage our glaucoma patients. 

1. Kusano M, Uematsu M, Kumagami T, et al. Evaluation of acute corneal barrier change induced by topically applied preservatives using corneal transepithelial electric resistance in vivo. Cornea. 2010 Jan;29(1):80-5.
2. McCarey B, Edelhauser H. In vivo corneal epithelial permeability following treatment with prostaglandin analogues with or without benzalkonium chloride. J Ocul Pharmacol Ther. 2007 Oct;23(5):445-51.
3. Ammar DA, Noekcer 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.
4. Whitson JT, Cavanagh HD, Lakshman N, Petroll WM. Assessment of corneal epithelial integrity after acute exposure to ocular hypotensive agents preserved with and without benzalkonium chloride. Adv Ther. 2006 Sep-Oct;23(5):663-71.
5. Kahook MY, Noecker R. Quantitative analysis of conjunctival goblet cells after chronic application of topical drops. Adv Ther. 2008 Aug;25(8):743-51.
6. Yamazaki S, Nanno M, Kimura T, et al. Effects of switching to sofZia-preserved travoprost in patients who presented with superficial punctate keratopathy while under treatment with latanoprost. Jpn J Ophthalmol. 2010 Jan;54(1):7-14.
7. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008 Aug;17(5):350-5.
8. Whitson JT, Trattler WB, Matossian C, et al. Ocular surface tolerability in prostaglandin analogs in patients with glaucoma or ocular hypertension. J Ocul Pharmacol Ther. 2010 Jun;26(3):287-92.
9. Noecker R, Miller K. Banzalkonium chloride in glaucoma medications. Ocul Surf. 2011 Jul;9(3):159-62.
10. Ghosh S, O’Hare F, Lamoureux E, et al. Prevalence of signs and symptoms of ocular surface disease in individuals treated and not treated with glaucoma medication. Clin Experiment Ophthalmol. 2012 Sep-Oct;40(7):675-81.
11. Abelson MB, Berdy GJ. BAK story. Ophth Management. 2009 Apr. Available at: www.ophthalmologymanagement.com/articleviewer.aspx?articleid=102798. Accessed March 2013.
12. Trocme S, Hwang LJ, Bean GW, Sultan MB. The role of benzalkonium chloride in the occurrence of punctate keratitis: a meta-analysis of randomized, controlled clinical trials. Ann Pharmacother. 2010 Dec;44(2):1914-21.
13. Tressler CS, Beatty R, Lemp MA. Preservative use in topical glaucoma medications. Ocul Surf. 2011 Jul;9(3):140-58.
14. Bartlett JD, Jaanus SD. Clinical Ocular Pharmacology. 5th ed. Philadelphia: Elsevier;2008:145-53.