Preservative-Free Alternatives

Options for decreasing ocular toxicity in patients with glaucoma.

By Arkadiy Yadgarov, MD, and Reena A. Garg, MD

Topical therapy is typically first-line treatment for patients with newly diagnosed glaucoma. All multidose ophthalmic medications are required to have a preservative to maintain an antimicrobial environment in the bottle, making it important for eye care providers to understand the effects of preservatives on the ocular surface.1 Unfortunately, most preservatives in ophthalmic medications disrupt the ocular surface and exacerbate preexisting ocular surface disease (OSD).2,3 Benzalkonium chloride (BAK) is the most widely used preservative in antihypertensive topical medicines, and many studies have clearly demonstrated BAK’s toxic effects on corneal and conjunctival epithelium.4,5 Although most antiglaucoma eye drops are manufactured with very little BAK, doses as small as 0.0001% are toxic to ocular tissue.5


• The prolonged use of eye drops preserved with benzalkonium chloride (BAK) is a strong risk factor for ocular surface disease in patients with glaucoma.

• In the past decade, the pharmaceutical industry has sought to address the need for BAK-free options to reduce ocular surface disease and increase patients’ comfort. These options fall into two categories: BAKfree preserved medicines (using alternative preservatives to BAK) and preservative-free medicines.

• Reducing patients’ overall preservative load may improve adherence, quality of life, and the patientdoctor relationship.

Because glaucoma is a chronic disease, the initiation of topical therapy also begins a patient’s long-term exposure to preservatives. The prolonged use of BAK-preserved drops is a strong risk factor for OSD in patients with glaucoma.6 Furthermore, the toxic effect of BAK is additive, and patients who must use two or more medications have worse OSD.6-8

It is no surprise, then, that the prevalence of OSD among individuals with glaucoma is high, with roughly half of all patients on long-term glaucoma therapy reporting adverse ocular symptoms.7,8 There is thus a clear need for BAK-free glaucoma treatment options to minimize OSD and to improve patients’ quality of life. Goldberg at al found that patients who switched to BAK-free medications needed fewer lubricant drops and reported an improvement in dry eye symptoms. The study also showed no significant change in IOP from prestudy levels.9

Fortunately, in the past decade, the pharmaceutical industry has sought to address the need for BAK-free options to reduce OSD and improve patients’ comfort. These products fall into two categories: BAK-free preserved medicines (using alternative preservatives to BAK) and preservative-free medicines (Tables 1 and 2).


The goal with these products is to maintain an antimicrobial environment in a multidose container while minimizing toxicity to the ocular surface. The two options currently available in the United States are Travatan Z (travoprost ophthalmic solution 0.004%; Alcon) and Alphagan P (brimonidine tartrate ophthalmic solution, 0.1% or 0.15%; Allergan).

Travatan Z is preserved with SofZia, which contains borate, zinc, and sorbitol. SofZia causes microbial death through oxidative damage. When exposed to the tear film, SofZia is inactivated by enzymes.10 In one study, Travatan Z resulted in less keratopathy and less conjunctival hyperemia than did travoprost preserved with BAK.11

Alphagan P is preserved with Purite, a stabilized oxychloro complex that has broad antimicrobial activity through oxidative damage. When the drop is instilled into the eye, light exposure causes the stabilized oxychloro complex to dissociate into nontoxic natural tear components. Noecker et al showed that brimonidine Purite 0.15% produced less conjunctival lymphocytic infiltration than latanoprost, timolol, or dorzolamide.12

Watch it Now

Sheri Rowen, MD, and Steven Vold, MD, discuss identifying and preventing dry eye disease in glaucoma patients in this episode of Glaucoma Today Journal Club.


Three topical glaucoma medications completely free of preservatives are available in the United States: Zioptan (tafluprost ophthalmic solution 0.0015%; Akorn), Cosopt PF (dorzolamide-timolol ophthalmic solution 2%/0.5%; Akorn), and Timoptic in Ocudose (timolol maleate ophthalmic solution 0.25% and 0.5%; Valeant Pharmaceuticals). Because of the lack of antimicrobial activity in the solution, all of these products are supplied as a sterile solution in a single-use container. Once it is opened, medication is applied to the eye, and patients should then immediately discard the container and its remaining contents. Zioptan must be stored refrigerated at 2º to 8°C (36º-46°F).

All three preservative-free solutions were better tolerated than their BAK-preserved counterparts. They decreased ocular surface inflammation, improved tear osmolarity, and reduced dry eye complaints.13,14

The major disadvantage of preservative-free therapy is its cost. For example, at as of this writing, a month’s supply of generic latanoprost cost roughly $20 cash with a coupon compared to $180 with a coupon for a month’s supply of Zioptan. Another potential drawback is that patients with poor dexterity may have difficulty handling the small containers. Finally, the risk of contamination is a concern, especially if a patient saves excess solution for later use.15


Clinicians encounter patients with burning, watery, irritated eyes all too often. It is therefore important to consider the effect of IOP-lowering drops’ preservatives on the ocular surface, especially among patients with a history of dry eye disease (see Watch It Now). Reducing the overall preservative load may improve adherence, quality of life, and the patient-doctor relationship. Several BAK-free preserved medicines and preservative-free products are available. These topical solutions have been proven to improve ocular tolerance without a reduction in efficacy. n

1. Food and Drug Administration. Guidance for industry—container and closure system integrity testing in lieu of sterility testing as a component of the stability protocol for sterile products. Rockville, MD: 2008;1-9.

2. Kuppens EV, de Jong CA, Stolwijk TR, et al. Effect of timolol with and without preservative on the basal tear turnover in glaucoma. Br J Ophthalmol. 1995;79(4):339-342.

3. Baudouin C, Pisella PJ, Fillacier K, et al. Ocular surface inflammatory changes induced by topical antiglaucoma drugs: human and animal studies. Ophthalmology. 1999;106(3):556-563.

4. Cha SH, Lee JS, Oum BS, Kim CD. Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro. Clin Experiment Ophthalmol. 2004;32(2):180-184.

5. 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;40(3):619-630.

6. Rossi GC, Pasinetti GM, Scudeller L, et al. Risk factors to develop ocular surface disease in treated glaucoma or ocular hypertension patients. Eur J Ophthalmol. 2013;23(3):296-302.

7. Fechtner RD, Godfrey DG, Budenz D, et al. Prevalence of ocular surface complaints in patients with glaucoma using topical intraocular pressure-lowering medications. Cornea. 2010;29(6):618-621.

8. Leung EW, Medeiros FA, Weinreb RN. Prevalence of ocular surface disease in glaucoma patients. J Glaucoma. 2008;17(5):350-355.

9. Goldberg I, Graham SL, Crowston JG, d’Mellow G; Australian and New Zealand Glaucoma Interest Group. Clinical audit examining the impact of benzalkonium chloride-free anti-glaucoma medications on patients with symptoms of ocular surface disease. Clin Experiment Ophthalmol. 2015;43(3):214-220.

10. 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;27(11):837-845.

11. Aihara M, Otani S, Kozaki J, et al. Long-term effect of BAK-free travoprost on ocular surface and intraocular pressure in glaucoma patients after transition from latanoprost. J Glaucoma. 2012;21(1):60-64.

12. Noecker RJ, Herrygers LA, Anwaruddin R. Corneal and conjunctival changes caused by commonly used glaucoma medications. Cornea. 2004;23(5):490-496.

13. Janulevicene I, Derkac I, Grybauskiene L, et al. Effects of preservative-free tafluprost on tear film osmolarity, tolerability, and intraocular pressure in previously treated patients with open-angle glaucoma. Clin Ophthalmol. 2012;6:103-109.

14. Jaenen N, Baudouin C, Pouliquen P, et al. Ocular symptoms and signs with preserved and preservative-free glaucoma medications. Eur J Ophthalmol. 2007;17(3):341-349.

15. Rosin LM, Bell NP. Preservative toxicity in glaucoma medication: clinical evaluation of benzalkonium chloride-free 0.5% timolol eye drops. Clin Ophthalmol. 2013;7:2131-2135.

Reena A. Garg, MD
•assistant professor of ophthalmology, New York Eye and Ear
•Infirmary of Mount Sinai, Icahn School of Medicine at Mount
Sinai, New York
(212) 231-3355; Twitter @ReenaGargMD
•financial interest: none acknowledged

Arkadiy Yadgarov, MD
•glaucoma fellow, New York Eye and Ear Infirmary of Mount Sinai,
Icahn School of Medicine at Mount Sinai, New York
•financial interest: none acknowledged


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