BAK in Topical Eyedrops: Should You Be Concerned?
The answer is complicated and several factors must be considered.
BY ROBERT J. NOECKER, M.D., M.B.A.
Topical medications currently used in clinical practice may often contain benzalkonium chloride (BAK). This compound acts primarily as a preservative, preventing microbial contamination of the multiuse bottles of eyedrops. BAK is compatible with most therapeutic compounds delivered topically to the eye and is readily available to all manufacturers. Because it has detergent-like properties, it can also help some less soluble agents remain in solution when present in adequate concentrations. As a result, the amount of BAK may vary from preparation to preparation.
Studies have shown that frequent application of BAK-containing artificial tears can cause disruption of the corneal epithelium. As result of this evidence, a myriad of non-BAK preserved artificial tears have been introduced while at the same time, some BAK-preserved brands are no longer available. This article will discuss the possible effects of prolonged exposure to BAK on the ocular surface and provide guidance, based on the available evidence, to clinicians who are questioning the safety of long-term BAK usage.
BAK in Glaucoma Medications
The advantages to BAK as a preservative include that it is relatively easy to work with, remaining stable at a wide range of pHs, and does not change the physical properties of the vehicles used in ophthalmic preparations. Additionally, spoilage is preventable when even relatively low levels of BAK are present in the bottle.
However, prolonged exposure to higher amounts of BAK has been shown to cause inflammatory changes to the ocular surface and perhaps underlying tissues.1 Furthermore, situations in which the ocular surface is already compromised may be the settings in which clinical damage is most readily induced. This is most apparent in disease states such as dry eye or other ocular surface conditions. In situations in which the tear film is not functioning properly or is inadequate in volume, frequent supplementation with artificial tear preparations may be necessary or desirable.
It has been demonstrated in many studies that BAK can be toxic to human and animal ocular tissues.2 While toxicity to BAK is nowhere near that seen with preservatives used in the past, such as thimerosal (an organomercury compound that had a high rate of allergic reactions), BAK has been thought to be a cause of chronic inflammation in some clinical situations. The degree of exposure to BAK seems to make a difference in whether a clinical problem may result. This may explain the disconnect between controlled laboratory studies and real-world clinical practice.
Until recently, there have been no viable alternative preservatives to BAK available in commercial ophthalmic preparations. However, there are now many ophthalmic preparations that are using oxidizing preservatives instead of BAK. While these preservatives are slightly less toxic to micro-organisms, they are significantly less toxic to mammalian cells than BAK. These compounds have been demonstrated to be minimally toxic to the ocular surface when used in usual dosing regimens. As a result, they have successfully been used chronically in several preparations resulting in few adverse effects on the ocular surface and, in some cases, improvement of the ocular surface.3
| Maintain a Healthy Ocular Surface in Glaucoma |
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BY CHRISTOPHE BAUDOUIN, M.D., Ph. D. Pharmaceutical companies make valuable (and expensive) efforts to develop efficient and safe drugs. Most clinical trials conclude in the short term to an acceptable efficacy/tolerance ratio, and authorities, as well as most glaucoma experts, based on those studies, consider that drug-induced side effects to the ocular surface are not a major concern and are almost never considered as a relevant topic in the literature and at major glaucoma meetings. However, clinical trials are not indicative of real-life situations and clinical practice shows that the ocular surface is almost as important to consider in glaucoma management as are trabecular meshwork, IOP or the optic nerve. A small, but increasing, number of glaucoma specialists in the world are concerned with the ocular tolerance of topical drugs and are focusing their efforts on the role of the preservative as the primary, albeit not the sole, cause of toxic side effects. Indeed, a large body of evidence exists from experimental and clinical studies showing that the long-term use of topical drugs may induce major ocular surface changes. Many clinical manifestations associated with a low-grade chronic inflammation have been described in patients receiving antiglaucoma treatments for long periods of time.1 Glaucoma treatment may cause chronic inflammation or aggravate a concomitant ocular surface disease. In clinical practice, glaucoma treatment often continues for decades. Patients may present with pre-existing ocular surface impairment, such as dry eye, meibomian gland dysfunction or chronic allergy, and are very frequently treated with two or more topical ophthalmic formulations. Indeed, the Ocular Hypertension Treatment Study reports that 40% of patients were using more than one drug after 5 years, and the Collaborative Initial Glaucoma Treatment Study showed 75% of patients using two or more drugs within 2 years of initial glaucoma treatment. These findings explain that clinical practice often does not fit the apparent safety profiles of drugs tested in clinical trials for short period of time, alone and only in patients without active ocular surface disorders. Evidence of Deleterious Effects The need for sterility in multidose eyedrops lead to the inclusion of an antimicrobial preservative in these solutions, most frequently the quaternary ammonium benzalkonium chloride (BAK). In some patients — and with long-term treatments — allergic or inflammatory reactions are experienced, including redness, stinging, burning, irritation, eye dryness or, less frequently, conjunctivitis or corneal damage. These effects are unlikely to be due to the active ingredients in all cases, because toxicity of the preservatives has been well documented experimentally as well as the harmlessness of most active compounds when unpreserved. BAK-containing eyedrops reduce the stability of the tear film via a detergent effect on the lipid layer that increases the rate of tear evaporation. These alterations to the function of the tear film are associated with a conjunctival inflammatory response and an epithelial metaplasia affecting goblet cells and transmembrane mucins. Ocular surface biopsies from glaucoma patients on long-term treatment show a reduction of almost 50% in the density of goblet cells, and conjunctival abnormalities have been observed in healthy controls after just 3 months treatment with BAK. A range of conjunctival epithelium changes is also observed in long-term users of antiglaucoma medication.2 These include conjunctival epithelium metaplasia, inflammatory infiltrates throughout the conjunctiva, increased release of proinflammatory cytokines and overexpression of immune-associated markers,3 such as HLA DR, interleukins or receptors associated to TH1 and TH2 cells. Immunohistochemical studies have indicated progressive subconjunctival fibrosis can occur, even without clinical signs of intolerance, which could directly influence the outcome of filtration surgery. The success rate of surgery thus varies widely, from 90% in previously non-treated patients down to 45% in patients receiving long-term treatments.4 Hence, it appears that prolonged use of topical antiglaucoma medications can compromise trabeculectomy. Given that ocular toxicity of preservatives is well documented in a large variety of experimental or in vitro studies,5 it seems highly likely that preservatives, particularly BAK, are associated with a higher risk of trabeculectomy failure. The use of preserved eyedrops thus induces side effects of variable intensity and severity, which affect the ocular surface as well as deeper ocular structures, and are not fully the reflection of short-term clinical trials. These side effects can decrease treatment compliance and may enhance the failure of glaucoma surgery, resulting in inadequate control of intraocular pressure in glaucoma patients. Studies both in vitro and in vivo have widely demonstrated that exposure to preservatives (even at low doses) results in histological, inflammatory and toxic changes at the surface of the eye. Therefore, on the basis of all these experimental and clinical reports, it is advisable to use BAK-free solutions whenever these are available on the market. All efforts from experts, companies and authorities worldwide to discuss, investigate and decrease or, whenever possible, suppress the impact of preservatives in patients treated over the long term should therefore be encouraged and, of course, congratulated. References
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| Christophe Baudouin, M.D., Ph.D., is professor and chair of the Department of Ophthalmology III at Quinze-Vingts National Ophthalmology Hospital in Paris. |
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| There are now many ophthalmic preparations that are using oxidizing preservatives instead of BAK. |
The amounts of BAK contained in currently used preparations for glaucoma vary tremendously, ranging from the highest level (0.02% in latanoprost [Xalatan, Pfizer]) to 0.005%, as seen in multiple newer products.4 No clear-cut reason exists as to why the amount of BAK is so variable in many preparations, but it appears that there is a trend toward more BAK in older preparations and less in more recently introduced medications.
Clinical Implications and Significance
Clinically, what does this mean for our glaucoma patients? The answer is multi-factorial. While laboratory studies can be well controlled, it can be much more difficult to discern meaningful differences in the human population. There is tremendous variability in the state of individuals' ocular surfaces, and putting different compounds on them may be deleterious, neutral or even beneficial. The addition of a preservative, such as BAK, may affect how an individual's ocular surface reacts to an eyedrop.
In terms of efficacy in lowering IOP, BAK does not seem to have a significant beneficial effect.5 Studies have shown that various beta blockers with and without BAK did not behave differently in extent and duration of IOP lowering. For some active ingredients, it is possible that BAK may even have an adverse effect on drug delivery into the eye. Studies on different formulations of brimonidine showed that a BAK-containing formulation of a higher 0.2% concentration of active drug lowered IOP equally as 0.1% and 0.15% brimonidine (Alphagan, Allergan) formulas preserved with a non-BAK preservative.
The most significant concern regarding BAK in topical medications is that it may cause chronic inflammation when used over a period of time. In the short term there may be a reduction of tear breakup time, which may translate into a foreign-body sensation for a period of time after instillation of an eyedrop.6 This effect is transient and may or may not be noticed by the patient, depending on the baseline state of the tear breakup time. Other factors, such as pH of the solution, or other components of the vehicle, such as the viscosity agent, may have more impact on patient comfort immediately after instillation of the drop.
The changes that occur over the longer term, i.e., months and years, are the major concern with BAK. Conjunctival biopsy studies performed on humans following years of glaucoma medication use show that a dose response effect can be demonstrated regarding the presence of inflammatory cells in the subepithelial conjunctival stroma. In a study by Badouion and colleagues,7 conjunctival biopsies were conducted on three different groups of patients: those that had used timolol alone for at least 1 year; those who were using multiple glaucoma medications for more than 1 year; and those who had not used glaucoma medications. The authors found that the presence of subconjunctival inflammatory cells could be consistently correlated to the amount of BAK-containing medication being applied to the ocular surface.
| The importance of BAK-induced effects in and around the human eye over long periods of time are unclear. |
More controlled rabbit studies have shown that the number of conjunctival inflammatory cells present after chronic dosing could be correlated to the concentration and amount of BAK used with monotherapy. In a study using more modern glaucoma agents, including latanoprost, bimatoprost (Lumigan, Allergan), brimonidine purite, dorzolamide (Trusopt, Merck), and timolol maleate, as monotherapy in typical dosing patterns, the effect of the concentration of BAK in individual medications was shown to be correlated to the presence of inflammatory cells in the subepithelial conjunctiva. The changes were evident after only 1 month of therapy with the glaucoma agents.
The importance of BAK-induced effects in and around the human eye over long periods of time are unclear. In truth, there are probably some people for whom these effects are important and others for whom there is not a discernable difference among exposure to a high amount, a low amount or no BAK. Clinically, we have seen patients who are intolerant to BAK in the form of an allergy to that compound alone vs. an allergy to the active ingredient. Also, there are some patients in whom the ocular surface is so compromised that the slightest amount of preservative can cause visible changes even in the short term, but lead to surface breakdown with longer-term use. When combined with the toxicity associated with some of the active ingredients used in glaucoma medications, the effects can be significant.
Weighing the Options
Benzalkonium chloride in glaucoma medications is sometimes a necessary evil. Some of the compounds that are commonly used today are not completely compatible with newer preservatives. Making novel non-preserved medications may not be possible without the use of BAK to increase the stability of the medication in aqueous solution. Also, non-preserved solutions usually need to be administered in unit dose vials, which increase the expense and difficulty of administration of the therapy. Therefore, the downside of using BAK is outweighed by the other more desirable attributes of the therapy.
In the real world, the benefits of using a BAK-free glaucoma medication are difficult to appreciate. Other than the reduction of tear breakup time in some patients, the short-term effects are few and an individual may actually experience more side effects due to the active ingredient of the medication or the other components of the vehicle. For instance, if the pH is lower in the non-BAK formulation, some individuals may experience more stinging. If other parts of the vehicle are changed, blurring may occur due to a difference in viscosity.
Most importantly, other inherent properties of a glaucoma medication may not be affected by the BAK or other preservative that is used. For instance, hyperemia, or short-term dilation of conjunctival blood vessels due to medication installation, is typically not a short-term side effect caused by BAK. Hyperemia is associated with the active ingredient in several glaucoma medications, including the prostaglandin analogues, the most commonly used medications today.8 The incidence of clinically apparent short-term hyperemia is not correlated to the amount of BAK in the preparation, and in fact, BAK may have a protective short-term effect that actually minimizes hyperemia.
How Much BAK Is a Problem?
For the most part, the benefit of avoiding BAK comes in the longer term. The minimization of exposure helps to avoid chronic conjunctival inflammation due to the use of topical glaucoma therapy. Avoiding BAK does not reverse pre-existing inflammation, especially that due to other causes such as dry eye. However, if removing the exposure to BAK contained in a medication occurs through a therapy switch, the BAK-related inflammation may be reversible over time.
Another question about BAK that is less easy to answer is where the cutoff level in terms of clinical relevance is. Most studies have looked at high concentrations of BAK vs. none at all. But exactly where the cutoff is for an individual is no one knows. Is a very low level acceptable? Or is any BAK bound to cause problems over time? One study that looked at the dose effect with multiple medications found somewhat of a dose effect. In patients using multiple medications with BAK for at least 1 year, almost all had detectable inflammatory cells present in the conjunctiva. In another group in which the patients were only on one medication for at least a year, inflammatory cells were present in 60% of biopsies vs. only about 20% of patients on no medications. However, the drugs involved had moderate to high levels of BAK. There are no human studies that look at medications with very low BAK concentrations on the rate of conjunctival inflammation. So clinically, some patients may tolerate lower levels of BAK well, while others may not tolerate any, depending on pre-existing ocular surface condition.
No Easy Answer
Many glaucoma patients are on multiple medications, so does eliminating or minimizing BAK in one make a difference if the others contain high amounts of BAK? While there are no data to support minimizing BAK, in theory if the strategy is to eliminate BAK, it is currently possible for some patients to be on three different classes of medications without BAK and maintain good IOP control. Once again, the practicality of doing this must be balanced against the efficacy of the drugs.
Finally, does any of this matter very much in the treatment of glaucoma? Glaucoma is a disease state in which the only proven therapy is to lower IOP, be it through medical, laser or surgical treatment. Efficacy is still the most important variable in glaucoma therapy, while safety, tolerability and cost are secondary factors that can make or break a given treatment regimen. Once again, the clinician must make the decision for an individual patient whether or not the benefit is outweighed by the cost. If similar efficacy can be achieved with a drug with BAK that is on second tier status of a formulary at $20/month, is it worth it to change a patient to a drug without BAK that has third tier status at $50/month? For some patients, like those with severe dry eyes, the difference may be significant enough to pay the premium price, while for others without signs or symptoms of a problem, the benefit may be not enough to justify the premium.
The available evidence indicates that the presence of BAK in a glaucoma regimen should be minimized if possible. For some patients, high amounts of BAK might have deleterious effects that could cause a significant decrease in a patient's quality of life or result in failure of treatment. However, for different patients, the clinical impact of BAK may be secondary to other features of the medication. Physicians should note the presence and amount of BAK in glaucoma medications and address its use appropriately in the clinical setting. OM
References
- Broadway DC, I. Grierson I, O'Brien C, Hitchings RA. Adverse effects of topical antiglaucoma medication. Arch Ophthalmol. 1994;112:1437-1445.
- Guenoun JM, Baudouin C, Rat P, Pauly A, Warnet J-M, Brignole-Baudouinet F. In vitro study of inflammatory potential and toxicity profile of latanoprost, travoprost, and bimatoprost in conjunctiva-derived epithelial cells. Invest Ophthalmol Vis Sci. 2005;46:2444-2450.
- Noecker RJ, Herrygers, LA. Effect of preservatives in chronic ocular therapy. Clinical & Surgical Ophthalmology. 2003;1/21:3.
- Pisella PJ, Debbasch C, Hamard P, et al. Conjunctival proinflammatory and proapoptotic effects of latanoprost and preserved and unpreserved timolol: an ex vivo and in vitro study. Invest Ophthalmol Vis Sci. 2004;45:1360-1368.
- Lewis RA, Katz G, Weiss MJ, et al. Travoprost 0.004% with and without benzalkonium chloride: a comparison of safety and efficacy. J Glaucoma. 2007;16:98-103.
- Baudouin C, de Lunardo C. Short term comparative study of topical 2% cartelol with and without benzalkonium chloride in healthy volunteers. Br J Ophthalmol. 1998;82:39-42.
- Baudouin C, Pisella PJ, Fillacier K, et al. Ocular surface inflammatory changes induced by topical antiglaucoma drugs. Ophthalmology. 1999;106:556-563.
- Leal BC, Medeiros FA, Medeiros FW, Santo RM, Susanna R Jr.Conjunctival hyperemia associated with bimatoprost use: a histopathologic study. Am J Ophthalmol. 2004;1387:310-313.
| Robert J. Noecker, M.D., M.B.A., is vice chair and director of the Glaucoma Service for the University of Pittsburgh Medical Center's Eye Center. Dr. Noecker is also associate professor of ophthalmology for the University of Pittsburgh School of Medicine. Contact him at (412) 647-2152. |
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