Topical Corticosteroids: Making Sense of the Options

Transcription

1 DICAL EDU G ME CA UIN TIO TIN CON CME N A CONTINUING MEDICAL EDUCATION PUBLICATION ISSUE 3 Topical Corticosteroids: Making Sense of the Options ERIC D. DONNENFELD, MD Topical corticosteroid prescribing decisions are based on differences in potency, formulation, side-effect profile, patient factors, and the intended use. Here we will review what distinguishes currently available agents and how prescribing patterns are evolving based on new options and new understandings of the importance of treating inflammation. Topical ophthalmic corticosteroids are frequently used to prevent or control ocular inflammation resulting from surgery, disease, or trauma. All surgical manipulation damages cellular membranes, releasing inflammatory mediators and triggering a cascade of events that can culminate in vasodilation, edema, and pain. In other parts of the body, this inflammatory response can be tolerated as a normal part of healing, but in the eye, uncontrolled or inadequately controlled inflammation can result in temporary or permanent vision loss. By binding glucocorticoid receptors within cells, corticosteroids block the expression of proinflammatory proteins and activate the expression of antiinflammatory proteins. Steroids inhibit phospholipase A2, the enzyme that initiates the arachidonic acid cascade; steroids also stabilize cell membranes, limit capillary dilation, and inhibit the proliferation of leukocytes and fibroblasts.1 But everything comes at a price: this broad antiinflammatory activity especially when continued for long periods of time may be accompanied by unwanted side effects. For topical ophthalmic steroids, these may include increased in- To obtain CME credit for this activity, go to traocular pressure (IOP), cataractogenesis, impaired wound healing, and reduced response to infection.1 In the great majority of cases, however, the risk from unchecked ocular inflammation far outweighs the risks associated with carefully monitored and appropriate corticosteroid use. STEROID POTENCY A number of factors interact to determine the activity of individual topical corticosteroid agents. While the antiinflammatory potency of the active molecule is critical, its influence is modified by the drug s bioavailability, which is determined by factors such as the agent s intrinsic potency, solubility, ocular surface contact time, and corneal penetration. In systemic application, dexamethasone is five to seven times more potent than prednisolone; but because drug from prednisolone acetate 1% suspension penetrates the cornea readily and achieves higher anterior chamber concentrations than dexamethasone (alcohol 0.1% solution or phosphate 0.1% suspension), prednisolone is regarded as a more potent topical ophthalmic steroid.2,3 See INSIDE for: Complications of Topical Antiinflammatory Agents by John R. Wittpenn, MD Punctate keratopathy associated with topical NSAID use. Topics in ANTIINFLAMMATORIES Supported by an unrestricted educationalocular grant from Bausch + Lomb, Inc. 1

2 Less potent steroids available to US ophthalmologists include fluorometholone 0.1% ophthalmic suspension, rimexolone 1.0% ophthalmic suspension, and loteprednol etabonate 0.2% ophthalmic suspension. While less suited to treating or preventing massive inflammatory insult, these agents are useful for treating inflammatory conditions of the ocular surface, such as allergic conjunctivitis. 4 Fluorometholone, for instance, penetrates the cornea but appears to have little activity in the anterior chamber. 4 Its greatest utility is in ocular surface inflammation, where it can be effective without as pronounced a tendency to induce IOP elevation or cataract formation as stronger steroids. Loteprednol etabonate 0.2% is FDA approved for the treatment of seasonal allergic conjunctivitis and has been found superior to placebo and to the antihistamine olopatadine 0.1% in reducing bulbar conjunctival injection and itching in affected patients. 1 Because allergic conjunctivitis tends to be chronic and recurring, corticosteroids, while extremely effective, should be used cautiously for this indication, typically for a short period to quell inflammation until topical antihistamines can be used for long term management. Patients should be educated about risks associated with long-term use. STRONG STEROIDS A higher (0.5%) concentration of loteprednol etabonate is available in several forms: a suspension, an ointment, and, most recently, a gel. A product of retrometabolic drug design, loteprednol etabonate was engineered from the prednisolone backbone. The substitution at the C-20 position of an ester group for the ketone found in all other topical corticosteroids (including prednisolone and dexamethasone) allows endogenous tissue esterases to break loteprednol down to inactive metabolites. (Other steroids have active metabolites.) The result is a moderately potent steroid with less propensity to increase IOP than prednisolone acetate, dexamethasone, or even fluorometholone. 5 The strongest ophthalmic cortico- TOPICS IN OCULAR ANTIINFLAMMATORIES, ISSUE 3 STATEMENT OF NEED The indications for topical ophthalmic antiinflammatory drugs (both steroidal and nonsteroidal) are evolving rapidly, as new agents and new applications emerge. Many of these are novel eg, the perioperative use of nonsteroidal antiinflammatory drugs (NSAIDs) to prevent cystoid macular edema and/or fly in the face of older thinking eg, the use of steroids to calm inflammation and reduce the risk of melting or scarring from infection. Neither of these important applications is on-label. In addition, new steroidal and nonsteroidal agents continue to come to market, expanding the utility of both classes. Antiinflammatory drugs are now used for: the treatment of ocular surface disease and allergic conjunctivitis; prevention of perioperative pain and inflammation in ocular surgery; infection management; cystoid macular edema prophylaxis following cataract surgery; haze prevention in PRK; and much more. What has regrettably not followed this expansion of indications, formulations, and new molecular entities are protocols for drug selection and use. 1 These are vital because significant differences in safety, tolerability, and efficacy exist between and within both antiinflammatory drug classes. C-20 ester steroids, for example, have a demonstrated lower risk of intraocular pressure (IOP) elevation than ketone steroids. 2,3 Since a range of steroid formulations and concentrations is available, clinicians need up-to-date information about the indications and optimum uses for each. 3 Although topical NSAID formulations have been associated with significant adverse events (keratopathy ranging from superficial punctate keratitis to corneal melt), recent work shows these to be uncommon and less severe with newer formulations. 4 Indeed, novel NSAIDs make use of lower concentrations and less frequent dosing, potentially impacting safety profiles and reducing risk from long-term use. 5 Although both are antiinflammatory, steroids and NSAIDs act at different points in the inflammatory cascade, and thus offer opportunities for physicians to fine-tune their drug selection. And although they are frequently used together, whether or not the two drug classes can act synergistically is controversial. In the context of recent clinical data, a clear mechanistic understanding of each drug class generally and of newer formulations specifically will equip clinicians to make effective, evidence-based prescribing decisions across the many situations that call for ocular inflammation control. REFERENCES 1. Dua HS, Attre R. Treatment of post-operative inflammation following cataract surgery a review. European Ophthalmic Review. 2012;6(2): Comstock TL, DeCory H. Advances in corticosteroid therapy for ocular inflammation: loteprednol etabonate. International Journal of Inflammation. 2012; doi: /2012/ 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: Singer M, Cid MD, Luth J, et al. Incidence of corneal melt in clinical practice: our experience vs a meta-analysis of the literature. Clin Exp Ophthalmol. 2012;S1: Cable M. Comparison of bromfenac 0.09% QD to nepafenac 0.1% TID after cataract surgery: pilot evaluation of visual acuity, macular volume, and retinal thickness at a single site. Clin Ophthalmol. 2012;6: OFF-LABEL USE STATEMENT This work discusses offlabel uses of antiinflammatory medications. GENERAL INFORMATION This CME activity is sponsored by the University of Florida College of Medicine and is supported by an unrestricted educational grant from Bausch + Lomb, Inc. Directions: Select one answer to each question in the exam (questions 1 10) and in the evaluation (questions 11 16). The University of Florida College of Medicine designates this activity for a maximum of 1.0 AMA PRA Category 1 Credit. There is no fee to participate in this activity. In order to receive CME credit, participants should read the report, and then take the posttest. A score of 80% is required to qualify for CME credit. Estimated time to complete the activity is 60 minutes. On completion, tear out or photocopy the answer sheet and send it to: University of Florida CME Office PO Box , Gainesville, FL PHONE: FAX: Or you can take the test online at System requirements for this activity are: For PC users: Windows 2000, XP, 2003 Server, or Vista; Internet Explorer 6.0 or newer, or Mozilla Firefox 2.0 or newer (JavaScript and Java enabled). For Mac users: Mac OS X 10.4 (Tiger ) or newer; Safari 3.0 or newer, Mozilla Firefox 2.0 or newer; (JavaScript and Java enabled). Internet connection required: Cable modem, DSL, or better. DATE OF ORIGINAL RELEASE October Approved for a period of 12 months. ACCREDITATION STATEMENT This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of Florida College of Medicine and Candeo Clinical/Science Communications, LLC. The University of Florida College of Medicine is accredited by the ACCME to provide continuing medical education for physicians. CREDIT DESIGNATION STATEMENT The University of Florida College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit. Physicians should only claim the credit commensurate with the extent of their participation in the activity. FACULTY AND DISCLOSURE STATEMENTS Lisa B. Arbisser, MD (Faculty Advisor), is an adjunct associate professor at the University of Utah Moran Eye Center in Salt Lake City, UT, and an ophthalmologist at Eye Surgeons Associates PC in Bettendorf, IA. She states that in the past 12 months, she has participated in a standalone Bausch + Lomb advisory board meeting. Penny A. Asbell, MD, FACS, MBA (Faculty Advisor), is a professor of ophthalmology and director of the cornea and refractive services at Icahn School of Medicine at Mount Sinai. She states that in the past 12 months, she has been a consultant for R-tech, Senju, and Bausch + Lomb, has given CME lectures for Merck, and has received a research grant from Alcon. William E. Smiddy, MD (Faculty Advisor), is a professor of ophthalmology at the Bascom Palmer Eye Institute, University of Miami Miller School of Medicine. He states that in the past 12 months, he has attended a steering committee meeting of Alimera Scientific. Eric D. Donnenfeld, MD, practices at Ophthalmic Consultants of Long Island and is a clinical professor of ophthalmology at New York University. He states that in the past 12 months, he has consulted for Allergan, Alcon, Bausch + Lomb, and Kala. John R. Wittpenn, MD, is a partner in Ophthalmic Consultants of Long Island and a clinical associate professor of ophthalmology at the State University of New York at Stony Brook. He is a consultant for and a member of the speaker s bureau for Bausch + Lomb. DISCLAIMER Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and professional development. The information presented in this activity is not meant to serve as a guideline for patient care. Procedures, medications, and other courses of diagnosis and treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patients conditions and possible contraindications or dangers in use, applicable manufacturer s product information, and comparison with recommendations of other authorities. COMMERCIAL SUPPORTERS This activity is supported by an unrestricted educational grant from Bausch + Lomb, Inc. 2 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to

3 steroid currently available is difluprednate 0.05% ophthalmic emulsion. Structurally similar to prednisolone, difluprednate is distinguished by the addition of two fluorine atoms (at the C-6 and C-9 positions) and a butyrate ester group at the C-17 position that increase the molecule s affinity for the glucocorticoid receptor. 6,7 An acetate ester at the C-21 position further boosts potency by facilitating tissue penetration. 6,7 Using a strong corticosteroid, such as prednisolone acetate or difluprednate, can be of particular advantage in the period before and after cataract or refractive surgery. Pretreatment, aggressive management, and rapid tapering may promote faster visual rehabilitation and reduce the need for long-term corticosteroid use. FORMULATION Formulation is an important consideration in ophthalmic steroid selection, as it can affect dose uniformity, ocular surface residence time, and corneal penetration. Lipophilic molecules like prednisolone acetate penetrate the lipid-rich corneal epithelial cells more readily than hydrophilic derivatives such as prednisolone phosphate. However, formulating a hydrophobic/ lipophilic molecule as a topical eyedrop is challenging. So in addition to steroid solutions like dexamethasone sodium phosphate 0.1% and prednisolone sodium phosphate 1.0%, many important ophthalmic steroids are formulated as suspensions. Because the particles in a suspension settle, suspensions must be shaken vigorously prior to use a barrier to patient adherence and to consistent dosing. Even when ophthalmic steroid suspensions are shaken, laboratory studies show significant variability in actual drug concentration delivered: when branded and generic prednisolone acetate 1.0% suspensions were stored upright, shaken, and dosed to simulate patient usage, actual drop concentrations fell within 10% of the declared value only 23% and 6% of the time, respectively. 8 It is therefore encouraging to see newer steroids in emulsion and gel formulations, which ensure drop-to-drop consistency of drug concentration without the need for shaking. Difluprednate 0.05% is formulated as a stable oil-in-water emulsion, in which surfactant molecules keep the oil-dissolved drug particles suspended in an aqueous phase. In the same study mentioned above, difluprednate drops were within 10% of declared concentration nearly 100% of the time, regardless of shaking or bottle orientation during storage. 8 A newly available non-settling gel formulation of loteprednol etabonate 0.5% also offers improved dose uniformity and ocular surface residence time over the suspension preparation. 5 And while ophthalmic steroids are generally well-tolerated by patients, this formulation, which also contains the ocular lubricants propylene glycol and glycerin, as well as a lower concentration of benzalkonium chloride than the suspension, may also offer improved comfort over the suspension. 5 SAFETY: CHANGING PATTERNS OF USE In general, the risk of steroid side effects correlates directly with the potency of the drug. To minimize the risks associated with high drug concentrations, prescribers often favored mod- CORE CONCEPTS Topical corticosteroid potency depends multiple factors, including the active molecule, its solubility, ocular surface retention, and corneal penetration. Degree of inflammation, anticipated duration of therapy, target tissue, and associated patient risk factors can help determine the selection of a strong vs a soft steroid. Less potent ophthalmic steroids, including fluorometholone, rimexolone, and loteprednol etabonate 0.2%, are well suited to treating conditions of the ocular surface. In general, the more potent the steroid, the greater the risk of side effects, including IOP increase, cataractogenesis, delayed wound healing, and secondary infection. Formulation can significantly affect the degree of certainty over the drug concentration dosed. erate doses for longer periods of time, with the goal of quelling an existing inflammatory response. Today, particularly in surgical applications, the aim of corticosteroid prescribing is first of all to prevent, rather than suppress, inflammation. The thought here is that side effects can be effectively minimized by reducing not the concentration of drug but the duration of therapy. To inhibit inflammation in cataract surgery patients, we begin dosing non-steroidal antiinflammatory drugs (NSAIDs) 3 days before surgery to reduce the level of endogenous prostaglandins in the tissue. We begin corticosteroid dosing just two hours prior to surgery, in a pulse of three or four doses. We then instruct patients to use their steroid drops 2 times per day postoperatively for 2 weeks and then taper to one drop a day for the third week. In addition to a history of glaucoma, ocular hypertension, or IOP elevation in response to prior topical steroid use, Chang and colleagues have identified younger age and high axial myopia as risk factors for steroid response in cataract surgery patients. 9 Indeed, their retrospective case control study found that cataract patients younger than 65 with an axial length of > 29.0 mm had a 35-fold increased risk of having steroid-induced IOP spike to over 34 mmhg. 9 Patients with any of these risk factors for elevated IOP during corticosteroid therapy should be monitored closely, particularly if a potent steroid such as difluprednate is used. When patients are expected to be on topical steroid therapy for an extended period of time, eg, in order to prevent graft rejection after keratoplasty, less potent steroids with fewer side effects, such as 0.1% fluorometholone and loteprednol, can be effective long-term. 10 In cases of corneal infection, steroid use is more controversial. It has been argued that adding steroid to antimicrobial therapy for infectious keratitis, for example, could improve the visual outcome by inhibiting the immune response that leads to scarring. Physicians have been hesitant To obtain CME credit for this activity, go to Topics in OCULAR ANTIINFLAMMATORIES 3

4 to employ this reasoning because the immunosuppressive effects of steroids also risk worsening an infection, particularly in the absence of effective antimicrobial therapy. A recent large-scale, randomized, double-masked, placebo-controlled trial of adjunctive steroids in the treatment of bacterial corneal ulcers did not demonstrate either significant benefit (measured by best corrected visual acuity or size of scar) or detriment of adjunctive steroid treatment. 11 Subgroup analyses and future studies may identify factors (eg, size of corneal defect, virulence of infecting agent, frequency of steroid dosing) that can guide adjunctive steroid treatment. This applies only to treatment of bacterial infections: viral, fungal, or Acanthamoeba etiologies should be ruled out before initiating adjunctive steroid treatment for an epithelial corneal infection. The most important factor is that the antimicrobial therapy control the infection if corticosteroids are going to be employed. CHALLENGES All of the thought physicians put into prescribing topical steroids can be compromised if substitutions are made at the pharmacy. Generic drugs are required to be bioequivalent to their branded counterparts that is, generics must have the same active ingredients in the same concentration, as well as identical dosage, route of administration, indications, and labeling. But while bioequivalence theoretically correlates with therapeutic equivalence (and it often does in reality), generic drugs are not typically required to prove this by undergoing clinical evaluation prior to approval. 12 In the case of prednisolone acetate 1%, investigations have found larger and less consistent particle sizes in generic vs branded suspensions, which leads to observed reductions in dose uniformity and the formation of clogging precipitates. 12 More worrisome than generics are substitutions of different entities entirely, such as prednisolone acetate for loteprednol etabonate. Specifying dispense as written or similar clear instructions for pharmacists can help prevent such substitutions; but patient education is also essential. We make a practice of including an image of the prescribed drug along with dosing instructions for patients, and we explain why it is important to us that they obtain the correct medication. The cost of medication must always be weighed in prescribing decisions. When we prescribe a generic drug to a cost-conscious patient, we ensure the patient understands the issues involved. When appropriate, we let patients know that the characteristics of their case and the differences between the branded and generic drug formulations merit serious consideration of the branded original, despite its cost. NEW DIRECTIONS Much has changed over the last two decades in topical ophthalmic steroid therapy. We now not only have more agents to choose from but also, increasingly, more sophisticated agents engineered for greater potency and lower associated risks. There remain areas of clinical application, however, in which steroids are underutilized, perhaps because of caution or longtime habits on the part of clinicians. Though they tend to be chronic and/or recurring in nature, ocular allergy and dry eye disease are two key therapeutic areas for which brief topical steroid therapy can be quite beneficial. Steroids suppress the proliferation of mast cells and block the prostaglandins, leukotrienes, and other inflammatory mediators involved in the allergic response. A pulse of steroid therapy can help curtail signs and symptoms of inflammation during an acute episode of allergic conjunctivitis and allow patients to be better managed on antihistamines, mast-cell stabilizers, or combination agents. 4 Likewise, short-term pulse therapy with steroids can help to hasten relief for dry eye patients beginning therapy with cyclosporine ophthalmic emulsion 0.05%, which may take a period of weeks or months to produce clinical improvement. 13 In addition to reducing inflammation and improving patient symptoms, steroids may help increase goblet cell density. For acutely inflammatory meibomian gland dysfunction, and for the marginal keratitis that may accompany this condition, a brief course of topical steroid may also be of benefit. 14 On the horizon, we have a new class of agents that also work by binding glucocorticoid receptors. These selective glucocorticoid receptor agonists (SEGRAs) operate with antiinflammatory activity similar to corticosteroids, but with a more limited scope of gene activation and thus, fewer unwanted side effects. 15 Mapracorat, a SEGRA currently under investigation as an ophthalmic suspension for the treatment of allergic conjunctivitis and post-cataract surgery pain and inflammation, has shown promise in preclinical studies. 15 In a rabbit model of dry eye, mapracorat was found to be as effective as dexamethasone sodium phosphate solution 0.1% at maintaining tear volume and tear-film breakup time but without the significant IOP elevations seen in dexamethasone-treated eyes. 15 SEGRAs thus represent a very exciting area of development in topical ophthalmic antiinflammatory therapy. CONCLUSION Topical ophthalmic steroids continue to be an essential component of postsurgical inflammation management. But their short-term use can meaningfully benefit other ocular surface and anterior segment inflammatory conditions where they may be less frequently used. Careful monitoring of steroid treatment is warranted, but steroids should not be avoided simply because they may carry significant risks the sequelae of ocular inflammation are very commonly worse than the side effects of steroid use, which, if detected promptly, can typically be managed without impairing vision. Taking advantage of newer formulations and prescribing aggressive, short-term dosing regimens with rapid tapering can help minimize risk and maximize benefit. Eric D. Donnenfeld, MD, practices at Ophthalmic Consultants of Long Island and is a clinical professor of ophthalmology at New York University. He states that in the past 12 months, he has consulted for Allergan, Alcon, Bausch + Lomb, and Kala. Managing editor Jennifer Zweibel assisted in the preparation of this article. 4 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to

5 REFERENCES 1. Comstock TL, DeCory HH. Advances in corticosteroid therapy for ocular inflammation: loteprednol etabonate. Int J Infl amm. 2012;Article ID Cunningham ET, Wender JD. Practical approach to the use of corticosteroids in patients with uveitis. Can J Ophthalmol. 2010;45; McGhee CNJ. Pharmacokinetics of ophthalmic corticosteroids. Br J Ophthalmol. 1992;76: Friedlaender MH. The current and future therapy of allergic conjunctivitis. Curr Opin Ophthalmol. 1998;9(4): Lyseng-Williamson KA. Loteprednol etabonate ophthalmic gel 0.5%: a review of its use in post-operative inflammation and pain following ocular surgery. Drugs. 2013;73: Donnenfeld ED. Difluprednate for the prevention of ocular inflammation postsurgery: an update. Clin Ophthalmol. 2011;5: Bikowski J, Pillai R, Shroot B. The position not the presence of the halogen in corticosteroids influences potency and side effects. J Drug Dermatol. 2006;5(2): Stringer W, Bryant R. Dose uniformity of topical corticosteroid preparations: difluprednate ophthalmic emulsion 0.05% versus branded and generic prednisolone acetate ophthalmic suspension 1%. Clin Ophthalmol. 2010;4: Chang DF, Tan JJ, Tripodis Y. Risk factors for steroid response among cataract patients. J Cataract Refract Surg. 2011;37: Shimazaki J, Iseda A, Satake Y, Shimazaki-Den S. Efficacy and safety of longterm corticosteroid eye drops after penetrating keratoplasty. Ophthalmology. 2012;119: Srinivasan M, Mascarenhas J, Rajaraman R, et al. The steroids for corneal ulcers trial. Arch Ophthalmol. 2012;130(2): Zore M, Harris A, Tobe LA, et al. Generic medications in ophthalmology. Br J Ophthalmol. 2013;97: Pflugfelder SC. Antiinflammatory therapy for dry eye. Am J Ophthalmol. 2004;137: Geerling G, Tauber J, Baudouin C, et al. The international workshop on meibomian gland dysfunction: report of the subcommittee on management and treatment of meibomian gland dysfunction. Invest Ophthalmol Vis Sci. 2011;52(4): Shafiee A, Bucolo C, Budzynski E, et al. In vivo ocular efficacy profile of mapracorat, a novel selective glucocorticoid receptor agonist, in rabbit models of ocular disease. Invest Ophthalmol Vis Sci. 2011;52: Complications of Topical Antiinflammatory Agents JOHN R. WITTPENN, MD Although they carry the potential for serious side effects, topical antiinflammatory agents are typically well tolerated and have become integral to ophthalmologic practice. Conscientious prescribing and follow up can mitigate their risks. An indispensible part of eyecare practice, topical antiinflammatory agents are effective across a range of preventive and therapeutic indications. Although each topical antiinflammatory drug is a unique combination of active and inactive molecules that carries a unique set of risks (and benefits), we often tend to think of risk in terms of drug class rather than individual agent. Because their side effect profiles differ, there are some significant advantages to selecting antiinflammatory agents not by class but by individual drug. CORTICOSTEROIDS AND INTRAOCULAR PRESSURE When using topical corticosteroids the risk that typically comes first to mind is intraocular pressure (IOP) elevation. This is particularly an issue in treating patients with chronic conditions such as iritis and ocular surface inflammatory problems, including common conditions like dry eye and blepharitis. These conditions often require prolonged antiinflammatory treatment, making it critical to balance the corticosteroid potency and duration of treatment required against the drug s potential to cause harmful side effects. Some commonly prescribed corticosteroids, including prednisolone acetate and difluprednate, are very effective at suppressing inflammation but place patients at a substantial risk for IOP elevation within weeks to months. In my experience, difluprednate offers excellent antiinflammatory potency with less frequent dosing but can produce IOP elevation in many patients within a matter of 2 to 3 weeks. CORE CONCEPTS In assessing antiinflammatory risk, look beyond drug class. The active agent, inactive ingredients, dosage, duration, and patient factors may all affect drug-related complications. Corticosteroids differ significantly in their propensity to cause IOP elevation. Loteprednol etabonate, an ester steroid, is associated with fewer IOP and cataract side effects than more potent steroids such as dexamethasone, prednisolone, and difluprednate. Elevated IOP is thought to relate to excess unmetabolized drug that impedes outflow through the trabecular meshwork. Corticosteroids should be avoided if active ocular herpes cannot be ruled out. The risk of NSAID-related corneal surface problems increases in patients with underlying corneal abnormalities but may occur in any patient. NSAID selection should be approached thoughtfully; generic formulations may not be exact replicas of their branded counterparts. To obtain CME credit for this activity, go to Topics in OCULAR ANTIINFLAMMATORIES 5

6 The mechanism for pressure increase is thought to involve an accumulation of corticosteroid within epithelial cells of the trabecular meshwork and interference with their filtering capacity. 1 One strategy for reducing risk is to switch patients who require chronic inflammation suppression, such as post-graft patients, from a maximally potent steroid like prednisolone acetate or difluprednate to a corticosteroid with less tendency to cause IOP elevation (eg, fluorometholone, rimexolone, or loteprednol etabonate) as soon as it is safe to do so. 2 PATIENT COMMUNICATION Regardless of the indication, the specific corticosteroid prescribed, or the intended duration, the need for clear patient communication and education when prescribing topical ocular corticosteroids cannot be overemphasized. This is particularly true for patients with chronic or potentially recurrent conditions. A complete discussion includes not only when to return for follow-up, but also why. Explaining corticosteroidassociated risks using the words cataracts and glaucoma may help patients take the risks seriously. SAFE PRESCRIBING OF CORTICOSTEROIDS Use the lowest dose of corticosteroid for the shortest period that will achieve the antiinflammatory aim. Minimize risk by choosing a lower potency agent or an ester steroid whenever possible for corticosteroid treatment of longer than 2 weeks. When prescribing both a corticosteroid and an NSAID (eg, for cystoid macular edema prophylaxis following cataract surgery), use the least toxic agents available. Never prescribe a corticosteroid or corticosteroid/ antibiotic combination without a full ophthalmic examination, including a documented examination of the cornea by slit lamp. Monitor patients on ocular corticosteroids closely for increased IOP and for development of infection. Tell patients the when, why, and who to see for follow up; emphasize the need to return to the eyecare provider for a full ocular exam should the condition recur. Institute an appointment reminder/missed appointment system to get patients on corticosteroids back for follow-up. Patients should also receive clear instruction to follow up with an eyecare practitioner. In the case of topical corticosteroids, it is critical to follow up with a physician who knows and has the ability to monitor IOP. Some years ago, a patient I had treated for blepharoconjunctivitis with combination tobramycin/dexamethasone presented more than a year after her last visit with an IOP of 38 mmhg. She had initially responded to treatment but failed to come back for her follow-up appointment at 2 to 3 weeks. Over the ensuing months, her condition recurred periodically, but instead of returning to our office she went to her primary care physician, who had simply refilled the original prescription without ever checking the patient s pressure. Fortunately, the patient s optic nerve was undamaged and she responded to IOP-lowering treatment. But it was a significant and alarming steroid response, and it illustrates something about patients perception of doctors roles. Some patients associate their eyecare provider with matters related to vision (eg, for glasses or visual complaints like blurriness) and think of their primary care physician as the person to call regarding disease, even diseases of the eye. After an initial referral, these patients may disappear from your practice, going back to the doctor they see as the person who treats disease. Careful communication about risks and necessary follow up may prevent such mishaps. CATARACT RISK Exposure to corticosteroids including topical or intravitreal ocular corticosteroids and inhaled nasal or systemic steroids can contribute to the development of posterior subcapsular cataracts. The mechanism is unclear but may involve glucocorticoid-induced gene transcription in lens epithelial cells and intralenticular glucocorticoid-protein adduct formation. 3-5 In patients who develop cataracts in their 60s or 70s, it may be difficult to tease out the contribution of corticosteroid medication, since they may have had multiple risk factors including their age and the intraocular inflammatory condition for which they received corticosteroid treatment. Naturally, though, it is important to limit corticosteroid exposure whenever possible to minimize cataract risk, especially in younger patients who may not otherwise be at risk. In addition to using the lowest dose and duration of corticosteroid, an ester steroid (eg, loteprednol etabonate) may reduce risk of cataractogenesis. 6 While the reasons are not fully understood, it is known that loteprednol is rapidly transformed by naturally occurring esterases to inactive metabolites. In addition, the absence of a ketone at the C20 position in loteprednol etabonate prevents formation of adducts with lens proteins, the reported first step in cataract formation with ketone steroids. 6 INFECTION Broad suppression of inflammation by corticosteroids also suppresses aspects of the body s natural immune response to bacteria and other pathogens, creating an opportunity for infections that might be smoldering on the ocular surface to effloresce. This was brought home to me by a patient I examined with a permanent corneal scar from a herpetic infection that was exacerbated by treatment with a topical steroid. The patient, a nurse, awoke on a Monday with a red eye, diagnosed herself with pink eye, and, keen to have it resolved before her wedding that weekend, asked a physician friend to give her something for it. The physician prescribed a topical antibiotic/steroid com- 6 Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to

7 bination, and by Thursday the nurse was photophobic and experiencing blurred vision. Examination by an ophthalmologist on Friday revealed a large herpetic corneal dendrite. A taper of the steroid was started along with antiviral treatment. The patient spent her rehearsal dinner, wedding, and honeymoon wearing dark sunglasses and was very uncomfortable. She was left with a permanent corneal scar, ongoing symptoms of glare, and a small drop in vision to 20/25 from 20/20. The lesson is simple: Corticosteroids should not be prescribed without a full eye exam. TOPICAL NSAIDS Topical ophthalmic NSAIDs are prescribed for their antiinflammatory effect mediated by blocking prostaglandin synthesis, thereby avoiding steroid-associated side effects. However, NSAIDs have their own risks, ranging from minor corneal surface irritation and punctate keratopathy which is common with generic NSAID formulations to frank corneal melting, which is rare (Figure 1). Although the number of significant corneal events has decreased since the removal of generic diclofenac from the market, care that the corneal surface is not compromised through use of topical NSAIDs remains important. 7 of corneal nerves. It is well known that diminished ocular surface sensation whether due to diabetes, herpetic infection, or surgical trauma can cause the corneal epithelium to break down, presumably due to loss of the feedback mechanism that signals damage to the ocular surface (and the need for repair). Blocking the corneal sensing mechanism with NSAIDs could, in theory, have a similar effect. Indeed, the vast preponderance of patients who suffered serious adverse corneal effects from NSAIDs had significant ocular surface problems prior to NSAID use. 9 SAFE PRESCRIBING OF NSAIDS Be cautious when prescribing generic NSAIDs; educate patients about the possibility of corneal side effects. When prescribing both a steroid and an NSAID (eg, for CME prophylaxis), use the least toxic agents that provide appropriate efficacy. Use of NSAIDs requires more frequent examination of patients with corneal anesthesia at baseline; these include patients with dry eye, recurrent ocular surface herpetic disease, diabetes, or multiple ocular surgeries. Educate patients regarding the early signs of corneal side effects. Tell them to call if they have increased burning following application of the drug. See these patients and stop the NSAID if exam reveals any corneal epithelial pathology. The one subgroup without prior corneal compromise consisted of patients treated with a particular generic formulation of diclofenac that was later removed from the market. 9 Current commonly prescribed NSAID options available in the US include diclofenac, branded and generic ketorolac, branded and generic bromfenac, and branded nepafenac. 8 FIGURE 1 Punctate keratopathy associated with topical NSAID use. (Image courtesy of John R. Wittpenn, MD.) Topical NSAIDs represent a chemically heterogeneous group of molecules. As a class, they are useful for perisurgical antiinflammatory prophylaxis, because they suppress prostaglandin production, which reduces vascular permeability and the risk for cystoid macular edema (CME). NSAIDs can be started a few days prior to surgery for maximal efficacy. In addition, NSAIDs augment analgesia and maintain pupillary dilation during surgery. 8 NSAID RISKS The mechanism of NSAID corneal toxicity is not entirely clear. Research in the 1990s, when severe events were first starting to be reported, showed that diclofenac and ketorolac caused not only analgesia but anesthesia via a direct blockade GENERIC NSAIDS All available NSAIDs have the potential to create a punctate keratopathy. 7 But the rate at which they do it varies greatly. One widely prescribed ocular NSAID, generic ketorolac, is concerning for several reasons. One is that the active agent (ketorolac) was associated with high rates of punctate keratopathy, even in its original branded form. Furthermore, generic agents pose a higher risk for idiopathic adverse effects since the complete formulation does not have to be scrutinized in clinical trials in the same way that branded agents have been. Unpublished data shows that up to 30% of healthy cataract surgery patients treated with generic ketorolac develop symptomatic punctate keratopathy by 3 to 4 weeks. Although, in my view, branded agents are safer because they have been more rigorously tested, any NSAID including the branded formulations may contribute to corneal damage. The jury is out regarding which among the branded NSAIDs is safest. Bromfenac was recently reformulated with a ph closer to that of the tear film, which enhances corneal penetration To obtain CME credit for this activity, go to Topics in OCULAR ANTIINFLAMMATORIES 7

8 and should allow for greater effect with lower concentration of drug; this could serve to improve safety even over older bromfenac formulations. Nepafenac has also recently been reformulated and is the first prodrug NSAID. 7 Nepafenac has been associated with toxicity when dropped on bare stroma in conjunction with PRK. 10,11 Also, in order to reduce the dosing frequency to once per day, the latest formulation of nepafenac uses a higher concentration of active ingredient and a formulation that increases the contact time of active molecule against the ocular surface. The effect of these features on corneal safety is not yet known. With any NSAID, it is good practice to limit use to 14 days for patients with baseline corneal abnormalities, including dry eye. OTHER NSAID CONCERNS All NSAIDs, including topical NSAIDs, carry a warning that they can potentiate bleeding on their label. This, however, is a far more serious concern with systemic agents than topical, and rarely is it an issue with ocular NSAIDs. Patients with sulfite allergy should avoid branded bromfenac, which contains a sulfite. 12 Sulfites are present in certain food products such as wines and cured meats; allergy to sulfites is rare but can be severe. Sulfite allergy is not to be confused with sulfate allergy, which is much more common. Patients with sulfate allergy react to sulfa drugs such as sulfamethoxazole but not to NSAIDs. CONCLUSION Safety profiles of antiinflammatory agents depend on the drug class, the individual molecule, and the inactive ingredients in the formulation. Safety may vary between branded and generic versions. Efforts to minimize risk have resulted in improved drugs in both corticosteroid and NSAID categories. Attention to potential side effects and good staff and patient communication are essential to all clinical efforts to control ocular inflammation. John R. Wittpenn, MD, is a partner in Ophthalmic Consultants of Long Island and a clinical associate professor of ophthalmology at the State University of New York at Stony Brook. He is a consultant for and a member of the speaker s bureau for Bausch + Lomb. Medical writer Noelle Lake, MD, assisted in the preparation of this article. REFERENCES 1. Jones R 3rd, Rhee DJ. Corticosteroid-induced ocular hypertension and glaucoma: a brief review and update of the literature. Curr Opin Ophthalmol. 2006;17: Bhattacherjee P, Paterson CA, Spellman JM, et al. Pharmacological validation of a feline model of steroid-induced ocular hypertension. Arch Ophthalmol Mar;117(3): James ER. The etiology of steroid cataract. J Ocul Pharmacol Ther. 2007;23: Amon M, Busin M. Loteprednol etabonate ophthalmic suspension 0.5 %: efficacy and safety for postoperative anti-inflammatory use. Int Ophthalmol. 2012;32: Manabe S, Bucala R, Cerami A. Nonenzymatic addition of glucocorticoids to lens proteins in steroid-induced cataracts. J Clin Invest November;74(5): Comstock DL, DeCory HH. Advances in corticosteroid therapy for ocular inflammation: loteprednol etabonate. Int J Inflam. 2012;2012: doi: /2012/ Gaynes BI, Onyekwuluje A. Topcal ophthalmic NSAIDs: a discussion with focus on nepafenac ophthalmic suspension. Clin Ophthalmol. 2008;2: Cho H, Wolf KJ, Wolf EJ. Management of ocular inflammation and pain following cataract surgery: focus on Bromfenac ophthalmic solution. Clin Ophthalmol. 2009;3: Congdon NG, Schein OD, Kulajta PV, et al. Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs. J Cataract Refract Surg. 2001;27: Feiz V, Oberg TJ, Kurz CJ, et al. Nepafenac-associated bilateral corneal melt after photorefractive keratectomy. Cornea. 2009;28: Trattler W, McDonald M. Double-masked comparison of ketorolac tromethamine 0.4% versus nepafenac sodium 0.1% for postoperative healing rates and pain control in eyes undergoing surface ablation. Cornea. 2007;26: Prolensa (bromfenac ophthalmic solution) 0.07% product information. Tampa, FL: Bausch and Lomb; Topics in OCULAR ANTIINFLAMMATORIES To obtain CME credit for this activity, go to

9 EXAMINATION QUESTIONS TOPICS IN OCULAR ANTIINFLAMMATORIES ISSUE 3 This CME program is sponsored by the University of Florida College of Medicine and supported by an unrestricted educational grant from Bausch + Lomb, Inc. Directions: Select the one best answer to each question in the exam (Questions 1 10) and in the evaluation (Questions 11 16) below by circling one letter for each answer. Participants must score at least 80% on the questions and complete the entire Evaluation section on the form below. The University of Florida College of Medicine designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit. There is no fee to participate in this activity. You can take the test online at 1. Difluprednate is distinguished by the presence of: A. Two chlorine atoms at the C-6 and C-9 positions B. A ketone group at the C-20 position C. Two fluorine atoms at the C-6 and C-9 positions D. None of the above 2. Which of the following topical corticosteroids is associated with both high potency and high risk for classic steroid side effects? A. Rimexolone B. Fluorometholone C. Difluprednate D. Loteprednol etabonate 3. Which of the following is true about generic formulations of prednisolone acetate 1%? A. Drug particle sizes may be more variable than in branded drug B. Mucoadhesive vehicle may clog dropper tips C. They contain a lower concentration of benzalkonium chloride D. They contain propylene glycol 4. FDA approval of a generic steroid formulation requires demonstration of: A. Noninferior clinical efficacy B. Bioequivalence C. Noninferior clinical safety D. All of the above 5. Which of the following is an NSAID prodrug? A. Nepafenac B. Bromfenac C. Ketorolac D. Diclofenac 6. Which of the following has been shown to correlate with a predisposition to a stronger steroid IOP response? A. Darkly colored irides B. Age > 80 C. Anterior chamber depth > 3 mm D. Axial length > 28 mm 7. NSAID use has been most frequently associated with: A. Cataract formation B. Punctate keratopathy C. IOP elevation D. Iris color change 8. Which of the following should be discussed when prescribing an antiinflammatory agent? A. Potential side effects and their early signs B. Where and when to follow up C. Which physician to see if the condition returns D. All of the above 9. Ocular corticosteroids should not be prescribed without: A. A baseline IOP measurement B. Careful corneal examination to rule out preexisting infection C. Examination of the peripheral retina D. Both A and B are correct 10. SEGRAs: A. Are being studied for adjunctive use alongside steroids B. Have steroid-like activity but are not suitable for topical application C. May have antiinflammatory potency similar to steroids with fewer side effects D. Both A and C are true EXAMINATION ANSWER SHEET TOPICS IN OCULAR ANTIINFLAMMATORIES ISSUE 3 This CME activity is jointly sponsored by the University of Florida and Candeo Clinical/Science Communications, LLC, and supported by an unrestricted educational grant from Bausch + Lomb, Inc. Mail to: University of Florida CME Office, PO Box , Gainesville, FL DIRECTIONS: Select the one best answer for each question in the exam above (Questions 1 10). Participants must score at least 80% on the questions and complete the entire Evaluation (Questions 11 16) to receive CME credit. CME exam expires September 30, ANSWERS: 1. A B C D 2. A B C D 3. A B C D 4. A B C D 5. A B C D 6. A B C D 7. A B C D 8. A B C D 9. A B C D 10. A B C D EVALUATION: 1=Poor 2=Fair 3=Satisfactory 4=Good 5=Outstanding 11. Extent to which the activity met the identified Objective 1: Objective 2: Rate the overall effectiveness of how the activity: Related to my practice: Will influence how I practice: Will help me improve patient care: Stimulated my intellectual curiosity: Overall quality of material: Overall met my expectations: Avoided commercial bias/influence: Will the information presented cause you to make any changes in your practice? Yes No 14. If yes, please describe: 15. How committed are you to making these changes? Are future activities on this topic important to you? Yes No If you wish to receive credit for this activity, please fill in the following information. Retain a copy for your records. PLEASE PRINT CLEARLY FIRST NAME LAST NAME DEGREE ORGANIZATION/INSTITUTE ADDRESS LINE 1 ADDRESS LINE 2 CITY STATE ZIP PHONE FAX ADDRESS To obtain CME credit for this activity, go to Topics in OCULAR ANTIINFLAMMATORIES 9