CLINICAL GUIDE to OPHTHALMIC DRUGS 21St21st Eeditiondition

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2017 CLINICAL GUIDE TO OPHTHALMIC DRUGS 21st21st EEditiondition

Ron Melton, Randall Thomas, Patrick Vollmer, OD OD, MPH OD

Plan your moves more precisely with these winning strategies from the masters.

A Supplement to

Supported by an unrestricted grant from Bausch + Lomb

FC_DG0517.indd 2 5/8/17 6:49 PM FROM THE AUTHORS

DEAR OPTOMETRIC COLLEAGUES: Supported by an Welcome to the 2017 edition of our annual Clinical Guide to Ophthalmic unrestricted grant from Drugs. Although the market has not yielded an avalanche of new drugs to Bausch + Lomb share with our readers this year, we will discuss myriad ways to better use most of the medicines already available. Further, we will offer a variety of clinical pearls to help you provide better care to your patients. CONTENTS The areas of eye care most germane to optometry involve two chronic conditions: dry eye disease and glaucoma. These two disease processes make up more than 50% of our patient population. The two newest drugs that Allergy Drugs ...... 3 currently, or soon will, grace our therapeutic armamentarium are designed for patients with these conditions: Xiidra (lifitegrast 5% ophthalmic solution) for treatment of signs and symptoms of dry eye disease, approved by the FDA in July 2016; and soon-to-be released Vyzulta (latanoprostene Antibiotic Agents...... 8 bunod 0.24% ophthalmic solution) for glaucoma, which would be the first

nitric oxide-donating prostaglandin F2 analog available for open-angle glaucoma or ocular hypertension. Plaquenil Toxicity ...... 15 As we become more seasoned clinicians and educators, we feel a duty to our profession to find the next generation of authors to carry on when we step aside in several years. Toward that end, we are pleased to introduce Dry Eye Therapy ...... 18 Patrick Vollmer, OD, a 2015 graduate of the Indiana University School of Optometry who completed his residency at William Jennings Bryan Dorn VA Medical Center, and who owns a private practice in Shelby, NC. Dr. Vollmer is contributing to this year’s drug guide, and we are happy to have Corticosteroid Use ...... 26 a third set of hands on this mammoth project. You can find Dr. Vollmer’s complete CV on our website, www.eyeupdate.com. We’d also like to thank our primary peer reviewers Bruce Onofrey, OD, RPh, FAAO, and Tammy Nonsteroidal Drugs ...... 33 Than MS, OD, FAAO, for taking time to review this publication. We are grateful that Bausch + Lomb and Review of Optometry continue to partner with us to produce this unique resource for our profession that we Antiviral Therapy ...... 34 have put out for more than two decades. We hope what is shared with you herein can enhance the excellent care you already provide your patients. Glaucoma Care ...... 40

With best wishes,

Randall K. Thomas, Ron Melton, OD, Patrick M. Vollmer, OD, OD, MPH, FAAO FAAO FAAO

Disclosure: Drs. Melton and Thomas are consultants to, but have no financial interests in, the following companies: Bausch + Lomb/Valeant and Icare. A PEER-REVIEWED Dr. Vollmer has no financial interests in any company. SUPPLEMENT

Note: The authors present unapproved and “off-label” uses of specific drugs in this guide.

002_dg0517_Intro_v2.indd 2 5/8/17 4:45 PM ALLERGY DRUGS

TAKE CONTROL OF OCULAR ALLERGY

Atopic diseases early one-third of the popu- IS IT ‘BURNING’ OR ‘ITCHING’? lation is affected by allergic • Itching: If the patient tells you itch- continue to disease, with an estimated ing is their primary concern, determine increase in 40% to 80% of these people if it’s an isolated symptom or associat- manifesting ocular involve- ed with parallel signs of inflammation, N1 prevalence. ment. Reports from studies around the and then treat accordingly. Remember: world indicate the prevalence of atopic Symptoms Only: Use an antihista- Here’s how diseases is continuing to increase, which mine/mast cell stabilizer has been well-documented over several Symptoms and Signs: Use a topical to help your decades of research.2,3 At the same time, steroid (such as Alrex, Lotemax gel ocular allergic disease is also on the rise. off-label or FML off-label) patients So, we need to understand more about • Burning: If the main symptom is with allergic the nature of the disease to better treat burning, consider dry eye as the foun- and manage our patients. dational condition and treat accord- conjunctivitis. Allergic eye disease, an IgE-mediated ingly. A full dry eye workup is in order. response and type I hypersensitivity reac- Of course, nothing in the rulebook tion, presents in numerous forms—from says a patient can’t have both of these a persistent itch to a potentially sight- symptoms concomitantly. Due to the threatening corneal ulcer (vernal kera- prevalence of dry eye across all ages, recognize and treat it whether or not it toconjunctivitis). According to the most is affiliated with allergic eye disease. recent epidemiological data, as many as two in five of your patients may have seasonal or perennial allergic conjunctivitis.4 Though the treatment options are essentially the same for perennial and seasonal allergic conjunctivitis, perennial allergic conjunctivitis follows a more in- dolent course, often requiring greater attention and persistent care by the at- tending doctor. Treatment for seasonal allergic conjunctivitis is more straightforward and includes antihistamines/mast cell stabilizers or corticosteroids. To find out whether your patients are experiencing just symptoms or also signs, first ask them: “Do your eyes burn Determine signs and symptoms by first or itch?” Many patients will be able to asking, “Do your eyes burn or itch?” provide an answer. For your patients who are unable to decide which symptom

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003_dg0517_Allergy_v2.indd 3 5/8/17 4:59 PM ALLERGY DRUGS

OLOPATADINE: THE CLASSIC GOLD DOSING OF A TOPICAL ANTIHISTAMINE: STANDARD OF ALLERGY TREATMENT WHICH IS BETTER—ONE OR TWO? The first dual-action antihistamine/mast cell stabilizer to Forget about prescribing pure mast cell stabilizing transform ocular allergy therapy was olopatadine 0.1% drugs, according to Mark Abelson, MD, a world- (Patanol, Alcon). In 1996, the FDA approved Patanol for renowned ocular allergist at Harvard Medical School. the treatment of signs and symptoms of allergic con- During a conversation with Dr. Abelson, he told

junctivitis. The drug is highly selective for the H1 receptor, us pure mast cell stabilizing drugs have little clinical and has shown in studies to apparently possess anti- use. Their lag period and mandatory chronic dosing inflammatory properties as well, inhibiting the release severely limits their clinical applicability. With the of leukotrienes, cytokines and adhesion molecules.1 advent of topical combination antihistamine/mast cell Olopatadine 0.1% was the first topical drop for allergic stabilizers, patients experience nearly instantaneous conjunctivitis approved for BID dosing, far surpassing the relief due to the rapid onset of action; bear in mind, second-generation antihistamines, which in their time had too, that the cost of an OTC combination drop is very advanced to QID. similar to a pure mast cell stabilizer. Remind your In 2010, olopatadine 0.2% (Pataday, Alcon) became patients that transient burning and stinging upon available with comparable efficacy and improved patient instillation is common. satisfaction, with relief from ocular symptomology for For patients who have symptomatic disease, one up to 18 hours. More recently, olopatadine 0.7% (Pazeo, drop in the morning may suffice to get them through Alcon) made its market debut in February 2015 with the the entire day. However, a subset of our patients efficacy for ocular itching surpassing 24-hour relief while finds solace with a second, additional drop later in maintaining a safety profile similar to the lesser concen- the evening. Which is correct? In the end, either is trations that came before it. appropriate, as patient care is not a one-size-fits-all but rather a tailored approach to symptomatic relief. 1. Ackerman S, Smith LM, Gomes PJ, et al. Ocular itch associated with allergic In your patients with severe allergy expression, conjunctivitis: latest evidence and clinical management. Ther Adv Chronic Dis. 2016 Jan; 7(1): 52–67. therapy is slightly more involved. In addition to an antihistamine/mast cell stabilizer BID, consider an ester-based corticosteroid such as Alrex (loteprednol distresses them the most, treatment with an ester-based 0.2%, Bausch + Lomb) or off-label use of Lotemax gel steroid drop (e.g., Alrex [loteprednol etabonate 0.2%, (loteprednol 0.5%, Bausch + Lomb) QID initially along Bausch + Lomb]) typically solves both complaints. with cold compresses. If patients report itching as their predominant symp- Once the inflammation settles down, the steroid tom, therapy is directed toward one of two paths, as ex- may be discontinued, preferably within two weeks, plained in upcoming pages. and the patient can remain on the antihistamine/mast cell stabilizer once or twice daily as needed. SYMPTOMS ONLY If the anterior segment exam shows minimal or unre- To date, there are six drugs in this class to choose from: markable signs of an allergic conjunctivitis (i.e., conjunc- • Alcaftadine (Lastacaft, Allergan) tival chemosis, conjunctival injection, eyelid edema and/ • Azelastine (Optivar, Meda Pharmaceuticals; generic or papillae), then treatment with a combination antihista- available) mine/mast cell stabilizer remains the ideal clinical choice. • Bepotastine (Bepreve, Bausch + Lomb)

FROM THE LITERATURE to these environmental changes.2 1. Björkstén B, Clayton T, Ellwood P, et al. Worldwide time trends for symptoms of rhinitis and conjunctivitis: More than 80% of patients who Phase III of the International Study of Asthma and suffer with allergies experience some Allergies in Childhood. Pediatr Allergy Immunol. 2008 ALLERGIC Mar;19(2):110-24. form of ocular symptomology (itch- CONJUNCTIVITIS IS ON 2. D’Amato G, Holgate ST, Pawankar R, et al. Meteo- THE RISE WORLDWIDE ing, chemosis, redness).3,4 In addition, rological conditions, climate change, new emerging various studies suggest that patients factors, and asthma and related allergic disorders. A According to the International Study statement of the World Allergy Organization. World of Asthma and Allergies in Childhood still vastly underreport the disease. Of Allergy Organ J. 2015; 8(1):25. (ISAAC), allergic conjunctivitis has equal significance are studies estab- 3. Singh K, Axelrod S, Bielory L. The epidemiology of ocular and nasal allergy in the United States, 1988-1994. shown a worldwide trend in increas- lishing the impact of ocular allergies J Allergy Clin Immunol. 2010 Oct;126(4):778-83.e6. ing prevalence.1 This has been attrib- on scholastic achievement, quality of 4. Blaiss MS. Allergic rhinoconjunctivitis: burden of dis- uted to changing climate, pollution, life and behavior, which confirms the ease. Allergy Asthma Proc. 2007 Jul-Aug; 28(4):393-7. necessity of early therapeutic inter- 5. Bielory L, Katelaris CH, Lightman S, et al. Treating the increased pollen and a heightened ocular component of allergic rhinoconjunctivitis and re- immunological sensitivity in response vention.5 lated eye disorders. MedGenMed. 2007 Aug 15;9(3):35.

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0003_dg0517_Allergy_v2.indd03_dg0517_Allergy_v2.indd 4 55/8/17/8/17 4:594:59 PMPM TIPS TO PREVENT EYE ALLERGIES Avoidance is one of the best ways to prevent triggering eye allergies. Other tips from the Asthma and Allergy Foundation of America include: • Don’t touch or rub the eye(s). • Wash hands often with soap and water. • Use a vacuum with a HEPA filter to reduce exposure to allergens. • Wash bed linens and pillow cases in hot water and detergent to reduce allergens. • Use allergen covers (encasements) for pillows, comforters, duvets and mattresses, and consider them for box springs. • Keep pets out of the bedroom to reduce pet dander allergen in bedding. • Wear sunglasses and a wide-brimmed hat to help keep pollen from getting into the eyes. • Close windows during high-pollen and mold seasons. Run the air conditioner in the car and at home, and consider using a HEPA filter.

Eye Allergies (Allergic Conjunctivitis). Asthma and Allergy Foundation of America. Available at: www.aafa.org/page/eye-allergy-conjunctivitis.aspx. Last accessed Dec 16, 2016.

• Epinastine (Elestat, Allergan; generic available) • Ketotifen (Zaditor, Alcon; many generics available. This drop is OTC.) • Olopatadine (Pazeo/Pataday/Pa- tanol, Alcon)

Of these, all are rated pregnancy category C except for Lastacaft, which is pregnancy category B. Not- withstanding other fine differences, all of the antihistamine subtype 1 receptor blockers nicely suppress ocu- some patients still require a second Interestingly, our observation in a lar itching. All are dosed initially BID additional drop later in the evening. variety of pharmacies reveals that the (except Pazeo, Pataday and Lasta- Perhaps the best news for the con- cost of the 10ml Alaway is very near caft, which are dosed QD). sumer was the loss of patent protec- to (and occasionally cheaper than) After two weeks of BID therapy, tion for Zaditor (Novartis). Since the price of its 5ml competitors. consider reducing instillation to QD 2007, ketotifen has been available When a prescription medication for maintenance dosing. Remember, generically and over the counter. In is preferred, perhaps a 10ml bottle as with any treatment, the lowest ef- addition to Zaditor, several brand- of Bepreve (using a standard copay) fective dose is always desired. In our name OTC ketotifen preparations would be of greatest cost value to the experience, once the inflammation is are available, including Alaway patient. Consider using a coupon to under control, less pharmaceutical (Bausch + Lomb) and others. All pay no more than $35 and consult- intervention is necessary to maintain come in 5ml bottles, except for Ala- ing www.goodrx.com to find the or suppress symptoms. Then again, way, which comes in a 10ml bottle. best price in your area.

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003_dg0517_Allergy_v2.indd 5 5/8/17 4:59 PM ALLERGY DRUGS

A ‘LOUSY’ REASON FOR ITCHING

Severe itching of the eyelids can be caused by crab lice. Don’t miss these. Using your toothed, curved tip forceps, simply remove them one by one. Slide one side of the forceps underneath the ventral aspect of the louse, gently close down on the dorsal side and slowly pull the critter off the tissues. Repeat for each louse you can find. Then have the patient apply an ophthalmic ointment at bedtime for a week, which will suffocate any juveniles you may have missed. Also have the patient do lid scrubs each evening before applying the ointment. In a week, the eyelid tissue should be restored to normal. Explain to the patient that these can be associated with sexual activity and any partner(s) should be examined by a physician.

OCULAR ALLERGY MEDICINES BRAND NAME GENERIC NAME MANUFACTURER PEDIATRIC USE BOTTLE SIZE(S) DOSING Acute Care Products Acular LS ketorolac tromethamine 0.4% Allergan, and generic 3 yrs 5ml, 10ml QID Alaway (OTC) ketotifen fumarate 0.035% Bausch + Lomb 3 yrs 10ml BID Alrex loteprednol etabonate 0.2% Bausch + Lomb 12 yrs 5ml, 10ml QID Bepreve bepotastine besilate 1.5% Bausch + Lomb 2 yrs 5ml, 10ml BID Elestat epinastine HCl 0.05% Allergan, and generic 3 yrs 5ml BID Emadine emedastine difumarate 0.05% Alcon 3 yrs 5ml QID Lastacaft alcaftadine 0.25% Allergan, and generic 2 yrs 3ml QD Optivar azelastine hydrochloride 0.05% Meda, and generic 3 yrs 6ml BID Pataday olopatadine hydrochloride 0.2% Alcon 3 yrs 2.5ml QD Patanol olopatadine hydrochloride 0.1% Alcon, and generic 3 yrs 5ml BID Pazeo olopatadine hydrochloride 0.7% Alcon 2 yrs 2.5ml QD Zaditor (OTC) ketotifen fumarate 0.035% Alcon, and generic 3 yrs 5ml BID

Chronic Care Products Alocril nedocromil sodium 2% Allergan, and generic 3 yrs 5ml BID Alomide lodoxamide tromethamine 0.1% Alcon 2 yrs 10ml QID Crolom cromolyn sodium 4% Bausch + Lomb, 4 yrs 10ml QID and generic

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003_dg0517_Allergy_v2.indd 6 5/8/17 4:59 PM ANTI-INFLAMMATORY EFFECTS OF TACROLIMUS sustained growth and developing ur- ban populations.3 Tacrolimus, a topical calcineurin inhibitor, is a potent anti-inflammatory. Doctors should keep Research has found that tacrolimus 0.1% can be highly effective in treating in mind that, while the disease is not severe allergic conjunctival diseases. life-threatening, the persistent symp- However, a recent study found that “tacrolimus eye drops often cause a toms experienced by those who suffer stinging sensation or conjunctival redness, especially in the beginning of treat- from ocular allergies can have a signifi- ment of severely inflamed eyes.” The authors recommended that “this can be cant impact on productivity and qual- avoided by topical steroid pretreatment before the use of topical tacrolimus.” ity of life. “In addition, tacrolimus eye drops did not have an immediate effect and Remember, allergy is an expression required one to two weeks to be effective. In contrast, topical steroids are of inflammation. In addition to the fast-acting and can immediately relieve allergic symptoms. Although treat- therapies listed above, don’t forget to ments eventually can be conducted without topical steroids, prompt relief of discuss palliative options such as daily symptoms merits topical steroids.” cold compresses to the inflamed eye. Also consider educating the patient on Miyazaki D, Fukushima A, Ohashi Y, et al. Steroid-sparing effect of 0.1% tacrolimus eye drop for treatment of shield ulcer and corneal epitheliopathy in refractory allergic ocular diseases. Ophthal- avoidance therapy. Telling your pa- mology. 2017 Mar;124(3):287-294. tients to place their allergy drops in the refrigerator until it’s time to instill the drop can add extra relief. DG SYMPTOMS AND SIGNS to an antihistamine/mast cell stabilizer 1. Kari O, Saari KM. Diagnostics and new developments Therapy for ocular allergies should be for ongoing symptomatic regulation. in the treatment of ocular allergies. Curr Allergy Asth- prophylactic, if at all possible. There- ma Rep. 2012;Jun;12(3):232-9. 2. Singh K, Axelrod S, Bielory L. The epidemiology of fore, in the setting of allergic conjunc- While originally considered to be ocular and nasal allergy in the United States. 1988– a “disease of affluence,” allergic con- 1994. J Allergy Clin Immunol. 2010 Oct;126(4):778-83. tivitis, therapy should be initiated early 3. Gomes PJ. Trends in prevalence and treatment of in the process, be sufficient to suppress junctivitis is now clearly recognized ocular allergy. Curr Opin Allergy Clin Immunol. 2014 Oct;14(5):451-6. the patient’s signs and symptoms, and around the world, with a sharp in- 4. Rosario N, Bielory L. Epidemiology of allergic be continued for long enough to pre- creasing prevalence in countries with conjunctivitis. Curr Opin Allergy Clin Immunol. 2011 Oct;11(5):471-6. vent conversion into a chronic disease. The basis of treating any allergic eye disease remains the same: Quell the ITCHY EYES ARE OFTEN DRY EYES inflammation early to help avoid potential late complications. In patients who present with symptoms of allergy as well as classic anterior segment findings, a topical, ester-based corticosteroid is a wonderful option. We recommend Alrex or off-label use of Lotemax gel (loteprednol 0.5%, Bausch + Lomb). Additionally, the generic, ketone- based corticosteroid FML ophthalmic suspension (fluorometholone 0.1%, Allergan) is a viable off-label therapy, although we have found it has a higher propensity to increase IOP compared to its ester-based Most patients with itchy eyes (consistent with allergic conjunctivitis) also loteprednol counterparts. suffer from dry eyes and hyperemia. Specifically, one study found the odds Frequency of instillation is tai- of patients with itchy eyes who also have dry eyes are more than twice that of lored to the severity of the patient’s patients with non-itchy eyes. The likelihood of these patients also experiencing signs and symptoms. Typically, we redness were more than seven times that of patients with non-itchy eyes. prescribe a steroid drop Q2H for two These results suggest that some symptomatic patients concomitantly days, then QID for one week, followed have features of allergic conjunctivitis and dry eye syndrome. by BID for one more week. When the Hom MM, Nguyen AL, Bielory L. Allergic conjunctivitis and dry eye syndrome. Ann Allergy Asthma Im- signs of allergic eye disease are sub- munol. 2012 Mar;108(3):163-6. dued, consider switching your patient

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003_dg0517_Allergy_v2.indd 7 5/8/17 5:32 PM ANTIBIOTIC AGENTS

EFFECTIVE USE OF ANTIBIOTIC AGENTS

Increasing ince the early 1940s, the use timated. More recent medical literature of antibiotics is well-docu- bemoans the egregious overprescribing of antibiotic mented in reducing illnesses systemic antibiotics, and begs physicians resistance and fatalities attributed to and other health care providers to use Smany infections worldwide. great restraint in such prescribing. sends many However, some bacteria are now resis- A recent report from the Centers for tant to the antibiotics that were at one Disease Control and Prevention warns clinicians time highly effective. This upward trend that antibiotic resistance causes two mil- is causing concern throughout medical lion bacterial and fungal illnesses, and scrambling for disciplines. Consequently, researchers are 23,000 deaths yearly. It also causes an forced to find different, more effective annual increase in direct health care costs more effective drugs to fight off bacterial infections. of $20 billion, plus $35 billion in lost pro- therapy. The Antibiotic dosing is widespread and ductivity.1 overprescribed. These drugs are generally Bear in mind that most studies on anti- key is to cheap and are offered as pills, liquids and biotic resistance have focused on systemic injections, so dosing is inherently easy for antibiotics. But in the past few years, re- select the patients of all ages. While antibiotics do searchers have begun to look at resistance right medicine have a history of being remarkably effec- to topical ophthalmic antibiotics. tive, drug resistance has been underes- and dose it ANTIBIOTICS FOR ACUTE ‘RED EYES’ WHY BACTERIAL DRUG correctly. RESISTANCE? In the setting of an acute red eye, we have Here’s how. - When a strain of bacteria becomes found that the etiology is nearly always resistant to an antibiotic, it becomes inflammatory, not infectious. An acute the dominant organism, as bacteria red eye with no mucopurulent discharge multiply quickly. is rarely the result of bacterial infection. - Animals raised for dietary consump- These inflammatory conditions require tion are often fed antibiotics, thus steroids, not antibiotics; yet time and time potentially increasing resistance that again clinicians prescribe an antibiotic can affect humans. drug that does not improve the patient’s - Antibiotics have been and continue condition. Generally speaking, infectious to be considerably overprescribed diseases produce a discharge whereas in- throughout the last 70 years. flammatory diseases do not. However, - Antibiotics continue to be prescribed the hesitancy to prescribe a steroid and inappropriately, such as in the setting uncertainty of diagnosis continues to set of a virus or inflammation. the stage for antibiotics to be inappropriately prescribed in optometric practice.

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0008_dg0517_Antibiotics_v2.indd08_dg0517_Antibiotics_v2.indd 8 55/8/17/8/17 5:085:08 PMPM TOPICAL ANTIBIOTIC DRUGS BRAND NAME GENERIC NAME MANUFACTURER PREPARATION PEDIATRIC USE BOTTLE/TUBE Fluoroquinolones Besivance besifloxacin 0.6% Bausch + Lomb suspension > 1 yr. 5ml Ciloxan ciprofloxacin 0.3% Alcon, and generic sol./oint. > 1 yr./ > 2 yrs. 5ml, 10ml/3.5g Moxeza moxifloxacin 0.5% Alcon solution > 4 mos. 3ml Ocuflox ofloxacin 0.3% Allergan, and generic solution > 1 yr. 5ml, 10ml Vigamox moxifloxacin 0.5% Alcon solution > 1 yr. 3ml Zymaxid gatifloxacin 0.5% Allergan, and generic solution > 1 yr. 2.5ml

Aminoglycosides Tobrex tobramycin 0.3% Alcon, and generic sol./oint. > 2 mos. 5ml/3.5g Garamycin gentamicin 0.3% Perrigo, and generic sol./oint. N/A 5ml/3.5g

Polymyxin B Combinations Polytrim polymyxin B/trimethoprim Allergan, and generic solution > 2 mos. 10ml Polysporin polymyxin B/bacitracin generic ointment N/A 3.5g Neosporin polymyxin B/neomycin/ generic solution N/A 10ml gramicidin polymyxin B/neomycin/ generic ointment N/A 3.5g bacitracin

Other Antibiotics AzaSite azithromycin 1% Akorn solution > 1 yr. 2.5ml Ilotycin erythromycin 0.5% Perrigo, and generic ointment > 2 mos. 3.5g Bacitracin bacitracin 500u/g Perrigo ointment N/A 3.5g

Accurate diagnosis and drug se- the frequency for eye drop adminis- (tobramycin, Alcon) or Besivance lection are paramount in patients tration depends almost exclusively (besifloxacin, Bausch + Lomb). presenting with red eyes. We have on the severity of the infectious ex- Now, let’s take a more in-depth seen hundreds of patients who were pression. look at this class of medicines. There treated elsewhere with topical antibi- In the setting of ocular infections, are many antibiotics; however, only otics and presented to us for a second antibiotics are prescribed almost a few should have widespread use. opinion when their condition did not exclusively in topical or oral form. resolve. We recognized the condition With the exception of besifloxacin— ANTIBIOTICS AND as inflammatory and initiated topical a suspension—all other antibiotic PREGNANCY steroids; the patient improved in sev- drops are solutions. Oral antibiotics Clinicians are almost inherently eral days. are most commonly prescribed as a overcautious when prescribing oral Thankfully, most of the com- tablet, capsule or liquid (the latter drugs for patients who are pregnant monly used antibiotic drops are used mostly in children). or breastfeeding. But like everyone broad-spectrum, and are generally In our practices, we prescribe else, pregnant women are just as sus- effective against many common bac- oral antibiotics more commonly ceptible to infections and should be terial pathogens. We have found than topical ones simply because treated appropriately. frequency of administration—rather we encounter more patients need- Generally speaking, in a review than particular drug selection—to be ing oral antibiotic therapy, such as of FDA categories (A-X), only cat- the key determining factor of clini- those with meibomian gland disease egory A and B drugs are considered cal outcome. Because most (but not (doxycycline), rosacea blepharitis safe for administration in pregnancy. all) of the currently approved topical (doxycycline) and internal hordeola While antibiotic usage in pregnancy antibiotics possess reasonable anti- (cephalexin). For uncommon acute is guarded due to ethical and legal is- microbial abilities, the more frequent bacterial conjunctivitis, we typically sues, obstetricians use several classes the administration of these drops, the prescribe generic Polytrim (polymyx- of drugs routinely with no harmful greater the clinical result. However, in B/trimethoprim, Allergan), Tobrex effects to the mother or baby.

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The three main drug classes that is the oldest macrolide and is FDA- This dosing is more sensible, as an are safe in pregnancy are: penicillins, classified as category B. ointment will blur the patient’s vi- cephalosporins and macrolides— One eye disease that must be treat- sion if dosed during waking hours. If with penicillins, by far, the most pre- ed with an oral medication (azithro- there is significant concurrent eyelid scribed antibiotic for pregnant wom- mycin) is adult chlamydial conjunc- margin inflammation, then perhaps en, based on our experience. All of tivitis. In one study comparing the an antibiotic-steroid combination these drugs are category B, with the efficacy of azithromycin and erythro- ointment such as generic Maxitrol exception of two macrolide drugs: mycin, 15 pregnant women took 1g (dexamethasone/neomycin/polymyx- clarithromycin and telithromycin of azithromycin during gestation for in B) would better serve the patient (category C). a chlamydial infection.1 Azithromy- than just an antibiotic ointment. Penicillins and cephalosporins cin was found to be better tolerated Additionally, bacitracin can be are considered category B due to a than erythromycin, and no adverse used at bedtime to provide overnight higher selective toxicity. This is be- affects to the baby were reported.2 coverage for moderate to severe ul- cause these drugs cause alterations Keep in mind that the more com- cerative keratitis. Be advised that for of the beta-lactam ring, a structure monly prescribed antibiotic drugs true bacterial corneal infections, a that is unique to bacteria. Spanning such as fluoroquinolones, amino- broad-spectrum antibiotic is always from first (more gram-positive cover- glycosides and tetracyclines are not preferred. In such cases, we dose age) to fourth (more gram-negative) safe in any stage of pregnancy due to besifloxacin ophthalmic suspension generation classes, cephalosporins documented harm to the fetus. As al- with Polysporin ophthalmic oint- are commonly used in eye care. First- ways, be mindful to comanage your ment (bacitracin/polymyxin B) be- generation drugs are especially com- pregnant patients with bacterial in- cause the polymyxin B is bactericidal mon; cephalexin (e.g., Keflex) is rou- fections with their obstetrician when against gram-negative pathogens. tinely used to treat internal hordeola prescribing oral therapy. and mild cases of preseptal cellulitis. THE AMINOGLYCOSIDES These drugs are perfectly fine to use BACITRACIN While these drugs do (quite unfairly) during pregnancy and can prevent Available since 1948, bacitracin, a carry a reputation for being poten- more serious disease sequelae. strictly gram-positive antibiotic, is of- tially corneotoxic, aminoglycosides Macrolides were first isolated in ten employed in the clinical setting of are relatively protected from bacteri- 1952, and quickly gained ground as staphylococcal blepharitis. It is only al resistance that comes from prima- a first choice of therapy for patients available in ointment form, which ry care use. Why? Due to ototoxicity allergic to penicillin. Bacterial pro- somewhat limits its practicality out- issues, they are not used systemical- tein synthesis is inhibited by linking side of bedtime dosing. After warm ly, thereby considerably lowering the to the 50S sub-unit of the bacterial compresses and lid scrubs, bacitracin potential for antibiotic resistance. ribosome, which is different from can be applied to the lid margins at Remember, it is the widespread sys- the human ribosome. Erythromycin night before the patient goes to bed. temic use of antibiotics that tends to promote resistance. In fact, these older generic aminoglycosides are some of the most highly efficacious antibiotic eye drops available. Aminoglycosides are often hesitantly prescribed due to their potential to cause a type IV hypersensitivity

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008_dg0517_Antibiotics_v2.indd 10 5/8/17 5:08 PM reaction on rare occasions. Neomycin ed from resistance, thus enabling it to thoprim) is an effective combination itself is broad-spectrum, but it does act as a powerful therapeutic agent antibiotic available in solution form. not cover Pseudomonas, which is for many decades. For example, baci- Polymyxin B is active only against why it is always packaged with poly- tracin was brought to market in the gram-negative bacteria. Trime- myxin B or another antibiotic to cov- 1940s and remains a superb, exclu- thoprim is broad-spectrum against er gram-negative organisms. In our sively gram-positive antibiotic today. many gram-positive and some gram- experience, type IV delayed hypersen- These medicines are highly effective, negative bacteria, and works by in- sitivity dermatoconjunctivokeratitis cheap and remain workhorse drugs terfering with the folic acid pathway. reactions are exceedingly rare when in contemporary eye care. Note that trimethoprim itself is not a the neomycin combination is used for We stress that bacterial infections sulfa drug, although it also inhibits no more than a week. are characterized by a mucopurulent the production of bacterial folic acid. The exception is the rare patient discharge. Sometimes this is grossly An advantage of Polytrim is that who has been previously exposed to visible; other times, the discharge is it is available in a 10mL bottle al- an aminoglycoside and already has more subtle and is only found via lowing more “bang for the buck.” immunosensitivity. Such patients slit-lamp observation of micropar- Its propensity to cause ocular surface can react to the aminoglycosides in ticulate debris in the lacrimal lake. toxicity is minimal, so we often like just a day or two, which may also be Both the aqueous humor and lacri- to use it in combination with a ban- the result of a type I hypersensitivity mal lake should be optically empty. dage soft contact lens when there is to initial exposure. Patient manage- Cellular and/or proteinaceous debris significant epithelial compromise, ment is to simply stop the medica- in the aqueous humor is exhibited in such as a corneal abrasion. tion. Again, these are non-serious, anterior uveitis, and debris in the lac- Polysporin. This drug, which com- annoying, superficial responses. In rimal lake is typically seen in more bines polymyxin B with bacitracin, our many years of clinical practice, subtle cases of acute bacterial ocular is available generically but only as we have seen only half a dozen such surface infection. an ophthalmic ointment. The pairing events, mostly with neomycin expo- Every time you are uncertain of the of polymyxin B’s gram-negative and sure of greater than a week, and of- diagnosis and are considering pre- bacitracin’s gram-positive predilec- ten when the drug was prescribed by scribing a topical antibiotic, always tion makes this an excellent nontoxic, primary care practitioners. reconsider this low-yield therapeutic broad-spectrum antibiotic. However, When neomycin (along with poly- approach. At the very least, consider because the preparation is only avail- myxin B) is packaged with a steroid, use of a combination antibiotic-ste- able in ointment form, its clinical util- such as generic Maxitrol, whatever roid with appropriate follow-up care ity is somewhat limited in patient care. expression of a hypersensitivity reac- in two to three days. The drug is often used in pediatric tion that may be occurring typically eye care, instilled along the lids and remains subthreshold, or subdued, POLYMYXIN B COMBINATIONS lashes, where body temperature melts courtesy of the concurrent steroid. Combination drugs that pair poly- the ointment and allows adequate oc- As stated above, the aminoglyco- myxin B with a complementary agent ular surface application of the drug. sides, used systemically, can cause can extend the total antibiotic cover- Of course, this principle can be ap- ototoxicity. For this reason they are age achieved. plied to patients of all ages. rarely, if ever, used in this way. Any Polytrim. Originally marketed by In cases of bacterial keratitis or a drug actively or passively reserved for Allergan and now generically avail- severe bacterial conjunctivitis, Poly- only topical use is relatively protect- able, Polytrim (polymyxin B/trime- sporin ointment can be especially

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useful at night for sustained antibac- THE EFFICIENT RED EYE EVALUATION terial coverage. KEEP IN MIND Each of these procedures generally takes about Neosporin. This triple-antibiotic two to three minutes in most cases. comprised of neomycin, bacitracin and polymyxin B is conveniently • Assess visual acuity (pinhole if indicated) available generically as an ophthal- • Note the degree of conjunctival injection mic ointment and solution (the solu- Mild: dry eyes, allergy, chlamydia, mild bacterial infections tion contains gramicidin, not baci- Marked: acute viral or non-specific bacterial infection, acute iritis tracin). Remember, both bacitracin • Note the degree of conjunctival injection pattern and Polysporin are available only as Sector injection: corneal infiltrate, episcleritis, phlyctenule, inflamed ointments. pinguecula We rarely use Neosporin in eye Global injection: uniform—bacterial or viral infection, or uveitis drop form, as we prefer generic Poly- More pronounced in fornices: bacterial infection trim (trimethoprim/polymyxin B), More pronounced paralimbally: uveitis tobramycin or Besivance, depending • Quality and quantity of discharge if any on the nature and severity of the in- Watery: viral fectious condition. However, we use Mucoid: dry eyes, allergy, chlamydia Neosporin ointment without hesita- Mucopurulent: bacteria tion for those rare occasions when • Preauricular lymphadenopathy (not grossly visible) overnight antibiosis is deemed neces- Most commonly, adenoviral sary to enhance a clinical cure. Less commonly, chlamydial To be clear, neomycin is an ef- Rarely, hyperacute conjunctivitis ficacious drug that can occasionally If grossly visible: Parinaud’s oculoglandular syndrome (cat-scratch disease) cause a delayed type IV hypersensitiv- • Follicles vs. papillae: clinically virtually meaningless ity reaction. Given that we have three Exception: Giant follicles in the inferior forniceal conjunctiva are highly alternatives (generic Polytrim, generic indicative of chlamydial infection tobramycin and Besivance) that are much less prone to cause any sort of • Character of cornea: Examine without, then with, fluorescein dye to rule allergic response, we prefer to follow out herpes keratitis, subtle abrasions, ulceration, through-and-through perforation (Seidel’s sign) this simpler path for most patients most of the time. • Measure the IOP if no contraindications exist • Evert the eyelid to rule out conjunctival foreign material or pathology THE FLUOROQUINOLONES • Examine the anterior chamber for cells/flare The options in this class have some notable differences. • Quick ophthalmoscopy to rule out concurrent intraocular disease Besifloxacin. Besivance, a unique, dual-halogenated fluoroquinolone, est concentration of an antibiotic at (up to more than 70% by day five) is the only topical ophthalmic antibi- which 90% of isolates are inhibited.) and bacterial eradication (more than otic that comes as a suspension. As As a suspension, this thick eye drop 90% by day five), and a low incidence with all fluoroquinolones, Besivance must be shaken prior to each use, and of adverse effects.”4 provides activity against DNA gyrase has been shown to maintain high con- For severe infectious processes such and topoisomerase IV. Its broad-spec- centrations on the ocular surface after as microbial keratitis, we dose Besiv- trum coverage combats gram-positive, instillation, with minimal systemic ex- ance hourly (while awake) for one gram-negative (including Pseudomo- posure. to three days, then taper the dose to nas), and anaerobic organisms, as well A study in the Journal of Oph- every two hours for a few more days, as methicillin-resistant Staphylococcus thalmology and Therapy concludes: then to four times a day for a few aureus (MRSA) and Staphylococcus “Large randomized, controlled clini- more days. Depending upon the sever- epidermis (MRSE). The latest research cal trials have established the efficacy ity and character of the infectious pro- (ARMOR) has demonstrated in vi- and safety of besifloxacin adminis- cess, we may adjunctively prescribe tro that besifloxacin and vancomycin tered three times daily for five days for Polysporin or Neosporin ointment at

share very low MIC90 levels against the treatment of acute bacterial con- bedtime. the common gram-positive ocular junctivitis in both adults and children, Ciprofloxacin. Ciloxan, a second- 3 pathogens. (MIC90 indicates the low- with high rates of clinical resolution generation fluoroquinolone, remains

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0008_dg0517_Antibiotics_v2.indd08_dg0517_Antibiotics_v2.indd 1212 55/8/17/8/17 5:095:09 PMPM a drug of choice against the gram- gamox, Moxeza has a xanthan gum Like all topical antibiotic medicines, negative Pseudomonas species, and base that affords a prolonged contact use it more frequently initially (i.e., ev- remains close in efficacy to the fourth- time and allows a slight reduction in ery one to two hours) until the condi- generation fluoroquinolones. How- dosing frequency. tion improves. Then reduce its use to ever, ciprofloxacin is a somewhat While all fluoroquinolones have four times a day for a few more days unstable solution that precipitates developed significant antibiotic re- until the condition is resolved. out when treating corneal ulcers and sistance, moxifloxacin appears to re- gives a fine powder-like appearance to main a satisfactory choice for bacterial SYSTEMIC AGENTS the ulcer bed, which is of no clinical conjunctivitis; personally, we would Oral antibiotics remain wonderful significance. Sight-threatening ulcers choose Besivance or fortified anti- options when used judiciously. Their must always be cultured for identity biotics (vancomycin or tobramycin) clinical indications are vast, and they and resistance to antibiotics. for bacterial keratitis because of their can be used in short-term to long-term Moxifloxacin. Two popular documented enhanced efficacy. or maintenance therapy (meibomian fourth-generation fluoroquinolones, Ofloxacin. A second-generation gland disease and rosacea blepharitis). topical moxifloxacin 0.5% available fluoro quinolone, ofloxacin is rarely For an acute internal hordeola, we as Moxeza (Alcon) and Vigamox used. However, because the drug is prefer the first-generation cephalo- (Alcon), function very similarly. Of generic, it remains a reasonable, inex- sporin, cephalexin (Keflex), at 500mg clinical note, Vigamox and Moxeza pensive option for bacterial conjuncti- BID for one week. If the condition is are the only preservative-free ophthal- vitis. It is also available as brand-name severe and/or the patient is large in mic fluoroquinolone antibiotics, thus Ocuflox (Allergan). size, 500mg QID for one week may be minimizing the potential for a toxic or Gatifloxacin. A fairly effective indicated. This predominantly gram- allergic response (although such is ex- fourth-generation fluoroquinolone, positive antibiotic has been shown ceedingly rare). Zymaxid is FDA-approved to treat to improve the infection in about a Patients should be informed that bacterial conjunctivitis. While useful, week. We may also prescribe generic the drop has a slight yellow color to this and all fourth-generation fluoro- Maxitrol ointment at night to the lid avoid the misconception that the drop quinolones are exhibiting increasing margins, after warm compresses and has gone bad. In comparison to Vi- bacterial resistance. lid scrubs. Remind the patient that the

THERAPEUTIC OPTIONS FOR CORNEAL ULCERS Thankfully, infectious corneal ulcers are very rare, but when they do occur, they are treated aggressively with topical antibiotic eye drops. For perspective, leu- kocytic infiltrates also create little white lesions in the anterior stroma that may have a relatively small epithelial defect over the center of the white infiltrate. These infiltrates are often naively and incorrectly referred to as “ulcers,” when in fact they possess no infectious potential. Rather, these are inflammatory expressions—almost always occurring at or near the limbus—and treatment with a steroid (a combination drug such as Zylet, generic Maxitrol or generic TobraDex) is required to suppress this pathophysiological process. Infectious ulcers come in two varieties: large, central ulcers; and small-to- large, noncentral ulcers. Central ulcers are most commonly treated with fortified tobramycin (for gram-negative coverage) and vancomycin (for gram-positive coverage). Most eye reference texts, such as the Wills Eye Manual, can guide you and the compounding pharmacy on how to make these preparations. Generally speaking, these medicines are used about every 30 minutes for the first few hours, then hourly while awake until obvious healing is occurring; every two hours for another few days; and finally, four times a day for a few more days. Rather than have the patients instill these drops around the clock, we prefer the use of Neosporin ophthalmic ointment at bedtime. Once good healing has occurred, the nocturnal ointment can be discontinued. Some patients are allergic to Neosporin, so alternatives exist (e.g., polysporin and Ciloxan, or even TobraDex ointment). For noncentral ulcers, we use Besivance (besifloxacin 0.6% ophthalmic suspension) every 30 minutes for a few hours, then hourly, as outlined in the preceding paragraph concerning use of the fortified eye drops. Neosporin (or Polysporin) or TobraDex ointment at bedtime is also used as above. We always cycloplege these patients, as they invariably will have a secondary anterior uveitis. Either atropine 1% or homatropine 5% is typically used to accomplish this purpose. The standard dosage is cycloplegia two to four times daily, depending upon the severity of the clinical condition.

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STRATEGIES TO CONQUER BLEPHARITIS Chronic anterior eyelid margin disease is most commonly caused by chronic, low-grade infection of Staphylococcus aureus and Staphylococcus epidermidis bacteria. These bacteria produce exotoxins, creating secondary inflammation to the adja- cent eyelid marginal tissues. (This is distinct from meibomian gland disease, which has a wholly different pathophysiology.) Occasionally, these exotoxins can cause inferior corneal epithelial compromise. Understanding the cascade of tissue compromise resulting from unchecked Staph. populations residing on the anterior lids perfectly provides the rationale for using a good antibiotic/corticosteroid combination drug for symptomatic blepharitis. No other drug or drug class even approximates the efficacy of such therapeutic intervention. Any of the available combination drugs would work well short term (less than two weeks), but given that blepharitis is a chronic, recurrent disease, the drug we find best suited for treating blepharitis is a combination of tobramycin (excellent anti-Staph. action) with loteprednol (excellent, safe, anti-inflammatory action) known by the popular brand name Zylet. Initiate treatment with Zylet four times daily for two weeks, depending upon the severity of the clinical disease, then just pulse dose four times a day for a week if or when breakthrough symptoms occur. Such pulse dosing is an effective and “steroid-sparing” therapeutic approach and one that we embrace for almost any chronic, recurrent ocular surface disease. The combination drugs TobraDex and Maxitrol are both generic and relatively inexpensive, but contain dexamethasone, which limits their usefulness beyond a couple of weeks. One would rarely ever employ dexamethasone for a chronic condition because of its propensity to increase intraocular pressure. All three of these drugs are suspensions and, as such, need to be shaken well. However, blepharitis is not treated exclusively with any eye drop. Concurrent use of eyelid scrubs is an essential component not only to help control the infectious/inflammatory disease, but as ongoing hygiene to maintain eyelid health. Avenova (hypochlorous acid 0.01%, NovaBay Pharmaceuticals) eyelid and eyelash cleanser has become quite popular, and does seem to help maintain healthy tissues in our patients. Further, with diminution of Staph. populations, there is a decreased risk of secondary styes and internal hordeola. In summary, the combined use of an effective, safe antibiotic/steroid and meticulous eyelid hygiene perfectly embodies rational care for patients with anterior eyelid margin disease.

infection is typically secondary to an of drugs. Always take a careful medi- tients who need antibiotic treatment overproduction of bacteria on their cal history to avoid the risk of an al- for chronic conditions such as mei- lids, and that continued warm com- lergic reaction. If a patient has a true bomian gland disease or rosacea presses and lid scrubs daily will help anaphylactic reaction to penicillin or blepharitis. We prescribe doxycycline reduce the risk of recurrences. penicillin-like drugs such as cephalo- at 50mg daily for three to six months. Patients tend to have allergies to sporin, we opt for Levaquin (500mg The dichotomous nature of doxycy- antibiotics more than other classes QD) or doxycycline (200mg QD), or cline (anti-infective at high dosage and Bactrim DS or Septra DS (both com- anti-inflammatory at low dosage) re- CUT THE PILL—AND THE mon brand names of trimethoprim quires different dosing based on clini- COST—IN HALF with sulfamethoxazole) prescribed as cal intent. The cost of brand name and two double-strength tablets BID for While both doxycycline hyclate and generic drugs is continually one week, which is the standard, com- doxycycline monohydrate are well- changing, and clinicians are con- monly prescribed dosage. tolerated, the monohydrate form ap- stantly faced with dynamic and If the patient is truly allergic to pen- pears to be a bit better tolerated. DG ever-changing pricing structures. icillin and sulfa, consider oral doxy- Regarding doxycycline, we have 1. Centers for Disease Control and Prevention. Anti- cycline 100mg BID for one week, or biotic Resistance Threats in the United States, 2013. found in several instances that the oral fluoroquinolone levofloxacin Available at: www.cdc.gov/drugresistance/pdf/ar- the 100mg units are cheaper than threats-2013-508.pdf (last accessed March 24, 2017). 500mg once daily for one week. For 2. Bush MR, Rosa C. Azithromycin and erythromycin in the 50mg units. To be more cost- perspective, the risk of a cross-sensi- the treatment of cervical chlamydial infection during effective for the patient, we occa- pregnancy. Obstet Gynecol. 1994 Jul;84(1):61-3. tivity reaction of a cephalosporin in a 3. Asbell PA, Sanfilippo CM, Pillar CM, et al. Anti- sionally prescribe 100mg doxy- biotic resistance among ocular pathogens in the cycline monohydrate tablets that patient who is truly allergic to penicil- United States: Five-Year results from the antibiotic lin is about 0.1%—but why ever take resistance monitoring in ocular microorganisms (AR- can be split in half. (Patients can MOR) surveillance study. JAMA Ophthalmol. 2015 purchase affordable pill-splitters the miniscule risk? Just prescribe an Dec;133(12):1445-54. 4. Mah FS, Sanfilippo CM. Besifloxacin: Efficacy and at most drug stores.) alternative class. safety in treatment and prevention of ocular bacterial Occasionally, we encounter pa- infections. Ophthalmol Ther. 2016 Jun; 5(1): 1-20.

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PROTECT PATIENTS FROM PLAQUENIL TOXICITY

Despite its irtually all optometrists have Since it is well-documented that a large patients taking hydroxychlo- minority of patients are overdosed on hy- potential for roquine (Plaquenil, AvKare). droxychloroquine, our prime responsibility This drug is most commonly is to help guide the prescribing physician retinal toxicity, 2 Vprescribed to moderate the on the proper dosage. Our exclusive goal this drug can expression of rheumatoid arthritis and sys- in providing this guidance is prevention of temic lupus erythematosus, but it is now vision loss. We have very professionally, be useful for being investigated for new applications in and very appropriately, corresponded with diabetes, heart disease and cancer. many rheumatologists over the decades. treating immune Despite its potential for retinal toxicity, Dr. Thomas has been an expert witness on hydroxychloroquine is a useful drug, and cases in which the optometrist was sued for or inflammatory has fewer systemic side effects than many failure to properly screen for hydroxychlo- diseases. Here of the alternative medications used for im- roquine toxicity when the patient suffered mune or inflammatory diseases. Hydroxy- vision loss; the rheumatologist was also a is the latest chloroquine is a major lifestyle-enhancing defendant in these cases—all preventable medication and a lifesaver for patients and had proper doctor-to-doctor communica- information rheumatologists alike. tion been accomplished for the benefit of This is why we all need to use exception- the patient. So, ODs must not only screen to guide your al clinical judgment in consulting with and patients appropriately but also advise our conversations advising prescribing physicians regarding medical colleagues and patients about stopping this medication. This discussion risks, safe dosing and appropriate screening with prescribing will give you the guidance needed to make procedures. Once you are armed with the these critical decisions. appropriate knowledge, you are as expert physicians. In keeping with our unrelenting admo- as anyone else to give appropriate, patient- nition to colleagues to read the literature, centric guidance. And, as such, you are the critical knowledge we share below was equally legally liable for failing to do so. gained from “Recommendations on Screen- Our primary responsibilities are (1) to ing for Chloroquine and Hydroxychloro- conduct a proper hydroxychloroquine quine Retinopathy (2016 Revision)” pub- screening and (2) to provide proper dos- lished in the June 2016 Ophthalmology.1 ing guidance to the prescribing physicians. Chloroquine has greater toxicity poten- Here, we address both goals by discussing tial than does hydroxychloroquine, and as select recommendations from the recent such, patients are now generally prescribed landmark article. Some quotes or in-con- hydroxychloroquine. Thus, this article fo- text paraphrases from this article, and our commentary (indicated in italics), follow. The classic appearance of cuses exclusively on hydroxychloroquine. Further, this update builds from our discus- • “Toxicity is not rare among long-term “bull’s eye” maculopathy from sions in the 2014, 2015 and 2016 Clinical users” of Plaquenil, and the risk is “highly hydroxychloroquine toxicity. Guide to Ophthalmic Drugs. dependent on the daily dose by weight.”

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• While non-Asian patients char- DEBATE ON PLAQUENIL DOSING acteristically exhibit damage involv- Given its basis in objective science, one would think that there would be uni- ing the central 2 to 8 degrees, Asian form agreement on such a topic as Plaquenil dosing, but that is not the case. patients characteristically show more In the October 2016 issue of The American Journal of Ophthalmology, we see peripheral damage, so perform a 24-2 how brilliant physicians differ on this critical issue in their commentaries.1,2 or 30-2 visual field with this subset of Points: patients. Be mindful that these two test • “The concentration [of hydroxychloroquine] in skin and fat were just patterns have only four central tested below those of muscle, indicating that the drug is stored to a similar level of points, so if even one such point is de- all of these tissues.” fective, there needs to be retesting with • Real body weight is more predictive of retinopathy than ideal weight over a 10-2 protocol—the recommended vi- the full range of body mass index (BMI).” sual field test for non-Asian patients. A • “Using real weight is simpler than performing unnecessary ideal body white (not red) target is recommended. weight calculations, and we strongly urge that patients stay below a daily • While previous discussions have dose of 5mg/kg,” (i.e., 300mg/day). The usual dosage of 6.5mg/kg—400mg centered on “ideal” body weight, or per day—of ideal body weight would overdose patients weighing less than 135 lean body weight, newer research has pounds, whereas if dosed at 5mg/kg of real body weight, this 300mg per day shown that hydroxychloroquine stores could be used in patients weighing as little as 105 pounds without increasing the risk of retinopathy. “primarily in melanotic tissue, liver, Counterpoints: and kidney, whereas concentrations • “The concentration of drug in muscle was 4.5 times that in fat.” are low in muscle, fat, and a variety • “The concentration of chloroquine in liver, lung and spleen were 38.9, 22.6 of other organs.” For this reason, the and 16.3 times the concentration in fat.” authors recommend that all patients • Safe dosing “cannot be based on either ideal body weight or actual body using hydroxychloroquine keep daily weight alone, as a consequence of their non-uniform distribution across fat dosage to less than 5mg/kg of real and other tissues. Properly performed, the lesser of ideal body weight and body weight. Just for perspective, the actual body weight should be used for calculating safe doses. For the com- historic dosage has been 6.5mg/kg of monly prescribed dose of hydroxychloroquine, 400mg per day, using ideal body weight, which equates to 135 body weight alone, is dangerous if the patient is asthenic [skinny]. Using actu- pounds of ideal weight, based on the al body weight alone is dangerous if the patient is short and obese.” most common dosage of 400mg per • “Obese individuals should be dosed on the basis of height, which allows day. With this newer dosage recom- estimation of asthenic or ‘ideal’ body weight.” mendation of less than 5mg/kg of ac- In summary, be attentive to the dosing of patients, especially small, short- tual weight, patients are relatively safe statured persons. Assuming the perspective that uptake of hydroxychloro- at a weight of 75 pounds or more. quine is less in fat, be mindful of how obesity, especially in the short-statured, Our practical conclusion is that could errantly influence one’s risk assessment. We still marvel that there is not 300mg/day can keep most patients a solid consensus on relative compartmental distribution of hydroxychloro- well-controlled, and that enables a quine in the body. Such firm knowledge would enable much simpler care. 25% overall reduction in drug expo- As well, there are several mechanisms to calculate ideal body weight. sure. This would enable many more Though there are slight differences, they are fairly close. Use your best judg- smaller-bodied patients (from 135 ment on which to use; after all, you are the one actually evaluating the patient. pounds down to 100 pounds) to also 1. Melles RB, Marmor MF. The prevalence of hydroxychloroquine retinopathy and toxic dosing, and the role of the ophthalmologist in reducing both. Am J Ophthalmol. 2016 Oct;170:240. realize a 25% reduction, and to safely 2. Browning DJ. The prevalence of hydroxychloroquine retinopathy and toxic dosing, and the role of the use this dosage of hydroxychloroquine. ophthalmologist in reducing both [reply]. Am J Ophthalmol. 2016 Oct;170:240-1. This newer approach makes proper dosing easier for the prescribing phy- tablet Monday, Wednesday and Fri- is “excessive daily dose by weight.” sician and the optometrist monitoring day, and two tablets on the alternate • “Even patients using a recom- for iatrogenic maculopathy. days. Or, for more refined dosing, take mended dose have significant risk after • “Patients staying with 5mg/kg per two tablets Monday, Wednesday and decades of use.” day of actual body weight of at least Friday, and one on the alternate days. • Hydroxychloroquine is cleared 100 pounds have less than 1% risk in Obviously, the total weekly exposure to a large degree by the kidneys, so the first five years of therapy and less will be nearly identical, but for the ul- renal disease effectively increases than 2% up to 10 years.” Since hy- timate on precision prescribing, these the circulating level of the drug, and droxychloroquine tablets come only are two easily accomplished options. the toxicity risk. Be sure to inquire as 200mg, “intermediate” dosing can • “The most critical risk factor” for about any significant kidney disease easily be accomplished by taking one the development of Plaquenil toxicity when assessing risk.

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0015_dg0517_plaquenil_v2.indd15_dg0517_plaquenil_v2.indd 1166 55/8/17/8/17 5:115:11 PMPM • Tamoxifen is a commonly used functional status.” Though CALCULATING “IDEAL” BODY WEIGHT drug to help treat or prevent breast baseline visual fields and IS STRAIGHTFORWARD cancer. A newer study found that SD-OCT are always use- • For women, starting at 5 feet and 100 pounds, concurrent use of tamoxifen with hy- ful, “it is not critical to ob- add 5 pounds for each additional inch in height. droxychloroquine increased the risk of tain them at baseline unless • For men, starting at 5 feet and 105 pounds, toxicity approximately five times. Be abnormalities are present add 5 pounds for each additional inch in height. keenly aware of this potential for ex- (e.g., focal macular lesion, acerbation. Furthermore, tamoxifen is glaucoma) that might affect screening spond more reliably than others. Prop- known to cause, albeit rarely, a crys- tests. The baseline examination also er field interpretation requires a sensi- talline maculopathy (as shown below). provides an opportunity for advising tive eye to the characteristic pattern of As you may be aware, tamoxifen is be- patients and prescribing physicians hydroxychloroquine loss.” ing slowly but steadily replaced with about proper dose levels (and the abil- • “As damage from hydroxychlo- newer agents known as aromatase ity to adjust them) and the importance roquine develops, the SD-OCT shows inhibitors; common brand names are of regular screening if they continue localized thinning of the photorecep- Arimidex (anastrozole, AstraZeneca), the medication long-term.” tor layers in the parafoveal region in Aromasin (exemestane, Pharmacia • “It is important to check the dos- non-Asian eyes or near the arcades in and Upjohn) and Femara (letrozole, age relative to weight at every visit and many Asian eyes. These localized ar- Novartis). Research suggests that these to ask about changes in systemic sta- eas of photoreceptor loss are strong newer medications to treat breast can- tus, such as major weight loss, kidney indications of toxicity.” As with all vi- cer do not cause an increase in risk as- disease or tamoxifen use.” You may sual field testing, if very early changes sociated with hydroxychloroquine use. think these considerations should be seem tenuous, the test can be repeated • Patients with underlying macular exclusively the responsibility of the or other tests can be performed for disease may be at higher risk for tox- prescribing physician, and we fully confirmation. As noted earlier: It is icity, although the degree of increased agree. But it is well-established that important to emphasize that hydroxy- risk is unknown and likely varies from many seem to be aloof in this regard. chloroquine is a useful drug with fewer person to person based on the charac- Bear in mind that life is a team sport side effects than many of the alterna- ter and expression of the macular tis- and that our patients also rely on us for tive medications, the authors stress. sues. We recommend baseline photos their well-being. We, as optometrists, “Thus, screening can be viewed as a of any underlying macular disease. need to have a keenly watchful eye on means of helping patients continue hy- • “All patients beginning long-term our patients and communicate appro- droxychloroquine (by not stopping the hydroxychloroquine therapy should priately with the prescribing physician. drug for uncertain findings).” have a baseline ophthalmologic exami- • “We recommend the use of both • “Ophthalmoscopy is not a screen- nation within the first year of starting automated visual fields and SD-OCT ing tool because photoreceptor dam- the drug to document any complicat- for routine primary screening because age is detectable with other techniques ing ocular conditions and to establish these are widely available.” They also well before visible changes in the fun- a record of the fundus appearance and recommend white SITA testing with dus.” pattern deviation plots, “which distin- • “Amsler grid testing is not consis- guish regional loss from background tent enough for reliable screening of sensitivity better than the gray scale.” subtle scotomas.” This is similar to glaucoma, whereas • “Color [vision] testing errors may the gray scale is excellent for detecting occur, but are not sensitive or specific.” and monitoring neurological disease. A critical part of our global patient • “The 10-2 field pattern has high care services involves being attentive to resolution within the macula and patients taking hydroxychloroquine. is excellent for non-Asian patients. We must be keenly aware of the clini- However, wider test patterns (24-2 or cal guidance set forth in this article and 30-2) are needed for Asian patients in apply it to the care of our patients. DG This patient, who was taking Tamoxifen, whom toxicity often manifests beyond 1. Marmor MF, Kellner U, Lai TY et al; American Acad- the macula. These larger patterns have emy of Ophthalmology. Recommendations on Screen- developed toxic maculopathy (not ing for Chloroquine and Hydroxychloroquine Retinop- only four central test spots, and even a athy – 2016. Ophthalmology. 2016 Jun;123(6):1386-94. concurrently taking Plaquenil) in the single central spot of reduced sensitiv- Available at: www.aao.org/clinical-statement/re- right eye. The left eye was identical. vised-recommendations-on-screening-chloroquine-h. ity should be taken seriously.” Acces sed January 6, 2017. Note the tiny crystalline deposits right at • “Visual fields can vary markedly 2. Melles RB, Marmor MF. The risk of toxic retinopathy the foveal tissues. in patients on long-term hydroxychloroquine therapy. between visits, and some patients re- JAMA Ophthalmol. 2014;132:1453-60.

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NEGOTIATING DRY EYE DISEASE PATHWAYS

Management nterest in dry eye disease is at an all-time With the meibomian glands, rather than high. In this chapter, we present ratio- the lacrimal glands, at center stage in the of dry eye nal, scientifically sound, patient-centric etiopathogenesis of this highly complex approaches to helping those with this disorder, our core therapeutic goal is to en- is shifting Iunique ocular surface disease. The goal hance meibomian gland function for all pa- is not to address the cascade of dry eye dis- tients. No matter what signs and symptoms from solely ease at the cellular level; it is to provide a they present with, we know they all require using tear comprehensive overview of our clinical rehabilitation to healthy meibomian gland perspective, bolstered by the peer-reviewed function. To address gland function, we replacement literature and expert commentary. have incorporated the essential methods of treating meibomian gland obstruction. strategies to PRIMARY FOUNDATION OF DED In an ideal world, we would all have also controlling Historically, the therapy for dry eye has LipiFlow (TearScience) or a similar device been to manage the signs and symptoms in our offices, which we would use on our inflammation. using tear replacement and tear conserva- dry eye patients every six to 24 months; tion strategies. In addition to the numerous however, in the absence of LipiFlow or Also, research tear replacement options, we also currently similar, we know that manual expression enjoy access to multiple medications for of the glands can be effective. Whether au- is targeting managing inflammation. tomated or manual, evacuating the gland meibomian Most encouraging is that scientific re- contents to improve gland function dimin- search has shifted our thinking and practice ishes the need for all other topical interven- gland disease to also address tear film instability—consid- tions for dry eye over the long term. ered to be the root cause of dry eye—along It is common knowledge that a defective as the primary with the most common cause of dry eye: lipid layer is the epicenter of precorneal tear meibomian gland disease (MGD), the pre- film dysfunction in most dry eye patients. driver. dominant driver of dry eye, as it results in With insufficient quantity and quality of a poor lipid layer that destabilizes the tear the lipid layer, aberrations of the volumi- film. Understanding that the ocular surface nous watery layer occur, leading to ocular cannot be rehabilitated in the absence of surface inflammation. Once the tear film healthy meibomian gland function has dra- begins to deteriorate and inflammation matically improved the care of our patients subsequently occurs, patients present to us and streamlined our overall approach. with the typical complaints of dry, burning, sandy or gritty, and itchy eyes. * Loteprednol (Lotemax) therapy for inflammation due to dry eye disease is SYMPTOMATOLOGY SIMPLIFIED considered an off-label use. All men- Diagnosing manifest dry eye disease can tions of such use herein reflects the views of the authors. be profoundly simple and largely defined by attentive history; however, this is not

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0018_dg0517_Dry18_dg0517_Dry eeye_v2.inddye_v2.indd 1188 55/8/17/8/17 5:255:25 PMPM DRY EYE DISEASE WITH CHRONIC PAIN SYNDROMES A small subset of dry eye patients may remain symptomatic even after trying exhaustive therapeutic interventions. These unfortunate patients may have a central (i.e., central nervous system) nociceptor malfunction that has nothing to do with their ocular surface status. A corneal subspecialist has no better tools than we do in this regard, and a neurology or pain clinic consultation may be in order. This concept of central pain receptor dysfunction is in its infancy, and remains elusive in both diagnostic and therapeutic intervention. Excerpts from a recent article help to explain this phenomenon:1 • Chronic pain syndromes are often described as conditions with chronic pain in one or more body parts without obvious tissue-level pathology. These conditions include irritable bowel syndrome, chronic pelvic pain and fibromyalgia (also known as chronic widespread pain syndrome), among others. • Dry eye patients with a self-reported chronic pain syndrome report worse dry eye symptoms, despite having the same or less severe clinical grading of their ocular surface disease than dry eye patients without a chronic pain syndrome. • Given the high prevalence of chronic pain syndromes in the general population, and especially in the dry eye population, these findings may help optometrists, ophthalmologists and family doctors understand the discrepancy between signs and symptoms in subgroups of patients with dry eye disease. • The finding of increased symptoms in dry eye disease patients with chronic pain syndrome adds further evidence to the theory that dry eye symptoms are, in part, a consequence of neuropathic ocular pain, instead of Allodynia: a condition in which typically non-noxious thinking of dry eye as a tear dysfunction syndrome stimuli elicit pain. It is the perception of pain/discomfort to only. Indeed, many studies have shown dysfunction in brushing, pressure, exposure to wind, light, heat or cold out the corneal pain system in dry eye settings, including of proportion, or beyond a normal response. the presence of spontaneous dysesthesias, allodynia, Hyperalgesia: Abnormally heightened sensitivity to pain. hyperalgesia and corneal nerve morphologic and functional abnormalities. • Results indicate that dry eye patients with a chronic pain syndrome, both in the general population and in the dry eye clinic, might have dysfunctional pain perception, and this should be considered, particularly when symptoms appear more severe than the ocular signs suggest. This subgroup represents a challenge to healthcare providers, as these patients may be more likely resistant to standard therapies of dry eye aimed at the ocular surface. • Based on this and other corroborating articles, it appears that there is indeed a small subset of dry eye-type patients beyond our current therapeutic reach. Our duty to these patients is to have them consult with specialists in neurology, rheumatology or a pain management clinic, all of which have limited resources to help these patients.

1. Vehof J, Sillevis Smitt-Kamminga N, Kozareva D, et al. Clinical characteristics of dry eye patients with chronic pain syndromes. Am J Ophthalmol. 2016;Feb;162:59-65.e2.

always the case. Once patients de- manage the manifest symptoms. question. We see no reason to have scribe the hallmark complaints, some To quantify the symptoms, Dr. patients complete any questionnaire clinicians choose to use a variety of Melton has developed an approach when we use this straightforward and in-office assessments beyond slit-lamp that is simply to ask the patient: “On practical approach. examination of the lacrimal lake and a scale from one to 10, how badly do measuring tear film break-up time, your eyes bother you?” TREATING AND MANAGING although we have found these evalua- The success of your therapeutic THE DRY EYE PATIENT tions to be superfluous. Our next step strategy in addressing symptoms can Besides capturing symptoms, how do is to develop an interventional plan to be ascertained by re-asking the same we best care for this population? It’s

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COMMONLY USED LIPID-BASED ARTIFICIAL TEARS

Brand Name Manufacturer Lipid Lubricants Preservative Refresh Optive Allergan castor oil carboxymethylcellulose, glycerin, Purite (stabilized oxychloro Advanced polysorbate 80 complex) Refresh Optive Allergan castor oil carboxymethylcellulose, glycerin, none Advanced polysorbate 80 Preservative Free Retaine MGD OcuSoft glycerol light mineral oil, mineral oil none Soothe XP Bausch + Lomb light mineral oil, polysorbate 80 polyquarternium-1 mineral oil Systane Balance Alcon mineral oil propylene glycol polyquarternium-1

nuanced and can be quite complex. open the meibomian gland orifices and This is quite helpful and should be per- Not all patients need all of the follow- improves what meibum flow is there. formed on every dry eye disease patient ing interventions. As with any chronic, progressive disease, care must be indi- NEUROPATHIC EYE PAIN AND IDIOPATHIC DRY EYE vidualized based on the time of diag- Thankfully, most dry eye patients can be helped with the myriad therapeutic nosis and specific patient characteris- approaches available. However, a small subset of patients remains symp- tics. What is common to all patients tomatic, no matter what is done. Their eyes appear healthy. That is, there is is the need for tear film stability to be no superficial punctate keratopathy; they also have good tear lake volume, restored. Beyond this, given that MGD normal tear film break-up time and so on, yet their eyes are uncomfortable. is one major driver of dry eye, mei- What’s going on? bomian gland rehabilitation and the Many of these patients have what is called somatosensory dysfunction, management of inflammation are key which accompanies such neuropathic eye pain. A yet-to-be-understood defect in the nociceptive system may be driving ocular pain in some patients approaches. with idiopathic dry eye disease. • The goal in treating meibomian As optometric clinicians, all this sounds pretty esoteric and daunting. Let gland obstruction is to evacuate the us share a few direct quotes from the expert literature to try to wrap our gland contents. This is not done by heads around this relatively newly appreciated somatosensory dysfunction. pressing the lower eyelid against the • Pain does not exist in isolation, and individuals experiencing one form of globe without protecting the globe chronic pain often have other chronic pain conditions—a concept termed from pressure, as that maneuver would chronic overlapping pain conditions. Dry eye symptoms may represent a require the intraocular pressure to be peripheral manifestation of a chronic overlapping pain condition.1 very high for it to be effective. Rather, • For a significant number of patients, there is a discordance between the use the Mastrota Meibomian Paddle signs seen on physical exam and the sensory symptoms these patients feel. (OcuSoft), a cotton swab, the butt end Nerve sensitization, genetic susceptibility to pain, neuropathic pain mecha- of your jeweler’s forceps, or other ap- nisms and psychological status have been proposed as mechanisms for this propriate instrument as a backstop (af- incongruity between signs and symptoms of dry eye disease.2 ter proparacaine instillation). Then ap- • Dry eye symptoms are not only manifestations of a local disorder, but also ply sufficient (uncomfortable) pressure involve somatosensory dysfunction beyond the trigeminal system.2 for 15 seconds in an attempt to express • Dry eye is also strongly associated with depression, post-traumatic stress the glandular contents. (Expression syndrome and anxiety, providing further evidence of centralized pain dis- can be enhanced by aggressively pre- order.1 heating the eyelids, but this is rarely • Quantitative sensory testing at a site remote from the eye, mainly at the practical in a busy office setting.) This forearm, implicates central sensitization as a mechanism modulating aber- 2 procedure can be effective and usually rant sensations in a subset of patients with ocular neuropathic pain. lasts two to four months. These patients may best be served by neurologists or pain management clinics. Of course, we need to exhaust all reasonable, prudent therapeutic • Clean the keratinized lid margins interventions before defaulting to such tertiary measures. by gently removing debris from the margin and mucocutaneous junction 1. Galor A, Levitt RC, McManus KT, et al. Assessment of somatosensory function in patients with idiopathic with a golf club spud (no topical an- dry eye symptoms. JAMA Ophthalmol. 2016 Nov 1;134(11):1290-8. 2. Rosenblatt MI. Remote quantitative sensory testing and neuropathic ocular pain. JAMA Ophthalmol. 2016 esthesia is needed for debridement). Nov 1;134(11):1298. It feels good to the patient, serves to

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0018_dg0517_Dry18_dg0517_Dry eeye_v2.inddye_v2.indd 2200 55/8/17/8/17 5:255:25 PMPM FROM THE LITERATURE • Lissamine green staining of intrapalpebral conjunctiva was the most important ocular sign in distinguishing SS TESTING FOR DED IN PATIENTS WITH from non-SS dry eye. SJÖGREN’S SYNDROME • These results highlight the importance of including Be mindful that a few of our patients may be harboring conjunctival staining when screening dry eye patients, as subclinical Sjögren’s syndrome (SS)—with dry eye symp- significant positive staining is associated with two of the toms being just the tip of the iceberg. As such, we should non-ocular diagnostic criteria for SS (positive labial sali- be cognizant of several key points. These excerpts from a vary gland biopsy and serology) and therefore are highly recent article serve to bring to our attention this entity.1 suggestive of Sjögren’s syndrome. • Early detection of SS is important because patients • Given the strong association between SS and lympho- who are started on biological agent treatment within the proliferative disease, eye care physicians serve an integral first five years of onset may be more likely to respond to role in screening for this debilitating and potentially life- treatment than those with delayed initiation of therapy. threatening syndrome. • The majority of patients first seek medical care for dry We all should be attentive to the real possibility that eye symptoms, but many are misdiagnosed as having non- we can serve a vital role in screening for Sjögren’s syn- autoimmune-related dry eye. drome. While the Sjö diagnostic test (Bausch + Lomb) is • Eye care physicians are severely hampered by the readily available and is virtuous, something as simple as absence of evidence-based screening tools that reli- attentive observation of the intrapalpebral bulbar conjunc- ably distinguish SS-related from non-SS-related dry eye tiva stained with lissamine green vital dye could help us patients, resulting in under-referrals and increased delays identify this small subset of patients harboring preclinical in the diagnosis of Sjögren’s syndrome. Sjögren’s syndrome. • Although many clinicians commonly use fluorescein 1. Bunya VY, Bhosai SJ, Heidenreich AM, et al. Association of dry eye test with staining of the cornea in their dry eye evaluation, few rou- extraocular signs among 3514 participants in the Sjögren’s syndrome international tinely assess ocular surface staining of the conjunctiva. registry. Am J Ophthalmol. 2016 Dec;172:87-93.

at every visit. There is no CPT code for troesophageal reflux. Bear in mind that to doxycycline, perhaps a trial of oral this maneuver, but it only takes about some women rapidly develop vaginal azithromycin could be initiated. 10 to 15 seconds per eyelid. yeast infections when on antibiotics, so • Start every dry eye disease patient • Place all of your dry eye patients be sure to discuss this possibility with on a lipid-based artificial tear and in- on a premium-quality omega-3 fish your female patients. And patients struct them to use it as often as they oil supplement at 2,000mg per day. should be warned about photosensitiv- care to, up to four to six times a day Let them know it can take four to six ity, which can occur at this low dose. initially. We prefer either Soothe XP months to slowly build up to a mean- The monohydrate salt is slightly more (Bausch + Lomb) or Systane Balance ingful degree. For the subset of patients patient-friendly than the hyclate salt (Alcon) because our mentor and friend, who have difficulty swallowing these form, but this is rarely a big deal. For Donald Korb, OD, a world-recognized relatively large capsules, two good liq- the patient who is allergic or intolerant expert in the area of meibomian gland

uid (and quite palatable) supplements Photo: Allergan that can be used are Coromega Orange In our 2016 Guide, we introduced a new Squeeze (coromega.com) and Nordic technology then in development called Naturals (nordicnaturals.com). We intranasal lacrimal neurostimulation (ILN), a recommend these be taken with break- battery-powered, handheld device used to fast, or certainly by lunch. stimulate lacrimation. The device, now called For those patients with advanced TrueTear, was recently FDA approved and is meibomian gland disease, with or marketed by Allergan. We are intrigued with without advanced rosacea blepharitis, this novel approach, and are hopeful it will be it may be that concurrent use of 50mg beneficial. We look forward to using TrueTear of doxycycline daily for about three to in the care of some of our dry eye patients. four months would more effectively As the tear film is essentially three-layered, jump-start the fatty acid metabolism and lacrimal stimulation is thought to enhance enhancement within the meibomian the watery layer, it will be critical to protect glands. Doxycycline needs to be taken this augmented aqueous layer with a robust with breakfast or lunch, not near bed- lipid layer. time, to reduce the small risk of gas-

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DESICCATING STRESS IN RISK FACTORS FOR SEVERE DRY EYE SJÖGREN’S SYNDROME Here is a summary of literature findings about risk factors for severe dry eye. A recent study evaluated the • Patients with neuropathic pain-like symptoms (hot/burning ocular pain response of the lacrimal func- and sensitivity to light and wind) had a more persistent and severe course of tion unit in Sjögren’s syndrome dry eye symptoms.1 (SS)-associated dry eye patients • Most patients with severe dry eye symptoms at baseline had persistent, exposed to two simulated daily severe symptoms at one year.2 life environmental conditions. • Patients with neuropathic pain (spontaneous burning pain, sensitivity to Here’s what the researchers light and sensitivity to wind) were associated with a chronic disease course reported: and a decreased response to local therapy.3 • Sjögren’s syndrome is a • Repeated (ocular surface) stress can lead to peripheral sensitization (to chronic, systemic autoimmune corneal nociceptors), which may subsequently lead to changes in the central disease characterized by lympho- nervous system.3 cytic infiltration of the exocrine Many risk factors and environmental stressors can set the stage for dry eye glands and mucosal epithelium. symptoms and worsening disease. These include: • Concentrations of some • Excess screen time tear molecules in severe dry eye • Inadequate blinking patients are consistently different • Meibomian gland dysfunction from those of healthy subjects. • Suboptimal levels of omega-3 essential fatty acids • Inflammation plays a major • Oral medicines known to affect tear function role in dry eye disease. Although • Sleep apnea/insomnia the exact etiopathogenesis of dry • Floppy eyelid syndrome eye disease is not yet completely • Exposure to dusty, drafty environments understood, there is global agree- • Pathologic hypersensitivity to pain • Conjunctivochalasis ment regarding its inflammatory

nature. 1. Crane AM, Feuer W, Felix ER, et al. Evidence of central sensitisation in those with dry eye symptoms Our take: This is why we are and neuropathic-like ocular pain complaints: incomplete response to topical anaesthesia and generalised heightened sensitivity to evoked pain. Br J Ophthalmol. 2017 Jan 18. [Epub ahead of print.] quick to start patients with 2. Ong ES, Alghamdi YA, Levitt RC, et al. Longitudinal examination of frequency of and risk factors for moderate-to-severe disease severe dry eye symptoms in US veterans. JAMA Ophthalmol. 2016 Dec 22. [Epub ahead of print.] on loteprednol for two to four 3. Galor A, Levitt RC, Felix ER, et al. Neuropathic ocular pain: an important yet underevaluated feature of dry eye. Eye (Lond). 2015 Mar;29(3):301-12. weeks; it is based on rock-solid science. • It has been previously dem- disease, recommends these. For those of the loteprednol formulations. Such onstrated that spontaneous blink patients truly needing a preservative- would not need to be done for all pa- rate while reading is lower com- free artificial tear formulation, Ocu- tients, as eyelid margin scraping and a pared to other actions (such as Soft’s Retaine MGD is excellent. Such lipid-based tear may suffice for most conversation). artificial tear use may well need to con- patients. Remember, no algorithm can • Meibomian gland disease tinue indefinitely, depending on each perfectly fit all patients; what we are was found in the vast majority of individual’s needs. attempting to do here is arm our fel- Sjögren’s syndrome patients. • Again, depending upon the pa- low clinicians with ample options from • Even a short exposure to a desiccating environment can tient’s symptomatology on a one to which to choose what best serves the produce a significant deteriora- 10 scale, we will initiate anti-inflam- individual needs of individual patients. tion of the lacrimal function unit matory therapy early in the disease. • If symptoms are moderate to ad- in female SS dry eye patients. Suffice it to say, it is universally ac- vanced, we always initiate therapy The often-unnoticed exposure to cepted that the foundation of dry eye with off-label use of Lotemax gel or these conditions during daily life symptoms is ocular surface inflamma- Lotemax original suspension (lotepre- may increase inflammatory activ- tion due to exposure, so appropriate dnol, Bausch + Lomb) QID for two ity rapidly, triggering an ocular suppression of inflammation is key to weeks, then BID for two weeks. Now surface deterioration. gaining symptomatic relief. Nothing, that Xiidra (lifitegrast 5%, Shire) is absolutely nothing, suppresses ocu- available, we can consider adding it López-Miguel A, Tesón M, Martín-Montañez lar surface inflammation as well as a after two weeks of Lotemax in hopes V, et al. Clinical and molecular inflammatory response in Sjögren syndrome-associated dry topical corticosteroid. Obviously, one that the level of inflammation suppres- eye patients under desiccating stress. Am J Ophthalmol. 2016 Jan;161:133-41.e1-2. would want to select an effective and sion with Lotemax will potentiate and relatively safe medicine such as one enable the nonsteroidal Xiidra to keep

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0018_dg0517_Dry18_dg0517_Dry eeye_v2.inddye_v2.indd 2222 55/8/17/8/17 5:265:26 PMPM KIDS, SCREENS AND DRY EYE DISEASE The multi-screen and screen-centric lifestyle is now occurring in younger children in epidemic proportions.1 With adults, just look around—many people have their faces “glued” to some sort of digital screen. This technology is ushering in, and exacerbating, the growing epidemic of dry eye disease. • It is well-established that visual attentive behavior suppresses the blink reflex, and thus exacerbates tear film evapo- ration, which results in clinical dry eye disease.2 • Note that vegetarian or vegan lifestyles may preclude adequate omega-3 essential fatty acid consumption. Supplemental flaxseed oil could likely provide adequate levels. • One study revealed a strong positive correlation between duration of smartphone use and dry eye disease, and a negative correlation with outdoor play (more outdoor play means less likelihood of dry eye disease).2 When smartphone use in the children with dry eye disease was restricted for four weeks, the children had a dramatic and significant decrease in both the signs and symptoms of dry eye disease. We do not know if a similar resiliency would be experienced in adults, whose meibomian glands may already be atrophically compromised. • “Evaporative dry eye disease associated with smartphone use is a lifestyle disease.”1

1. White, DE. Pediatric dry eye disease: The next generation of dry eye patients is already here. Ocular Surgery News U.S. Edition, January 25, 2017. 2. Moon JH, Kim KW, Moon NJ, et al. Smartphone use is a risk factor for pediatric dry eye disease according to region and age: a case control study. BMC Ophthalmol. 2016 Oct 28;16(1):188.

FROM THE LITERATURE • The beneficial effects of UPDATE ON OMEGA-3 ESSENTIAL FATTY omega-3 EFAs ACIDS AND DRY EYE DISEASE on reducing bul- Any ambiguity about the benefits of omega-3 essential bar hyperemia fatty acids (EFAs) in the care of patients with dry eye dis- were first appar- ease is put to rest with an excellent article in the January ent at day 30 2017 issue of Ophthalmology. Here are the highlights: and were main- • A 30% reduction in the risk of dry eye disease was tained at day 90. found for each additional gram of omega-3 essential fatty • Bulbar acids consumed per day. hyperemia was • In fish oil, the omega-3 EFAs are stored as triacylg- the first clinical lycerides. But in krill oil, a major component of the EPA sign to demonstrate improvement with omega-3 EFA and DHA are esterified in phospholipid form; this poten- supplementation, with a significant reduction evident at tially influences their tissue distribution and bioavailability. day 30 compared with placebo. The observed decrease Krill oil also contains the carotenoid antioxidant astaxan- in ocular redness may relate to omega-3 EFA supplemen- thin, which improves its stability. tation imparting ocular anti-inflammatory effects. Indeed, • The fish oil used in this study supplied 1,000mg/day topical loteprednol 0.5%, a corticosteroid with potent of EPA and 500mg/day of DHA. The krill oil supplied anti-inflammatory properties, reduced clinical markers of 945mg/day of EPA and 510mg/day of DHA. These were inflammation, including conjunctival injection, in patients from commercially available sources. with DED over a two-week treatment period. • Study authors reported they • This study demonstrated the beneficial effect of long- previously found tear film break-up chain omega-3 EFA supplementation for reducing key time to be highly sensitive (82%) and clinical signs and symptoms of mild to moderate DED specific (94%) for diagnosing dry eye over a three-month treatment duration. disease. Our take is that probably all patients with dry eye dis- • Krill oil slightly outperformed ease should be taking a premium quality fish oil or krill oil fish oil in ameliorating the signs and supplement. If the dry eye disease expression is moder- symptoms of dry eye disease. ate to severe, consider off-label loteprednol 0.5% QID • Moderate (roughly 1,000mg EPA for two weeks, then BID for two more weeks to suppress and roughly 500mg DHA) daily doses the inflammatory component. Do this concurrent with of both forms of long-chain omega- the fish/krill oil, since it may take a month or two for the 3 EFAs were found to significantly omega-3 essential fatty acids to build up in the tissues. reduce tear osmolarity, improve tear stability and reduce ocular bulbar Deinema LA, Vingrys AJ, Wong CY, et al. A randomized, double-masked, placebo-controlled clinical trial of two forms of omega-3 supplements for treat- redness. ing dry eye disease. Ophthalmology. 2017 Jan;124(1):43-52.

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XIIDRA: THE FIRST FOUR WEEKS ARE CRUCIAL Lifitegrast can be quite helpful for most patients, as it was shown to significantly improve symptoms of eye dryness vs. placebo in participants with dry eye disease.1 However, we must coach patients through the first four weeks of therapy. This is a critical time point. In our experience, and that of our polled audiences, most patients experience one or more of three potential side effects associated with lifitegrast: instillation site irritation, dysgeusia (a metallic aftertaste) and/or blurred vision immediately following use. (Also be aware that this medication comes in a single-use vial. Instill one drop of Xiidra twice daily, approximately 12 hours apart, into each eye and then discard the single-use container immediately after using in each eye.2) However, these annoying side effects tend to lessen after two to three weeks of consistent use. So, if we can get patients to adhere to therapy for this crucial four weeks, most achieve symptomatic relief. Have an open conversation with all of your new starts to help keep them on track—it can yield huge benefits.

1. Holland EJ, Luchs J, Karpecki PM, et al. Lifitegrast for the treatment of dry eye disease: results of a phase III, randomized, double-masked, placebo-controlled trial (OPUS-3). Ophthalmology. 2017 Jan;124(1):53-60. 2. Full Prescribing Information: XIIDRATM (lifitegrast ophthalmic solution) 5%, for topical ophthalmic use. Available at www.accessdata.fda.gov/drugsatfda_docs/ label/2016/208073s000lbl.pdf. Last accessed April 26, 2017.

ocular surface inflammation below WHY SYMPTOMS AND SIGNS DON’T ALWAYS AGREE symptomatic threshold while the ocu- Why is there discordance between symptoms and signs in patients with dry lar surface is rehabilitated. eye disease? • Alternatively, there is strong sci- • There is “growing evidence that part of the dry eye population may show entific evidence that once the inflam- signs of dysfunctional somatosensory pathways, indicating neuropathic ocular mation is suppressed with Lotemax pain.” (QID for two weeks, then BID for two • Patients with chronic pain syndromes (CPSs) had 30% greater symptoms weeks), pulse-dosing at QID for one than signs. Important CPSs are irritable bowel syndrome, fibromyalgia, chronic week, once or twice a year, can main- pelvic pain and osteoarthritis. tain suppression of inflammation, • Many patients with itchy eyes also have dry eyes. “Patients with atopy or provided a patient is compliant with allergy have a sensitized ocular surface because of inflammatory processes their other therapies. We have been influencing corneal nerves, which can lead to symptoms of dry eye even when using this cost-effective approach for the homeostasis of the ocular surface is minimally compromised.” over a decade with excellent success. Vehof J, Sillevis Smitt-Kamminga N, Nibourg SA, Hammond CJ. Predictors of discordance between symptoms • Another viable option for those and signs in dry eye disease. Ophthalmology. 2017 Mar;124(3):280-286. patients with mild to moderate symptoms is to initiate anti-inflammatory can be easier and more convenient for and may involve advanced dry eye care therapy with Xiidra, and maintain patients to dispense than the single- considerations, e.g., scleral lenses, BID therapy for as long as needed. Af- dose vials. amniotic ter twice-daily Xiidra for three to four • Once obstruction is treated, membranes. months, the patient could try once-dai- we hope omega-3 fish oil supple- ly dosing (in the morning time) to see mentation along with occasional if this reduced therapy could maintain eyelid cleaning (debridement), and anti-inflammatory control. There are perhaps the use of a lipid-based no studies to support this, but as with artificial tear, will keep our pa- all medicines, every effort should be tients below symptomatic threshold. made to dose the least amount needed However, for the to achieve the desired result. tougher patients • We have found that Xiidra or those with achieves a much quicker onset of ac- more advanced tion—two to six weeks—vs. Resta- disease, the sis (cyclosporine 0.05%, Allergan) decision-mak- at three to six months in our clinics. ing process However, certain patients do report regarding Restasis now comes in both its traditional unit-dose container, but that Restasis offers some improvement therapy can be thanks to advanced technology, also comes in a preservative-free, sooner. Be aware that Restasis is now significantly multidose bottle. available in a multidose bottle, which more complex

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018_dg0517_Dry eye_v2.indd 24 5/8/17 5:34 PM • A properly prescribed scleral punctal occlusion, first suppress the • Keep in mind, as well, that contact lens can be a lifesaver to the ocular surface inflammation so as not warm soaks with a Bruder mask or small subset of dry eye patients in- to counterproductively concentrate a similar device that applies heat to sufficiently controlled with the other pro-inflammatory cytokines on the the external lid surface can be help- measures discussed above. There is ocular surface, thereby risking wors- ful as adjunctive therapy for many a growing network of highly com- ening of symptoms. Quiet the ocular patients. petent colleagues prescribing scleral surface, preferably with Lotemax, • Last, be sure to diagnose and lenses, so intraprofessional coopera- then consider punctal plugs after two treat conditions such as blephari- tion and comanagement may well be to four weeks in patients where lacri- tis or Demodex, as these conditions the best approach for some patients. mal output is depressed. contribute to symptoms of dry eye • Punctal plugs are greatly unde- • Lacrisert dissolvable devices when they are left untreated. rused. However, before considering can be another approach to a small Thankfully, there are now suffi- subset of dry eye patients for whom cient tools readily available to help us To help educate your patients who are other, more commonly employed in- meet the needs of most patients with just beginning Xiidra therapy, copy the terventions fail to achieve satisfac- symptomatic dry eye disease without handout below and give it to them. tory results. becoming highly specialized. DG

WHAT YOU NEED TO KNOW ABOUT XIIDRA

In July 2016, the FDA approved Xiidra for treating “the signs and symptoms” of dry eyes. It is the only drug approved specifically for this purpose.

The eye drop solution is to be instilled twice daily, about 12 hours apart, and can be used indefinitely to keep your eyes comfortable.

As with most drugs, some patients experience one or more side effects with Xiidra, the most common of which are:

• Irritation upon instillation

• An unpleasant metallic aftertaste

• Blurred vision

For most all people, these side effects tend to go away within two to three weeks of consistent use, and do not cause any permanent damage.

Relief from burning, scratchy, gritty, sandy, itchy, dry eye symptoms generally takes four to six weeks to occur.

Please read the “package insert” that comes with this medicine for complete details.

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CAPITALIZE ON CORTICOSTEROIDS

The extensive The eye is vulnerable to damage from intraocular inflammation. If left untreated, inflammation may lead to temporary or even permanent vision loss. Steroids suppress cellular benefits of infiltration, collagen deposition, fibroblast proliferation and scar formation. They stabi-

lize cell membranes and block phospholipase A2—a critical initial step in the inflamma- these drugs tory cascade of the arachidonic acid pathway. considerably Topical corticosteroids are based on two different molecular classes: ketones and esters. Ketone-based steroids (e.g., dexamethasone, prednisolone, fluorometholone) outweigh their have a higher propensity over time for unwanted side effects, compared to ester-based steroids (e.g., loteprednol). Why? Our bodies have limited means to actively degrade potential, the ketone molecules, whereas esters are rapidly broken down by physiological esterases into inert substances shortly after providing effective anti-inflammatory effects. but rare and This greatly lowers the risk for increased intraocular pressure, and there have been no reports of cataract formation with the use of loteprednol. For either category, the risks manageable, associated with short-term topical use are minimal. Remember: Suppressing ocular inflammation early in the process substantially side effects, decreases the potential for tissue damage. Uncontrolled intraocular inflammation is yet these much more dangerous than a steroid eye drop.

drugs are still epeat aloud: “I will not be antibiotic/steroid—could cause the condi- prescribed with afraid to prescribe my patient tion to worsen; however, these are exceed- a topical steroid.” Year after ingly rare presentations with clinically dis- unwarranted year, antiquated teaching strat- tinct features. Regies focusing more on the pos- In all cases of disease management, prop- apprehension. sible side effects of oral and topical cortico- er follow-up and careful patient education steroids continue to trump the far-reaching are vital. After explaining the condition benefits of these important drugs. In the and plan of action to the patient, always setting of acute red eyes, we have always ask, “Do you have any more questions for been strong advocates for the use of topi- me?” By doing so, the patient will have the cal ophthalmic steroids, either alone or in opportunity to eliminate any misconcep- combination with an antibiotic. tions or worries about their disease or the While there are plenty of clinical indica- selected therapy. Also, open discussion in- tions for topical steroids, the only contra- creases the paramount doctor-patient trust indication is active epithelial herpetic infec- and minimizes a second opinion that can tion.1 In addition, the only precaution for potentially further delay care. using these drugs bears explanation. With a difficult-to-diagnose Acanthamoeba or fun- NEED FOR FOLLOW-UP gal keratitis, especially in the early stages, When prescribing topical steroids, having the use of a steroid—even a combination the patient return to you in a judicious

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0026_dg0517_Corticosteroids_v2.indd26_dg0517_Corticosteroids_v2.indd 2626 55/8/17/8/17 5:415:41 PMPM TOPICAL CORTICOSTEROID DRUGS BRAND NAME GENERIC NAME MANUFACTURER PREPARATION BOTTLE/TUBE Maximum Strength Steroids Durezol difluprednate 0.05% Alcon emulsion 5ml Lotemax gel loteprednol etabonate 0.5% Bausch + Lomb gel-drops 5g Lotemax ointment loteprednol etabonate 0.5% Bausch + Lomb ointment 3.5g Pred Forte prednisolone acetate 1% Allergan + Generic suspension 5ml, 10ml, 15ml generic prednisolone prednisolone sodium generic solution 5ml, 10ml, 15ml sodium phosphate phosphate 1% Maxidex dexamethasone 0.1% Alcon suspension 5ml

Moderate and Lesser Strength Steroids Alrex loteprednol etabonate 0.2% Bausch + Lomb suspension 5ml, 10ml Flarex fluorometholone acetate 0.1% Alcon suspension 5ml, 10ml FML fluorometholone alcohol 0.1% Allergan + Generic suspension 5ml, 10ml, 15ml FML ointment fluorometholone alcohol 0.1% Allergan ointment 3.5g Pred Mild prednisolone acetate 0.12% Allergan suspension 5ml, 10ml

and timely manner will illuminate in- treatment, but to the treatment of any Durezol. Introduced in 2008, Du- effective treatments or misdiagnosed eye condition.) rezol is often used as the “big gun” of conditions. By seeing the patient back topical corticosteroids (but don’t shy sooner rather than later, you will be away from it). Because of its potency, able to refine the diagnosis and alter it is typically prescribed when inflam- the therapy, if necessary. If you are mation needs to be rapidly brought truly concerned, get the patient’s pre- under control. Durezol is an emulsion ferred telephone number and call the and does not need to be shaken before patient in a couple of days to check on use. their progress. (Patients love having The drug has a long history of use in their doctors call to check on them.) the setting of severe or non-resolving For example, let’s say you see a pa- anterior uveitis, and more recently is tient with a typical lesion that could This inflamed pingueculum should be gaining recognition as a popular postoperative drug. Clinically, we prefer be Thygeson’s or herpetic. Since most treated with a topical steroid. Once red eyes are inflammatory in nature, it over Pred Forte for several reasons: the inflammation is under control, we are inclined to initiate therapy we have found it to be more effective, the ocular surface must be kept with a steroid. However, in the uncer- it does not need to be shaken prior to properly lubricated to prevent further tainty of the diagnosis, we would tell instillation and it does not need to be inflammatory expression. the patient something like this: “This dosed as often as Pred Forte, thereby medicine should help your eye get increasing patient compliance. better quickly; however, at this time Durezol’s glucocorticoid bind- the diagnosis of your condition is not MAXIMUM EFFICACY ing affinity for the active metabolite completely clear, and there is a chance STEROIDS difluprednate was found to be 56 your eye could actually worsen on this Don’t let ocular inflammation linger times stronger than prednisolone.2 medicine. It is important that you let by hesitantly prescribing topical ste- A derivative of prednisolone, diflu- me see you again in a couple of days. I roids. Rather, dose the corticosteroid prednate’s structural modifications will be glad to work you in any time.” frequently until the inflammation has enable it to have a stronger affin- As previously mentioned, this truly subsided before electing to taper the ity and a more consistent potency caring conversation is crucial for opti- medication if necessary. compared with its counterpart. As a mum patient care and rapport. Clinically, we have found the two general rule, the more powerful the All of this is called “patient man- most efficacious topical ophthalmic drug, the more potential for adverse agement,” and is far more than just steroids in the last several years to side effects. Durezol is no exception, disease management alone. Trying to be Durezol emulsion (difluprednate as it can be associated with an elevat- manage the disease without managing 0.05%, Alcon) and Pred Forte sus- ed IOP. Thus, standard of care prac- the patient often results in frustration pension (prednisolone acetate 1%, Al- tices must be engaged, with frequent for the doctor and the patient. (This lergan)—but not generic prednisolone follow-ups to monitor the condition not only applies to corticosteroid acetate. (More on this below.) and check IOP.

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thereby increasing its efficacy and DUREZOL: UNIFORMITY FOR ALL penetration into cell membranes. Steroid molecules are lipophilic in nature. Their inability to dissolve in solutions Additionally, loteprednol etabonate makes the majority of corticosteroids on the market available only in suspen- 0.5% is able to undergo rapid de-es- sion form. But ophthalmic suspensions settle over time, causing the active terification to an inactive metabolite ingredient to fall to the bottom. In order for homogenous distribution, patients after exerting its effect, minimizing must vigorously shake the bottle prior to instillation. the risks of drug toxicity while main- If the bottle is not shaken adequately, the patient risks subtherapeutic taining good clinical efficacy. dosing, rendering less than desirable outcomes despite full compliance with Lotemax gel is a non-settling eye drops. (It may be noteworthy to mention the opposite here, as well: When drop that does not require shaking a patient is at the end of a tapering schedule and perhaps at the bottom of before instillation. Although labeled the bottle, not shaking the suspension could result in concentrations much as a gel, once on the ocular surface higher than what they should be, resulting in unsuccessful tapering even it becomes a viscous liquid. (See though fewer drops are being administered.) Even when the bottle is shaken “Lotemax Gel vs. Lotemax Oint- as directed, the particles still have tendencies to agglomerate, especially as the particle size of the drug increases. This causes dosage inconsistencies and ment,” page 29.) potential frustrations for the doctor and the patient. We often prefer Lotemax gel as In 2008, the FDA approved difluprednate ophthalmic emulsion 0.05% for an “off-label” treatment in many of the treatment of inflammation and pain associated with ocular surgery. The our dry eye patients, but we also use drop was formulated as a stable oil-in-water emulsion, giving optimum dose it to treat many other chronic, recur- consistency, while eliminating the need for shaking. In clinical trials, the drop rent, inflammatory conditions such showed therapeutic dose consistency far surpassing generic prednisolone as stromal herpes simplex keratitis, acetate suspension 1% and branded prednisolone acetate suspension 1%. Thygeson’s SPK, uveitis, inflamed Durezol’s excellent uniformity and decreased dosing suggests increased pinguecula and pterygia, etc. compliance and more predictable results vs. other steroids in its class. While the drug is not quite as efficacious as prednisolone and Durezol, its Pred Forte. While not as clinically Next in clinical efficacy are Lotemax ester-based derivatives also correlate effective as Durezol, prednisolone ac- gel (loteprednol 0.5%, Bausch + to fewer unwanted side effects (e.g., etate 1% also possesses impressive Lomb), generic prednisolone sodium subcapsular cataracts, elevated intra- anti-inflammatory efficacy. Its use is phosphate 1% solution (original brand ocular pressure). In Phase III studies widespread in ocular inflammatory name Inflamase Forte) and generic for instance, only two out of 409 pa- conditions and is most notably em- prednisolone acetate 1%. Dexametha- tients on Lotemax gel had an increase braced postoperatively as well as in sone, either the solution or suspension in intraocular pressure greater than cases of anterior uveitis. Remind your form, is also in this category. 10 mmHg after 18 days of treatment.4 patients that because the drop is a sus- Lotemax gel. Perhaps one of the When used for post-op cataract sur- pension, they must vigorously shake most commonly used drugs among gery inflammation, loteprednol 0.5% the bottle before instillation. the corticosteroid class is loteprednol suspension was as effective as pred- Some pharmacists dispense generic etabonate 0.5% (Lotemax, Bausch nisolone acetate, and with less effect prednisolone acetate even when you + Lomb). An ester-based steroid, its on intraocular pressure.5 have indicated “dispense as written.” propensity to raise intraocular pres- Prednisolone sodium phosphate Although less expensive, the generics sure is substantially less than its ke- 1%. Although generic, this drug re- are considerably less effective.3 When tone-based counterparts. mains a viable option when an in- maximum efficacy is required, nothing Lotemax is highly lipophilic, 10 expensive, potent steroid is needed. surpasses Durezol. times greater than dexamethasone, Unlike many of the other topical

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026_dg0517_Corticosteroids_v2.indd 28 5/8/17 5:41 PM KEEP IT LOCAL WITH LOTEMAX A study of ocular absorption examined the clinical efficacy of loteprednol etabonate 0.5% in rabbit corneas.1 After instillation, the researchers assessed each tissue structure in the eye. The cornea was found to have the highest ratio of metabolite to loteprednol etabonate 0.5%, followed by a much lesser concentration in each subsequent tissue posteriorly. Most notably, the aqueous humor concentration of loteprednol etabonate 0.5% was 100 times lower than the concentration found in the cornea. By keeping high levels of the drug out of the aqueous humor, the trabecular meshwork was less affected, and the propensity to increase intraocular pressure was considerably less than other topical steroids. Of equal significance, when the drug was absorbed systemically, it was rapidly excreted through bile and urine. The prompt de-esterification of Lotemax and its ability to be expelled promptly with any systemic absorption should make the prescribing doctor eager to apply its therapeutic effects in patient care.

1. Druzgala P, Wu WM, Bodor N. Ocular absorption and distribution of loteprednol etabonate, a soft steroid, in rabbit eyes. Curr Eye Res. 1991 Oct;10(10):933-7.

steroids, the drop is prepared as a LOTEMAX GEL VS. LOTEMAX OINTMENT solution—not a suspension—and Patients, practitioners and pharmacists may mix up these two does not need to be shaken before medicines, so let’s set the record straight. instillation. The drop remains an ex- • Lotemax gel. Though called a gel, this comes in a dropper cellent choice for older patients with bottle, like a solution. However, inside the bottle it is indeed arthropathies, where shaking a bottle a highly viscous, semisolid gel formulation. But, through a can present a challenge. It’s also good process called adaptive viscosity, it becomes a liquid when for soft contact lens wearers because squeezed out of the dropper. And upon instillation in the eye, it won’t precipitate on the lens to the the formulation loses its gel structure altogether as the poly- extent of other drops. carbophil polymer interacts with the electrolytes in tears. Prednisolone acetate 1%. Generic Still, the drop is rather thick upon instillation, and will cause prednisolone acetate suspension is a a moment of initial blur until the gel fully converts into a liq- reasonable choice for mild to moder- uid. We advise patients to allow the drop to spread out on ate acute inflammatory conditions, the ocular surface for four to five seconds before blinking, especially if cost is a concern—but not so that the initial blink does not displace the drop onto the preferred in the setting of advanced eyelid. anterior uveitis and episcleritis. Make Because of the nature of this unique gel, the steroid does not settle out of sure that you indicate “brand name the vehicle, so it does not require shaking. (It is best to tip the bottle back and forth once to make sure the drug enters the tip of the dropper prior to necessary” when prescribing for clini- instillation, but no actual shaking is necessary.) Also, unlike suspensions, this cal situations that are potentially vision delivery system provides a perfectly uniform dose at every instillation.1 threatening. Rather than battle with • Lotemax ointment.2 This preparation comes in a 3.5g tube and contains the pharmacy or insurance company, inactive ingredients of white petrolatum and mineral oil. Because it is an perhaps prescribe Durezol to bypass ester-based corticosteroid and also because it is a preservative-free prepa- such bureaucratic hassles. ration, it may provide a safety advantage over fluorometholone ointment. Lotemax ointment is indicated for the treatment of postoperative inflamma- MODERATE EFFICACY tion and pain, but is also applicable in many other cases in which an ointment STEROIDS is useful for suppression of inflammation. The two most common topical steroids in this category are fluorometholone 1. Marlowe ZT, Davio SR. Dose uniformity of loteprednol etabonate ophthalmic 0.1% suspension and Alrex suspension gel (0.5%) compared with branded and (loteprednol 0.2%, Bausch + Lomb), generic prednisolone acetate ophthalmic suspension (1%). Clin Ophthalmol. both of which must be shaken prior to 2014;8:23-9. instillation. 2. Comstock TL, Paterno MR, Singh A, et al. Safety and efficacy of loteprednol • Fluorometholone 0.1%. There are etabonate ophthalmic ointment 0.5% for two derivatives of fluorometholone the treatment of inflammation and pain following cataract surgery. Clin Ophthalmol. 0.1% suspension—the alcohol (FML, 2011;5:177-86. Allergan, and generic) and the acetate (Flarex and Alcon). The acetate moiety gives the fluorometholone molecules Fluorometholone alcohol is avail- does have a diminished propensity to some additional anti-inflammatory ef- able generically and is thus reasonably raise intraocular pressure than other fectiveness over the alcohol moiety.6 inexpensive. While fluorometholone ketone steroids, we are not nearly as

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TIPS FOR TAPERING or recalcitrant dry eye disease may be kept on low-dose steroids for life. Some patients require one drop of ste- Ever had a challenge tapering a patient off a topical roid daily to maintain control over their condition. corticosteroid? Steroids are wonderful for short-term While older ketone-based steroids have been used therapy, but carry intrinsic risks when used long-term. for long-termg therapypy in the past, we would recom- Here are a couple of thoughts: mend ester-based loteprednol You can usually get the patient 0.5% gel off-label once daily for down to three or two times a day, or even once daily before a relapse these protracted dosing sched- occurs. If a relapse does happen, ules. (The ketone-based steroids you have to increase the dosage sseem to work well in this low-dose again and try a longer, slower aapproach, yet it stands to reason taper. tthat loteprednol, being an ester- In addition, try adding a topical bbased steroid, is preferable because NSAID such as Prolensa (brom- oof its enhanced safety profile.) fenac, Bausch + Lomb) or Ilevro Though Lotemax gel initially can (nepafenac ophthalmic suspen- seseem cost prohibitive for patients sion, Novartis) once daily, or wwithout drug coverage, most eligible generic diclofenac or ketorolac cocommercially insured patients pay QID as you begin the next step- no more than a $35 co-pay for their down of the corticosteroid. This ffirstirs prescription and eligible refills may offer enough supplemen- aatt Walgreens and other participat- tal anti-inflammatory support iningg independent pharmacies, and to enable the continuation of didiscounteds pricing is also available for the steroid taper. Or, try the oral NSAIDSAID route: eligibleli uninsured patients according Celebrex (celecoxib, Pfizer) 100mg per day for a few to Bausch + Lomb’s website. weeks. As well, Alcon offers various coupons for Durezol (dif- There are instances when long-term steroid use is luprednate). And when there is no getting around cost indicated. Some patients who have had corneal trans- issues for the patient, generic FML (fluorometholone plants, stromal immune corneal disease, chronic uveitis 0.1%, Allergan) is another option.

comfortable using it long-term as we (fluorometholone 0.25%, ophthal- STEROID OINTMENTS are with the ester-based loteprednol. mic suspension) is not recommended The ophthalmic ointments enjoy a Since the lowest effective dose because fluorometholone 0.1% rep- wide array of clinical indications. should be used in all cases, FML Forte resents the top of the dose response Three steroids that merit frequent use curve—meaning that the 0.25% is no in the ointment formulation include: RELATIVE CLINICAL more efficacious than the 0.1%. • Lotemax ointment. The only EFFICACY OF TOPICAL • Alrex. An ester-based corticoste- ester-based steroid ointment avail- STEROIDS roid, Alrex is an excellent off-label able is Lotemax ophthalmic ointment Here, based on our clinical experi- treatment option when a patient needs (loteprednol 0.5%, Bausch + Lomb). ence and comparative information long-term therapy. We often use Al- It is indicated for postoperative in- we have available, we rate the rela- rex (loteprednol 0.2%) in our patients flammation and pain, but also has tive efficacy of the topical steroids, with allergic eye disease when clinical many off-label clinical uses: dry eye, starting with the most efficacious: signs of conjunctival injection, che- allergy, corneal transplant protection, • Difluprednate 0.05% mosis or eyelid swelling accompany blepharitis, giant papillary conjuncti- • Prednisolone acetate 1% itching. In such cases, Alrex (or even vitis, chronic uveitis, stromal immune Lotemax gel) will best help subdue the herpetic keratitis, Thygeson’s SPK, • Loteprednol 0.5% patient’s condition. We typically dose recurrent corneal erosion, augmen- • Fluorometholone acetate 0.1% Alrex (or Lotemax gel) QID for one tation of steroid eye drop therapy in • Dexamethasone 0.1% week, then BID for one month. acute advanced uveitis or episcleritis, • Fluorometholone alcohol 0.1% Beyond awareness of the various de- contact dermatitis and other inflam- • Loteprednol 0.2% livery systems (suspensions, solutions, matory conditions. Lotemax oint- • Prednisolone 0.125% emulsions, gels and ointments), know- ment is ideally suited for patients who ing the clinical efficacy of these drugs complain of how badly their eyes feel • Hydrocortisone 1% is important. upon awakening.

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026_dg0517_Corticosteroids_v2.indd 30 5/8/17 5:41 PM THE VIRTUE OF TOPICAL CORTICOSTEROIDS Regarding dry eye disease, we know that topical The three main conditions in which steroids can be neces- NSAIDs and cyclosporine are suboptimal suppressors of sary to achieve protracted maintenance of inflammation inflammation. Indeed, in the case of topical cyclosporine, include: chronic anterior uveitis, chronic recurrent stromal the FDA’s 2013 proposed draft guidance characteriza- immune herpes simplex and prevention of corneal trans- tion of this drug was that it provides “modest efficacy.” plant rejection. Many patients afflicted with one of these If these two drugs (or drug classes) were continually conditions are said to be on the “steroids-for-life” thera- meritorious for treating dry eye disease, we would have peutic program. no need for topical steroids, or even newer drugs such as We have had topical NSAIDs and topical cyclosporine lifitegrast (Xiidra, Shire). for many years, yet they do not possess the requisite We strongly argue for the safety of ester-based anti-inflammatory firepower to achieve the desired thera- loteprednol, used off-label, for long-term treatment of, peutic outcome. Interestingly, most patients with one of and maintenance control of, dry eye disease (along with a these conditions use only one drop of corticosteroid per lipid-based artificial tear and omega-3 supplementation). day to maintain remission of disease expression. Because That said, it would be desirable to embrace the general of this low dose, it is exceedingly rare that these patients concept of “steroid-sparing” therapy. This is where lifite- develop ocular hypertension or cataract formation. grast can have a significant role in patient care. It has Historically, prednisolone acetate has been the most been our experience that once a steroid (loteprednol commonly used drug in these situations. We would argue 0.5% or 0.2%) has achieved control of dry eye inflamma- that loteprednol 0.5% would be a wiser choice in the care tion (usually within one month), lifitegrast can adequately of any chronic ocular condition because you get ade- maintain such control indefinitely. quate suppression of inflammation with a drug known to Consider: Rheumatologists rely heavily on oral steroids have a much safer therapeutic profile than prednisolone to gain control of rheumatoid arthritis and systemic lupus acetate. erythematosus, but once control is achieved they try to For perspective, dry eye disease is accompanied embrace the steroid-sparing therapy of hydroxychloro- by varying degrees of ocular surface inflammation. quine for maintenance control. Just as in dry eye disease, Therefore, a topical corticosteroid would clearly be a drug some arthritis/lupus patients experience symptomatic of choice to help manage this disease. Just as with the breakthrough, and a “pulse-dose” of oral prednisone is three conditions above, in cases of dry eye, steroids are required to regain control. In like manner with dry eye dis- used aggressively initially to achieve inflammation control; ease, if a patient using any nonsteroidal drug experiences only when control is achieved can the steroid be tapered. symptomatic breakthrough, a pulse-dose of a topical Ultimately, the patient is maintained with an enduring corticosteroid is required to regain control. Of course, our low-maintenance dose, as set forth above. hope is that the patient can return to a nonsteroidal main- The degree of tissue inflammation expression in dry tenance of suppression of inflammation indefinitely. eye disease is less extreme than that seen with the We likely all have some patients whose rheumatolo- other three aforementioned chronic conditions. Yet, gists have them on 2mg to 10mg of oral prednisone similar to the other inflammatory processes, dry eye long-term, as that is the lowest dose that can keep these must be treated aggressively during the first few weeks patients comfortable. Similarly, we likely all have some to gain control of the inflammatory process. Once dry eye patients who require once-daily or twice-daily inflammatory control is achieved, a lower amount of loteprednol long-term to manage their disease. therapeutic potency is required to maintain suppression Bottom line: We always seek the lowest level of inter- of inflammation. vention needed to adequately treat any condition.

• FML Ointment. Used much the • Triamcinolone 0.1% cream. This same as Lotemax ointment, FML is a dermatological preparation that ophthalmic ointment (fluorometho- works well for periocular dermati- lone 0.1%, Allergan) is indicated for tis conditions. Triamcinolone 0.1% inflammation of the palpebral and cream, which became generic long ago, bulbar conjunctiva, cornea and ante- has been our favorite drug for many rior segment of the globe, and any of years to treat contact blepharodermati- the off-label uses mentioned above. tis. It comes in 15g and 30g tubes, each The only minor difference is to keep a costing about $10 in most markets. closer watch on the patient for steroid- Be sure to tell the patient that on the related adverse effects. side of the tube is the statement “Not for Ophthalmic Use,” but that the drug is perfectly fine to use as we have pre- Dermatologic triamcinolone cream can scribed. We explain that triamcinolone be used to treat periocular dermatitis. is often used by retina subspecialists for

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THOUGHTFUL PRESCRIBING FOR Now, if—and that is a strong if—patients faithfully use CONTROLLING INFLAMMATION their lipid-based artificial tears and omega-3 supplements, When we encounter anterior uveitis, we know it is an ocular surface inflammation should remain subclinical. inflammatory condition. Certainly, there are various Scientifically, this all makes perfectly good sense. For expressions of the disease, but for most patients most of most patients, there is the time, we use Durezol initially every two hours while no reason to use any awake. Had we used the traditional prednisolone acetate eye drop once or twice suspension, we would have to dose the patient hourly a day forever. Control while awake, at least initially. So, we choose Durezol for the inflammation two reasons: it has a more powerful molecule in a more upfront, and keep it elegant emulsion vehicle that requires no shaking, mini- controlled with omega- mizes dosing frequency, and provides a protracted ocular 3 supplementation and surface residency time. Another attribute: It’s BAK-free. proper ocular surface Does every uveitis patient require such aggressive dos- lubrication. Punctal ing, or could a more conservative dosing schedule be plugs can enhance the efficacy if needed after a month of used while increasing patient compliance? The answer is steroid therapy to quiet the surface inflammation. that there are likely cases in which a less aggressive dos- • Other considerations. Cost is also a significant deter- ing schedule would be appropriate, but since this cannot rent to compliance. Simple arithmetic shows that one be fully known, we use a therapeutic approach shown to or two bottles of loteprednol is vastly less expensive be highly effective in virtually all cases. (especially with the “pay no more than $35” coupons with • Inflammation in different settings. Let’s compare the most commercial insurances) than any of the protracted, suppression of inflammation in anterior uveitis to that of enduring, twice-daily therapies. Additionally, the patient dry eye. A question arises: How aggressive do we need to may appreciate the short and effective therapy with be to suppress the inflammatory component? pulse-dosing as needed, as opposed to indefinite therapy Given that inflammation in the setting of dry eye dis- with other agents. ease is quantitatively less than that seen in more severe • A final note. Some patients do not properly adhere to diseases such as anterior uveitis, a drug such as Durezol their omega-3 and/or artificial tear protocols, and other would be overkill—but would most certainly do the job. patients’ inflammation simply “breaks through.” In these So, should we prescribe loteprednol 0.5%, loteprednol cases, we perform the time-honored maneuver of pulse- 0.2%, a topical NSAID, lifitegrast 5.0% or cyclosporine dosing. In our practices, such symptomatic breakthroughs 0.05%? There are some patients in whom any of these are controlled by off-label use of loteprednol QID for one would suffice—but the clinical dilemma is that we have no week, then we stop (no taper is needed). A few patients way of knowing which patients those are, and our primary will need such a “booster shot” once or twice a year. This job at this point is to adequately suppress inflammation. is a safe, effective and cost-saving maneuver to help keep Therefore, it stands to reason that prescribing lotepred- patients with dry eye well controlled and comfortable. nol (a safety profile-enhanced, ester-based topical steroid As in all clinical circumstances, thoughtful prescribing is that does not require shaking) would be rational initia- virtuous and merits enthusiastic embrace. tion of therapy. Sound, scientific articles in peer-reviewed 1. Sy A, O’Brien KS, Liu MP, et al. Expert opinion in the management of aque- journals have firmly established the efficacy and safety of ous Deficient Dry Eye Disease (DED). BMC Ophthalmol. 2015 Oct 13;15:133. 1,2 such a clinical approach. Following the consensus in the 2. Pflugfelder SC, Maskin SL, Anderson B, et al. A randomized, double-masked, expert literature, we prescribe loteprednol 0.5% QID for placebo-controlled, multicenter comparison of loteprednol etabonate ophthalmic suspension, 0.5%, and placebo for treatment of keratoconjunc- two weeks, and then BID for two more weeks. At the end tivitis sicca in patients with delayed tear clearance. Am J Ophthalmol. 2004 of a month, the inflammatory component is controlled. Sep;138(3):444-57.

2. Donnenfeld ED. Difluprednate for the prevention FDA-approved injection into the eye. tion of any stripe. Their widespread of ocular inflammation postsurgery: an update. Clin In other words, if some of the triam- usage confirms that ocular inflam- Ophthalmol. 2011;5:811-6. 3. Roberts CW, Nelson PL. Comparative analysis of cinolone cream gets into the patient’s mation is the most common clinical prednisolone acetate suspensions. J Ocul Pharmacol eyes, it’s nothing to worry about. Doc- manifestation seen in eye care. It is Ther. 2007 Apr;23(2):182-7. 4. FDA Center for Drug Evaluation and Research. tors should be cautioned about using imperative that all doctors of optom- Deputy Division Director Review for NDA 202-872. 2012 Sep 27. Available at: www.accessdata.fda.gov/ this only for short-term relief, as long- etry come to terms with this reality drugsatfda_docs/nda/2012/202872Orig1s000MedR. term use can result in skin atrophy and and strive to become very comfortable pdf. Last accessed March 7, 2017. 5. Lane SS, Holland EJ. Loteprednol etabonate 0.5% in some cases elevated IOP. caring for patients with inflammatory versus prednisolone acetate 1.0% for the treatment DG of inflammation after cataract surgery. J Cataract Re- eye disease. fract Surg. 2013 Feb;39(2):168-73. Corticosteroids are the most essen- 6. Leibowitz HM, Hyndiuk RA, Lindsey C, Rosenthal tial and highly prescribed medicines 1. Easty DL, Carter C. Mechanisms of resistance and AL. Fluorometholone acetate: clinical evaluation in hypersensitivity in herpes simplex keratitis. Trans the treatment of external ocular inflammation. Ann for the treatment of ocular inflamma- Ophthalmol Soc U K 1979 Apr;99(1):126-33. Ophthalmol. 1984 Dec;16(12):1110-5.

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NSAIDs: WHAT’S NEW & WHAT’S PRUDENT All topical ecause of the rare, but real, po- (77% to 82%) were pain-free at one day tential for corneal toxicity and post-op compared with those given only NSAIDs are melting, use nonsteroidal anti- vehicle (48% to 62%). Also, more patients inflammatory drugs (NSAIDs) given BromSite were free of inflammation generally cautiously when there is preex- at 15 days post-cataract surgery compared B 1 approved isting corneal epithelial compromise. As a with patients given only the vehicle. general rule, we never prescribe any topi- BromSite is dosed BID, preserved with for treating cal NSAID for use beyond two weeks—ex- benzalkonium chloride (BAK) 0.005%, cept for a case of cystoid macular edema, and comes in a 5ml supply. postoperative which we treat with a topical NSAID for a • Prolensa. This NSAID, Prolensa month concurrently with a potent steroid. (bromfenac 0.07%, Bausch + Lomb), inflammation, While steroids are often initially dosed potentiates penetration of the bromfenac and as such as frequently as hourly for a few days, we molecule thereby allowing for a slightly recommend that NSAID use not exceed the lower concentration (0.07%) than Brom- they are used FDA-approved dosing frequency. Always Site, yet providing once-daily dosing. remember that steroids reign supreme in Also, Prolensa has pH of 7.8 vs. the 8.3 much more for inflammation control; topical NSAIDs are pH of generic bromfenac 0.09% (formerly never an appropriate substitute when the brand-name Bromday). This pH modifica- perioperative condition merits a topical corticosteroid. tion enables the lower 0.07% concentra- care than for In recent years, the following NSAIDs tion of Prolensa to clinically perform as have come to market: well as the generic 0.09% concentration. primary eye • BromSite. Approved by the FDA in Prolensa is preserved with BAK 0.005% April 2016, BromSite (bromfenac 0.075%, and comes in two quantities: 1.6ml and care. Sun Pharma) is the first NSAID specifical- 3ml (both in 7.5ml bottles). ly indicated for preventing ocular pain in Because BromSite and Prolensa are so- patients undergoing cataract surgery. Like lutions, not suspensions, shaking the bot- other NSAIDs, it’s also indicated for treat- tle before use is not required. ing postoperative inflammation. • Ilevro. The other topical NSAID BromSite achieves its low with once-daily dosing, Ilevro (nepafenac 0.075% concentration due 0.3%, Alcon) achieves this by increasing to its DuraSite delivery ve- the concentration from the earlier-gener- hicle (developed by InSite ation Nevanac (nepafenac 0.1%, Alcon). Vision), which is believed to Ilevro comes in a 1.7ml quantity, whereas extend the drug’s residence Nevanac is dispensed as 3ml. Because Il- time on the ocular surface. evro is a suspension, the bottle must be In Phase III trials, a greater shaken before the drop is instilled. DG number of patients treated 1. BromSite [prescribing information]; Cranbury NJ: Sun with twice-daily BromSite Pharma Industries, Inc; Apr 2016.

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EFFECTIVE ANTIVIRAL THERAPY

Herpetic he herpes virus (HSV) can similar presentation as seen in dry eye. Re- manifest in a wide range of member that in early HSV, corneal lesions eye disease ocular conditions—from a may not present in their classic dendrite remains the mild vesicular lid lesion to an formation. Document the corneal staining Taggressive retinitis. Clinicians pattern carefully and monitor closely if leading cause should be aware that the virus has the you suspect a possible HSV infection. ability to affect every ocular tissue, and Clinical pearl: Limbal dendrites are of corneal treat the patient accordingly. typically more recalcitrant to treatment than central dendrites because the im- blindness HERPES SIMPLEX munological armamentarium (antibodies worldwide. The herpes simplex virus is a DNA virus and leukocytes) is abundantly present in primarily spread by close personal con- the limbal microvasculature.2 Early diagnosis tact. Usually seen in children and young Recurrent infections may occur at any adults, the disease can be broken down age. Up to 25% of patients with a primary and treatment into two types: herpes simplex-1 (oral/ infection will have a recurrence of the dis- facial/ocular) or herpes simplex-2 (geni- ease later in life. Additionally, up to 50% can help tal), although HSV can also cross infect with a recurrent infection will have an- dampen the between type 1 and type 2.1 other outbreak within two to five years.3 Disease expression often occurs in two Neurotrophic keratitis is a much more impact of this phases—prodromal and outbreak. In the serious complication of herpes simplex setting of periocular skin disease, the pa- keratitis (HSK) and may occur secondari- disease. tient may have confined prodromal symp- ly to previous keratitis outbreaks where toms consisting of mild pain, tingling, the basement membrane was damaged. itching or burning before the lesion po- These patients are often in minimal or no tentially progresses through the following pain due to the widespread damage of the stages: macule, papule, vesicle, encrusta- corneal nerves. In essence, their corneas tion and healing (without scarring). Only are now “permanently anesthetized.” after the skin lesions are crusted over is Neurotrophic keratitis is clinically seen the primary disease no longer contagious. as round defects with rolled edges, and In secondary ocular disease expression, the potential for stromal thinning and the patient presents with a unilateral in- subsequent perforation is increased. It is jected eye with a mild, watery discharge. especially important to evaluate the ante- (This is in contrast with epidemic kera- rior chamber in these patients, as there is toconjunctivitis, where profuse tearing is often a mild anterior iritis that accompa- commonly observed in a much more in- nies the keratitis. jected eye.) A staining pattern on the cor- Because there is no active viral repli- nea (early microdendrites) may resemble a cation seen in neurotrophic keratitis, the

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0034_dg0517_Antiviral_v2.indd34_dg0517_Antiviral_v2.indd 3344 55/8/17/8/17 5:565:56 PMPM CORNEAL PRESENTATION WITH HSK the face being the second most common site found after the trunk.5 When caught early on in the infection process, herpes simplex keratitis Fortunately, due to the advent of may initially appear as nothing more the childhood Varivax vaccine (live than superficial punctate keratitis varicella virus, Merck), which came to secondary to dry eye. However, these market in 1995, there are now genera- primarily unilateral, coarse, punctate tions of people who will never have lesions will not respond to dry eye shingles because they will never con- therapy alone and are more com- tract chicken pox. monly found centrally. This, however, is a double-edged As the disease progresses, the sword. Prior to the Varivax vaccine, lesions become early microdendrites there were always children among us that eventually develop into the clas- with chicken pox in various stages sically recognized dendritic ulcers. of contagion. This allowed the adult These linear or branching ulcers have population to come into contact swollen terminal end bulbs that stain with the virus during the course of with rose bengal or lissamine green, daily living, stimulating their immu- while the necrotic cells in the center nity against the varicella zoster virus. of the lesions uptake sodium fluores- Since Varivax, such immune-stimula- cein (NaFL)—keep in mind that only tion diminishes each year. infected cells stain with lissamine Keep in mind that as we age, our green or rose bengal, not NaFL. (The immune systems become less robust epithelial lesions of simplex infections and, in these underexposed individu- stain very positively with NaFL dye, als, some degree of shingles is even whereas the epithelial lesions associated with zoster disease stain negatively more likely to occur. Thus, we could and really do not mimic each other.) Occasionally, mild stromal edema can be detected directly underneath the epithelial infection (which resolves once the be facing another 30 to 50 years of epithelium heals). increased occurrence of shingles in When misdiagnosed and treated inappropriately with a topical steroid, these those patients who have not had suf- fine lesions can turn into geographic ulcers. ficient exposure to boost their immu- If the diagnosis is uncertain early on, always see the patient back within a day nity against it, so clinicians need to or two for a follow-up evaluation. Artificial tears can be used in the interim. be ready to competently care for this expanding population.

disease is treated with a different ap- examination. The need to culture is FROM CHICKEN POX proach. A bland antibiotic ointment exceedingly rare, but when in doubt, TO SHINGLES can be instilled BID-QID alongside the virus can be cultured by lifting The varicella virus (chicken pox) is the a cycloplegic agent BID. Culturing and swabbing the base of the lesion. initial or primary infection of the her- should be considered, and the poten- While the disease process is self-lim- pes zoster disease process. Herpes zos- tial for corneal perforation should iting, treatment should be initiated ter (shingles) is the reactivation of the be monitored daily. For non-healing to decrease the likelihood of corneal varicella virus most commonly seen lesions, consider consultation with a scarring and subsequent vision com- in the sixth to seventh decade of life. corneal specialist. promise. When a patient is initially exposed Other serious complications of to chicken pox, the virus becomes HSK consist of a necrotizing stromal HERPES ZOSTER latent in the sensory ganglion keratitis and necrotizing interstitial Up to 30% of patients will of the trigeminal nerve. If the keratitis. Both can rapidly lead to develop a herpes zoster out- disease is reactivated, the virus stromal scarring and perforation if break in their lifetime. Better travels down the ganglion to its not treated quickly with cycloplegics, known as “shingles” to the respective afferent peripheral antivirals and topical steroids. Refer general public, the preva- nerves and dermatome (an patients with these conditions to a lence is well-documented area of skin that is mainly corneal specialist for evaluation. to be increasing over the supplied by a single spinal Fortunately, diagnosis of herpetic past decade.4 Nearly one nerve). eye disease is nearly always made million Americans develop A shingles outbreak is al- with a careful history and clinical shingles every year, with ways unilateral, and will not

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cross the midline of the patient—mak- TOPICAL ANTIVIRAL OPTIONS ing it one of the most recognized disease processes in medicine. Fortunate- Trifluridine Ganciclovir ly, the recurrence of the zoster virus Viroptic (Pfizer) and generic Zirgan (Bausch + Lomb) is rather low—less than 6%; if there is another outbreak, the patient could Old drug New drug possibly be immunocompromised.6 Indiscriminate cellular expression Specific for infected cells Herpes zoster ophthalmicus (HZO) Potentially toxic Minimally toxic is present in up to 25% of all zoster outbreaks, and occurs when the vi- More frequent dosing Less frequent dosing rus affects the first branch of the tri- Refrigerate until opened No refrigeration needed geminal nerve (V1, or the ophthalmic branch).7 If the tip of the nose is in- Thimerosal preserved BAK preserved volved (Hutchinson’s sign, indicating Solution (7.5ml bottle) Gel (5g tube) involvement of the nasociliary nerve that innervates corneal and intraocu- is confined to the epithelium, never • The most evident benefit from lar tissues), the eye is too. With this treat with topical steroids as that will the patient’s perspective is using branch innervating the structures of merely enhance viral replication that a drop only five times a day (as the eye, it is easy to see why nearly can progress into a potential sight- opposed to every two hours with every ocular tissue can be affected by threatening geographic ulcer. These trifluridine). this viral reactivation. patients need to be aggressively treat- • The issue of refrigeration is con- Ocular involvement presents as in- ed with antivirals to prevent ongo- fusing to both patients and phar- flammatory uveitis or inflammatory ing viral replication with subsequent macists (just like with latano- keratitis, or both. Uveitic involvement stromal scarring. prost). Both trifluridine and manifests as inflammatory cells in the Viroptic ophthalmic solution is less latanoprost should be kept under anterior chamber. Corneal involve- commonly used now to treat HSK. refrigeration at the pharmacy; ment manifests as stromal inflamma- This medication is instilled as one but once dispensed to the pa- tion. If the trabecular meshwork is in- drop every two hours until the ulcer tient, these two medications can flamed, the intraocular pressure may has re-epithelialized, then tapered be kept at room temperature. rise. Should the IOP be sufficiently el- down to one drop every four hours • The potential corneal toxic- evated, then temporary dampening of for another week. Because the drop is ity of trifluridine is minimized the IOP can be best accomplished by preserved with thimerosal, it is often with ganciclovir because ganci- a topical beta-blocker such as timo- found to be corneotoxic with pro- clovir (like all oral antivirals) is lol or the alpha-adrenergic agonist longed therapy. activated by viral enzymes. The brimonidine for a few days. To some A newer treatment option is Zirgan potential reaction to the thimero- degree, conjunctival injection accom- gel (preserved with benzalkonium sal-preserved trifluridine is mini- panies these scenarios. chloride), which allows for much less mized as well. Treatment for ocular involvement frequent dosing alongside a decreased It should be evident that Zirgan is is available in topical and oral form; risk for toxicity. Instill one drop of a major advance in caring for patients now let’s look at our options. this medication into the affected eye with herpetic epithelial keratitis and five times daily until the corneal ulcer may well be so, to some degree, for TOPICAL THERAPY heals, then one drop three times daily adenoviral infections as well. Topical antiviral therapy for the her- for a week. Dosed appropriately, over For patients who have ocular in- pes simplex virus consists of Zirgan 95% of HSK cases resolve over the volvement in the setting of herpes (ganciclovir gel 0.15%, Bausch + course of two weeks or less. zoster ophthalmicus, the treatment Lomb) or Viroptic (trifluridine 1%, Zirgan’s advantages over trifluri- is much different. Typically, an ag- Pfizer, and generic). If the disease dine are many: gressive treatment approach with cycloplegia and topical steroids is deployed. We prescribe homatropine 5% BID to QID, along with Durezol (difluprednate 0.05%, Alcon) every one to two hours for a few days until the inflammation is well controlled. Only then is tapering initiated.

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0034_dg0517_Antiviral_v2.indd34_dg0517_Antiviral_v2.indd 3366 55/8/17/8/17 5:575:57 PMPM Recurrent flare-ups may require after three days, the opportunity for FROM THE maintenance therapy as a prophylac- medical intervention has passed—just LITERATURE tic measure. Once the inflammation that there is decreasing clinical effi- is brought fully under control with cacy with each day of delay in seek- THIS VIRUS HAS Durezol, we switch the topical steroid ing care. With more virulent expres- SOME NERVE! to Lotemax gel—always trying to sions, especially in older individuals, By adulthood, most of find the minimal therapeutic dosing concurrent therapy with oral predni- the population has herpes to achieve the desired result. The se- sone (usually 40mg to 60mg/day for a simplex antibodies, with the quence would be something like this: week) can help decrease the pain and majority exposed by age 12. TID for one month, BID for two to inflammation, and may dampen the The virus is spread by close four months and then once daily for expression of post-herpetic neuralgia. personal contact, with an several more months. Oral antivirals are extremely safe incubation period of three and effective. Their only Achilles’ to nine days. Once primary ORAL THERAPY heel is that they are metabolized by infection has occurred, the It is recognized that the herpes vi- the kidneys. Thus, if a patient has virus lies dormant in the rus can be treated with oral as well clinically significant renal disease, the trigeminal nerve (cranial as topical antivirals. When shingles antiviral dosage needs to be reduced. nerve 5). It is believed to be presents as an uncomplicated skin Phone consultation with the patient’s reactivated by several factors, disease, as evidenced by pain, ery- primary care physician or nephrolo- from physiological stress to thema and vesicular expression, the gist is of utmost importance in deter- sunlight exposure (though this was never confirmed treatment is an oral antiviral for mining the optimum dosage. Com- by the Herpetic Eye Disease seven to 10 days. We find two such puter programs and mobile apps can Study). Once reactivated, medications equivalent in their thera- calculate the proper dosage based on the disease travels down the peutic effectiveness (dose specified for renal function parameters of creatine first branch of the trigeminal zoster disease): clearance and glomerular filtration nerve (the ophthalmic branch, • Acyclovir 800mg five times daily rates, which the physician will have or V1). From here, the virus • Valacyclovir 1,000mg three on hand. We have never had to have can invade any ocular tissue. times daily such a consultation, but we are cer- These have enhanced bioavailabil- tainly prepared to do so if we encoun- Schillinger JA, Xu F, Sternberg MR, et al. Seroprevalence and coinfection with herpes ity, which enables them to be used ter such a patient. simplex virus type 1 and type 2 in the United States, 1988-1994. J Infect Dis. 2002 Apr less frequently. If cost is a barrier to As shingles can be devastatingly 15;185(8):1019-24. patients, acyclovir taken five times painful, it is satisfying to provide ef- a day for a week is, by far, the least fective acute care to those who are expensive therapeutic approach. As suffering. The diagnosis is almost DISEASE STUDY a quick rule, the strength of the anti- always clearly evident, and the medi- Originally undertaken to evaluate the viral drug is doubled; halved to treat cal intervention is straightforward in usefulness of oral acyclovir in stromal simplex disease. most cases. Treatment of this disease HSV disease, the Herpetic Eye Dis- Remember that antiviral drugs are is an area in which we should all be ease Study (HEDS) looked at more most efficacious during the early rep- experts, as we are likely to see more than 700 patients with various mani- licative phase of the infection (initial cases in the coming years. festations of ocular HSV infection.8 72 hours). This does not mean that HERPETIC EYE The study concluded that:

TOPICAL THERAPY FOR HERPES SIMPLEX/ZOSTER BRAND NAME GENERIC NAME MANUFACTURER PEDIATRIC USE PREPARATIONS DOSING Viroptic trifluridine 1% Pfizer 6+ solution 8x/day Zirgan ganciclovir 0.15% Bausch + Lomb 2+ gel 5x/day

ORAL THERAPY FOR HERPES SIMPLEX/ZOSTER BRAND NAME GENERIC NAME MANUFACTURER PEDIATRIC USE HSV DOSE HZV DOSE Zovirax acyclovir GlaxoSmithKline Adjusted dose for 400mg 5x/day 800mg 5x/ infants day Valtrex valacyclovir GlaxoSmithKline Adjusted dose for 500mg TID 1,000mg TID infants

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EKC DIAGNOSIS AND TREATMENT Acute adenoviral infection can be as devastating as shingles; in both, delay in seeking competent care magnifies the potential for bad outcomes. Improperly treated epidemic keratoconjunctivitis (EKC) can lead to visually com- promising subepithelial infiltrates (SEIs), just as improperly or delayed care of shingles can lead to postherpetic neuralgia. Both conditions can be effectively and successfully managed when the diagnosis and appropriate treatment is initiated early in the disease process. Treatments for EKC and for shingles are most effective • An eight-day latency period (from the time of virus when the virus is actively replicating. If patients delay seek- exposure until the onset of the acute red eye) ing care for either of these conditions, or if they receive • An eight-day period of acute infectious conjunctivitis inappropriate care, the window of opportunity may pass, (the acute red, watery eye) and then only steroids (topically for EKC, orally for zoster) • Eight days later (if the condition is not treated), subepi- can be used to try to mitigate downstream sequelae. thelial infiltrates tend to develop The most readily available and effective chemotherapeu- It is in the acute replicatory phase (the acute red eye tic agent we have against EKC-related pathogenic adenovi- phase) where Betadine can play a crucial role in disease rus is topical Betadine 5% Sterile Ophthalmic Prep Solution abatement. This is the protocol we typically use: (povidone-iodine, Alcon).1 We remain distressed at how the 1. Anesthetize both eyes with 0.5% proparacaine professional literature consistently ignores this medicine or (because the Betadine stings). poorly represents its proper clinical use. 2. Instill two or three drops of Betadine and have the Our awareness of Betadine use for EKC came from a patient roll their eyes around to enhance distribution. 2002 article about a cornea specialist who treated 60 EKC 3. Using a gloved hand or cotton swab, rub the excess patients with off-label Betadine 5%; all had successful out- Betadine along the lid margin to kill any resident virus. comes. The rationale and treatment protocol sounded very 4. After 45 to 60 seconds of Betadine exposure, lavage reasonable to us, and more than a decade ago we began the eye to flush the Betadine. off-label use of Betadine 5% to treat EKC. We have now By the way, Betadine is standard-of-care for ocular sur- helped more than 100 patients with EKC over that time face sterilization prior to cataract surgery and intravitreal who would have otherwise suffered needlessly. injections. Such use is the only proven preventive measure While relieving acute pain and distress quickly is grati- against endophthalmitis. So we believe the off-label use fying, there is another major bonus to truncating ocular of Betadine 5% is a rational, intelligent method of treating surface exposure to this virus: prevention of subepithelial patients who present with EKC. Also, it is affordable—about infiltrates. The infiltrates are immune responses to viral $20 for a 30ml container (which can be ordered from many antigens, and can take many weeks or months to dissipate. medical supply companies). If the infiltrates significantly impair vision, then off-label Clinical pearl: Use empty bottles of Fluress (fluorescein use of Lotemax gel (loteprednol etabonate 0.5%, Bausch + sodium and benoxinate hydrochloride, Akorn) to create Lomb) needs to be used to help clear the vision while bio- “single-use” Betadine droppers. We thoroughly clean these logical attrition of the antigenic load occurs. Very generally bottles and droppers with soap and water, let them air speaking, if we were to encounter a late-presenting patient dry, keep in a sealed plastic bag until the need arises to afflicted with visually significant SEIs, we would treat with open a new container of Betadine 5%. Whatever amount of off-label Lotemax gel QID for one month, then TID for one Betadine remains from the original container is then poured month, then BID for one month and then once daily for into two to four of these clean Fluress bottles to have at the another month. Such a regimen may have to be modified, ready for the next patient with EKC.

depending upon the individual response to the steroid. 1. Yazar H, Yarbag A, Balci M, et al. The effects of povidone iodine (pH 4.2) on For perspective, EKC generally follows the “rule of 8s”: patients with adenoviral conjunctivitis. J Pak Med Assoc. 2016 Aug; 66(8):968-70.

The study concluded that: • Additionally, oral acyclovir did dosed BID for one year resulted in a • Epithelial disease alone did not not improve outcomes in stromal 45% decrease in the chance of recur- make future recurrences more keratitis cases, nor did it prevent rence for all forms of ocular involve- likely, but stromal disease defi- stromal involvement. ment; however, the effect was stopped nitely did. • Stromal disease was best man- upon discontinuation of the drug.9 So, • With regards to patients who aged with topical steroids, which strongly consider lifetime treatment had epithelial dendrites, oral acy- did not increase recurrence rate. with oral acyclovir in patients who clovir did not reduce the rate of As revealed in the Acyclovir Pre- have two or more outbreaks in a year, stromal disease. vention Trial, oral acyclovir 400mg or a recurrent disciform keratitis.

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034_dg0517_Antiviral_v2.indd 38 5/8/17 5:57 PM TAKE A SHOT ON ZOSTAVAX FROM THE Patients often ask, “Should I get the LITERATURE vaccine if I’ve already had shingles?” The answer depends on the age of The Epidemiology of Shingles: Facts You Should Know the patient. The Zostavax vaccine is • About one million cases of shingles occur annually in the US. highly recommended to individuals • About one-third of American citizens will over the age of 60, and reduces the develop shingles in their lifetimes. risk of having shingles by 50%. • Because of universal varicella (chicken However, having a case of shingles pox) vaccination in the young, leading to is much more effective in preventing fewer so-called booster exposures within future flare-ups than having the shin- the community to maintain cell-mediated gles vaccine. A case of shingles pow- immunity, reports predict increasing erfully reboots the immune system to numbers of patients expected to seek help prevent subsequent disease out- treatment for this disease. Keep in mind break. Once a patient has shingles, that the first division of the trigeminal the risk of recurrence drops some- nerve (cranial nerve V: face and head distribution) is the second-most common where between 2% to 5%. There- site of expression after the trunk of the body. Thus, we need to be fully fore, the Zostavax shot after shingles prepared to care for our patients who present with facial and ophthalmic would only lower the risk of getting zoster disease. an additional outbreak to around 1% • The most common ophthalmic manifestations are keratitis, uveitis and to 2.5%. As mentioned before, it is conjunctivitis. (Do note that conjunctivitis in the setting of zoster disease our opinion that a patient who devel- is an expression of inflammation, not infection.) ops shingles and is older than age 50 Our take: The key to a successful clinical outcome is timely presentation to most likely would not benefit from a competent diagnostician and rapid institution of treatment with the proper the vaccine. dosage of an oral antiviral. Be sure to remind your patient • In a study at a VA medical center, the recurrence rate of shingles was that Zostavax only provides relative about 6%, slightly more than the 4% to 5% in most other reports. immunity for about eight years, so • Interestingly, in about half of cases, the site of recurrence was at a differ- repeat vaccinations may be in order. ent area than the initial site. Such repeat vaccination is currently • Recurrences were more likely in those patients with zoster-associated pain under evaluation. DG of 30 days or longer, immunocompromised status, female gender and age older than 50 at initial presentation. 1. Waggoner-Fountain LA, Grossman LB. Herpes • Age was not a determinant of risk of recurrence in that there was no sta- simplex virus. Pediatr Rev. 2004 Mar;25(3):86-93. 2. Dua HS, Gomes JA, Singh A. Corneal epi- tistically significant difference in risk of recurrence in younger versus older thelial wound healing. Br J Ophthalmol. 1994 patients. May;78(5):401-8. 3. Liesegang TJ. Epidemiology of ocular her- • The vast majority of cases occurred between the ages of 50 and 80, with pes simplex. Natural history in Rochester, Minn, highest incidence in the 60s. 1950 through 1982. Arch Ophthalmol. 1989 Aug;107(8):1160-5. • Uveitis and ocular hypertension were risk factors for both recurrent and 4. Kawai K, Gebremeskel BG, Acosta CJ. System- chronic disease. atic review of incidence and complications of herpes zoster: towards a global perspective. BMJ • There is biological plausibility that chronic and recurrent disease can Open. 2014 Jun 10;4(6):e004833. be caused by active viral replication and infection, by an inflammatory 5. Harpaz R, Ortega-Sanchez IR, Seward JF; Ad- response to the virus, or both. Studies suggest that clinical latency is not a visory Committee on Immunization Practices (ACIP) Centers for Disease Control and Preven- true period of latency, but rather an active period of subclinical viral tran- tion (CDC). Prevention of herpes zoster: recommendations of the Advisory Committee on Immu- scription and translation held in check by an intact cell-mediated immune nization Practices (ACIP). MMWR Recomm Rep. response. As such, recurrent disease may represent an active infection, an 2008 Jun 6;57(RR-5):1-30. immune response or both, and thus both antiviral and anti-inflammatory 6. Tseng HF, Chi M, Smith N, et al. Herpes zoster vaccine and the incidence of recurrent herpes agents may be useful in the treatment of chronic and recurrent varicella zoster in an immunocompetent elderly popula- zoster virus infection. tion. J Infect Dis. 2012 Jul 15;206(2):190-6. 7. Catron T, Hern HG. Herpes Zoster Ophthalmic- Our take: Prompt initiation of either 800mg of acyclovir five times a day us. West J Emerg Med. 2008 Aug; 9(3): 174-6. or 1,000 mg of valacyclovir three times a day for seven to 14 days is critical. 8. Barron BA, Gee L, Hauck WW, et al. Herpetic Eye Disease Study. A controlled trial of oral acy- Furthermore, if the globe is involved (keratitis and/or uveitis), aggressive sup- clovir for herpes simplex stromal keratitis. Oph- pression with a topical corticosteroid is equally critical. thalmology. 1994 Dec;101(12):1871-82. 9. Herpetic Eye Disease Study Group. Acyclo- Tran KD, Falcone MM, Choi DS, et al. Epidemiology of herpes zoster ophthalmicus. Ophthalmology. vir for the prevention of recurrent herpes sim- 2016 Jul;123(7):1469-75. plex virus eye disease. N Engl J Med. 1998 Jul 30;339(5):300-6.

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THE COMPLEXITIES OF GLAUCOMA: NO PRESSURE

As the rom a patient’s perspective, glaucomatous optic neuropathy is missed glaucoma can be perplexing. because a “normal” intraocular pressure numbers of Even with the same available lured the clinician into complacency, and ophthalmologists data, one doctor’s interpreta- intensive study of the optic nerve head is Ftion of the results (with subse- not done. entering the field quent initiation of therapy—or not) may However, this “normal” pressure, or vary tremendously from the approach of low-tension glaucoma, can be found in level out, and another clinician. How is this possible? 25% to 40% of patients diagnosed with The answer is rarely straightforward. the disease. Thoroughly analyzing the op- the population But remember that glaucoma is not a dis- tic nerve with close attention to the neural of patients ease that progresses quickly, so take the retinal rim tissue is absolutely paramount time to make a careful diagnosis and a to establishing this diagnosis. developing thoughtful decision regarding initiation of • Perform tonometry (and at different therapy. times of the day). While the prevalence of glaucoma With the volume of glaucoma patients glaucoma certainly increases with higher rising, and numbers of new ophthal- intraocular pressure, absolute diagnosis increases, mologists entering the field staying level, should almost never be made from a single optometrists management of glaucoma should be a reading alone. welcomed opportunity in our offices, and It is good practice to get at least three must be at the referral should be rare.1-3 Here, we review readings, with at least one reading taken some best practices and reminders for a in the early morning. Large-scale popu- forefront of proper diagnostic glaucoma evaluation. lation studies have determined that the • Carefully observe the optic nerve mean intraocular pressure (IOP) is around caring for this head. This is the foundation for the rest 15.5mm Hg. Two standard deviations on population. of the glaucoma workup. Many times either side of this value approximate a Here’s how. DON’T LOSE SIGHT OF THE OPTIC DISC Ancillary testing in glaucoma workups is crucial. While it is true that the more data you can collect the better, don’t forget what glaucoma really is: a disease of the optic nerve. The typical optic nerve head is slightly oval and more vertically oriented. Within the disc lies the optic cup, a paler central depression that is devoid of any ganglion cell axons with visibility of the lamina cribrosa. The tissue that lies between the cup and the edges of the disc is referred to as the neural retinal rim. Subtle changes to the neural retinal rim can result in large changes in a patient’s visual field, so carefully scrutinize this tissue. Remember that the sizes of the disc and the cup are typically closely related; a larger disc will usually have a larger cup.

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0040_dg0517_Glaucoma_v2.indd40_dg0517_Glaucoma_v2.indd 4040 55/8/17/8/17 6:076:07 PMPM PACHYMETRY AND GLAUCOMA RISK ASSESSMENT is most commonly seen at the infero- Since the 2002 Ocular Hypertension Treatment Study (OHTS) revealed the temporal (macular vulnerability zone) critical importance of corneal thickness (or corneal thinness) in assessing and/or superotemporal rim tissues. the risk of glaucoma development or progression, most eye doctors have This is primarily a result of the rela- acquired such (relatively inexpensive) technology, and use it routinely in tively sparse glial support in this area. their practices. For those who have not yet come to materially appreciate • Bring up the patient’s history. the virtues of corneal pachymetry, there is a new device now available from Glaucoma tends to be familial. When SonoGage. It looks and wears like a large wristwatch and is uniquely conve- we see patients who have glaucoma nient. We encourage you to evaluate it at www.sonogage.com. If you do not or who are labeled as high-risk glau- have a corneal pachymetric instrument in your office or offices, we urge you coma suspects, we always ask about to bring your diagnostic armamentarium up siblings. We have found that siblings to state-of-the-art. of glaucoma patients have an increased risk of developing glaucoma, with the risk increasing with age. We strongly urge our patients to recommend to their siblings that they seek an optometric glaucoma evaluation in the area where they live. Such screening has been shown to yield additional diagnoses, and to positively impact public health. • Check blood pressure in-office. Carefully assess the patient’s systemic conditions, especially treatment for systemic hypertension. It has been found, particularly in low-tension glaucoma patients, that when blood normal range to be between 10mm sive Treatment Study (OHTS), central pressure medicines are taken in the Hg to 21mm Hg. corneal thickness has a major effect evening or at bedtime, they can Diurnal IOP variation is well docu- on IOP readings. Without a pachym- pathologically lower nocturnal blood mented to be higher in the mornings eter, IOP is relatively meaningless. pressure, which can exacerbate glau- and lower in the evenings in most Keep in mind that a physiologically comatous progression by decreasing patients. Normal diurnal variation is thin cornea appears to be an indepen- optic nerve head perfusion.4 We find less than 3mm Hg; fluctuations great- dent risk factor for glaucomatous op- ourselves more and more often writ- er than 6mm Hg necessitate taking a tic neuropathy, and this needs to be ing letters to primary care physicians few more IOP measurements to try factored into the patient risk assess- explaining this relatively new knowl- to establish the IOP profile for such ment. edge and asking them to consider hav- patients. • Evaluate the neuroretinal rim. ing patients take blood pressure medi- • Check central corneal thickness. Remember the ISNT rule? It goes like cines in the morning. Once the PCPs Having a pachymeter readily avail- this: inferior > superior > nasal > tem- have this scientific explanation, good able is crucial in establishing a true poral. Let’s refresh: cooperation is generally the rule. measure of IOP. We regularly see In a normal optic nerve head, the Along the same line, many patients referrals for a glaucoma evaluation inferior tissues are usually the thick- with asthma can use a topical beta- in patients who have an IOP in the est, followed by slightly thinner su- blocker very successfully. However, mid- to upper 20s, with 0.2 or 0.3 perior rim tissues, then slightly thin- we never prescribe a topical beta- central cups and corneal thicknesses nernasal rim, with the temporal rim blocker for such patients without first of 620µm to 640µm. These patients being the thinnest. This is not a bullet- writing to the primary care physician most commonly have a 100% normal proof concept, but it is a good general for clearance, and securing written workup. If all optometrists would guide. documentation from that doctor to simply measure the central corneal Even in much larger cup-to-disc place in our medical records attest- thickness in these pseudo-ocular hy- ratios, the focal rim tissue can still ing to such. We have, with proper pertensives, it would be an immense be healthy and well-perfused, with consultative advice, used topical be- service to patients and our profession. no pathological process present. If ta-blockers for a handful of patients According to the Ocular Hyperten- erosion of the rim tissue is found, it with asthma without incident, and

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TOPICAL GLAUCOMA DRUGS BRAND NAME GENERIC NAME MANUFACTURER CONCENTRATION BOTTLE SIZE Beta Blockers Betagan levobunolol hydrochloride Allergan, and generic 0.25% 5ml, 10ml 0.5% 5ml, 10ml, 15ml Betimol timolol hemihydrate Akorn 0.25% 5ml 0.5% 5ml, 10ml, 15ml Betoptic-S betaxolol hydrochloride Alcon 0.25% 5ml, 10ml, 15ml Istalol timolol maleate Bausch + Lomb 0.5% 2.5ml, 5ml Timoptic timolol maleate Valeant Ophthalmics, 0.25% 5ml, 10ml, 15ml and generic 0.5% 5ml, 10ml, 15ml Timoptic (preservative-free) timolol maleate Valeant Ophthalmics 0.25% unit-dose 0.5% unit-dose Timoptic-XE timolol maleate Valeant Ophthalmics, 0.25% 2.5ml, 5ml and generic 0.5% 2.5ml, 5ml

Prostaglandin Analogs Bimatoprost bimatoprost generic 0.03% 2.5ml, 5ml, 7.5ml Lumigan bimatoprost Allergan 0.01% 2.5ml, 5ml, 7.5ml Travatan Z travoprost Alcon 0.004% 2.5ml, 5ml Travoprost travoprost generic 0.004% 2.5ml, 5ml Xalatan latanoprost Pfizer, + generic 0.005% 2.5ml Zioptan tafluprost Akorn 0.0015% unit-dose

Alpha Agonists Alphagan P brimonidine Allergan 0.1%, 0.15% 5ml, 10ml, 15ml Brimonidine brimonidine generic 0.15%, 0.2% 5ml, 10ml, 15ml

Carbonic Anhydrase Inhibitors Azopt brinzolamide Alcon 1% 5ml, 10ml, 15ml Trusopt dorzolamide Merck, + generic 2% 5ml, 10ml

Combination Glaucoma Medications Combigan brimonidine/timolol Allergan 0.2%/0.5% 5ml, 10ml Cosopt dorzolamide/timolol Akorn, + generic 2%/0.5% 5ml, 10ml Cosopt PF dorzolamide/timolol Akorn 2%/0.5% unit-dose Simbrinza brinzolamide/brimonidine Alcon 1%/0.2% 8ml Authors’ Note: Be advised that this is not an exhaustive list of the topical beta-blockers. Several less commonly used drugs have been omitted for space. successfully obtained target IOP. As as many of these patients have blood ly helpful in tracking any progression an aside, we also find ourselves com- pressure that is too low, which can of- of glaucoma. In addition to standard municating more with rheumatolo- ten explain progression of glaucoma retinal nerve fiber layer scans, a quick gists, since many of these specialists despite achievement of target intraoc- ganglion cell layer analysis through have a proclivity to overdose patients ular pressure. Small, forearm (radial) taking hydroxycholoroquine. (See devices for measuring blood pressure “Protect Patients from Plaquenil are inexpensive, simple to use by an- Toxicity,” page 15.) Sending a copy cillary personnel, and can be of enor- of the EMR is an extremely poor mous value to human health and to substitute for a brief letter. glaucoma assessment. Measuring systemic blood pres- • Analyze the retinal nerve fiber sure can accomplish two key goals: layer and macular ganglion cell lay- screening for the epidemic of uncon- ers, if available. While in no way is trolled (or undercontrolled) systemic optical coherence tomography absolutely diagnostic, the added benefits of hypertension and fine-tuning our un- Wrist-based blood pressure device. derstanding of low-tension glaucoma, such ancillary testing can be immense-

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040_dg0517_Glaucoma_v2.indd 42 5/8/17 6:08 PM KNOW YOUR TYPE OF GLAUCOMA Gonioscopy is especially important in patients with moderate to high hy- Type Intraocular Pressure Optic Nerve peropia, particularly if a progressive Primary Open-Angle Elevated Glaucomatous nuclear sclerotic cataract is further Glaucoma narrowing the iridocorneal angle. Most patients with pigment dis- Ocular Hypertension Elevated Normal persion syndrome or exfoliation are Normal Pressure Glaucoma Normal/Low Glaucomatous at higher risk for increased intraocu- Normal Pressure Glaucoma Normal/Low Suspicious lar pressure due to biological debris Suspects clogging the trabecular meshwork. Screening for pigment dispersion can The definition of glaucoma has evolved. Once thought to be exclusively a be accomplished by carefully examin- disease of high intraocular pressure, we now know that glaucomatous optic ing the corneal endothelial tissues and neuropathy can occur in 25% to 40% of patients with normal IOPs. Don’t let a retroilluminating the non-dilated iris normal IOP distract you from careful nerve head observation and potentially to look for radial (or splotchy) iris delayed treatment. transillumination defects. Conversely, exfoliation can be easily missed unless the macula can potentially give the or it is abnormal but corresponds to the pupil is pharmacologically dilated. clinician more information than what your assessment of the optic nerve Otherwise, deposits on the face of the was understood a decade ago. (See head. The problem is that many ini- lens can be obscured. Qualifying and “Add Macular Assessment to Ana- tial (and, to some degree, subsequent) quantifying such debris in the angle lyze Glaucoma,” below.) The latest VF results are just plain “noisy” and can be critically important, especially literature suggests a growing body fruitless. in the setting of increased or increas- of evidence revealing that very early Once a repeatable VF defect is ing intraocular pressure. glaucomatous damage can involve the present, follow the patient over time Beyond assessing the patency of the macula, specifically the inferotempo- with serial VFs. Nerve fiber layer ana- iridocorneal angle, evaluate the pig- ral portion of the macular ganglion lyzers are more helpful in staging risk mentation of the angle tissues. This cell layers. As always, the more infor- or helping to detect early glaucoma, is essential to know when contem- mation you collect, the more confi- whereas serial VFs are optimal for plating laser trabeculoplasty because dent you can be in your decision mak- following patients with established pigments absorb the laser energy, ening process. VF defects. abling a positive therapeutic response. • Perform perimetry (repeat, if any • Look at the angle. When per- If there is little or no pigmentation doubt). Ultimately, glaucoma is a dis- forming gonioscopy, we recommend of the trabecular meshwork tissues, ease that affects the visual field (VF). a four-mirror lens. This procedure there will be little or no therapeutic Humphrey visual field 24-2 SITA Fast can be performed relatively quickly response to laser trabeculoplasty. Go- testing remains our VF assessment of after an anesthetic drop. While the nioscopy also should be performed to choice. One test result, especially in a non-contact Van Herick assessment is rule out causes such as angle reces- naïve-to-visual field test patient, can handy, it may not be as sensitive or as sion, neovascularization, etc. be misleading unless: It is normal, specific as gonioscopy. Clinical pearl: Laser trabeculoplasty generally is more effective in phakic eyes than in pseudophakic ADD MACULAR ASSESSMENT TO ANALYZE GLAUCOMA eyes. This is critical knowledge to en- Though many clinicians assume glaucoma is a disease that affects only able maximum clinical patient care. peripheral vision, don’t pass up the opportunity to analyze the patient’s gan- We typically repeat gonioscopy about glion cell layer in addition to retinal nerve fiber layer scans. Research has shown that this sensitive area, specifically the inferior/tem- every five years, or sooner if there is poral ganglion cells of the macula, is highly vulnerable to early glaucomatous an unexplained increase in intraocu- damage.1 These macular fibers are associated with entering the inferior por- lar pressure. tion of the optic disc, resulting in a superior “comma defect” on a 10-2 VF.1 To summarize the diagnostic For glaucoma patients complaining of “hazy vision,” or if any central evaluation: defects are seen on a 24-2 VF, strongly consider ganglion cell analysis in (1) Acutely study the optic nerve addition to a 10-2 VF. Having both types of information can greatly enhance with slit lamp-enabled ophthalmos- the care of your patients. copy. (2) Note the intraocular pressure. 1. Hood, DC, et. al. Glaucomatous damage of the macula. Prog Retin Eye Res. 2013:32C 1-21. (3) Check central corneal thickness.

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DON’T DIAGNOSE GLAUCOMA FROM ONE VF latanoprost (Xalatan) paved the way Try not to make the common mistake of diagnosing glaucoma from a single for prostaglandins as first-line thera- VF. There is an undeniable learning curve when taking these tests; certainly, py to treat glaucoma. Prostaglandins no one wants to be told they have glaucoma with subsequent, indefinite treat- lower IOP by elevating the presence ment. Depending on the level of risk and concern by the doctor or patient, do of extracellular metalloproteinases your due diligence to repeat the field in a few weeks to months, looking for that break down the collagen ma- defect repeatability. trix, thereby enhancing uveoscleral Also, remember that glaucomatous visual field defects are most commonly outflow. As a result, prostaglandins arcuate shaped. Patients can have irregularities in their fields that are not glau- commonly reduce baseline pressures comatous and, depending upon the pattern, may necessitate other routes of by 25% to 33%. investigation. Once you’ve firmly established the diagnosis of glaucoma, the Prostaglandins also have an excel- next step is initiating drop therapy. Never make a change in medical therapy lent diurnal effect and are typically based on the results of a single VF dosed in the evening, although any test, as it is well-established that time of the day works almost as well. repeating visual field testing three The difference in morning vs. eve- to four times is necessary before ning instillation of a prostaglandin one can confirm true VF progres- is somewhere in the vicinity of 1mm sion. Remember that glaucoma left Hg, so good adherence in the morn- untreated tends to progress only at ing is much preferred to poorer ad- 1 a rate of approximately 3% a year. herence in the evening. Additionally, Take note: Glaucoma manage- prostaglandins’ long duration of ac- ment is like sailing—there is no tion can be seen for up to 72 hours, wisdom in making rapid changes which is quite convenient in less-than- in course, as there is little benefit in making rushed decisions when man- compliant patients. aging this disease. Side effects, while minimal, include iris color darkening, increased eyelid pigmentation, hypertrichosis and con- 1. Quigley HA. The progression of glaucoma: it isn’t what you think. In peril to the nerve — junctival hyperemia. Another side ef- glaucoma and clinical neuro-ophthalmology. fect is deepening of the superior eyelid When in doubt, repeat the field. Kugler Publications; 1998: 3-11. sulcus. This is quite dramatic in some patients and is not trivial to them. Beyond these three prime maneu- plation and comprehensive assess- Prostaglandins can be contraindi- vers, take a careful family history, ment. Also, don’t forget that we are cated in patients with a history of uve- especially of the brothers and sisters; not treating a condition or disease; we itis, herpes simplex and aphakia (due obtain nerve fiber layer measure- are treating a human patient, so in- to the slight increased risk of macular ments, baseline VFs and perform volving them in the decision-making edema). gonioscopy. Lastly, check blood pres- process is appropriate. Generic latanoprost is a commonly sure, especially in the setting of low- This is a drug guide, not a text- prescribed glaucoma drop, and for tension glaucoma. By doing all these book. We assume a significant level of many patients, it is often the best ini- things, missing glaucoma would be knowledge on the part of the reader. tial choice because of cost. However, nearly impossible. Remember, there can be exceptions choosing the right medicine is highly to everything said herein, and every complicated due to diverse and ever- THERAPEUTIC PERSPECTIVES patient has to be cared for in a highly changing marketing promotions (e.g., Currently, lowering the intraocular individualized manner. That being coupons) by the companies manu- pressure is the only proven treatment said, let’s take a look at the various facturing brand-name products. As a for glaucoma. And, knowing when to glaucoma medications we have in our result, there may be situations where initiate therapy is the Holy Grail of armamentarium. a brand-name-protected product, at patient management. Equally compe- least initially, can be less expensive. tent doctors have different thresholds FIRST-LINE THERAPY To further complicate matters, dif- and different philosophies. By and With very few exceptions, prostaglan- ferent insurance companies have dif- large, there is no rush to treat because dins or timolol remain the traditional ferent drug formularies. You’re not glaucoma is almost always a slowly frontrunners when treating our pa- entirely on your own to navigate this progressive neuropathy. The decision tients with glaucoma. dynamic and maddening landscape; to treat requires much care, contem- Since its initial release in 1996, the apps/websites GoodRx.com, Mi-

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040_dg0517_Glaucoma_v2.indd 44 5/8/17 6:08 PM cromedex and UpToDate, for exam- acknowledging that BAK is not as meets this need. The main downside ple, can assist you in your research offensive as is commonly touted. In to Zioptan is that, like latanoprost as you make your way through this fact, the 0.01% formulation with the and trifluridine, it has to be stored convoluted decision-making process. higher BAK concentration was found under refrigeration at the pharmacy. In our patients, the 0.01% for- to have better corneal penetration. Timolol, a non-selective beta- mulation of Lumigan is much better In patients who have a reaction blocker, lowers IOP by decreasing tolerated with less hyperemia than to BAK, Travatan Z (travoprost, Al- aqueous humor production. It was the 0.03% (which is generically avail- con) is instead preserved with SofZia. the first topical beta-blocker used as able), yet there is four times as much However, for those rare patients who an ocular hypotensive for glaucoma benzalkonium chloride (BAK) in the truly need a preservative-free option, in the United States, and for decades lesser concentrated formula, thus Zioptan (tafluprost, Akorn) nicely was considered the gold standard by

LEFT, TOP: Since the inferior and superior neural tissues have the least robust glial tissue support, they are most prone to sustain loss. Here the loss of neuroretinal rim is manifested as clinical “notching,” a hallmark observation in many glaucoma patients.

LEFT, MIDDLE: This optic nerve sustained severe loss of neural tissue, thus showing a C/D ratio of 0.8.

LEFT, BOTTOM: Side effect of prostaglandins include periorbital fat atrophy that gives rise to marked deepening of the superior lid sulcus, which can result in ptosis and enophthal- mos; beyond the obvious cosmetic concerns, such altered lid/orbital anatomy can make applanation tonometry challenging.

RIGHT, TOP: This optic nerve head was judged to be 0.1 by a previous doctor, but a careful look will show a very thinned neuroretinal rim in a shallow cup. Note also the peripapillary atrophy.

RIGHT, BOTTOM: Because this patient’s IOP was 16mm Hg, we surmise the prior eye doctor failed to carefully study the optic nerve head. Note the pronounced inferior erosion of the neuroretinal rim, which manifested as a superior hemispheric visual field defect.

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FROM THE TIMOLOL EYE DROPS FOR MIGRAINE HEADACHE? LITERATURE Acute migraine headaches may be reduced in intensity or stopped altogether with beta blocker eye drops. While the NEW PERSPECTIVES daily use of beta-blocker pills has proved effective in ON TARGET IOP preventing chronic migraine headaches, they have been “Meta-analysis shows mean IOP unsuccessful in treating acute, sudden-onset migraines. reduction with prostaglandin Beta-blocker eye drops, however, are absorbed more analogues ranges from 28-33%. quickly than pills by tear duct drainage onto the nasal Slightly smaller IOP reduction mucosa, achieving therapeutic plasma levels “within min- is typically achieved with beta- utes.” blockers whereas alpha-agonists and carbonic anhydrase inhibitors Migliazzo CV, Hagan JC. Beta-blocker eyedrops for treatment of acute migraine. Missouri Medicine. 2014; 111(4):283-8. will usually reduce IOP by 15-20%.”

Clement CI, Bhartiya S, Shaarawy T. New perspectives on target intraocular prescribed in combination with other For those patients who need a pre- pressure. Surv Ophthalmol. 2014 Nov- Dec;59(6):615-26. drugs, timolol must be dosed BID be- servative-free beta-blocker, Timoptic cause of its other active ingredient. in Ocudose (a unit-dose container) is So, for example, when pairing once- available (though, not generically). which all other drops to treat glau- a-day timolol with a BID drug such coma were compared. as brimonidine or dorzolamide, the Timolol typically lowers pressures beta-blocker must be dosed BID as 25% from baseline. Unlike prosta- well; but, theoretically, this overdoses glandins, this drop is best dosed in the the beta-blocker.) morning. Remember, beta-blockers Perhaps the greatest asset of ge- act on the sympathetic nervous sys- neric timolol is its cost—at roughly tem, which is greatly down-regulated $5 for a 5mL bottle, you won’t find a during sleeping hours. There is no better price point on the market. This proven benefit of dosing this drop in cost efficiency can be critically impor- the evening or more than once a day. tant because cost is a well-recognized Keep in mind that clinical manage- (It is important to note that, when reason for patient noncompliance. ment occurs within the context of patient management, and multiple factors have to be taken into account to NEW PROSTAGLANDIN ON DECK decide which drug will best serve the More than 20 years after Xalatan made its debut in 1996, a new prosta- patient overall. glandin is on the horizon: latanoprostene bunod (LBN) is a unique, single- entity, nitric-oxide donating prostaglandin. In a 28-day head-to-head trial ADJUNCTIVE THERAPY (VOYAGER study) with latanoprost, latanoprostene bunod demonstrated If a prostaglandin was prescribed for superior diurnal reductions in IOP from baseline (although the incidence of initial therapy, worked well, yet did adverse effects, mostly mild, were increased with latanoprostene bunod). not achieve the proposed target range Latanoprostene bunod exerts its therapeutic effect when exposed to ubiq- of IOP reduction, we would then uitous esterases in the eye. The molecule is split into a prostaglandin receptor agonist and a nitric oxide moiety. Nitric oxide has been shown to relax the choose a beta-blocker as adjunctive trabecular meshwork, enhancing the outflow of aqueous fluid. therapy. We never prescribe the more In the VOYAGER study, four different concentrations of LBN (0.006%, expensive Timoptic-XE or generic 0.012%, 0.024% and 0.040%) were compared with Xalatan. All demonstrated equivalents as we have found that a greater IOP reduction than Xalatan, with the higher concentrations of LBN they don’t perform any better than (0.024% and 0.040%) showing the greatest IOP reduction from baseline. the less expensive original solution. Because the two higher concentrations of LBN ended up having similar clini- When this new drop is added to a cal efficacy (probably due to receptor saturation), the 0.024% dose was current one, the patient instills one selected for further clinical evaluation. drop of the beta-blocker in the af- Bausch + Lomb, which will market ophthalmic LBN solution as Vyzulta, fected eye(s) in the morning, and one expects to launch it later in 2017. drop of the prostaglandin in the evening. Most of the time, the incorpora- Weinreb RN, Ong T, Scassellati Sforzolini B, et al. A randomized, controlled comparison of latanoprostene bunod and latanoprost 0.005% in the treatment of ocular hypertension and open-angle tion of one additional drop is easily glaucoma: the VOYAGER study. Br J Ophthalmol. 2015;99(6):738-45. accomplished for the patient, and this

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040_dg0517_Glaucoma_v2.indd 46 5/8/17 6:09 PM FROM THE LITERATURE absence of normal aging effects with this parameter allows better estimates of glaucoma-related damage than with AGING ALONE CAN EXACERBATE the neuroretinal parameters.” PROGRESSION IN GLAUCOMA PATIENTS • “Our findings indicate that aging in healthy control subjects leads to a significant reduction of neuroretinal It stands to reason that natural quantitative loss of optic parameters and may explain a large proportion of the nerve fibers over time can contribute to glaucomatous deterioration observed in patients with treated glaucoma. optic neuropathy. An article in Ophthalmology (December Furthermore, both cross-sectional and longitudinal studies 2015) gives important insights into the impact of natural of healthy subjects show patterns of regional loss similar to aging on visual field compromise in the setting of glau- those in patients with glaucoma, suggesting that age-relat- coma progression, per these excerpts: ed regional susceptibility may be accelerated in glaucoma. • “Age-related loss of neuroretinal parameters may Because several previous longitudinal studies of structural explain a large proportion of the deterioration observed progression of glaucoma lacked a control population, the in treated patients with glaucoma and should be carefully observed changes were attributed to glaucoma, perhaps considered in estimating rates of changes.” overestimating the rate of change in treated glaucoma. • “Because there is accumulating evidence that aging in Therefore, without an understanding of the significant otherwise healthy subjects also results in statistically signif- normal age-related changes, there could be errors in rate icant change, often with patterns resembling those in glau- estimates and the diagnostic accuracy of glaucoma-related coma, the clinical assessment of glaucomatous progression progression.” can be challenging.” Thankfully, there are many other metrics and parameters • “The effect of IOP variability on than just visual fields to guide us in clinical decision mak- ONH parameters is probably related ing. However, this article does serve to make us more ana- to changes in laminar position and lytical in considering changes in visual fields. Remember, prelaminar tissue compression.” to establish true progression, we would have to do three • “Because mean deviation (MD) or four fields about every six to 12 months. This is why it is is age adjusted, it is likely that the so challenging and minimally productive to micromanage In this patient, a pronounced the visual field component of the comprehensive glaucoma inferior erosion of the neuroretinal assessment. rim manifested as a superior Vianna JR, Danthurebandara VM, Sharpe GP, et. al. Importance of normal aging in estimating the rate of glaucomatous neuroretinal rim and retinal nerve fiber hemispheric visual field defect. layer loss. Ophthalmology; 2015;122(12):2392-8.

combined therapy usually achieves One drop is instilled within 20 to In our experience, the addition target IOP. 30 minutes after waking, followed of 0.2% brimonidine has two main If the beta-blocker is contraindi- by a second drop of brimonidine be- limitations. The first is that the drop cated (as in a patient with asthma), tween 4pm and 5pm in the afternoon. is dosed BID as adjunctive therapy— our next preferred drop is the alpha-2 Though FDA-approved dosing for the the patient will now be instilling a to- selective adrenergic agonist 0.2% bri- medication is TID, the use of brimo- tal of three drops in the affected eye monidine. (For some unexplained rea- nidine off-label BID as an adjunctive per day. The second potential setback son, 0.2% brimonidine is less costly therapy tends to work well for about is the possibility of ocular surface al- than 0.15%, although we would pre- eight hours, and does very little dur- lergic disease. We have found this fer the latter; both are generic.) While ing the sleep cycle; thus, the late after- type IV conjunctival hypersensitivity 1% apraclonidine does demonstrate noon instillation of the drop provides response in about 30% of patients a much more rapid decrease in IOP, maximum therapeutic benefit. after six to 12 months. the drop is reserved for short-term adjunctive use due to a slight propensity to cause tachyphylaxis (i.e., rapid decrease in response to a given drug after repeated administration) when used longer than one month. Alpha-2 adrenergic agonists exert their effects by decreasing aqueous humor production and increasing uveoscleral outflow. The average IOP reduction is around 26%.5

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The drop can be prescribed as FROM THE brand-name Alphagan P (0.1% bri- LITERATURE monidine); Purite is the preservative, decreasing chances for adverse ef- STUDY COMPARES FIRST-LINE MEDICATIONS FOR fects. PRIMARY OPEN-ANGLE GLAUCOMA Patients may also experience an This article in Ophthalmology (January 2016) definitively confirms what clini- increased prevalence of dry mouth cians have witnessed over the last decade: All the prostaglandins work very and nose while on an alpha-2 adren- similarly. Some quotes from this article provide unique insights: ergic agonist. As with prescribing any • “The objective of this article is to assess the comparative effectiveness of medication, the prospect of adverse first-line medical treatments for lowering IOP in patients with POAG or ocular side effects should be brought to the hypertension through a systematic review and network meta-analysis and to patient’s attention before starting provide relative rankings of these treatments. By using a systematic review treatment. and network meta-analysis, we estimated the pairwise comparative effective- Carbonic anhydrase inhibitors ness of 14 first-line IOP-lowering drugs used in patients with POAG or ocular (CAIs) reduce IOP by reducing aque- hypertension.” ous production by up to 15% when • “Drugs in the prostaglandin class were more efficacious than drugs in used as monotherapy, and an addi- other classes, although the within-class differences were generally small. tional 15% when used in combina- Bimatoprost 0.01% is no more effective than latanoprost or travoprost in low- tion with a prostaglandin or beta- ering IOP at three months. Brimonidine lowered IOP more than apraclonidine; blocker. CAIs also have to be used and unoprostone and betaxolol lowered IOP the least.” twice daily. Both of these factors • “In conclusion, we found that all active first-line drugs are effective com- limit their clinical usefulness. pared with placebo and that prostaglandins were more efficacious in lowering IOP at three months than beta-blockers, alpha-agonists, or carbonic anhy- The most common side effects are drase. Bimatoprost, latanoprost, and travoprost are among the most effica- mild burning and a lingering metal- cious drugs, although the within-class differences were small and may not be lic taste after instillation. Although clinically meaningful. All factors, including side effects, patient preferences CAIs have a sulfa side chain, we have and cost, should be considered in selecting a drug for a given patient.” observed little or no cross-reactivity This final statement is a clinically practical admonishment. A key factor the in those people who have an allergy authors failed to mention is frequency of administration. While cost is a pre- to sulfonamide antimicrobials. Be ad- eminent factor, ease of use is similarly so. We find topical timolol to be cheap, vised that in patients with endothelial simple and safe (in non-asthmatic patients), which is why we often start there compromise, topical CAIs may hin- in select patients. It is most definitely our go-to second-line drug when target der endothelial function, so be cau- IOP is not achieved with a prostaglandin. tious in using these eyedrops in this Tianjing Li, Lindsley K, Rouse B, et al. Comparative effectiveness of first-line medications for primary setting. open-angle glaucoma. Ophthalmology. 2016;123(1):129-40. This drug class is available as a solution (generic dorzolamide) and a suspension (Azopt [brinzolamide, Al- COMBINATION DROPS 0.2% dorzolamide, Akorn), Com- con]). Only Azopt and Simbrinza are Many patients who have glaucoma bigan (0.5% timolol with 0.2% bri- glaucoma suspensions, which have to are treated with more than one drop monidine, Allergan) and Simbrinza be shaken before instillation. Brimo- during the duration of the disease. (0.2% brimonidine with 1% brinzo- nidine and dorzolamide are found in Three combination drops are on the lamide suspension, Alcon). combination with 0.5% timolol. market: Cosopt (0.5% timolol with Simbrinza is the only suspension combination drug available to treat QUOTABLE glaucoma, and this formulation must be shaken before use. Unlike the other combination glaucoma drops, “PRIMARY OPEN-ANGLE GLAUCOMA IS DEFINED AS A Simbrinza does not contain a beta- MULTIFACTORIAL OPTIC NEUROPATHY IN WHICH THERE IS blocker. Thus, for a patient with asth- A CHARACTERISTIC ACQUIRED LOSS OF RETINAL GANGLION ma or one who is nonresponsive to beta-blockers, Simbrinza would likely CELLS (RGC) AND ATROPHY OF THE OPTIC NERVE.” be an ideal add-on to a prostaglandin drug, once individual trials of both American Academy of Ophthalmology Preferred Practice Patterns Committee Glaucoma Panel. Preferred practice patterns. Primary Open-Angle Glaucoma. San Francisco, Calif: American Academy of Ophthal- brinzolamide and brimonidine have mology; 2000: 1-38. been found to be efficacious.

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0040_dg0517_Glaucoma_v2.indd40_dg0517_Glaucoma_v2.indd 4848 55/8/17/8/17 6:096:09 PMPM EYE DROP INSTILLATION: The carbonic anhydrase inhibitors PATIENT & PHARMACIST CORRESPONDENCE reduce IOP by suppressing aqueous production, and do so by only about Dear Patient, 15%. Like brimonidine, they are approved as TID products, yet we To control the pressure inside your eyes, you have been prescribed one of these tend to use them twice daily in gen- combination eye medicines circled below. This means there are two individual eral clinical care. Dorzolamide is an medicines combined into one bottle. There are many reasons we prefer the ophthalmic solution (original brand single medicine as prescribed, yet it may be more costly than the two individual name Trusopt), and brinzolamide is medicines. There are many advantages, however, to using a single bottle over an ophthalmic suspension (original two separate bottles, and we urge you to use the single bottle prescribed. brand name Azopt). When we need to prescribe one of these, we dose twice • Combigan daily: first dose in early morning, and 0.5% timolol with 0.2% brimonidine the second drop about eight hours later (just as we do with brimonidine). • Cosopt In summary, we typically initiate 0.5% timolol with 2% dorzolamide (both in standard bottle, and as preserva- glaucoma therapy with a prostaglan- tive-free unit-dose) din, and add timolol 0.25% or 0.5% once daily (in the morning) if target • Simbrinza (shake well) IOP is not reached with the prosta- 1% brinzolamide suspension with 0.2% brimonidine glandin alone. (generic dorzolamide solution can be used in place of brinzolamide) We still regularly initiate glaucoma therapy with a beta-blocker, particularly when only a 5mm Hg to 6mm To: Pharmacist Hg reduction in IOP is needed or If the patient prefers to use two lesser expensive medicines, then you may sub- when we believe that cost is a critical stitute the prescribed combination medicine for the ingredient drugs above. factor in patient compliance. A 5mL The sig is the same: For timolol, it is one drop daily, shortly after awakening. The bottle of timolol is widely available other medicines (brimonidine, dorzolamide and brinzolamide) must be used for about $4. Be mindful that we have twice daily: one drop shortly after awakening and a second drop about 4pm- found prostaglandins generally reduce 5pm. Always wait about 10 minutes between any two eyedrops. intraocular pressure by about 30%, whereas nonselective beta-blockers Please join us in trying to find the least expensive combination eye drop, and, reduce IOP by about 25%. That’s a if even that is too expensive, then default to the least expensive options shown separation of only about 1mm Hg to above. 3mm Hg. Do not lose sight of the fact that beta-blockers remain an excellent Thank you, choice for reducing IOP. Taking this together, it is apparent ______OD that initial therapeutic interventions are easy, but if the patient is a pros- ______(Date) taglandin nonresponder or has active asthma, establishing a plan becomes If your first-line therapy was with a more like a chess game; it involves prostaglandin and the IOP reduction considerable thought and therapeutic fell just short of target, it is possible trials until target IOP is achieved. that adding generic brinzolamide or Glaucoma should be readily em- generic brimonidine alone will get braced in optometric clinics. While the IOP to target, so using a more ex- it does remain one of the leading pensive combination drug may not be causes of blindness worldwide, out- necessary. right blindness in developed coun- Cosopt is unique in that it is avail- tries (when managed appropriately) able generically in a traditional bottle is uncommon. Optimal care neces- and as a brand-name-protected, pre- sitates appropriate ancillary testing servative-free unit-dose product. when needed, treatment initiation

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CREATIVE USE OF COMBINATION DRUGS generic dorzolamide suspension (replacing the brand Treating glaucoma is like a chess game: every move has name-protected brinzolamide [Azopt]) with a clinically consequences. The goal for all treatment is efficacy; but equivalent topical carbonic anhydrase inhibitor solu- cost and convenience must also be considered, because tion twice daily. No shaking is required and this option they affect compliance. provides a cost savings from using two generics over We appreciate the convenience of combination one brand name-protected combination drug. Again, therapy and the reduction of preservative exposure, but have the patient use the second set of drops about eight combination medicines can also be more costly. So, if the hours after the morning instillation and wait five to 10 patient has limited financial resources and simply can’t minutes between drops. afford the cost of brand name products, then judicious, Last, and perhaps most important in our experience, critical thinking skills have to come into play to do the just a single generic drug, usually added to a prostaglan- best we can to care for these patients. din, will sufficiently achieve target IOP. This means we As such, doctors sometimes have to get creative in can use one of the following as an additive option: 0.25% their prescribing to finesse the best solution for the or 0.5% timolol as a once-daily add-on (our preferred individual patient. For example, if you’re considering choice because it’s a once-daily drug and by far the least Combigan but the patient is concerned about cost, pre- expensive), 0.2% brimonidine used twice daily, or 0.2% scribe 0.5% timolol to be used once daily in the morning, dorzolamide used twice daily. and 0.2% brimonidine to be used every morning and Remember, a small percentage of patients are non- again in the late afternoon. Not as convenient, but less responders, so to blindly use a combination drug may be expensive for the patient and equally effective. entirely unnecessary if one of the ingredient drugs brings Two things to remember: (1) Neither timolol nor brimo- nothing to the table. So, the intelligent use of any combi- nidine do much (if anything) to reduce intraocular pres- nation drug requires a therapeutic trial of the component sure during the sleep cycle; (2) the effect of brimonidine drugs to first establish efficacy prior to even thinking of is about eight hours, so using the second drop around using them in a combination product. 4pm captures the maximum efficacy of the drug. We wish such combination drugs offered two key Likewise, when cost is of paramount importance with components: guaranteed efficacy of both ingredient Simbrinza, a brand name-protected drug, prescribe drugs, and more affordable pricing. If they did, we would generic 0.2% brimonidine to be used twice daily and use them much more often.

FROM THE LITERATURE when indicated and always a close observation of the optic nerves at every follow-up to prevent vision loss. THE MONOCULAR TRIAL: IS IT VALUABLE? As medical practitioners of the eye, it We have always embraced the value of a therapeutic monocular trial in the care seems appropriate that we should be of patients for whom we contemplate therapeutic intervention. Some dismiss the first-line providers for the major- this approach; some advocate for it. Here’s some wisdom from the literature. ity of glaucoma patients. DG If a prostaglandin has a therapeutic effect on the first eye, then it almost certainly will have a therapeutic effect on the second eye, and the magnitude 1. Tham Y-C, Li X, Wong TY, et al. Global prevalence of this response will be similar in both eyes. This finding argues against the of glaucoma and projections of glaucoma burden through 2040. Ophthalmology. Nov 2014;121(11): requirement of additional clinic visits to assess the response of treatment in the 2081–90. second eye. 2. U.S. Department of Health and Human Services The monocular trial of therapy is effective in accurately predicting the Health Resources and Services Administration Bureau of Health Professions October 2006. Physician Supply response of an untreated eye to monotherapy with a prostaglandin analogue and Demand: Projections to 2020. Available at: bhw. hrsa.gov/sites/default/files/bhw/nchwa/projections/ at all daytime points measured. There is no requirement for patients to be seen physician2020projections.pdf. Last accessed March at the same time of day after treatment has commenced. The effect in the first 7, 2017. eye predicts both the likelihood and magnitude of an effect in the second eye 3. U.S. Department of Health and Human Services Health Resources and Services Administration Bureau at all time points during office hours, and negates the requirement for an addi- of Health Professions December 2008. The Physician tional visit to check the therapeutic effect when commencing therapy in the Workforce: Projections and Research into Current Is- sues Affecting Supply and Demand. Available at: bhw. second eye. hrsa.gov/sites/default/files/bhw/nchwa/projections/ Our take: This is in keeping with our 70-plus combined years of glaucoma physiciansupplyissues.pdf. Last accessed March 7, 2017. patient care, and we commonly embrace the monocular therapeutic trial in 4. De Moraes CG. NTG: The Nocturnal Blood Pressure most of our patients most of the time. Factor. Rev Ophthalmol. 2014; 24(2):54-57. 5. Mishra D, Sinha BP, Kumar MS, et al. Comparing King AJ, Rotchford AP. Validity of the monocular trial of intraocular pressure-lowering at differ- the efficacy of latanoprost (0.005%), bimatoprost ent time points in patients starting topical glaucoma medication. JAMA Ophthalmol. 2016; Jul (0.03%), travoprost (0.004%), and timolol (0.5%) in 1;134(7):742-7. the treatment of primary open angle glaucoma. Ko- rean J Ophthalmol. 2014 Oct; 28(5): 399–407.

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0040_dg0517_Glaucoma_v2.indd40_dg0517_Glaucoma_v2.indd 5050 55/8/17/8/17 6:096:09 PMPM FROM THE LITERATURE PEARLS ON OCT USE IN GLAUCOMA DIAGNOSIS • Evaluation of structural (optic TIMOLOL TREATMENT FOR MONOCULAR OSCILLOPSIA nerve head) and retinal nerve Oscillopsia is a rare monocular, intermittent, rapid, small-amplitude sort of fiber layer and functional (visual micro-tremor resulting from spastic contraction of the superior oblique mus- field) components is a mainstay of cle. Such spastic episodes typically occur multiple times on a daily basis. These glaucoma diagnostics. Of the two, spasms are not grossly visible, and are best seen at the slit lamp. evaluation of structural changes In the April 2014 issue of Journal of Optometry, Christopher J. Borgman, OD, is the initial, fundamental step.1 described how the use of timolol 0.5% twice daily may be a sound first-choice Structural changes serve as the pri- trial for patients afflicted with this disorder. mary sign of glaucoma likelihood; “A localized effect with topical beta-blockers at the trochlear nerve endings they provide the basis of the initial and/or superior oblique tissues themselves is responsible for the treatment glaucoma-diagnostic indication as effect,” Dr. Borgman suggested. to whether patients will undergo Consult this superb article for a thorough discussion of this largely idio- further examination or treatment. pathic condition. Thus, accurate evaluation of glaucomatous structural damage is Borgman CJ. Topical timolol in the treatment of monocular oscillopsia secondary to superior oblique myokymia: A review. J Optom. 2014;7(2):68-74. indispensable for appropriate diagnosis of glaucoma. • Despite its remarkable glaucoma- BREAKTHROUGH IN HOME TONOMETRY diagnostic performances confirmed Glaucoma suspects and patients often have their highest intraocular pressure in a number of studies, SD-OCT readings outside of office hours. In fact, a remains an ancillary glaucoma- segment of patients go on to develop glau- diagnostic device rather than a 2 coma although their office-based IOP is nor- stand-alone modality. mal, while others demonstrate progressive • In reality, clinicians exercise dis- visual field loss even though their in-office cretion in accepting OCT results IOP appears to be controlled. As such, eye or not based on their impressions care professionals need information about gained from clinical examination. IOP after office hours. Thankfully, technol- Thus, the diagnostic role of OCT ogy that will provide us with such data was should be considered within the cleared by the FDA in March. context of the process of clinical Most eye doctors are familiar with decision-making. rebound tonometry, known by the brand • Bottom line: Objective (and sub- name Icare tonometer. This technology has been redeveloped into a home jective) testing can be quite help- tonometer that can be used by the patient to measure IOP at various times ful, but only in the context of a beyond office hours. thoughtful, comprehensive assess- The Icare Home device can be successfully used by most, but not all, patients. ment by a qualified OD or MD. At-home IOP assessments can offer doctors a much more complete picture 1. Thomas R, Loibl K, Parikh R, et al. Evaluation of the patient’s intraocular pressure profile, and will likely enhance diagnostic of a glaucoma patient. Indian J Ophthalmol. capabilities. The device collects IOP data, but does not disclose it to the patient 2011 Jan; 59(Suppl1): S43–52. 2. Kim KE, Oh S, Jeoung JW, et al. Spectral- (which we consider to be an excellent approach); the on-board computer domain optical coherence tomography covertly stores the data until downloaded by the eye doctor. For more informa- in manifest glaucoma: its additive role in structural diagnosis. Am J Ophthalmol. 2016; tion on this new technology, visit http://icare-usa.com. Nov;171:18-26.

SYSTEMIC MEDICINE AND IOP Understanding associations between systemic medication use and IOP may help our management of glaucoma patients who are being treated for systemic comorbidities, a recent study recommended. A few highlights: • “Participants taking systemic beta-blockers had lower IOPs.” If a glaucoma patient or suspect stops or decreases their systemic beta-blocker, reassess their IOP. • “Multiple longitudinal studies show no increased risk of primary open-angle glaucoma for persons with diabetes.” • “IOP alone is a poor tool for identifying whether an individual has glaucoma.” Glaucoma diagnosis “requires a careful assessment of all relevant risk factors, an expert examination of the optic disc and assessment of the visual field.”

Foster PJ, Khawaja AP. The association of systemic medication and disease with intraocular pressure. JAMA Ophthalmol. 2017 Mar 1;135(3):203-204.

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