A NOVEL WAY TO CENTER THE KAMRA P. 18 • MASTERS: 10 THINGS NOT TO DO P. 52

Review of Ophthalmology Vol. XXIII, No. 11 • November 2016 • A Stepwise No. 11 • November Approach to Dry EyeReview of Ophthalmology Vol. XXIII, Dry-eye Therapies • Alternative • Autologous Serum Topical Skin-care Agents AVOID TRAPS WITH HYDROXYCHLOROQUINE P. 57 • OCULOPLASTICS: PEELS AND POTIONS P. 65 CAN A DROP TREAT PRESBYOPIA? P. 68 • WILLS EYE RESIDENT CASE STUDY P. 79

NovemberNovember 2016

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Tips from the experts on how you can properly diagnose patients, stage the disease and select the right therapy.

A Stepwise Guide Dry Eye: The Pros and Cons to Management Beyond Drops Of Autologous Serum P. 28 P. 38 P. 44

001_rp1116_fc.indd 1 10/21/16 10:47 AM A DROP OF PREVENTION FOR YOUR CATARACT SURGERY PATIENTS

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Indications and Usage surface diseases (e.g., dry eye syndrome), rheumatoid arthritis, BromSite™ (bromfenac ophthalmic solution) 0.075% is a or repeat ocular surgeries within a short period of time may be nonsteroidal anti-infl ammatory drug (NSAID) indicated for at increased risk for corneal adverse events which may become the treatment of postoperative infl ammation and prevention sight threatening. Topical NSAIDs should be used with caution in of ocular pain in patients undergoing cataract surgery. these patients. Post-marketing experience with topical NSAIDs Important Safety Information also suggests that use more than 24 hours prior to surgery or • Slow or Delayed Healing: All topical nonsteroidal anti- use beyond 14 days postsurgery may increase patient risk for the infl ammatory drugs (NSAIDs), including BromSite (bromfenac occurrence and severity of corneal adverse events. ophthalmic solution) 0.075%, may slow or delay healing. • BromSite should not be administered while wearing contact Topical corticosteroids are also known to slow or delay healing. lenses. The preservative in BromSite, benzalkonium chloride, Concomitant use of topical NSAIDs and topical steroids may may be absorbed by soft contact lenses. increase the potential for healing problems. • The most commonly reported adverse reactions in 1% to 8% of • Potential for Cross-Sensitivity: There is the potential for patients were anterior chamber infl ammation, headache, vitreous cross-sensitivity to acetylsalicylic acid, phenylacetic acid fl oaters, iritis, eye pain, and ocular hypertension. derivatives, and other NSAIDs, including BromSite (bromfenac You are encouraged to report negative side effects of prescription drugs ophthalmic solution) 0.075%. Therefore, caution should be to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. used when treating individuals who have previously exhibited sensitivities to these drugs. Please see brief summary of full Prescribing Information • Increased Bleeding Time of Ocular Tissue: With some on the adjacent page. NSAIDs, including BromSite (bromfenac ophthalmic solution) NSAID=nonsteroidal anti-infl ammatory drug. 0.075%, there exists the potential for increased bleeding time References: 1. BromSite [package insert]. Cranbury, NJ: Sun Pharmaceutical due to interference with platelet aggregation. There have been Industries, Inc.; 2016. 2. Hosseini K, Hutcheson J, Bowman L. Aqueous humor reports that ocularly applied NSAIDs may cause increased concentration of bromfenac 0.09% (Bromday™) compared with bromfenac in DuraSite® 0.075% (BromSite™) in cataract patients undergoing phacoemulsifi cation bleeding of ocular tissues (including hyphemas) in conjunction after 3 days dosing. Poster presented at: ARVO Annual Meeting; May 5-9, 2013; with ocular surgery. Seattle, Washington. 3. Bowman LM, Si E, Pang J, et al. Development of a It is recommended that BromSite be used with caution in patients topical polymeric mucoadhesive ocular delivery system for azithromycin. J Ocul Pharmacol Ther. 2009;25(2):133-139. 4. ClinicalTrials.gov. Aqueous humor with known bleeding tendencies or who are receiving other concentration of InSite Vision (ISV) 303 (bromfenac in DuraSite) to Bromday once medications which may prolong bleeding time. daily (QD) prior to cataract surgery. https://clinicaltrials.gov/ct2/show/results/ • Use of topical NSAIDs may result in keratitis. Patients with evidence NCT01387464?sect=X70156&term=insite+vision&rank=1. Accessed July 18, 2016. 5. Si EC, Bowman LM, Hosseini K. Pharmacokinetic comparisons of bromfenac in of corneal epithelial breakdown should immediately discontinue DuraSite and Xibrom. J Ocul Pharmacol Ther. 2011;27(1):61-66. use of topical NSAIDs, including BromSite (bromfenac ophthalmic solution) 0.075%, and should be closely monitored for corneal Sun Ophthalmics is a division of Sun Pharmaceutical Industries, Inc. © 2016 Sun Pharmaceutical Industries, Inc. All rights reserved. health. Patients with complicated ocular surgeries, corneal DuraSite® and BromSite™ are trademarks of Sun Pharma Global FZE. denervation, corneal epithelial defects, diabetes mellitus, ocular SUN-OPH-BRO-014 09/2016

RP1116_Sun.indd 1 10/13/16 10:55 AM BromSite™ (bromfenac ophthalmic solution) 0.075% USE IN SPECIFIC POPULATIONS Brief Summary Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women to inform any drug associated risks. Treatment of pregnant rats and rabbits with oral bromfenac did INDICATIONS AND USAGE not produce teratogenic effects at clinically relevant doses. BromSite™ (bromfenac ophthalmic solution) 0.075% is a nonsteroidal Clinical Considerations anti-inflammatory drug (NSAID) indicated for the treatment of postoperative Because of the known effects of prostaglandin biosynthesis-inhibiting drugs on the inflammation and prevention of ocular pain in patients undergoing cataract surgery. fetal cardiovascular system (closure of ductus arteriosus), the use of BromSite during DOSAGE AND ADMINISTRATION late pregnancy should be avoided. Recommended Dosing Data One drop of BromSite should be applied to the affected eye twice daily (morning Animal Data and evening) 1 day prior to surgery, the day of surgery, and 14 days postsurgery. Treatment of rats with bromfenac at oral doses up to 0.9 mg/kg/day (195 times a Use with Other Topical Ophthalmic Medications unilateral daily human ophthalmic dose on a mg/m2 basis, assuming 100% absorbed) BromSite should be administered at least 5 minutes after instillation and rabbits at oral doses up to 7.5 mg/kg/day (3243 times a unilateral daily dose of other topical medications. on a mg/m2 basis) produced no structural teratogenicity in reproduction studies. However, embryo-fetal lethality, neonatal mortality and reduced postnatal growth Dosage Forms and Strengths were produced in rats at 0.9 mg/kg/day, and embryo-fetal lethality was produced Topical ophthalmic solution: bromfenac 0.075%. in rabbits at 7.5 mg/kg/day. Because animal reproduction studies are not always CONTRAINDICATIONS predictive of human response, this drug should be used during pregnancy only if None the potential benefit justifies the potential risk to the fetus. WARNINGS AND PRECAUTIONS Lactation Slow or Delayed Healing There are no data on the presence of bromfenac in human milk, the effects on the All topical nonsteroidal anti-inflammatory drugs (NSAIDs), including BromSite breastfed infant, or the effects on milk production; however, systemic exposure to (bromfenac ophthalmic solution) 0.075%, may slow or delay healing. Topical bromfenac from ocular administration is low. The developmental and health benefits corticosteroids are also known to slow or delay healing. Concomitant use of topical of breastfeeding should be considered along with the mother’s clinical need for NSAIDs and topical steroids may increase the potential for healing problems. bromfenac and any potential adverse effects on the breast-fed child from bromfenac or from the underlying maternal condition. Potential for Cross-Sensitivity There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid Pediatric Use derivatives, and other NSAIDs, including BromSite (bromfenac ophthalmic solution) Safety and efficacy in pediatric patients below the age of 18 years 0.075%. Therefore, caution should be used when treating individuals who have have not been established. previously exhibited sensitivities to these drugs. Geriatric Use Increased Bleeding Time of Ocular Tissue There is no evidence that the efficacy or safety profiles for BromSite differ With some NSAIDs, including BromSite (bromfenac ophthalmic solution) 0.075%, in patients 65 years of age and older compared to younger adult patients. there exists the potential for increased bleeding time due to interference with NONCLINICAL TOXICOLOGY platelet aggregation. There have been reports that ocularly applied NSAIDs may Carcinogenesis, Mutagenesis and Impairment of Fertility cause increased bleeding of ocular tissues (including hyphemas) in conjunction Long-term carcinogenicity studies in rats and mice given oral doses of bromfenac up with ocular surgery. to 0.6 mg/kg/day (129 times a unilateral daily dose assuming 100% absorbed, on a It is recommended that BromSite be used with caution in patients with known mg/m2 basis) and 5 mg/kg/day (540 times a unilateral daily dose on a mg/m2 basis), bleeding tendencies or who are receiving other medications which may prolong respectively revealed no significant increases in tumor incidence. bleeding time. Bromfenac did not show mutagenic potential in various mutagenicity studies, including Keratitis and Corneal Reactions the bacterial reverse mutation, chromosomal aberration, and micronucleus tests. Use of topical NSAIDs may result in keratitis. In some susceptible patients, Bromfenac did not impair fertility when administered orally to male and female rats continued use of topical NSAIDs may result in epithelial breakdown, corneal at doses up to 0.9 mg/kg/day and 0.3 mg/kg/day, respectively (195 and 65 times a thinning, corneal erosion, corneal ulceration or corneal perforation. These events unilateral daily dose, respectively, on a mg/m2 basis). may be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately discontinue use of topical NSAIDs, including BromSite (bromfenac PATIENT COUNSELING INFORMATION ophthalmic solution) 0.075%, and should be closely monitored for corneal health. Slow or Delayed Healing Post-marketing experience with topical NSAIDs suggests that patients with Advise patients of the possibility that slow or delayed healing may occur complicated ocular surgeries, corneal denervation, corneal epithelial defects, while using NSAIDs. diabetes mellitus, ocular surface diseases (e.g., dry eye syndrome), rheumatoid Concomitant Topical Ocular Therapy arthritis, or repeat ocular surgeries within a short period of time may be at increased If more than one topical ophthalmic medication is being used, advise patients to risk for corneal adverse events which may become sight threatening. Topical NSAIDs administer BromSite at least 5 minutes after instillation of other topical medications. should be used with caution in these patients. Concomitant Use of Contact Lenses Post-marketing experience with topical NSAIDs also suggests that use more than Advise patients not to wear contact lenses during administration of BromSite. 24 hours prior to surgery or use beyond 14 days postsurgery may increase patient The preservative in this product, benzalkonium chloride, may be absorbed by risk for the occurrence and severity of corneal adverse events. soft contact lenses. Contact Lens Wear Sterility of Dropper Tip/Product Use BromSite should not be administered while wearing contact lenses. The preservative Advise patients to replace the bottle cap after use and do not touch the dropper in BromSite, benzalkonium chloride, may be absorbed by soft contact lenses. tip to any surface as this may contaminate the contents. ADVERSE REACTIONS Advise patients to thoroughly wash hands prior to using BromSite. Clinical Trial Experience Rx Only Because clinical trials are conducted under widely varying conditions, adverse Distributed by: Sun Pharmaceutical Industries, Inc. Cranbury, NJ 08512 reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The most commonly reported adverse reactions in 1–8% of patients were: anterior chamber inflammation, headache, vitreous floaters, iritis, eye pain BromSite is a trademark of Sun Pharma Global FZE. and ocular hypertension. SUN-OPH-BRO-017 09/2016

RRP1116_SunP1116_Sun PPI.inddI.indd 1 110/13/160/13/16 10:3810:38 AMAM REVIEW NEWS Volume XXIII • No. 11 • November 2016 Examining the Link Between Osteoporosis Drugs and AMD

A study published in the August phonate therapy; it found the rate ra- other large epidemiologic studies.” issue of the American Journal of tio was 1.22 (95% CI: 0.76-1.95) after “This information is interesting and Ophthalmology has suggested a one year of bisphosphonate exposure, should be verifi ed by randomized clin- link between the use of oral bis- which rose to 1.87 (95% CI: 1.32-2.67) ical trials,” comments David S. Boyer, phosphonates, often prescribed to after fi ve years of exposure. The ratio MD, a retina specialist in Los Angeles help prevent osteoporosis, and wet didn’t differ signifi cantly between men and part of the clinical faculty at the age-related macular degen- Doheny Eye Institute, USC eration. The study, con- School of Medicine. “Data duc ted by researchers at from excellent long-term stud- the University of British ies such as the AREDs studies

Columbia in Vancouver, MD Carl Regillo, and population studies such as Cana da, used three different Blue Mountain, as well as the designs to evaluate the data: randomized clinical trials used a disproportionality anal - for approval of the anti-osteo- ysis; a case-control study arthritis medications, would and a self-controlled case also be useful.” series. The fi rst of these “There are signifi cant limi- used relevant data from the tations to this kind of study,” U.S. Food and Drug Ad- notes Jason Hsu, MD, as- ministration Adverse Event sistant director of retina re- Reporting System data base search at Wills Eye Hospital gathered between 2004 and in Philadelphia. “In particular, 2014. The latter two study the authors did not control for designs used data from the potential confounders such as British Columbia Ministry of smoking. It’s conceivable that Health databases. and women. more patients on bisphosphonates The disproportionality analysis “Bisphosphonates are pro-infl am- may have been smokers, especially found reported odds ratios for de- matory drugs that have been shown given the well-established association veloping macular degeneration of to cause infl ammatory eye condi- between smoking and increased risk of 3.82 (2.94-4.96) for alendronate, 2.40 tions such as uveitis and scleritis,” ex- osteoporosis. Smoking also signifi cant- (1.49-3.86) for ibandronate and 2.87 plains study author Mahyar Etminan, ly increases the risk of AMD and may (1.58-5.19) for risedronate. The case- PharmD, MSc, assistant professor of have therefore falsely contributed to control analysis, including 6,367 cases ophthalmology and visual sciences at the appearance that bisphosphonates of macular degeneration and 63,670 The University of British Columbia. are to blame. It will be critical that controls, found that subjects regularly “We hypothesized that these drugs future studies take into account more using oral bisphosphonates for three might increase the risk of wet macular of these potential confounders before years had an adjusted odds ratio of degeneration, another infl ammatory we can draw any conclusions about the 1.59 (1.38-1.82) for developing wet eye condition. In terms of our study’s association between bisphosphonates AMD. The self-controlled case series limitations, we didn’t have informa- and AMD.” analysis included 193 cases of macular tion on body mass index or smoking, degeneration on continuous bisphos- and our study needs to be validated by (continued on page 8)

4 | Review of Ophthalmology | November 2016

004_rp1116_news.indd 4 10/21/16 4:15 PM RP0716_Tearlab.indd 1 6/6/16 3:50 PM Ophthalmic Product Development Insights Matthew Chapin, Andrew Warner, Esq., and Sena Biswas, PhD • Ora Inc., Andover, Mass. REVIEW

Convertible Financing 101 for the Entrepreneur automatically convert into equity. Without taking into account the conversion discount n this month’s installment of Ophthalmic other institutional investors are often not and/or capped price per share (valuation Product Development Insights, we’ll willing to invest prior to seeing proof of cap), the amount of equity (in number of Iexplore convertible notes for seed fi nanc- concept? The targeted disease, the in-vivo shares) received by the investor will be ing for the early-stage entrepreneur. (As target, the signaling pathways, the clinical equal to the principal amount plus interest a general rule, neither this article nor any development path and the regulatory path accrued divided by the share price offered to article constitutes legal advice and you are just a few of the considerations at the other investors at the qualifi ed fi nancing. In should always consult your attorney when forefront of the potential investor’s mind, any order to account for the fact that the initial getting down to the specifi cs.) one of which could be a gating item to their investor (noteholder) put her money in at an Before discussing how to approach and use investment (a gating item is something that earlier stage than the other investors (involv- a convertible note, it helps to defi ne some the investor needs to see before proceeding ing more risk due to less proof of concept/ terms. A convertible note is essentially an to the next step). Objective manifestations of effi cacy), the note will generally grant the I.O.U. issued by the entrepreneur’s company value such as: a crucial animal model show- noteholder a conversion discount and/or to the investor in exchange for the investor ing effi cacy against the standard of care; an capped price per share (or valuation cap). making a loan to that company. The note can in-vivo pharmacokinetics study demonstrat- The conversion discount is a multiplier that usually be paid back in cash or equity and ing sustained release of the delivery plat- allows the noteholder to essentially get more it is usually set up to automatically convert equity (shares) for the same dollar amount. into equity upon a subsequent fi nancing By way of example, if the share price event (usually referred to as qualifi ed is $1 and the conversion discount fi nancing). While there are certainly is 20 percent, then the $1 million a few more details to keep in mind, note (interest omitted for simplicity) the beauty of a note is that it al- would autoconvert into 1.2 million lows the entrepreneur to access shares at the qualifi ed fi nancing. much needed fi nancing with simple The conversion discount is a useful documentation and without the tool when entrepreneur and inves- need to negotiate the terms of a larger tor are far apart with regard to their equity fi nancing. The note also allows respective views on the value of the asset/ the entrepreneur to avoid the complications company at the time the note is issued. and costs that can arise from negotiating a Additionally, if the investor and entrepre- company’s valuation without key data points, form; or a pre-investigational new drug FDA neur are less far apart regarding the asset/ the impact of that valuation on incentive meeting to fi rmly establish the development company valuation when the note is issued, equity/stock option grants, and the related plan and approvable endpoints will help the the toggles referred to as capped price per potential tax implications of equity and/or potential investor get comfortable enough share (or valuation cap) can be used to stock options, giving him the ability to focus to make that leap. Yet, the achievement of account for the same concept of the initial more of his time and energy on advancing these milestones can’t happen without some investor putting money in at a more risky his vision. On the investor side, the variables, basic funding. In these types of situations, stage. The capped price per share and valu- or toggles, referred to as the conversion a convertible note may allow you to access ation cap toggles create the same net effect discount and/or capped price per share this much needed early-stage capital to fund because they both put a maximum on the (or valuation cap) can allow investors to the efforts necessary to reach these initial share price that the investor (noteholder) will have the amount of their loan, plus accrued proof points and help facilitate a subsequent, pay at the qualifi ed fi nancing stage, regard- interest, converted into equity at a reduced much larger pharma, biotech or VC deal. less of what other investors are paying. price relative to the other investors in the The reader should note that this paradigm is Finally, it should be noted that the share subsequent, qualifi ed-fi nancing round. The not only applicable to attainment of the fi rst price paid by other investors at the qualifi ed investors receive these terms to offset some round of substantial external investment, but fi nancing round may be solely derived from of the early-stage risk they are taking on, as may also be applied to increase asset value a formal valuation of the asset/company at compared to later investors. between rounds of investment. Here is an or around the time of the qualifi ed fi nanc- Now, on to connecting the dots. example of how a note might work: ing or it may simply be negotiated by the Say you have an idea—maybe even a Imagine an investor agrees to loan an en- other investors and the entrepreneur (taking patent fi led—and some early, “reason-to- trepreneur $1 million in exchange for a note into account valuation on some level). The believe” evidence. The evidence could be in the amount of $1 million plus interest that take-home lesson is that the basic structure preclinical or clinical data and all you need to accrues at a rate of 4 percent per year. The of the note (simplifi ed here) is adaptive and do is move the project forward to some value note stipulates that the investor can require thus opens the door to attractive scenarios infl ection point in order to attract investment. the entrepreneur to pay the loan back in for both entrepreneur and early investor. Therein lies the proverbial “chicken-or-the- cash or equity on or after the maturity date Bearing in mind the adaptive nature of con- egg” scenario: How do you fi nance the of the note. The note further stipulates that vertible notes and further expanding upon activities necessary to get to the larger value when the entrepreneur is able to raise $4 their potential application, the entrepreneur infl ection point when pharma companies, million in fi nancing from other investors should note that the loan/investment can biotech companies, venture capitalists and (the qualifi ed fi nancing step) the note will also be made in the form of discounted or

6 | Review of Ophthalmology | November 2016

004_rp1116_news.indd 6 10/21/16 4:16 PM “free” services-in-kind. For example, you may be looking for a loan because: you may require key proof-of-concept preclinical work; external consultants may be needed to Inamura* Capsulorrhexis hone clinical development plans; or maybe a pre-IND meeting is critical to convincing VC Cystotome Forceps investors to support the budget for further clinical trials, and medical writing and regu- latory support is needed. In such scenarios, an entity that provides those services may be willing to provide them at no charge or at a discount in exchange for the issuance of a convertible note. This bartering services d for equity is an especially powerful catalyst se lo C because it makes it easier for the investor to es lad make the investment (and invest more) since B s p his investment isn’t in the form of cash. e c The convertible note is a critical fi nancing r o F arrow in the entrepreneur’s quiver. As you’re likely to also be managing a busy clinical e m practice, these arrangements can allow o t o quick, easy access to funding so that you t s can focus on creating value with R&D. The d y e C n key to ensuring a successful transaction is e s p i maintaining an open dialogue so that both x O e s h entrepreneur and investor understand each e r d r la o other’s objectives and sensitivities. Topics B l u such as dilution, granting increased upside in s p s 12mm Formed exchange for early investment, protection of a C Blades Designed downside risk, timing of potential licens- * ra u To Relieve Stress ing/exit transactions and considerations of m a On The Incision. whether such an event is expected prior to or In : after a qualifi ed fi nancing and the mechanics 9 2 s Unique Direct Acting Jaws of how such an event is dealt with, etc., will 14 -0 Able To Fit Through A Minimal most likely arise. We will be delving into them 08 in subsequent columns. With a spirit of col- Incision. laboration and the goal of a win-win scenario front and center, the convertible note can s Special Cystotome Tips Designed To be an effi cient tool for funding early-stage Open The Capsule In One Maneuver. Micro Gap Between assets, supporting established program The Blades To Prevent Iris Pickup. acceleration and/or setting the stage for a s Reusable, Autoclaveable, Made In The USA, Guaranteed mutually fruitful endeavor. For Life, And Available For A 30-Day Surgical Evaluation Without Obligation. Mr. Chapin is senior vice president of the Corporate Development Group and Mr. Warner is corporate counsel at Ora Inc. Mr. Contact 727-209-2244 Biswas is managing director at ORA Vision For More Information. Ventures. Ora provides a comprehensive range of development, clinical-regulatory and product consulting services for develop- ers, investors and buyers; preclinical and turnkey clinical trial services; assistance with regulatory submissions; and the integration of assets, business partnering and fi nancing support in ophthalmology. We welcome your comments or questions. 3360 Scherer Drive, Suite B, St. Petersburg, FL 33716 Please send correspondence to mchapin@   s4EL  s&AX   oraclinical.com or visit www.oraclinical.com. %MAIL)NFO 2HEIN-EDICALCOMs7EBSITEWWW2HEIN-EDICALCOM $EVELOPED)N#OORDINATION7ITH-IKIO)NAMURA -$ 0H$

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004_rp1116_news.indd 7 10/21/16 4:16 PM REVIEW News

(continued from page 4) try in the southern part of the country. her task of tagging the genetic risk fac- “The study will take three years,” says tors, Dr. Wiggs will compare the DNA In the meantime, Dr. Etminan be- Dr. George. “The fi rst two years will of those with glaucoma to those with- lieves that doctors prescribing these consist of patient data collection. All out, focusing on their genetic differ- drugs should perform a risk-benefi t the members of these consanguine- ences in the hopes of identifying some analysis. “If a patient is at high risk of ous families will have a detailed eye genetic precursor to the disease. future osteoporosis, the benefi ts of the examination measuring more than 15 In addition to identifying risk factors drugs may outweigh the risks,” he says. different parameters in each person, for glaucoma, one of the study’s long- “However, the risk of macular degen- such as intraocular pressure and optic term goals is to use this approach to eration and other adverse events in nerve measurements. The research- develop and support a genotype/phe- women who have a low risk of fracture ers will then use the patients’ genetic notype database that will enable inves- might outweigh its benefi ts.” information to try and identify the ge- tigators to discover, assess and validate netic factors that are responsible for genes and biomarkers responsible for these parameters. The study endpoints traits that contribute to other complex U.S. and India to will be the identifi cation of the genetic ocular diseases. risk factors.” By identifying the genes for disor- Collaborate on U.S. researchers will focus on ge- ders such as glaucoma, the investiga- netic analyses to identify the risk fac- tors hope to get a better idea of these Glaucoma Research tors that might be associated with glau- diseases’ underlying causes. Ideally, In a joint effort, researchers from coma, an effort that will be headed up they say, this knowledge will lead to the United States and India have by Janey Wiggs, MD, PhD, associate new methods of diagnosis and treat- begun to look at the genetic risk fac- director of the Ocular Genomics In- ment. “The results will not be directly tors and traits linked to glaucoma in stitute at Massachusetts Eye and Ear/ applicable to the management of glau- a study funded by the National Eye Harvard Medical School. Both she and coma,” says Dr. George. “However, Institute and India’s Department of Dr. George emphasize the fact that the analyzing the genes and pathways for Biotechnology. study is a collaborative effort and that, factors that infl uence the disease This new study will build upon a re- without both study arms, the study could help identify potential drug port from 2010 that looked at the value would not be possible. To accomplish targets.” of genetic mapping to identify traits that are risk factors for diseases such as News Briefs glaucoma and macular degeneration— age-related diseases that are the lead- ing cause of blindness in many coun- • CyPass launches. Alcon announced the U.S. launch of the CyPass Micro-Stent at the tries, are costly to treat and threaten annual meeting of the American Academy of Ophthalmology in Chicago. The device was patients’ ability to live independently. approved by the U.S. Food and Drug Administration in July for use in conjunction with Dr. Ronnie George, senior consultant cataract surgery to lower intraocular pressure in adult patients with mild-to-moderate in the Department of Glaucoma at the primary open-angle glaucoma. Implanted during cataract surgery just below the surface of Vision Research Foundation, explains the eye and into the supraciliary space, the device is designed to lower IOP by enhancing the aim of the joint venture: “The goals aqueous outfl ow through one of the natural drainage pathways of the eye, with minimal of the project are to identify genetic tissue disruption. The CyPass Micro-Stent was developed by Transcend Medical, which markers for glaucoma and factors that Alcon acquired in February 2016. Two-year data from the COMPASS study, published in the infl uence glaucoma, like intraocular online edition of Ophthalmology, demonstrated safe and sustained two-year reduction in pressure and the optic disc, by target- IOP and glaucoma medication use after CyPass implantation. ing families with consanguineous pedi- • Lens calculators go live. Alcon and AMO recently announced the launch of their grees,” he says. Earlier studies have online toric intraocular lens calculators. The Alcon calculator (acrysoftoriccalculator.com) suggested that consanguineous pedi- is equipped with the Barrett Toric Algorithm, which theoretically accounts for posterior grees of suffi cient size and structure corneal astigmatism, calculates patient-specifi c effective lens position and is designed will provide more signifi cant, quantita- to improve preop refractive predictability by using a centroid value for surgically induced tive trait mapping than a similarly sized astigmatism. AMO’s calculator (https://www.amoeasy.com) compensates for posterior collection of nuclear families. corneal astigmatism using calculations based on the work of Doug Koch, MD, of Houston, In India, the study will look at 400 an expert in factoring PCA into lens calculations. people from 30 families of close ances-

8 | Review of Ophthalmology | November 2016

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RP1116_Oculus.indd 1 10/4/16 2:10 PM Editorial

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10 | Review of Ophthalmology | November 2016

0004_rp1116_news.indd04_rp1116_news.indd 1100 110/21/160/21/16 4:164:16 PMPM Down, Boy. Help Tame Postoperative Ocular Inflammation and Pain With LOTEMAX® GEL Indication LOTEMAX® GEL (loteprednol etabonate ophthalmic gel) 0.5% is indicated for the treatment of post-operative infl ammation and pain following ocular surgery. Important Safety Information about LOTEMAX® GEL • LOTEMAX ® GEL is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal diseases of ocular structures. • Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. If this product is used for 10 days or longer, IOP should be monitored. • Use of corticosteroids may result in posterior subcapsular cataract formation. • Use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation and occurrence of perforations in those with diseases causing corneal and scleral thinning. The initial prescription and renewal of the medication order should be made by a physician only after examination of the patient with the aid of magnification, and where appropriate, fluorescein staining. • Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infection. In acute purulent conditions, steroids may mask infection or enhance existing infection. • Use of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and exacerbate the severity of many viral infections of the eye (including herpes simplex). • Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. • Patients should not wear contact lenses when using LOTEMAX® GEL. • The most common ocular adverse drug reactions reported were anterior chamber inflammation (5%), eye pain (2%) and foreign body sensation (2%). Please see brief summary of Prescribing Information on adjacent page. ®/™ are trademarks of Bausch & Lomb Incorporated or its affi liates. © 2015 Bausch & Lomb Incorporated. All rights reserved. Printed in USA. US/LGX/15/0041(1)

RO1015_BL Lotemax.indd 1 9/15/15 2:24 PM BRIEF SUMMARY OF PRESCRIBING INFORMATION ossification) and teratogenic (increased incidence of meningocele, abnormal This Brief Summary does not include all the information needed to left common carotid artery, and limb flexures) when administered orally prescribe Lotemax Gel safely and effectively. See full prescribing to rabbits during organogenesis at a dose of 3 mg/kg/day (35 times information for Lotemax Gel. the maximum daily clinical dose), a dose which caused no maternal toxicity. The no-observed-effect-level (NOEL) for these effects was 0.5 mg/kg/day (6 times the maximum daily clinical dose). Oral treatment (loteprednol etabonate ophthalmic gel) 0.5% Lotemax of rats during organogenesis resulted in teratogenicity (absent innominate Rx only artery at ≥5 mg/kg/day doses, and cleft palate and umbilical hernia Initial Rx Approval: 1998 at ≥50 mg/kg/day) and embryotoxicity (increased post-implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal INDICATIONS AND USAGE ossification with ≥50 mg/kg/day). Treatment of rats with 0.5 mg/kg/day LOTEMAX is a corticosteroid indicated for the treatment of post-operative (6 times the maximum clinical dose) during organogenesis did not result inflammation and pain following ocular surgery. in any reproductive toxicity. Loteprednol etabonate was maternally toxic DOSAGE AND ADMINISTRATION (significantly reduced body weight gain during treatment) when administered Invert closed bottle and shake once to fill tip before instilling drops. to pregnant rats during organogenesis at doses of ≥5 mg/kg/day. Apply one to two drops of LOTEMAX into the conjunctival sac of the affected Oral exposure of female rats to 50 mg/kg/day of loteprednol etabonate from eye four times daily beginning the day after surgery and continuing the start of the fetal period through the end of lactation, a maternally toxic throughout the first 2 weeks of the post-operative period. treatment regimen (significantly decreased body weight gain), gave rise to decreased growth and survival, and retarded development in the offspring CONTRAINDICATIONS during lactation; the NOEL for these effects was 5 mg/kg/day. Loteprednol LOTEMAX, as with other ophthalmic corticosteroids, is contraindicated in etabonate had no effect on the duration of gestation or parturition when most viral diseases of the cornea and conjunctiva including epithelial herpes administered orally to pregnant rats at doses up to 50 mg/kg/day during the simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in fetal period. mycobacterial infection of the eye and fungal diseases of ocular structures. There are no adequate and well controlled studies in pregnant women. WARNINGS AND PRECAUTIONS LOTEMAX should be used during pregnancy only if the potential benefit Intraocular Pressure (IOP) Increase justifies the potential risk to the fetus. Prolonged use of corticosteroids may result in glaucoma with damage to the Nursing Mothers optic nerve, defects in visual acuity and fields of vision. Steroids should be It is not known whether topical ophthalmic administration of corticosteroids used with caution in the presence of glaucoma. If this product is used for 10 could result in sufficient systemic absorption to produce detectable quantities days or longer, intraocular pressure should be monitored. in human milk. Systemic steroids appear in human milk and could suppress Cataracts growth, interfere with endogenous corticosteroid production, or cause other Use of corticosteroids may result in posterior subcapsular cataract formation. untoward effects. Caution should be exercised when LOTEMAX is administered Delayed Healing to a nursing woman. The use of steroids after cataract surgery may delay healing and increase the Pediatric Use incidence of bleb formation. In those diseases causing thinning of the cornea Safety and effectiveness in pediatric patients have not been established. or sclera, perforations have been known to occur with the use of topical Geriatric Use steroids. The initial prescription and renewal of the medication order should No overall differences in safety and effectiveness have been observed be made by a physician only after examination of the patient with the aid between elderly and younger patients. of magnification such as slit lamp biomicroscopy and, where appropriate, NONCLINICAL TOXICOLOGY fluorescein staining. Carcinogenesis, Mutagenesis, Impairment Of Fertility Bacterial Infections Long-term animal studies have not been conducted to evaluate the Prolonged use of corticosteroids may suppress the host response and carcinogenic potential of loteprednol etabonate. Loteprednol etabonate was thus increase the hazard of secondary ocular infections. In acute purulent not genotoxic in vitro in the Ames test, the mouse lymphoma tk assay, or in conditions of the eye, steroids may mask infection or enhance existing a chromosome aberration test in human lymphocytes, or in vivo in the single infection. dose mouse micronucleus assay. Treatment of male and female rats with up Viral Infections to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, Employment of a corticosteroid medication in the treatment of patients with (600 and 300 times the maximum clinical dose, respectively) prior to and a history of herpes simplex requires great caution. Use of ocular steroids may during mating did not impair fertility in either gender. prolong the course and may exacerbate the severity of many viral infections PATIENT COUNSELING INFORMATION of the eye (including herpes simplex). Administration Fungal Infections Invert closed bottle and shake once to fill tip before instilling drops. Fungal infections of the cornea are particularly prone to develop Risk of Contamination coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been Patients should be advised not to allow the dropper tip to touch any surface, used or is in use. Fungal cultures should be taken when appropriate. as this may contaminate the gel. Contact Lens Wear Contact Lens Wear Patients should not wear contact lenses during their course of therapy with Patients should be advised not to wear contact lenses when using LOTEMAX. LOTEMAX. Risk of Secondary Infection ADVERSE REACTIONS If pain develops, redness, itching or inflammation becomes aggravated, the Adverse reactions associated with ophthalmic steroids include elevated patient should be advised to consult a physician. intraocular pressure, which may be associated with infrequent optic nerve damage, visual acuity and field defects, posterior subcapsular cataract Bausch & Lomb Incorporated formation, delayed wound healing and secondary ocular infection from Tampa, Florida 33637 USA pathogens including herpes simplex, and perforation of the globe where US Patent No. 5,800,807 there is thinning of the cornea or sclera. ©Bausch & Lomb Incorporated The most common adverse drug reactions reported were anterior chamber inflammation (5%), eye pain (2%), and foreign body sensation (2%). ®/™ are trademarks of Bausch & Lomb Incorporated or its affiliates. USE IN SPECIFIC POPULATIONS Pregnancy US/LGX/15/0042 Teratogenic Effects: Pregnancy Category C. Based on 9269100-9269200 Revised: 9/2012 Loteprednol etabonate has been shown to be embryotoxic (delayed

RRO1015_BLO1015_BL LLotemaxotemax PI.inddPI.indd 1 99/15/15/15/15 2:292:29 PMPM November 2016 • Volume XXIII No. 11 | reviewofophthalmology.com Cover Focus 28 | Managing Dry-eye Patients, Step by Step By Christopher Kent, Senior Editor Surgeons offer advice on making sense of today’s diagnostic and treatment options. 38 | Treating Dry Eye: Beyond Drops Michelle Stephenson, Contributing Editor Ophthalmologists’ armamentarium for treating dry eye continues to grow.

44 | Thicker Than Water: Autologous Serum Kristine Brennan, Senior Associate Editor The benefits and limitations of this unique corneal therapy.

Cover image: iStock November 2016 | reviewofophthalmology.com | 13

013_rp1116_toc.indd 13 10/21/16 2:11 PM Departments

4 | Review News 18

18 | Technology Update Lights, KAMRA, Action! A surgeon has developed a novel method for centering the AcuFocus KAMRA corneal inlay.

52 | Masters of Surgery 10 Things NOT to Do as a Surgeon Sometimes, you can do what’s right just by knowing what’s wrong.

57 | Retinal Insider Avoiding the Traps of Hydroxychloroquine Use Proper communication between specialties and using the right dosing formula can curb toxicity. 52

65 | Plastic Pointers Periocular Peels and Potions A look at the chemical agents patients can use topically in an effort to fight the effects of aging.

68 | Therapeutic Topics Making Accommodation for the Aging Eye A review of presbyopia and treatments that are either available or in development.

72 | Research Review Prostaglandin Use Associated with MGD

65 74 | Products

76 | Classified Ads

79 | Wills Eye Resident Case Series

82 | Advertising Index

14 | Review of Ophthalmology | November 2016

013_rp1116_toc.indd 14 10/21/16 2:11 PM 9GNNVJKU CHANGES THIINGS / iwÀÃÌ«ÀiÃVÀˆ«Ìˆœ˜iÞi`Àœ« Ƃ‡>««ÀœÛi`̜ÌÀi>Ì LœÌ Ì iÈ}˜Ã>˜`Ãޓ«Ìœ“Ãœv ÀÞ Þi ˆÃi>Ãi

Indication Xiidra™ NKƂVGITCUVQRJVJCNOKEUQNWVKQP KUKPFKECVGFHQT Xiidra is a lymphocyte VJGVTGCVOGPVQHUKIPUCPFU[ORVQOUQHFT[G[GFKUGCUG &'&  function-associated antigen-1 Important Safety Information +PENKPKECNVTKCNUVJGOQUVEQOOQP .(# CPVCIQPKUVVJGƂTUV CFXGTUGTGCEVKQPUTGRQTVGFKPQHRCVKGPVUYGTGKPUVKNNCVKQPUKVG medication in a new class KTTKVCVKQPF[UIGWUKCCPFTGFWEGFXKUWCNCEWKV[1VJGTCFXGTUGTGCEVKQPU 1 TGRQTVGFKPVQQHVJGRCVKGPVUYGTGDNWTTGFXKUKQPEQPLWPEVKXCN of drugs. J[RGTGOKCG[GKTTKVCVKQPJGCFCEJGKPETGCUGFNCETKOCVKQPG[G FKUEJCTIGG[GFKUEQOHQTVG[GRTWTKVWUCPFUKPWUKVKU Check it out at Xiidra-ECP.com 6QCXQKFVJGRQVGPVKCNHQTG[GKPLWT[QTEQPVCOKPCVKQPQHVJGUQNWVKQP Reference: 1. (&#CRRTQXGUPGYOGFKECVKQPHQT RCVKGPVUUJQWNFPQVVQWEJVJGVKRQHVJGUKPINGWUGEQPVCKPGTVQVJGKT FT[G[GFKUGCUG(&#0GYU4GNGCUG,WN[ G[GQTVQCP[UWTHCEG http://www.fda.gov/newsevents/newsroom/ %QPVCEVNGPUGUUJQWNFDGTGOQXGFRTKQTVQVJGCFOKPKUVTCVKQPQH:KKFTC pressannouncements/ucm510720.htm. #EEGUUGF CPFOC[DGTGKPUGTVGFOKPWVGUHQNNQYKPICFOKPKUVTCVKQP ,WN[ 5CHGV[CPFGHƂECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH[GCTUJCXG PQVDGGPGUVCDNKUJGF

For additional safety information, see accompanying Brief Summary of Safety Information on the following page and Full Prescribing Information on Xiidra-ECP.com.

Marks designated ® and ™>ÀiœÜ˜i`LÞ- ˆÀiœÀ>˜>vwˆ>Ìi`Vœ“«>˜Þ° ^Óä£È- ˆÀi1-˜V°i݈˜}̜˜] ƂäÓ{Ó£-£Óä{ÎäÇÉ£È

RP0916_Shire.indd 1 8/24/16 10:36 AM Animal Data .KƂVGITCUVCFOKPKUVGTGFFCKN[D[KPVTCXGPQWU +8  KPLGEVKQPVQTCVUHTQORTGOCVKPIVJTQWIJIGUVCVKQPFC[ ECWUGFCPKPETGCUGKPOGCPRTGKORNCPVCVKQPNQUU and an increased incidence of several minor skeletal CPQOCNKGUCVOIMIFC[TGRTGUGPVKPIHQNF Rx Only the human plasma exposure at the RHOD of Xiidra, based on AUC. No teratogenicity was observed in the rat at BRIEF SUMMARY: OIMIFC[ HQNFVJGJWOCPRNCUOCGZRQUWTGCV Consult the Full Prescribing Information for complete VJG4*1&DCUGFQP#7% +PVJGTCDDKVCPKPETGCUGF product information. incidence of omphalocele was observed at the lowest FQUGVGUVGFOIMIFC[ HQNFVJGJWOCP INDICATIONS AND USAGE RNCUOCGZRQUWTGCVVJG4*1&DCUGFQP#7% YJGP :KKFTCv NKƂVGITCUVQRJVJCNOKEUQNWVKQP KUKPFKECVGF CFOKPKUVGTGFD[+8KPLGEVKQPFCKN[HTQOIGUVCVKQPFC[U for the treatment of the signs and symptoms of dry eye VJTQWIJ#HGVCN0Q1DUGTXGF#FXGTUG'HHGEV.GXGN FKUGCUG &'&  01#'. YCUPQVKFGPVKƂGFKPVJGTCDDKV Lactation DOSAGE AND ADMINISTRATION 6JGTGCTGPQFCVCQPVJGRTGUGPEGQHNKƂVGITCUVKPJWOCP Instill one drop of Xiidra twice daily (approximately 12 milk, the effects on the breastfed infant, or the effects on JQWTUCRCTV KPVQGCEJG[GWUKPICUKPINGWUGEQPVCKPGT OKNMRTQFWEVKQP*QYGXGTU[UVGOKEGZRQUWTGVQNKƂVGITCUV Discard the single use container immediately after using HTQOQEWNCTCFOKPKUVTCVKQPKUNQY6JGFGXGNQROGPVCNCPF in each eye. Contact lenses should be removed prior to JGCNVJDGPGƂVUQHDTGCUVHGGFKPIUJQWNFDGEQPUKFGTGF VJGCFOKPKUVTCVKQPQH:KKFTCCPFOC[DGTGKPUGTVGF along with the mother’s clinical need for Xiidra and any minutes following administration. potential adverse effects on the breastfed child from Xiidra. ADVERSE REACTIONS Clinical Trials Experience Pediatric Use Because clinical studies are conducted under widely 5CHGV[CPFGHƂECE[KPRGFKCVTKERCVKGPVUDGNQYVJGCIGQH varying conditions, adverse reaction rates observed in [GCTUJCXGPQVDGGPGUVCDNKUJGF clinical studies of a drug cannot be directly compared to rates in the clinical trials of another drug and may Geriatric Use PQVTGƃGEVVJGTCVGUQDUGTXGFKPRTCEVKEG+PƂXGENKPKECN No overall differences in safety or effectiveness have been UVWFKGUQHFT[G[GFKUGCUGEQPFWEVGFYKVJNKƂVGITCUV observed between elderly and younger adult patients. ophthalmic solution, 1401 patients received at least FQUGQHNKƂVGITCUV QHYJKEJTGEGKXGFNKƂVGITCUV NONCLINICAL TOXICOLOGY  6JGOCLQTKV[QHRCVKGPVU  JCFŰOQPVJUQH Carcinogenesis, Mutagenesis, Impairment of Fertility VTGCVOGPVGZRQUWTGRCVKGPVUYGTGGZRQUGFVQ Carcinogenesis: Animal studies have not been conducted NKƂVGITCUVHQTCRRTQZKOCVGN[OQPVJU6JGOCLQTKV[ VQFGVGTOKPGVJGECTEKPQIGPKERQVGPVKCNQHNKƂVGITCUV QHVJGVTGCVGFRCVKGPVUYGTGHGOCNG  6JGOQUV Mutagenesis: .KƂVGITCUVYCUPQVOWVCIGPKEKPVJGin vitro EQOOQPCFXGTUGTGCEVKQPUTGRQTVGFKPQHRCVKGPVU #OGUCUUC[.KƂVGITCUVYCUPQVENCUVQIGPKEKPVJGin vivo were instillation site irritation, dysgeusia and reduced mouse micronucleus assay. In an in vitro chromosomal XKUWCNCEWKV[1VJGTCFXGTUGTGCEVKQPUTGRQTVGFKP aberration assay using mammalian cells (Chinese VQQHVJGRCVKGPVUYGTGDNWTTGFXKUKQPEQPLWPEVKXCN JCOUVGTQXCT[EGNNU NKƂVGITCUVYCURQUKVKXGCVVJGJKIJGUV hyperemia, eye irritation, headache, increased concentration tested, without metabolic activation. lacrimation, eye discharge, eye discomfort, eye pruritus Impairment of fertility: .KƂVGITCUVCFOKPKUVGTGFCV and sinusitis. KPVTCXGPQWU +8 FQUGUQHWRVQOIMIFC[ HQNFVJGJWOCPRNCUOCGZRQUWTGCVVJG USE IN SPECIFIC POPULATIONS TGEQOOGPFGFJWOCPQRJVJCNOKEFQUG 4*1& QH Pregnancy NKƂVGITCUVQRJVJCNOKEUQNWVKQP JCFPQGHHGEVQP 6JGTGCTGPQCXCKNCDNGFCVCQP:KKFTCWUGKPRTGIPCPV fertility and reproductive performance in male and women to inform any drug associated risks. Intravenous female treated rats. +8 CFOKPKUVTCVKQPQHNKƂVGITCUVVQRTGIPCPVTCVUHTQO RTGOCVKPIVJTQWIJIGUVCVKQPFC[FKFPQVRTQFWEG teratogenicity at clinically relevant systemic exposures. +PVTCXGPQWUCFOKPKUVTCVKQPQHNKƂVGITCUVVQRTGIPCPV /CPWHCEVWTGFHQT5JKTG75+PE5JKTG9C[.GZKPIVQP/# rabbits during organogenesis produced an increased incidence of omphalocele at the lowest dose tested, (QTOQTGKPHQTOCVKQPIQVQYYY:KKFTCEQOQTECNN OIMIFC[ HQNFVJGJWOCPRNCUOCGZRQUWTGCV Marks designated ®CPFvCTGQYPGFD[5JKTG the recommended human ophthalmic dose [RHOD], QTCPCHƂNKCVGFEQORCP[ DCUGFQPVJGCTGCWPFGTVJGEWTXG=#7%?NGXGN 5KPEG 5JKTG75+PE JWOCPU[UVGOKEGZRQUWTGVQNKƂVGITCUVHQNNQYKPI 752CVGPVU ocular administration of Xiidra at the RHOD is low, the CPF CRRNKECDKNKV[QHCPKOCNƂPFKPIUVQVJGTKUMQH:KKFTCWUGKP pending patent applications. humans during pregnancy is unclear. .CUV/QFKƂGF5

RRP0916_ShireP0916_Shire PPI.inddI.indd 1 88/24/16/24/16 10:3810:38 AMAM

Technology Update

REVIEW Edited by Michael Colvard, MD, and Steven Charles, MD

Lights, KAMRA, Action! A surgeon has developed a novel method for centering the AcuFocus KAMRA corneal inlay using a widely available digital camera. Kristine Brennan, Senior Associate Editor

resbyopia remains an inevitable In a September presentation to the must be moved from the OR to the Ppart of aging, but corrective lenses 34th Congress of the European Soci- AcuTarget HD, and then back to the don’t have to be, thanks to emerging ety of Cataract and Refractive Sur- OR if inlay position is unacceptable.” corneal inlay technologies. Approved geons in Copenhagen, Denmark, Dr. This back-and-forth, he cautions, by the FDA in 2015, KAMRA (Acu- Will demonstrated his novel system, might lead surgeons to settle for sub- Focus, Irvine, Calif.), is an opaque, which supplements the AcuTarget optimal KAMRA placements to main- permeable, small-aperture inlay that HD (AcuFocus) diagnostic and surgi- tain effi ciency in the operating room. improves near vision in the non-dom- cal planning tool by providing direct Dr. Will’s repurposed digital camera inant eye by concentrating incoming intraoperative guidance for KAMRA and its accompanying software helps light through a 1.6- KAMRA inlay surgery mm opening. The flow smoothly with- KAMRA inlay is im- out sacrificing preci-

planted in a stromal Brian Will, MD sion, to help spare pocket made with a patients from subse- femtosecond laser. quent repositioning Optimal centration of surgery. “In some cas- the 3.8-mm diameter es the inlay surgery is inlay is key to patient performed in a dedi- satisfaction. Brian cated surgical center Will, MD, in private that may not have an practice at Will Vi- AcuTarget HD sys- sion & Laser Centers, tem, where the sys- based in Vancouver, tem is in a different Wash., and adjunct clinic miles away. As clinical professor of The KAMRA inlay’s position is analyzed intraoperatively in the OR by the system’s a result, the centra- ophthalmology at the metrology software, which was developed by Brian Will, MD. tion can’t be checked Loma Linda Univer- until another day—a sity School of Medicine, Loma Linda, centration. “We still recommend the bit too late to make intraoperative ad- Calif., has developed a precise way of AcuTarget HD as the fi nal gold stan- justments,” he says. “The value of this streamlining the centration process dard,” he notes. “The challenge is that system is speed and the ability to make using an ordinary Sony digital camera. to use the AcuTarget HD, the patient accurate decisions intraoperatively.”

18 | Review of Ophthalmology | November 2016 This article has no commercial sponsorship.

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RP1016_Alcon Cypass.indd 1 9/8/16 12:23 PM Technology

REVIEW Update

Dr. Will’s invention uses a digital camera because, unlike a surgical microscope with a camera attached, it provides CyPass® Micro-Stent a single-lens, coaxial view of the surgical fi eld, elimating offset error. The Sony Alpha a7 RII digital camera has a 44- MP sensor, and a black-and-white setting aids centration IMPORTANT PRODUCT INFORMATION in eyes with dark irides. “We need the highest resolution CAUTION: FEDERAL (USA) LAW RESTRICTS THIS DEVICE possible to mitigate against image pixelation caused by the TO SALE BY OR ON THE ORDER OF A PHYSICIAN. digital sensor in the camera,” he says. INDICATION: The CyPass® Micro-Stent is indicated for use in Clear, error-free visualization is critical to outcomes that conjunction with cataract surgery for the reduction of intraocular will enhance near vision while minimizing impact on dis- pressure (IOP) in adult patients with mild to moderate primary open- angle glaucoma (POAG). tance vision in the implanted eye. Using his system in the OR, Dr. Will can get constant feedback and redirection, CONTRAINDICATIONS: Use of the CyPass Micro-Stent is contrain- dicated in the following circumstances or conditions: (1) in eyes with positioning the KAMRA in the stromal pocket until he hits angle-closure glaucoma; and (2) in eyes with traumatic, malignant, his target, which is pre-programmed into his software. uveitic, or neovascular glaucoma or discernible congenital anomalies of “We have a software program that performs the neces- the anterior chamber angle. sary calculations, then provides the surgeon with a graphic MRI INFORMATION: The CyPass Micro-Stent is magnetic resonance (MR) Safe: the implant is constructed of polyimide material, a non- showing target position, achieved position and the metrics conducting, non-metallic, non-magnetic polymer that poses no known describing the centration error. It also provides directions hazards in all magnetic resonance imaging environments. on where to move the inlay, and by how much, in order WARNINGS: Gonioscopy should be performed prior to surgery to to bring achieved position versus target to an acceptable exclude peripheral anterior synechiae (PAS), rubeosis, and other angle margin,” he explains. Another plus of the digital camera is abnormalities or conditions that would prohibit adequate visualization of the angle that could lead to improper placement of the stent and pose immediate transfer of images onto his computer worksta- a hazard. tion. “We can’t be sitting around waiting to pull an SD card PRECAUTIONS: The surgeon should monitor the patient or take one photo at a time,” Dr. Will notes. postoperatively for proper maintenance of intraocular pressure. At the ESCRS meeting, he discussed the use of his sys- The safety and effectiveness of the CyPass Micro-Stent has not been established as an alternative to the primary treatment of glaucoma tem in 24 patients. He explains, “Using the feedback from with medications, in patients 21 years or younger, in eyes with our system, we were able to obtain much better accuracy significant prior trauma, chronic inflammation, eyes with an abnormal compared to the method of using just the AcuTarget HD, anterior segment, eyes with chronic inflammation, eyes with glaucoma associated with vascular disorders, pseudophakic eyes with glaucoma, as we could quickly move the inlay based on the intraopera- eyes with uveitic glaucoma, eyes with pseudoexfoliative or pigmentary tive feedback from the system, without having to move the glaucoma, eyes with other secondary open-angle glaucomas, eyes patient.” He compared 42 consecutive eyes implanted with that have undergone prior incisional glaucoma surgery or cilioablative procedures, eyes with laser trabeculoplasty performed ≤ 3 months prior KAMRA using manual marking and deductive reckoning to the surgical screening visit, eyes with unmedicated IOP less than 21 based on anatomic landmarks in the OR, to 24 consecutive mmHg or greater than 33 mmHg, eyes with medicated IOP greater than eyes implanted using his camera-based centration system 25 mmHg, in the setting of complicated cataract surgery with iatrogenic injury to the anterior or posterior segment, and when implantation is in the OR. Dr. Will’s experimental group showed a signifi - without concomitant cataract surgery with IOL implantation for visually cantly lower average centration error, at 85 µm (standard significant cataract. The safety and effectiveness of use of more than a deviation: 24 µm; range: 22 to 155 µm), versus 171 µm CyPass Micro-Stent single has not been established. (standard deviation: 33 µm; range: 57 to 263 µm) for the ADVERSE EVENTS: In a randomized, multicenter clinical trial manual-marking group. comparing cataract surgery with the CyPass Micro-Stent to cataract surgery alone, the most common postoperative adverse events included: Dr. Will’s adaptation of a conventional camera body BCVA loss of 10 or more letters at 3 months after surgery (8.8% for the is garnering the interest of surgeons and vendors alike. CyPass Micro-Stent vs. 15.3% for cataract surgery only); anterior chamber “We are considering taking this system to a commercial cell and flare requiring steroid treatment 30 or more days after surgery (8.6% vs. 3.8%); worsening of visual field mean deviation by 2.5 or more product,” he says. Although its current iteration is meant decibels (6.7% vs. 9.9%); IOP increase of 10 or more mmHg 30 or more to assist in KAMRA inlay surgery, he thinks its applications days after surgery (4.3% vs. 2.3%); and corneal edema 30 or more days could expand. “We believe that it can be used to check inlay after surgery, or severe in nature (3.5% vs. 1.5%). position for the Raindrop (ReVision Optics, Lake Forest, ATTENTION: PLEASE REFER TO THE INSTRUCTIONS Calif.) and Flexivue inlays (Presbia, Irvine, Calif.), as well,” FOR A COMPLETE LIST OF CONTRAINDICATIONS, WARNINGS, PRECAUTIONS, AND ADVERSE EVENTS. he says.

Dr. Will has no fi nancial relationships to any of the compa- nies mentioned in this article.

© 2016 Novartis 08/16 US-CYP-16-E-3239

0018_rp1116_tech18_rp1116_tech update.inddupdate.indd 2200 110/21/160/21/16 2:312:31 PMPM Monthly MACKOOL ONLINE CME CME SERIES | SURGICAL VIDEOS

MackoolOnlineCME.com MONTHLY Video Series

I would like to welcome you to a new concept in surgeon education, Mackool Online CME.

To view CME video Demonstrating ophthalmic surgical techniques has go to: long been part of my everyday practice. Now, thanks to educational grants from several ophthalmic companies, www.MackoolOnlineCME.com you are able to virtually sit at the microscope with me and see the techniques and instrumentation I use with my own patients. The only editing is to show a diff erent camera Richard J. Mackool, MD view or to remove down time – every step of every Episode 11: procedure will be shown just as if you are with me in the OR. We will release “Full Thickness one new surgical video every month, allowing you to earn CME credits or (Penetrating) LRIs to simply watch the video. Correct Astigmatism During Multifocal CME Accredited Surgical Training Videos Now IOL Insertion” Available Online: www.MackoolOnlineCME.com Surgical Video by: Richard J. Mackool, MD Richard Mackool, MD, a world renowned anterior segment ophthalmic microsurgeon, has assembled a web-based video collection of surgical cases that encompass both routine and challenging cases, demonstrating Video Overview: both familiar and potentially unfamiliar surgical techniques using a variety During this case I demonstrate of instrumentation and settings. the diff erences between This educational activity aims to present a series of Dr. Mackool’s surgical phaco aspiration vs videos, carefully selected to address the specifi c learning objectives of this phacoemulsifi cation of activity, with the goal of making surgical training available as needed online the nucleus, as well as the for surgeons motivated to improve or expand their surgical repertoire. use of Penetrating Limbal Learning Objectives: Relaxing Incisions to control After completion of this educational activity, participants should be able to: astigmatism in a 1. Describe the use of full-thickness (penetrating) limbal relaxing incisions multifocal IOL patient. (PLRIs) to correct astigmatism 2. Discuss methods to safely divide the nucleus with the horizontal chopping technique 3. Determine which techniques minimize the use of ultrasonic energy during nucleus removal 4. Describe a technique to protect the integrity of the posterior capsule during removal of lens cortex 5. Discuss the benefi ts of epithelium removal from the under-surface of the anterior capsule Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of the Institute for the Advancement of Human Behavior (IAHB) and Postgraduate Healthcare Education, LLC (PHE). IAHB is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Statement IAHB designates this live activity for a maximum of .25 AMA PRA Category 1 CreditsTM. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Endorsed by: Jointly Provided by: Supported by an unrestricted independent Commercially supported by: medical educational grant from: Review of Ophthalmology® Glaukos Video and Web Production by: IAHB Crestpoint Management Institute for the & JR Snowdon, Inc Advancement of Human Behavior Alcon MST

Mackool_OnlineSeries-Episode11.indd 1 9/21/16 1:43 PM New Indication. New Dosing Regimen. HUMIRA is administered by subcutaneous injection INITIAL DOSE FOLLOWED BY

given every other week starting 80 mg 40 mg 1 week after the initial dose The fi rst injection should be given under the supervision of a healthcare professional. A patient may self-inject HUMIRA after appropriate training and monitoring by a healthcare professional. Visit www.HumiraPro.com to learn more about our education programs for NI uveitis.* *Intermediate, posterior, and panuveitis. Indication¹ Uveitis: HUMIRA is indicated for the treatment of non-infectious intermediate, posterior, and panuveitis in adult patients. IMPORTANT SAFETY INFORMATION FOR HUMIRA® (adalimumab)1 SERIOUS INFECTIONS ƒIf an infection develops, monitor carefully and initiate Patients treated with HUMIRA are at increased risk for appropriate therapy. developing serious infections that may lead to hospitalization ƒDrug interactions with biologic products: A higher rate of serious or death. Most patients who developed these infections infections has been observed in rheumatoid arthritis patients treated were taking concomitant immunosuppressants such as with rituximab who received subsequent treatment with a TNF methotrexate or corticosteroids. blocker. Concurrent use of HUMIRA with biologic DMARDs (e.g., Discontinue HUMIRA if a patient develops a serious infection anakinra or abatacept) or other TNF blockers is not recommended or sepsis. based on the possible increased risk for infections and other potential Reported infections include: pharmacological interactions. ƒActive tuberculosis (TB), including reactivation of latent MALIGNANCY TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Test patients for Lymphoma and other malignancies, some fatal, have been latent TB before HUMIRA use and during therapy. Initiate reported in children and adolescent patients treated with treatment for latent TB prior to HUMIRA use. TNF blockers, including HUMIRA. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell ƒInvasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, lymphoma, have been reported in patients treated with TNF blastomycosis, and pneumocystosis. Patients with blockers, including HUMIRA. These cases have had a very histoplasmosis or other invasive fungal infections may aggressive disease course and have been fatal. The majority present with disseminated, rather than localized, disease. of reported TNF blocker cases have occurred in patients Antigen and antibody testing for histoplasmosis may be with Crohn’s disease or ulcerative colitis and the majority negative in some patients with active infection. Consider were in adolescent and young adult males. Almost all of empiric anti-fungal therapy in patients at risk for invasive these patients had received treatment with azathioprine or fungal infections who develop severe systemic illness. 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of ƒBacterial, viral, and other infections due to opportunistic pathogens, including Legionella and Listeria. HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. Carefully consider the risks and benefits of treatment with HUMIRA prior to initiating therapy in patients: 1. with chronic or ƒConsider the risks and benefits of HUMIRA treatment prior to initiating recurrent infection, 2. who have been exposed to TB, 3. with a or continuing therapy in a patient with known malignancy. history of opportunistic infection, 4. who resided in or traveled ƒIn clinical trials, more cases of malignancies were observed among in regions where mycoses are endemic, 5. with underlying HUMIRA-treated patients compared to control patients. conditions that may predispose them to infection. Monitor ƒNon-melanoma skin cancer (NMSC) was reported during clinical trials patients closely for the development of signs and symptoms of for HUMIRA-treated patients. Examine all patients, particularly those infection during and after treatment with HUMIRA, including with a history of prolonged immunosuppressant or PUVA therapy, for the possible development of TB in patients who tested negative the presence of NMSC prior to and during treatment with HUMIRA. for latent TB infection prior to initiating therapy. ƒIn HUMIRA clinical trials, there was an approximate 3-fold higher ƒDo not start HUMIRA during an active infection, including rate of lymphoma than expected in the general U.S. population. localized infections. Patients with chronic inflammatory diseases, particularly those with ƒPatients older than 65 years, patients with co-morbid conditions, highly active disease and/or chronic exposure to immunosuppressant and/or patients taking concomitant immunosuppressants may be at therapies, may be at higher risk of lymphoma than the general greater risk of infection. population, even in the absence of TNF blockers.

RP0816_Abbvie.indd 2 7/21/16 3:47 PM NOW APPROVED

HUMIRA for NI intermediate, posterior, and panuveitis* A steroid-sparing option proven to prolong time to a combination of disease fl are† and decrease of visual acuity.1

†Disease flare is defined by an increase in 1 or more inflammatory markers: AC cells, vitreous haze, and/or development of new chorioretinal, and/or retinal vascular lesions.

ƒPostmarketing cases of acute and chronic leukemia were reported HEMATOLOGIC REACTIONS with TNF blocker use. Approximately half of the postmarketing ƒRare reports of pancytopenia, including aplastic anemia, have been cases of malignancies in children, adolescents, and young adults reported with TNF blockers. Medically significant cytopenia has been receiving TNF blockers were lymphomas; other cases included rare infrequently reported with HUMIRA. malignancies associated with immunosuppression and malignancies ƒ Consider stopping HUMIRA if significant hematologic abnormalities not usually observed in children and adolescents. occur. HYPERSENSITIVITY CONGESTIVE HEART FAILURE Anaphylaxis and angioneurotic edema have been reported following ƒ ƒWorsening or new onset congestive heart failure (CHF) may occur; HUMIRA administration. If a serious allergic reaction occurs, stop exercise caution and monitor carefully. HUMIRA and institute appropriate therapy. HEPATITIS B VIRUS REACTIVATION AUTOIMMUNITY ƒTreatment with HUMIRA may result in the formation of autoantibodies ƒUse of TNF blockers, including HUMIRA, may increase the risk of and, rarely, in development of a lupus-like syndrome. Discontinue reactivation of hepatitis B virus (HBV) in patients who are chronic treatment if symptoms of a lupus-like syndrome develop. carriers. Some cases have been fatal. ƒEvaluate patients at risk for HBV infection for prior evidence of HBV IMMUNIZATIONS infection before initiating TNF blocker therapy. ƒPatients on HUMIRA should not receive live vaccines. ƒExercise caution in patients who are carriers of HBV and monitor them ƒPediatric patients, if possible, should be brought up to date with all during and after HUMIRA treatment. immunizations before initiating HUMIRA therapy. ƒDiscontinue HUMIRA and begin antiviral therapy in patients who ƒThe safety of administering live or live-attenuated vaccines in infants develop HBV reactivation. Exercise caution when resuming HUMIRA exposed to HUMIRA in utero is unknown. Risks and benefits should after HBV treatment. be considered prior to vaccinating (live or live-attenuated) exposed NEUROLOGIC REACTIONS infants. ƒTNF blockers, including HUMIRA, have been associated with rare ADVERSE REACTIONS cases of new onset or exacerbation of central nervous system and ƒThe most common adverse reactions in HUMIRA clinical trials (>10%) peripheral demyelinating diseases, including multiple sclerosis, optic were: infections (e.g., upper respiratory, sinusitis), injection site neuritis, and Guillain-Barré syndrome. reactions, headache, and rash. ƒExercise caution when considering HUMIRA for patients with these disorders; discontinuation of HUMIRA should be considered if any of these disorders develop. ƒThere is a known association between intermediate uveitis and central demyelinating disorders.

Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: AbbVie Inc. Please see Brief Summary of full Prescribing Information on the following page. ©2016 AbbVie Inc. North Chicago, IL 60064 64C-1859319 June 2016 Printed in U.S.A.

RP0816_Abbvie.indd 3 7/21/16 3:47 PM ® (adalimumab) PROFESSIONAL BRIEF SUMMARY HUMIRA CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION Uveitis In controlled trials of other TNF blockers in adult patients at higher risk for WARNING: SERIOUS INFECTIONS AND MALIGNANCY HUMIRA is indicated for the treatment of non-infectious intermediate, malignancies (i.e., patients with COPD with a significant smoking history SERIOUS INFECTIONS posterior and panuveitis in adult patients. and cyclophosphamide-treated patients with Wegener’s granulomatosis), a Patients treated with HUMIRA are at increased risk for developing CONTRAINDICATIONS greater portion of malignancies occurred in the TNF blocker group compared serious infections that may lead to hospitalization or death [see to the control group. None. Warnings and Precautions]. Most patients who developed these Non-Melanoma Skin Cancer WARNINGS AND PRECAUTIONS infections were taking concomitant immunosuppressants such as During the controlled portions of 39 global HUMIRA clinical trials in adult methotrexate or corticosteroids. Serious Infections patients with RA, PsA, AS, CD, UC, Ps, HS and UV, the rate (95% confidence Discontinue HUMIRA if a patient develops a serious infection or Patients treated with HUMIRA are at increased risk for developing serious interval) of NMSC was 0.8 (0.52, 1.09) per 100 patient-years among sepsis. infections involving various organ systems and sites that may lead to HUMIRA-treated patients and 0.2 (0.10, 0.59) per 100 patient-years among Reported infections include: hospitalization or death [see Boxed Warning]. Opportunistic infections control-treated patients. Examine all patients, and in particular patients • Active tuberculosis (TB), including reactivation of latent TB. due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other with a medical history of prior prolonged immunosuppressant therapy or Patients with TB have frequently presented with disseminated opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, psoriasis patients with a history of PUVA treatment for the presence of or extrapulmonary disease. Test patients for latent TB before coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis NMSC prior to and during treatment with HUMIRA. HUMIRA use and during therapy. Initiate treatment for latent TB and tuberculosis have been reported with TNF blockers. Patients have Lymphoma and Leukemia frequently presented with disseminated rather than localized disease. prior to HUMIRA use. In the controlled portions of clinical trials of all the TNF-blockers in adults, • Invasive fungal infections, including histoplasmosis, The concomitant use of a TNF blocker and abatacept or anakinra was more cases of lymphoma have been observed among TNF-blocker-treated coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and associated with a higher risk of serious infections in patients with patients compared to control-treated patients. In the controlled portions of pneumocystosis. Patients with histoplasmosis or other invasive rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and 39 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, UC these biologic products is not recommended in the treatment of patients Ps, HS and UV, 2 lymphomas occurred among 7973 HUMIRA-treated patients fungal infections may present with disseminated, rather than [see Warnings and Precautions and Drug Interactions] localized, disease. Antigen and antibody testing for histoplasmosis with RA . versus 1 among 4848 control-treated patients. In 52 global controlled and may be negative in some patients with active infection. Consider Treatment with HUMIRA should not be initiated in patients with an active uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, empiric anti-fungal therapy in patients at risk for invasive fungal infection, including localized infections. Patients greater than 65 years of CD, UC, Ps, HS and UV with a median duration of approximately 0.7 years, infections who develop severe systemic illness. age, patients with co-morbid conditions and/or patients taking concomitant including 24,605 patients and over 40,215 patient-years of HUMIRA, the • Bacterial, viral and other infections due to opportunistic immunosuppressants (such as corticosteroids or methotrexate), may be at observed rate of lymphomas was approximately 0.11 per 100 patient-years. pathogens, including Legionella and Listeria. greater risk of infection. Consider the risks and benefits of treatment prior to This is approximately 3-fold higher than expected in the general U.S. initiating therapy in patients: population according to the SEER database (adjusted for age, gender, and Carefully consider the risks and benefits of treatment with HUMIRA race). Rates of lymphoma in clinical trials of HUMIRA cannot be compared to prior to initiating therapy in patients with chronic or recurrent • with chronic or recurrent infection; • who have been exposed to tuberculosis; rates of lymphoma in clinical trials of other TNF blockers and may not predict infection. the rates observed in a broader patient population. Patients with RA and other Monitor patients closely for the development of signs and • with a history of an opportunistic infection; chronic inflammatory diseases, particularly those with highly active disease symptoms of infection during and after treatment with HUMIRA, • who have resided or traveled in areas of endemic tuberculosis or and/or chronic exposure to immunosuppressant therapies, may be at a higher including the possible development of TB in patients who tested endemic mycoses, such as histoplasmosis, coccidioidomycosis, or risk (up to several fold) than the general population for the development of negative for latent TB infection prior to initiating therapy [see blastomycosis; or lymphoma, even in the absence of TNF blockers. Post-marketing cases of Warnings and Precautions and Adverse Reactions]. • with underlying conditions that may predispose them to infection. acute and chronic leukemia have been reported in association with TNF- MALIGNANCY Tuberculosis blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than Lymphoma and other malignancies, some fatal, have been Cases of reactivation of tuberculosis and new onset tuberculosis infections reported in children and adolescent patients treated with TNF the general population for the development of leukemia. have been reported in patients receiving HUMIRA, including patients who Malignancies in Pediatric Patients and Young Adults blockers including HUMIRA [see Warnings and Precautions]. have previously received treatment for latent or active tuberculosis. Reports Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), included cases of pulmonary and extrapulmonary (i.e., disseminated) Malignancies, some fatal, have been reported among children, adolescents, a rare type of T-cell lymphoma, have been reported in patients tuberculosis. Evaluate patients for tuberculosis risk factors and test for and young adults who received treatment with TNF-blockers (initiation treated with TNF blockers including HUMIRA. These cases have latent infection prior to initiating HUMIRA and periodically during therapy. of therapy ≤ 18 years of age), of which HUMIRA is a member [see Boxed Warning] had a very aggressive disease course and have been fatal. The Treatment of latent tuberculosis infection prior to therapy with TNF blocking . Approximately half the cases were lymphomas, including majority of reported TNF blocker cases have occurred in patients agents has been shown to reduce the risk of tuberculosis reactivation Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a with Crohn’s disease or ulcerative colitis and the majority were during therapy. variety of different malignancies and included rare malignancies usually in adolescent and young adult males. Almost all these patients associated with immunosuppression and malignancies that are not usually had received treatment with azathioprine or 6-mercaptopurine Consider anti-tuberculosis therapy prior to initiation of HUMIRA in patients observed in children and adolescents. The malignancies occurred after a (6–MP) concomitantly with a TNF blocker at or prior to diagnosis. with a past history of latent or active tuberculosis in whom an adequate median of 30 months of therapy (range 1 to 84 months). Most of the patients It is uncertain whether the occurrence of HSTCL is related to use course of treatment cannot be confirmed, and for patients with a negative were receiving concomitant immunosuppressants. These cases were of a TNF blocker or a TNF blocker in combination with these other test for latent tuberculosis but having risk factors for tuberculosis infection. reported post-marketing and are derived from a variety of sources including immunosuppressants [see Warnings and Precautions]. Despite prophylactic treatment for tuberculosis, cases of reactivated registries and spontaneous postmarketing reports. tuberculosis have occurred in patients treated with HUMIRA. Consultation INDICATIONS AND USAGE with a physician with expertise in the treatment of tuberculosis is Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF Rheumatoid Arthritis recommended to aid in the decision whether initiating anti-tuberculosis [see Boxed Warning] therapy is appropriate for an individual patient. blockers including HUMIRA . These cases have had a very HUMIRA is indicated for reducing signs and symptoms, inducing major aggressive disease course and have been fatal. The majority of reported TNF clinical response, inhibiting the progression of structural damage, and Strongly consider tuberculosis in the differential diagnosis in patients who blocker cases have occurred in patients with Crohn’s disease or ulcerative improving physical function in adult patients with moderately to severely develop a new infection during HUMIRA treatment, especially in patients colitis and the majority were in adolescent and young adult males. Almost active rheumatoid arthritis. HUMIRA can be used alone or in combination who have previously or recently traveled to countries with a high prevalence all of these patients had received treatment with the immunosuppressants with methotrexate or other non-biologic disease-modifying anti-rheumatic of tuberculosis, or who have had close contact with a person with active azathioprine or 6-mercaptopurine (6–MP) concomitantly with a TNF blocker drugs (DMARDs). tuberculosis. at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is Monitoring Juvenile Idiopathic Arthritis related to use of a TNF blocker or a TNF blocker in combination with these HUMIRA is indicated for reducing signs and symptoms of moderately Closely monitor patients for the development of signs and symptoms other immunosuppressants. The potential risk with the combination of to severely active polyarticular juvenile idiopathic arthritis in patients 2 of infection during and after treatment with HUMIRA, including the azathioprine or 6-mercaptopurine and HUMIRA should be carefully considered. years of age and older. HUMIRA can be used alone or in combination with development of tuberculosis in patients who tested negative for latent Hypersensitivity Reactions methotrexate. tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis Anaphylaxis and angioneurotic edema have been reported following HUMIRA infection may also be falsely negative while on therapy with HUMIRA. Psoriatic Arthritis administration. If an anaphylactic or other serious allergic reaction occurs, Discontinue HUMIRA if a patient develops a serious infection or sepsis. For immediately discontinue administration of HUMIRA and institute appropriate HUMIRA is indicated for reducing signs and symptoms, inhibiting the a patient who develops a new infection during treatment with HUMIRA, progression of structural damage, and improving physical function in adult therapy. In clinical trials of HUMIRA in adults, allergic reactions (e.g., allergic closely monitor them, perform a prompt and complete diagnostic workup rash, anaphylactoid reaction, fixed drug reaction, non-specified drug patients with active psoriatic arthritis. HUMIRA can be used alone or in appropriate for an immunocompromised patient, and initiate appropriate combination with non-biologic DMARDs. reaction, urticaria) have been observed. antimicrobial therapy. Hepatitis B Virus Reactivation Ankylosing Spondylitis Invasive Fungal Infections Use of TNF blockers, including HUMIRA, may increase the risk of reactivation HUMIRA is indicated for reducing signs and symptoms in adult patients with If patients develop a serious systemic illness and they reside or travel in active ankylosing spondylitis. of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In regions where mycoses are endemic, consider invasive fungal infection in some instances, HBV reactivation occurring in conjunction with TNF blocker Adult Crohn’s Disease the differential diagnosis. Antigen and antibody testing for histoplasmosis therapy has been fatal. The majority of these reports have occurred in patients HUMIRA is indicated for reducing signs and symptoms and inducing may be negative in some patients with active infection. Consider appropriate concomitantly receiving other medications that suppress the immune system, and maintaining clinical remission in adult patients with moderately to empiric antifungal therapy, taking into account both the risk for severe which may also contribute to HBV reactivation. Evaluate patients at risk for severely active Crohn’s disease who have had an inadequate response to fungal infection and the risks of antifungal therapy, while a diagnostic HBV infection for prior evidence of HBV infection before initiating TNF blocker conventional therapy. HUMIRA is indicated for reducing signs and symptoms workup is being performed. To aid in the management of such patients, therapy. Exercise caution in prescribing TNF blockers for patients identified and inducing clinical remission in these patients if they have also lost consider consultation with a physician with expertise in the diagnosis and as carriers of HBV. Adequate data are not available on the safety or efficacy of response to or are intolerant to infliximab. treatment of invasive fungal infections. treating patients who are carriers of HBV with anti-viral therapy in conjunction Pediatric Crohn’s Disease Malignancies with TNF blocker therapy to prevent HBV reactivation. In patients who develop HUMIRA is indicated for reducing signs and symptoms and inducing and Consider the risks and benefits of TNF-blocker treatment including HUMIRA HBV reactivation, stop HUMIRA and initiate effective anti-viral therapy with maintaining clinical remission in pediatric patients 6 years of age and prior to initiating therapy in patients with a known malignancy other appropriate supportive treatment. The safety of resuming TNF blocker therapy older with moderately to severely active Crohn’s disease who have had than a successfully treated non-melanoma skin cancer (NMSC) or when after HBV reactivation is controlled is not known. an inadequate response to corticosteroids or immunomodulators such as considering continuing a TNF blocker in patients who develop a malignancy. Neurologic Reactions azathioprine, 6-mercaptopurine, or methotrexate. Malignancies in Adults Use of TNF blocking agents, including HUMIRA, has been associated with Ulcerative Colitis In the controlled portions of clinical trials of some TNF-blockers, including rare cases of new onset or exacerbation of clinical symptoms and/or HUMIRA is indicated for inducing and sustaining clinical remission in adult HUMIRA, more cases of malignancies have been observed among TNF- radiographic evidence of central nervous system demyelinating disease, patients with moderately to severely active ulcerative colitis who have had blocker-treated adult patients compared to control-treated adult patients. including multiple sclerosis (MS) and optic neuritis, and peripheral an inadequate response to immunosuppressants such as corticosteroids, During the controlled portions of 39 global HUMIRA clinical trials in adult demyelinating disease, including Guillain-Barré syndrome. Exercise azathioprine or 6-mercaptopurine (6-MP). The effectiveness of HUMIRA patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing caution in considering the use of HUMIRA in patients with preexisting or has not been established in patients who have lost response to or were spondylitis (AS), Crohn’s disease (CD), ulcerative colitis (UC) plaque psoriasis recent-onset central or peripheral nervous system demyelinating disorders; intolerant to TNF blockers. (Ps), hidradenitis suppurativa (HS), and uveitis (UV) malignancies, other than discontinuation of HUMIRA should be considered if any of these disorders develop. There is a known association between intermediate uveitis and Plaque Psoriasis non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.7 (0.48, 1.03) per 100 patient-years central demyelinating disorders. HUMIRA is indicated for the treatment of adult patients with moderate to among 7973 HUMIRA-treated patients versus a rate of 0.7 (0.41, 1.17) per Hematological Reactions severe chronic plaque psoriasis who are candidates for systemic therapy 100 patient-years among 4848 control-treated patients (median duration Rare reports of pancytopenia including aplastic anemia have been or phototherapy, and when other systemic therapies are medically less of treatment of 4 months for HUMIRA-treated patients and 4 months for appropriate. HUMIRA should only be administered to patients who will be reported with TNF blocking agents. Adverse reactions of the hematologic [see control-treated patients). In 52 global controlled and uncontrolled clinical system, including medically significant cytopenia (e.g., thrombocytopenia, closely monitored and have regular follow-up visits with a physician trials of HUMIRA in adult patients with RA, PsA, AS, CD, UC, Ps, HS and Boxed Warning and Warnings and Precautions]. leukopenia) have been infrequently reported with HUMIRA. The causal UV, the most frequently observed malignancies, other than lymphoma and relationship of these reports to HUMIRA remains unclear. Advise all patients Hidradenitis Suppurativa NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies to seek immediate medical attention if they develop signs and symptoms HUMIRA is indicated for the treatment of moderate to severe hidradenitis in HUMIRA-treated patients in the controlled and uncontrolled portions of the suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, suppurativa. studies were similar in type and number to what would be expected in the bleeding, pallor) while on HUMIRA. Consider discontinuation of HUMIRA general U.S. population according to the SEER database (adjusted for age, therapy in patients with confirmed significant hematologic abnormalities. gender, and race).

RRP0816_AbbvieP0816_Abbvie PPII 11.indd.indd 1 77/21/16/21/16 3:553:55 PMPM Use with Anakinra In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF- or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg trials and in long-term follow up studies for up to 36 months duration. blocker, was associated with a greater proportion of serious infections and every other week) in adult patients with CD with a control period duration The population had a mean age of 54 years, 77% were female, 91% were neutropenia and no added benefit compared with the TNF-blocker alone in ranging from 4 to 52 weeks, ALT elevations ≥ 3 x ULN occurred in 0.9% of Caucasian and had moderately to severely active rheumatoid arthritis. Most patients with RA. Therefore, the combination of HUMIRA and anakinra is not HUMIRA-treated patients and 0.9% of control-treated patients. In the Phase patients received 40 mg HUMIRA every other week. recommended [see Drug Interactions]. 3 trial of HUMIRA in pediatric patients with Crohn’s disease which evaluated Table 1 summarizes reactions reported at a rate of at least 5% in patients Heart Failure efficacy and safety of two body weight based maintenance dose regimens treated with HUMIRA 40 mg every other week compared to placebo and with following body weight based induction therapy up to 52 weeks of treatment, Cases of worsening congestive heart failure (CHF) and new onset CHF have an incidence higher than placebo. In Study RA-III, the types and frequencies ALT elevations ≥ 3 x ULN occurred in 2.6% (5/192) of patients, of whom 4 of adverse reactions in the second year open-label extension were similar to been reported with TNF blockers. Cases of worsening CHF have also been were receiving concomitant immunosuppressants at baseline; none of these observed with HUMIRA. Exercise caution when using HUMIRA in patients those observed in the one-year double-blind portion. patients discontinued due to abnormalities in ALT tests. In controlled Phase Table 1. Adverse Reactions Reported by ≥5% of Patients Treated who have heart failure and monitor them carefully. 3 trials of HUMIRA (initial doses of 160 mg and 80 mg on Days 1 and 15 Autoimmunity with HUMIRA During Placebo-Controlled Period of Pooled RA respectively, followed by 40 mg every other week) in patients with UC with Studies (Studies RA-I, RA-II, RA-III, and RA-IV) Treatment with HUMIRA may result in the formation of autoantibodies and, control period duration ranging from 1 to 52 weeks, ALT elevations rarely, in the development of a lupus-like syndrome. If a patient develops ≥3 x ULN occurred in 1.5% of HUMIRA-treated patients and 1.0% of control- HUMIRA Placebo symptoms suggestive of a lupus-like syndrome following treatment with treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 40 mg subcutaneous HUMIRA, discontinue treatment [see Adverse Reactions]. 80 mg then 40 mg every other week) in patients with Ps with control period Every Other Week Immunizations duration ranging from 12 to 24 weeks, ALT elevations ≥ 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients. In Adverse Reaction (Preferred Term) (N=705) (N=690) In a placebo-controlled clinical trial of patients with RA, no difference was controlled trials of HUMIRA (initial doses of 160 mg at Week 0 and 80 mg at detected in anti-pneumococcal antibody response between HUMIRA and Week 2, followed by 40 mg every week starting at Week 4), in subjects with Respiratory placebo treatment groups when the pneumococcal polysaccharide vaccine HS with a control period duration ranging from 12 to 16 weeks, ALT elevations Upper respiratory infection 17% 13% and influenza vaccine were administered concurrently with HUMIRA. ≥ 3 x ULN occurred in 0.3% of HUMIRA-treated subjects and 0.6% of control- Patients on HUMIRA may receive concurrent vaccinations, except for live treated subjects. In controlled trials of HUMIRA (initial doses of 80 mg at Week Sinusitis 11% 9% vaccines. No data are available on the secondary transmission of infection 0 followed by 40 mg every other week starting at Week 1) in patients with Flu syndrome 7% 6% by live vaccines in patients receiving HUMIRA. uveitis with an exposure of 165.4 PYs and 119.8 PYs in HUMIRA-treated and It is recommended that pediatric patients, if possible, be brought up to date control-treated patients, respectively, ALT elevations ≥ 3 x ULN occurred in Gastrointestinal with all immunizations in agreement with current immunization guidelines 2.4% of HUMIRA-treated patients and 2.4% of control-treated patients. Nausea 9% 8% prior to initiating HUMIRA therapy. Patients on HUMIRA may receive Immunogenicity concurrent vaccinations, except for live vaccines. Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time Abdominal pain 7% 4% The safety of administering live or live-attenuated vaccines in infants points for antibodies to adalimumab during the 6- to 12-month period. Laboratory Tests* exposed to HUMIRA in utero is unknown. Risks and benefits should be [see Approximately 5% (58 of 1062) of adult RA patients receiving HUMIRA considered prior to vaccinating (live or live-attenuated) exposed infants developed low-titer antibodies to adalimumab at least once during Laboratory test abnormal 8% 7% Use in Specific Populations]. in vitro treatment, which were neutralizing . Patients treated with concomitant Hypercholesterolemia 6% 4% Use with Abatacept methotrexate (MTX) had a lower rate of antibody development than patients In controlled trials, the concurrent administration of TNF-blockers and on HUMIRA monotherapy (1% versus 12%). No apparent correlation of Hyperlipidemia 7% 5% antibody development to adverse reactions was observed. With monotherapy, abatacept was associated with a greater proportion of serious infections than Hematuria 5% 4% the use of a TNF-blocker alone; the combination therapy, compared to the patients receiving every other week dosing may develop antibodies more use of a TNF-blocker alone, has not demonstrated improved clinical benefit frequently than those receiving weekly dosing. In patients receiving the Alkaline phosphatase increased 5% 3% in the treatment of RA. Therefore, the combination of abatacept with TNF- recommended dosage of 40 mg every other week as monotherapy, the blockers including HUMIRA is not recommended [see Drug Interactions]. ACR 20 response was lower among antibody-positive patients than among Other ADVERSE REACTIONS antibody-negative patients. The long-term immunogenicity of HUMIRA is Headache 12% 8% unknown. The most serious adverse reactions described elsewhere in the labeling Rash 12% 6% include the following: In patients with polyarticular JIA who were 4 to 17 years of age, adalimumab [see Warnings and Precautions] antibodies were identified in 16% of HUMIRA-treated patients. In patients Accidental injury 10% 8% • Serious Infections receiving concomitant MTX, the incidence was 6% compared to 26% with • Malignancies [see Warnings and Precautions] HUMIRA monotherapy. In patients with polyarticular JIA who were 2 to <4 Injection site reaction ** 8% 1% Clinical Trials Experience years of age or 4 years of age and older weighing <15 kg, adalimumab Back pain 6% 4% The most common adverse reaction with HUMIRA was injection site antibodies were identified in 7% (1 of 15) of HUMIRA-treated patients, and reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA the one patient was receiving concomitant MTX. Urinary tract infection 8% 5% developed injection site reactions (erythema and/or itching, hemorrhage, In patients with AS, the rate of development of antibodies to adalimumab in Hypertension 5% 3% pain or swelling), compared to 14% of patients receiving placebo. Most HUMIRA-treated patients was comparable to patients with RA. injection site reactions were described as mild and generally did not In patients with PsA, the rate of antibody development in patients receiving * Laboratory test abnormalities were reported as adverse reactions in necessitate drug discontinuation. HUMIRA monotherapy was comparable to patients with RA; however, in European trials The proportion of patients who discontinued treatment due to adverse patients receiving concomitant MTX the rate was 7% compared to 1% in RA. ** Does not include injection site erythema, itching, hemorrhage, pain reactions during the double-blind, placebo-controlled portion of studies In adult patients with CD, the rate of antibody development was 3%. or swelling in patients with RA (i.e., Studies RA-I, RA-II, RA-III and RA-IV) was 7% for In pediatric patients with Crohn’s disease, the rate of antibody development Juvenile Idiopathic Arthritis Clinical Studies patients taking HUMIRA and 4% for placebo-treated patients. The most in patients receiving HUMIRA was 3%. However, due to the limitation of the common adverse reactions leading to discontinuation of HUMIRA in these RA assay conditions, antibodies to adalimumab could be detected only when In general, the adverse reactions in the HUMIRA-treated patients in the studies were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%). serum adalimumab levels were < 2 mcg/mL. Among the patients whose polyarticular juvenile idiopathic arthritis (JIA) trials (Studies JIA-I and JIA-II) Infections were similar in frequency and type to those seen in adult patients [see serum adalimumab levels were < 2 mcg/mL (approximately 32% of total Warnings and Precautions and Adverse Reactions] In the controlled portions of the 39 global HUMIRA clinical trials in adult patients studied), the immunogenicity rate was 10%. . Important findings and differences from adults are discussed in the following paragraphs. patients with RA, PsA, AS, CD, UC, HS and UV, the rate of serious infections In patients with moderately to severely active UC, the rate of antibody was 4.3 per 100 patient-years in 7973 HUMIRA-treated patients versus a development in patients receiving HUMIRA was 5%. However, due to the In Study JIA-I, HUMIRA was studied in 171 patients who were 4 to 17 rate of 2.9 per 100 patient-years in 4848 control-treated patients. Serious limitation of the assay conditions, antibodies to adalimumab could be years of age, with polyarticular JIA. Severe adverse reactions reported infections observed included pneumonia, septic arthritis, prosthetic detected only when serum adalimumab levels were < 2 mcg/mL. Among the in the study included neutropenia, streptococcal pharyngitis, increased and post-surgical infections, erysipelas, cellulitis, diverticulitis, and patients whose serum adalimumab levels were < 2 mcg/mL (approximately aminotransferases, herpes zoster, myositis, metrorrhagia, and appendicitis. pyelonephritis [see Warnings and Precautions]. 25% of total patients studied), the immunogenicity rate was 20.7%. Serious infections were observed in 4% of patients within approximately 2 Tuberculosis and Opportunistic Infections years of initiation of treatment with HUMIRA and included cases of herpes In patients with Ps, the rate of antibody development with HUMIRA simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. In 52 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD, monotherapy was 8%. However, due to the limitation of the assay UC, Ps, HS and UV that included 24,605 HUMIRA-treated patients, the rate conditions, antibodies to adalimumab could be detected only when serum In Study JIA-I, 45% of patients experienced an infection while receiving of reported active tuberculosis was 0.20 per 100 patient-years and the rate adalimumab levels were < 2 mcg/mL. Among the patients whose serum HUMIRA with or without concomitant MTX in the first 16 weeks of of positive PPD conversion was 0.09 per 100 patient-years. In a subgroup adalimumab levels were < 2 mcg/mL (approximately 40% of total patients treatment. The types of infections reported in HUMIRA-treated patients of 10,113 U.S. and Canadian HUMIRA-treated patients, the rate of reported studied), the immunogenicity rate was 20.7%. In Ps patients who were on were generally similar to those commonly seen in polyarticular JIA patients active TB was 0.05 per 100 patient-years and the rate of positive PPD HUMIRA monotherapy and subsequently withdrawn from the treatment, the who are not treated with TNF blockers. Upon initiation of treatment, the conversion was 0.07 per 100 patient-years. These trials included reports rate of antibodies to adalimumab after retreatment was similar to the rate most common adverse reactions occurring in this patient population of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases observed prior to withdrawal. treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in occurred within the first eight months after initiation of therapy and may In subjects with moderate to severe HS, the rate of anti-adalimumab reflect recrudescence of latent disease. In these global clinical trials, cases patients receiving HUMIRA was granuloma annulare which did not lead to antibody development in subjects treated with HUMIRA was 6.5%. discontinuation of HUMIRA treatment. of serious opportunistic infections have been reported at an overall rate of However, because of the limitation of the assay conditions, antibodies 0.05 per 100 patient-years. Some cases of serious opportunistic infections to adalimumab could be detected only when serum adalimumab levels In the first 48 weeks of treatment in Study JIA-I, non-serious hypersensitivity and TB have been fatal [see Warnings and Precautions]. were < 2 mcg/mL. Among subjects who stopped HUMIRA treatment for reactions were seen in approximately 6% of patients and included primarily Autoantibodies up to 24 weeks and in whom adalimumab serum levels subsequently localized allergic hypersensitivity reactions and allergic rash. In the rheumatoid arthritis controlled trials, 12% of patients treated with declined to < 2 mcg/mL (approximately 22% of total subjects studied), the In Study JIA-I, 10% of patients treated with HUMIRA who had negative HUMIRA and 7% of placebo-treated patients that had negative baseline ANA immunogenicity rate was 28%. baseline anti-dsDNA antibodies developed positive titers after 48 weeks of titers developed positive titers at week 24. Two patients out of 3046 treated In patients with non-infectious uveitis, anti-adalimumab antibodies were treatment. No patient developed clinical signs of autoimmunity during the with HUMIRA developed clinical signs suggestive of new-onset lupus-like identified in 4.8% (12/249) of patients treated with adalimumab. However, clinical trial. syndrome. The patients improved following discontinuation of therapy. No due to the limitation of the assay conditions, antibodies to adalimumab Approximately 15% of patients treated with HUMIRA developed mild- patients developed lupus nephritis or central nervous system symptoms. could be detected only when serum adalimumab levels were < 2 mcg/mL. to-moderate elevations of creatine phosphokinase (CPK) in Study JIA-I. The impact of long-term treatment with HUMIRA on the development of Among the patients whose serum adalimumab levels were < 2 mcg/mL Elevations exceeding 5 times the upper limit of normal were observed in autoimmune diseases is unknown. (approximately 23% of total patients studied), the immunogenicity rate was several patients. CPK levels decreased or returned to normal in all patients. Liver Enzyme Elevations 21.1%. Using an assay which could measure an anti-adalimumab antibody Most patients were able to continue HUMIRA without interruption. titer in all patients, titers were measured in 39.8% (99/249) of non-infectious There have been reports of severe hepatic reactions including acute liver In Study JIA-II, HUMIRA was studied in 32 patients who were 2 to <4 years uveitis patients treated with adalimumab. No correlation of antibody of age or 4 years of age and older weighing <15 kg with polyarticular JIA. failure in patients receiving TNF-blockers. In controlled Phase 3 trials of development to safety or efficacy outcomes was observed. HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with The safety profile for this patient population was similar to the safety profile control period duration ranging from 4 to 104 weeks, ALT elevations ≥ 3 The data reflect the percentage of patients whose test results were seen in patients 4 to 17 years of age with polyarticular JIA. x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control- considered positive for antibodies to adalimumab or titers, and are highly In Study JIA-II, 78% of patients experienced an infection while receiving treated patients. Since many of these patients in these trials were also dependent on the assay. The observed incidence of antibody (including HUMIRA. These included nasopharyngitis, bronchitis, upper respiratory tract taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), neutralizing antibody) positivity in an assay is highly dependent on several infection, otitis media, and were mostly mild to moderate in severity. Serious the relationship between HUMIRA and the liver enzyme elevations is not factors including assay sensitivity and specificity, assay methodology, infections were observed in 9% of patients receiving HUMIRA in the study clear. In a controlled Phase 3 trial of HUMIRA in patients with polyarticular sample handling, timing of sample collection, concomitant medications, and included dental caries, rotavirus gastroenteritis, and varicella. JIA who were 4 to 17 years, ALT elevations ≥ 3 x ULN occurred in 4.4% and underlying disease. For these reasons, comparison of the incidence of In Study JIA-II, non-serious allergic reactions were observed in 6% of of HUMIRA-treated patients and 1.5% of control-treated patients (ALT antibodies to adalimumab with the incidence of antibodies to other products patients and included intermittent urticaria and rash, which were all mild more common than AST); liver enzyme test elevations were more frequent may be misleading. in severity. Other Adverse Reactions among those treated with the combination of HUMIRA and MTX than those Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies treated with HUMIRA alone. In general, these elevations did not lead to Rheumatoid Arthritis Clinical Studies HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two discontinuation of HUMIRA treatment. No ALT elevations ≥ 3 x ULN occurred The data described below reflect exposure to HUMIRA in 2468 patients, placebo-controlled trials and in an open label study and in 393 patients with in the open-label study of HUMIRA in patients with polyarticular JIA who including 2073 exposed for 6 months, 1497 exposed for greater than one ankylosing spondylitis (AS) in two placebo-controlled studies. The safety were 2 to <4 years. year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, profile for patients with PsA and AS treated with HUMIRA 40 mg every other

RRP0816_AbbvieP0816_Abbvie PPI2.inddI2.indd 1 77/21/16/21/16 4:024:02 PMPM week was similar to the safety profile seen in patients with RA, HUMIRA with other biologic DMARDS (e.g., anakinra and abatacept) or other TNF TNF-blockers including HUMIRA [see Boxed Warning and Warnings and Studies RA-I through IV. blockers is not recommended based upon the possible increased risk for Precautions]. Adult Crohn’s Disease Clinical Studies infections and other potential pharmacological interactions. Juvenile Idiopathic Arthritis HUMIRA has been studied in 1478 adult patients with Crohn’s disease (CD) Live Vaccines In Study JIA-I, HUMIRA was shown to reduce signs and symptoms of active in four placebo-controlled and two open-label extension studies. The safety Avoid the use of live vaccines with HUMIRA [see Warnings and Precautions]. polyarticular JIA in patients 4 to 17 years of age [see Clinical Studies]. In profile for adult patients with CD treated with HUMIRA was similar to the Cytochrome P450 Substrates Study JIA-II, the safety profile for patients 2 to <4 years of age was similar safety profile seen in patients with RA. to the safety profile for patients 4 to 17 years of age with polyarticular JIA The formation of CYP450 enzymes may be suppressed by increased levels [see Adverse Reactions] Pediatric Crohn’s Disease Clinical Studies of cytokines (e.g., TNFα, IL-6) during chronic inflammation. It is possible . HUMIRA has not been studied in patients with HUMIRA has been studied in 192 pediatric patients with Crohn’s disease in for a molecule that antagonizes cytokine activity, such as adalimumab, polyarticular JIA less than 2 years of age or in patients with a weight below one double-blind study (Study PCD-I) and one open-label extension study. The to influence the formation of CYP450 enzymes. Upon initiation or 10 kg. safety profile for pediatric patients with Crohn’s disease treated with HUMIRA discontinuation of HUMIRA in patients being treated with CYP450 substrates The safety of HUMIRA in patients in the polyarticular JIA trials was generally was similar to the safety profile seen in adult patients with Crohn’s disease. with a narrow therapeutic index, monitoring of the effect (e.g., warfarin) or similar to that observed in adults with certain exceptions [see Adverse Reactions] During the 4 week open label induction phase of Study PCD-I, the most drug concentration (e.g., cyclosporine or theophylline) is recommended and . common adverse reactions occurring in the pediatric population treated the individual dose of the drug product may be adjusted as needed. Pediatric Crohn’s Disease with HUMIRA were injection site pain and injection site reaction (6% and USE IN SPECIFIC POPULATIONS The safety and effectiveness of HUMIRA for reducing signs and 5%, respectively). Pregnancy symptoms and inducing and maintaining clinical remission have been A total of 67% of children experienced an infection while receiving HUMIRA Limited clinical data are available from the Humira Pregnancy Registry. established in pediatric patients 6 years of age and older with moderately in Study PCD-I. These included upper respiratory tract infection and Excluding lost-to-follow-up, data from the registry reports a rate of 5.6% for to severely active Crohn’s disease who have had an inadequate nasopharyngitis. major birth defects with first trimester use of adalimumab in pregnant women response to corticosteroids or immunomodulators such as azathioprine, A total of 5% of children experienced a serious infection while receiving with rheumatoid arthritis (RA), and a rate of 7.8% and 5.5% for major birth 6-mercaptopurine, or methotrexate. Use of HUMIRA in this age group HUMIRA in Study PCD-I. These included viral infection, device related sepsis defects in the disease-matched and non-diseased comparison groups [see is supported by evidence from adequate and well-controlled studies of (catheter), gastroenteritis, H1N1 influenza, and disseminated histoplasmosis. Data]. Adalimumab is actively transferred across the placenta during the HUMIRA in adults with additional data from a randomized, double-blind, 52-week clinical study of two dose levels of HUMIRA in 192 pediatric In Study PCD-I, allergic reactions were observed in 5% of children which third trimester of pregnancy and may affect immune response in the in-utero exposed infant [see Clinical Considerations]. In an embryo-fetal perinatal patients (6 to 17 years of age) with moderately to severely active Crohn’s were all non-serious and were primarily localized reactions. disease [see Clinical Studies]. The safety and effectiveness of HUMIRA has Ulcerative Colitis Clinical Studies development study conducted in cynomolgus monkeys, no fetal harm or malformations were observed with intravenous administration of adalimumab not been established in pediatric patients with Crohn’s disease less than HUMIRA has been studied in 1010 patients with ulcerative colitis (UC) in two during organogenesis and later in gestation, at doses that produced exposures 6 years of age. placebo-controlled studies and one open-label extension study. The safety up to approximately 373 times the maximum recommended human dose Geriatric Use profile for patients with UC treated with HUMIRA was similar to the safety (MRHD) of 40 mg subcutaneous without methotrexate [see Data]. A total of 519 RA patients 65 years of age and older, including 107 patients profile seen in patients with RA. The estimated background risk of major birth defects and miscarriage for 75 years of age and older, received HUMIRA in clinical studies RA-I through Plaque Psoriasis Clinical Studies the indicated populations is unknown. In the U.S. general population, the IV. No overall difference in effectiveness was observed between these HUMIRA has been studied in 1696 subjects with plaque psoriasis (Ps) in estimated background risk of major birth defects and miscarriage in clinically patients and younger patients. The frequency of serious infection and placebo-controlled and open-label extension studies. The safety profile for recognized pregnancies is 2-4% and miscarriage is 15-20%, respectively. malignancy among HUMIRA treated patients over 65 years of age was subjects with Ps treated with HUMIRA was similar to the safety profile seen Clinical Considerations higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population, use in subjects with RA with the following exceptions. In the placebo-controlled Fetal/Neonatal adverse reactions portions of the clinical trials in Ps subjects, HUMIRA-treated subjects had a caution when treating the elderly. higher incidence of arthralgia when compared to controls (3% vs. 1%). Monoclonal antibodies are increasingly transported across the placenta OVERDOSAGE Hidradenitis Suppurativa Clinical Studies as pregnancy progresses, with the largest amount transferred during the third trimester [see Data]. Risks and benefits should be considered prior to Doses up to 10 mg/kg have been administered to patients in clinical trials HUMIRA has been studied in 727 subjects with hidradenitis suppurativa (HS) administering live or live-attenuated vaccines to infants exposed to HUMIRA without evidence of dose-limiting toxicities. In case of overdosage, it is in three placebo-controlled studies and one open-label extension study. in utero [see Use in Specific Populations]. recommended that the patient be monitored for any signs or symptoms The safety profile for subjects with HS treated with HUMIRA weekly was of adverse reactions or effects and appropriate symptomatic treatment consistent with the known safety profile of HUMIRA. Data instituted immediately. Human Data Flare of HS, defined as ≥25% increase from baseline in abscesses and NONCLINICAL TOXICOLOGY inflammatory nodule counts and with a minimum of 2 additional lesions, In a prospective cohort pregnancy exposure registry conducted in the Carcinogenesis, Mutagenesis, Impairment of Fertility was documented in 22 (22%) of the 100 subjects who were withdrawn from U.S. and Canada between 2004 and 2013, 74 women with RA treated with adalimumab at least during the first trimester, 80 women with RA Long-term animal studies of HUMIRA have not been conducted to evaluate HUMIRA treatment following the primary efficacy timepoint in two studies. the carcinogenic potential or its effect on fertility. Uveitis Clinical Studies not treated with adalimumab and 218 women without RA (non-diseased) were enrolled. Excluding lost-to-follow-up, the rate of major defects in the PATIENT COUNSELING INFORMATION HUMIRA has been studied in 464 patients with uveitis (UV) in placebo- adalimumab-exposed pregnancies (N=72), disease-matched (N=77), and Patient Counseling controlled and open-label extension studies. The safety profile for patients non-diseased comparison groups (N=201) was 5.6%, 7.8% and 5.5%, Provide the HUMIRA “Medication Guide” to patients or their caregivers, and with UV treated with HUMIRA was similar to the safety profile seen in respectively. However, this study cannot definitely establish the absence of patients with RA. provide them an opportunity to read it and ask questions prior to initiation any risk because of methodological limitations, including small sample size of therapy and prior to each time the prescription is renewed. If patients Postmarketing Experience and non-randomized study design. Data from the Crohn’s disease portion of develop signs and symptoms of infection, instruct them to seek medical The following adverse reactions have been identified during post-approval the study is in the follow-up phase and the analysis is ongoing. evaluation immediately. use of HUMIRA. Because these reactions are reported voluntarily from a In an independent clinical study conducted in ten pregnant women Advise patients of the potential benefits and risks of HUMIRA. population of uncertain size, it is not always possible to reliably estimate with inflammatory bowel disease treated with HUMIRA, adalimumab • Infections their frequency or establish a causal relationship to HUMIRA exposure. concentrations were measured in maternal serum as well as in cord Gastrointestinal disorders: Diverticulitis, large bowel perforations including blood (n=10) and infant serum (n=8) on the day of birth. The last dose of Inform patients that HUMIRA may lower the ability of their immune perforations associated with diverticulitis and appendiceal perforations HUMIRA was given between 1 and 56 days prior to delivery. Adalimumab system to fight infections. Instruct patients of the importance of associated with appendicitis, pancreatitis concentrations were 0.16-19.7 μg/mL in cord blood, 4.28-17.7 μg/mL in contacting their doctor if they develop any symptoms of infection, infant serum, and 0-16.1 μg/mL in maternal serum. In all but one case, including tuberculosis, invasive fungal infections, and reactivation of General disorders and administration site conditions: Pyrexia hepatitis B virus infections. Hepato-biliary disorders: the cord blood level of adalimumab was higher than the maternal serum Liver failure, hepatitis level, suggesting adalimumab actively crosses the placenta. In addition, • Malignancies Immune system disorders: Sarcoidosis one infant had serum levels at each of the following: 6 weeks (1.94 μg/mL), Counsel patients about the risk of malignancies while receiving HUMIRA. Neoplasms benign, malignant and unspecified (including cysts and polyps): 7 weeks (1.31 μg/mL), 8 weeks (0.93 μg/mL), and 11 weeks (0.53 μg/mL), • Allergic Reactions Merkel Cell Carcinoma (neuroendocrine carcinoma of the skin) suggesting adalimumab can be detected in the serum of infants exposed in utero for at least 3 months from birth. Advise patients to seek immediate medical attention if they experience Nervous system disorders: Demyelinating disorders (e.g., optic neuritis, any symptoms of severe allergic reactions. Advise latex-sensitive patients Guillain-Barré syndrome), cerebrovascular accident Lactation that the needle cap of the prefilled syringe contains latex. Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis, Risk Summary • Other Medical Conditions pulmonary embolism Limited data from case reports in the published literature describe the Advise patients to report any signs of new or worsening medical Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema presence of adalimumab in human milk at infant doses of 0.1% to 1% conditions such as congestive heart failure, neurological disease, multiforme, new or worsening psoriasis (all sub-types including pustular and of the maternal serum level. There are no reports of adverse effects of autoimmune disorders, or cytopenias. Advise patients to report any palmoplantar), alopecia adalimumab on the breastfed infant and no effects on milk production. The symptoms suggestive of a cytopenia such as bruising, bleeding, or Vascular disorders: Systemic vasculitis, deep vein thrombosis developmental and health benefits of breastfeeding should be considered persistent fever. along with the mother’s clinical need for HUMIRA and any potential adverse DRUG INTERACTIONS effects on the breastfed child from HUMIRA or from the underlying maternal Methotrexate condition. AbbVie Inc. HUMIRA has been studied in rheumatoid arthritis (RA) patients taking Pediatric Use North Chicago, IL 60064, U.S.A. concomitant methotrexate (MTX). Although MTX reduced the apparent Safety and efficacy of HUMIRA in pediatric patients for uses other than US License Number 1889 adalimumab clearance, the data do not suggest the need for dose polyarticular juvenile idiopathic arthritis (JIA) and pediatric Crohn’s adjustment of either HUMIRA or MTX. α disease have not been established. Due to its inhibition of TNF , HUMIRA Ref: 03-B374 Revised July 2016 Biological Products administered during pregnancy could affect immune response in the In clinical studies in patients with RA, an increased risk of serious infections in utero-exposed newborn and infant. Data from eight infants exposed to has been seen with the combination of TNF blockers with anakinra or HUMIRA in utero suggest adalimumab crosses the placenta [see Use in 64C-1865519 MASTER abatacept, with no added benefit; therefore, use of HUMIRA with abatacept Specific Populations]. The clinical significance of elevated adalimumab levels or anakinra is not recommended in patients with RA [see Warnings and in infants is unknown. The safety of administering live or live-attenuated Precautions] vaccines in exposed infants is unknown. Risks and benefits should be . A higher rate of serious infections has also been observed 64C-1859319 in patients with RA treated with rituximab who received subsequent considered prior to vaccinating (live or live-attenuated) exposed infants. treatment with a TNF blocker. There is insufficient information regarding the Post-marketing cases of lymphoma, including hepatosplenic T-cell concomitant use of HUMIRA and other biologic products for the treatment of lymphoma and other malignancies, some fatal, have been reported among RA, PsA, AS, CD, UC, Ps, HS and UV. Concomitant administration of HUMIRA children, adolescents, and young adults who received treatment with

RRO0816_AbbvieO0816_Abbvie PPI3.inddI3.indd 1 77/21/16/21/16 4:064:06 PMPM ENRICH YOUR PRACTICE

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2015_rp_tsrad.indd 90 11/12/15 11:42 AM Dry Eye REVIEW Cover Focus Managing Dry-eye Patients, Step by Step Christopher Kent, Senior Editor

Surgeons offer ith our understanding of says. “You can have a patient with a the nature and causes of dry lot of symptoms but minimal fi ndings, advice on making Weye growing, and options for or a patient with a lot of fi ndings but diagnosis and treatment expanding minimal symptoms. Second, there’s sense of today’s every year, effectively managing dry- a misconception among many oph- eye patients is becoming increasingly thalmologists that dry-eye disease is diagnostic and complex. Some doctors still treat all simply a quantitative problem—not treatment options. dry-eye patients with the same basic enough tears. In reality, it may be a approach, but others are choosing to tear-quality problem as well. An ab- take the bull by the horns and up their normality in any part of the tear fi lm, game, helping more of their patients including the mucin layer and the oily while also improving outcomes in ar- layer, can lead to dry eye.” eas such as refractive surgery. Esen Akpek, MD, a professor of In response to this changing land- ophthalmology and rheumatology at scape, doctors have attempted to Johns Hopkins University School of create algorithms to help clinicians Medicine and director of the Ocular navigate the management process. Surface Disease and Dry Eye Clinic The fi rst algorithms, such as the In- at the Wilmer Eye Institute, notes that ternational Task Force Guidelines for general ophthalmologists often don’t Dry Eye, were created about 10 years appreciate the value of treating dry ago; however, many clinicians still are eye. “Clinicians may assume that be- not using them. Today, several new cause dry eye is not blinding, it has no algorithms are in the works. implications for a patient’s vision,” she Mark S. Milner, MD, FACS, an as- says. “In fact, any irregularity in the sociate clinical professor at Yale Uni- tear fi lm or epithelium can decrease versity School of Medicine and a part- quality of life because it blurs vision.” ner and cornea specialist at the Eye Here, five doctors with extensive Center of Southern Connecticut, is experience treating dry eye share their participating in several dry-eye stud- thoughts on diagnosis, treatment and ies and will soon be publishing his the issues surrounding the creation of own dry-eye management algorithm. a dry-eye management algorithm. He points out that dry-eye disease can be clinically challenging, for two Conducting the Exam reasons. “First of all, dry-eye signs and symptoms can be disparate,” he “Dry eye is a complex topic and an

28 | Review of Ophthalmology | November 2016 This article has no commercial sponsorship.

0028_rp1116_F1.indd28_rp1116_F1.indd 2828 110/20/160/20/16 3:233:23 PMPM Karl Stonecipher, MD inexact science,” notes Christopher tify ocular surface disease. If either of J. Rapuano, MD, director of the cor- the answers is positive, we proceed to nea service at Wills Eye Hospital and perform some basic tests. One survey professor of ophthalmology at Sidney found that about two-thirds of patients Kimmel Medical College at Thomas had ocular surface complaints, even Jefferson University in Philadelphia. though it wasn’t the main reason for “Diagnosis is largely based on the clin- the visit.” ical exam, meaning on the symptoms • Ocular surface staining. Ev- and signs. Tests can be helpful in some eryone agrees that this is an essential cases, but not all.” Tear breakup time testing reveals rapid part of any dry-eye exam. “For surface (<7 seconds) tear dissolution. Francis Mah, MD, who special- staining I like to use lissamine green izes in cornea, external disease and and fl uorescein separately,” says Dr. refractive surgery at Scripps Health to look at tear-fi lm breakup time and Akpek. “I test conjunctiva and cornea System in San Diego, is a member corneal staining, and then lissamine separately, because Sjögren’s-related of the American Society of Cataract green dye to look at the conjunctiva. dry eye tends to be associated with and Refractive Surgery committee Finally, we do a Schirmer I test with- conjunctival staining; other types of that is developing a new algorithm for out anesthesia. dry eye such as blepharitis or evapo- dry-eye management. Dr. Mah says “In some patients we also measure rative-related dry eye tend to stain the his basic exam for a dry-eye patient is corneal sensitivity using the Cochet- cornea more. I follow the ocular sur- straightforward. “First, I look at the Bonnet esthesiometer,” he adds. “In face staining scoring published in 2010 tear-film meniscus to see what the certain chronic dry-eye conditions in the American Journal of Ophthal- tear lake looks like,” he says. “Then I such as shingles or herpes zoster, cor- mology by John Whitcher, MD,1 be- do conjunctival and corneal stainings, neal sensation is reduced. The lack of cause my main goal is to differentiate typically with fl uorescein. Lissamine nerve stimulus causes the eye to stop Sjögren’s from non-Sjögren’s dry eye green is much more sensitive for iden- producing tears.” and identify patients who will need tifying conjunctival staining, but it’s prescription eye drops.” become diffi cult to get the compound- Using the Tools • Infl ammaDry. Dr. Mah says he ed 1% lissamine green solution, and performs the Infl ammaDry test if the the strips are notoriously inconsistent. One factor adding confusion to patient is complaining about ocular Next, I do a tear-fi lm breakup test with dry-eye treatment today is the pro- surface symptoms, or if he gets a posi- the fl uorescein that’s still in the eye. liferation of point-of-service tests. “I tive result from the SPEED question- Finally, I press on the lower eyelid to think there are two reasons to do any naire. “If the Infl ammaDry is positive, assess the consistency of the meibum.” of these tests,” says Dr. Mah. “The then we follow it with the TearLab Stephen C. Pfl ugfelder, MD, a pro- fi rst is to make diagnosis and manage- osmolarity test,” he says. “If the In- fessor at Baylor College of Medicine ment a little bit easier for the clinician. fl ammaDry is negative, indicating that in Houston and director of the Ocu- The second reason is to reassure the there’s little or no infl ammation, I be- lar Surface Center at Baylor’s Cullen patient. It’s helpful to be able to show lieve the osmolarity test is still impor- Eye Institute, often sees complex cas- the patient solid evidence that we’ve tant as a follow-up. In my experience, es—patients who have been treated pinned down the problem, and that infl ammation will be present whether elsewhere without getting relief. “We our treatment may help resolve it.” the problem is blepharitis, meibomian have a standardized evaluation that Doctors share their thoughts about gland dysfunction or an aqueous defi - helps us identify problems that are the different tools that may come in ciency, or even if the problem is allergy less obvious,” he says. “Patients fi ll out handy when diagnosing the problem: or infection. So if there’s any problem two questionnaires: an ocular surface • Dry-eye questionnaire. Dr. at all, the Infl ammaDry should turn disease index questionnaire and a fi ve- Mah says if a patient is not complain- up positive. However, I would never question visual analog scale measuring ing of ocular surface symptoms, his dismiss a patient’s complaint because the frequency and severity of their technicians have the patient answer a of a negative test.” irritation. Then we perform anterior simple questionnaire. “We use a Stan- Dr. Rapuano points out that this segment OCT and corneal topography dard Patient Evaluation of Eye Dry- test doesn’t tell you what’s causing to look at the smoothness of the cor- ness, or SPEED questionnaire,” he the inflammation. “Nevertheless, it nea. Next, we do tear osmolarity, fol- explains. “It’s essentially two questions might lead you to use steroids or an lowed by instillation of fl uorescein dye that have been validated to help iden- anti-infl ammatory rather than punctal

November 2016 | reviewofophthalmology.com | 29

028_rp1116_F1.indd 29 10/20/16 3:23 PM Cover Dry Eye

REVIEW Focus Cynthia I. Tung, MD plugs, so it can be helpful,” he says. Dr. the Klyce indices that evaluate the Pfl ugfelder also notes that because it’s regularity of the rings reflected off a threshold test, it doesn’t provide a the cornea and provide a numerical number to help grade severity. score,” he says. “People with more • TearLab osmolarity test. “If the corneal epithelial disease from dry eye Infl ammaDry test reveals infl amma- have higher scores. The Klyce Surface tion, the TearLab tests can help iden- Regularity Index, or SRI, is valuable tify, at least to a small degree, whether Anterior segment OCT can be used to because it correlates with visual acuity or not it’s an evaporative problem,” measure tear meniscus height. Left: healthy and the severity of epithelial disease. says Dr. Mah. “The osmolarity test also tear production. Right: Low tear production. So if someone has dry eye and the SRI gives us something that we can estab- is high and their vision is reduced, that lish as a baseline, a number the patient icant dry eye has underlying Sjögren’s,” would tell me that epithelial disease is can follow.” adds Dr. Akpek. “Only a third of these probably the cause of it.” “There are multiple conflicting patients have a diagnosis.” • Schirmer test. Although this test studies regarding the effectiveness of • The Oculus keratograph. “The is not reimbursable, it’s easy to per- this test,” notes Dr. Akpek. “A normal keratograph does a noninvasive tear form, inexpensive and familiar to ev- test result does not guarantee that the breakup measurement and gives you eryone, so many doctors still perform eye has no dry-eye disease, but an ab- a map of the areas where the tear fi lm it. “This test can be helpful, especially normal result is a good indication that is breaking up more rapidly,” says Dr. if the result is very low or very high,” there’s a problem.” Pfl ugfelder. “It can also measure the says Dr. Rapuano. “If it’s in the middle Dr. Pfl ugfelder says he uses it on all inferior tear meniscus height, which is range, as many results are, it’s not that of his dry-eye patients, but has found it among the most valuable information helpful to me.” to be highly variable. “I don’t fi nd that you can collect to determine whether Dr. Akpek still likes to do the the test results correlate with disease patients have an aqueous-defi cient or Schirmer test, without anesthesia. “It’s severity or treatment response,” he suffi cient-tear dysfunction. However, a good way to differentiate Sjögren’s- says. “In my experience this measure- we measure the tear meniscus height related dry eye from non-Sjögren’s- ment is most useful when it’s high; if with anterior segment OCT.” (See ex- related dry eye,” she notes. Dr. Pfl ug- it’s high, something is wrong. But a ample, above.) felder also does the test, but says he ‘normal’ reading doesn’t tell me much.” • LipiView. “The LipiView instru- fi nds the anterior OCT measurement Dr. Rapuano agrees about the vari- ment helps us assess the quality of of the tear meniscus height to be a ability, but says the test can still be the meibomian glands, revealing trun- more valuable measure of tear volume. valuable. “We’ve found that the vari- cation of the glands and meibomian ability is much higher in dry-eye pa- gland dropout,” explains Dr. Milner. Dry-eye Treatment: The Basics tients than in normals,” he says. “If a “It also measures the lipid layer thick- patient scores 280 at one visit—which ness and can assess how many times Doctors largely seem to agree about sounds great—but they’re 320 at the the patient blinks, and how many of the fi rst treatment steps to take when next visit and then 340 and then 280 those were partial blinks.” confronted with a dry-eye patient. again, that indicates abnormality in the “Meibomian gland imaging can be “We usually start with over-the-coun- tear fi lm. Healthier eyes tend to pro- useful,” says Dr. Akpek. “It’s pretty ob- ter drops, mostly preservative-free,” duce similar readings at every visit. So vious when the glands are permanent- says Dr. Akpek. “We’ll add a prescrip- it’s important for clinicians to under- ly and irreversibly damaged. At this tion anti-infl ammatory eye drop after a stand that a one-time measurement point, however, I haven’t seen enough few months if the patient isn’t getting is not necessarily the best way to use evidence to establish a correlation be- relief, although we prescribe that right the test.” tween the imaging and the meibum away in patients with a known underly- • The Sjö test. Dr. Pflugfelder secretion quality or the ocular surface ing systemic infl ammatory condition.” believes the Sjö test has clear value. staining scoring.” “If the problem is primarily aque- “You’re identifying people with an au- • Topography. Dr. Pflugfelder ous defi ciency, our stepwise approach toimmune condition and the test may notes that some topographers provide is to start with preserved tears, then allow you to identify them earlier,” he a measure of the smoothness of the switch to tears without preservatives, says. corneal surface, which can be relevant then to tear gels and then tear oint- “It’s important to remember that to dry eye. “The topographer we use ments,” says Dr. Rapuano. “Typically one in 10 patients with clinically signif- has validated measurements called I use Restasis as the next step if the

30 | Review of Ophthalmology | November 2016

028_rp1116_F1.indd 30 10/20/16 3:23 PM RP0815_Lombart.indd 1 7/21/15 10:07 AM Cover Dry Eye

REVIEW Focus

Can a Dry-eye Algorithm Really Work?

“We don’t really have a reliable and agreed-upon algorithm “The ASCRS algorithm has to be approved at several levels be- for diagnosing and treating dry eye,” says Esen Akpek, MD, a fore it’s released,” he adds, “but we hope it will become available professor of ophthalmology and rheumatology at Johns Hopkins within the next year.” University School of Medicine. “There are two established classifi - Christopher J. Rapuano, MD, director of the cornea service at cation systems that include treatment guidelines: the Delphi panel Wills Eye Hospital, sees advantages to creating a more general recommendations, published in 2006, and the Dry Eye Workshop algorithm. “The DEWS and Delphi Dry Eye algorithms featured treatment protocol published in 2007. Unfortunately, neither of treatment suggestions for mild, moderate and severe disease,” these systems is widely used in clinic.” he notes. “I believe it makes sense to do some things earlier in Dr. Pfl ugfelder see a couple of problems with creating a dry-eye treatment and some things later, but dry eye can be multifactorial management algorithm. “One issue is that clinicians need to and patients respond differently to the treatments. Also, patients have the right tools to obtain the measurements suggested in the don’t always want a given treatment. So trying to spell out steps in algorithm,” he says. “For example, the protocol I follow includes a certain order may not be helpful.” measuring the tear volume. To do that, doctors have to have OCT Mark S. Milner, MD, FACS, an associate clinical professor at Yale or the keratograph.” Dr. Pfl ugfelder says another issue is that not University School of Medicine, however, also sees drawbacks to every useful measurement is currently reimbursable, making their some of the more general algorithms. “A severity-based approach performance potentially too costly. can be problematic because so many things contribute to dry Nevertheless, several groups and individuals are hard at work eye,” he notes. “I believe we should be treating these patients developing algorithms that they hope will help clinicians, including based on their diagnosis, not their severity level.” the corneal clinical committee at ASCRS, of which Francis Mah, Dr. Akpek is taking part in the Dry Eye Workshop’s current MD, who specializes in cornea, external disease and refractive attempt to develop new guidelines for dry-eye management. surgery at Scripps Health System in San Diego, is a member. “The “Unfortunately, I’m not sure that having a classifi cation or treat- algorithm we’re developing should function as a step-by-step de- ment algorithm is going to be helpful when it comes to real clinical cision tree,” says Dr. Mah. “If a patient shows up and has certain situations, and I don’t know if the results of our efforts will be symptoms, you go in one direction; if not, you go in another direc- followed by the majority of clinicians,” she says. “Today, half of all tion. If one test is positive or negative, you should do this test next. dry-eye patients need more treatment than just over-the-counter It’s meant to be very comprehensive. We hope that it will develop artifi cial tears, but only eight percent are currently getting a pre- into something you can hang in the offi ce for reference. It might scription for dry eye. I think we’ll have to better educate clinicians even be possible to turn it into an app, where you plug in the infor- about dry eye if we want them to follow an algorithm.” mation that you have and the app makes a recommendation. —CK

problem is chronic and not getting patients. If the patient is using artifi cial lar infl ammation associated with kera- better. Then I use punctal plugs. How- tears more than four or fi ve times a toconjunctivitis sicca,” says Dr. Milner. ever, it’s important to note that you day, I recommend starting Restasis or “Both cyclosporine and lifi tegrast are don’t want to use punctal plugs if the Xiidra. I don’t wait too long to add one anti-inflammatory agents, and they patient has a significant meibomian of these, because we now believe that both appear to do an excellent job.” gland problem because you can end dry eye may be chronic and progres- Dr. Milner notes that combining up making unhealthy tears sit on the sive; treating it earlier may help keep the drugs might also be an option. eye, irritating it.” it from getting worse.” “Although there are no head-to-head “If a patient who has never used The approval of Xiidra—which was studies or studies combining the two artifi cial tears comes in with mild dry- found to be effective in treating both drugs, many of us in the dry-eye world eye disease and no keratitis, I recom- signs and symptoms of dry eye—raises believe that because they affect T-cells mend artificial tears first,” says Dr. the question of whether to use it or in different ways, they will probably be Milner. “I prefer nonpreserved tears, Restasis. Generally, doctors are saying synergistic,” he says. “Combined, they but I may start with preserved tears it’s much too early to know when Xii- may be a better option for patients who for reasons of cost and convenience. dra or Restasis might be the better op- require more than one treatment. I’ve If the problem is more serious, I rec- tion. “Restasis, topical cyclosporine, is already had a number of patients on ommend nonpreserved tears because indicated to increase tear production both Restasis and Xiidra for a month we know preservatives can exacerbate in patients whose tear production is and a half since Xiidra’s approval, and infl ammation and irritation in dry-eye presumed to be depressed due to ocu- so far, I’m seeing good results.”

32 | Review of Ophthalmology | November 2016

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RP1016_Capital One.indd 1 9/12/16 12:26 PM Cover Dry Eye

REVIEW Focus

Another treatment option is topical DEWS Treatment Recommendations (by severity level)* steroids. “Many of us are using steroids off-label concurrently with Restasis Level 1: Level 3: or Xiidra, early in treatment, to let Education and environmental/dietary If Level 2 treatments are inadequate, add: modifi cations the steroids eliminate some of the in- Serum Eliminate offending systemic medications Contact lenses flammation while the other drug is Artifi cial tear substitutes, gels/ointments Permanent punctal occlusion starting to work,” says Dr. Milner. “Of Eyelid therapy course, the risk of side effects such as glaucoma and cataract make steroids a Level 2: Level 4: poor choice for long-term treatment. If Level 1 treatments are inadequate, add: If Level 3 treatments are inadequate, add: The other caveat is to be sure to use Anti-infl ammatories Systemic anti-infl ammatory agents a ‘surface steroid’ such as Lotemax or Tetracyclines (for meibomianitis, rosacea) Surgery (lid surgery, tarsorrhaphy; mucus fl uorometholone, which have a lower Punctal plugs membrane, salivary gland, amniotic mem- Secretogogues brane transplantation) risk of causing side effects.” Moisture chamber spectacles Dr. Mah says he also advises dry- *Modifi ed from: International Task Force Guidelines for Dry Eye eye patients to take a supplement containing omega-3 fatty acids. “I’ll explain to the patient that omega-3 short breaks or using drops during missed. You can treat for other causes, fatty acids are not only good for the long stretches in front of the monitor.” but if you miss patients who have in- eyes, but also for the heart to prevent complete blink, they’re going to re- stroke, and for the skin and hair,” he Mucin Defi ciency & Exposure main dry because their lids aren’t com- says. “This basic regimen is kind of a pletely covering the ocular surface. shotgun approach, but it will improve In terms of diagnosis, most dry-eye Once diagnosed, you can try having signs and symptoms in the majority of disease can be separated into aque- these patients tape their lids closed at patients.” ous defi ciency or evaporative-based. night, or send them to an oculoplastics Dr. Rapuano says he also some- “The majority of evaporative dry eye specialist if the problem is severe. In times prescribes Lacrisert, which acts is caused by blepharitis or meibomian any case, even if the problem is expo- to stabilize and thicken the precor- gland dysfunction,” says Dr. Milner. sure from an open eye, there may be neal tear film and prolong tear-film “However, there are two other causes infl ammation that could be helped by breakup time, as well as lubricate and of evaporative dry eye that are often cyclosporine or lifi tegrast.” (Dr. Mah protect the eye. “These are little colla- overlooked, and they require different says another option is to have the pa- gen pellets that sit in the lower cul-de- treatment approaches. tient use a gel or ointment at bedtime.) sac and dissolve over the course of the “One is goblet cell defi ciency, which day,” he says. “However, the patient leads to mucin defi ciency,” he explains. Meibomian Gland Dysfunction has to have some tears to make them “Mucin is critical to keeping the tears dissolve. If the eye is bone dry, the on the eye longer. Patients with a gob- “If the patient has a meibomian Lacrisert won’t dissolve and will act as let cell defi ciency could include any- gland problem, we prescribe warm an irritant. one with cicatricial conjunctivitis, such compresses and lid scrubs fi rst,” says “Sometimes a bandage soft contact as Stevens-Johnson Syndrome; toxic Dr. Akpek. “If the patient doesn’t im- lens can be used to help relieve symp- epidermal necrolysis; pemphigoid; prove, I add a topical antibiotic, and toms,” he adds, “but you have to be chemical injuries; or even patients if that isn’t suffi cient I also have the careful because dry-eye patients are who have chronic irritation from glau- patient take an oral antibiotic for sev- at a higher risk of infection.” coma drops. In terms of treatment, eral months. Lastly, I resort to tear- Dr. Mah adds that changes in the Allergan’s Phase III study showed that conserving strategies such as tear duct patient’s environment might also be cyclosporine caused a 191-percent plugs or cauterization. Any patient appropriate. “If a patient spends sig- increase in goblet cell density at six who has used topical over-the-counter nifi cant time in front of a computer, months, compared to a 13-percent in- tears and anti-infl ammatory treatment for example, it’s important to educate crease for the vehicle alone. for several months and still has aque- the patient on the connection to dry “Another subset of evaporative dry ous tear defi ciency might benefi t from eye,” he says. “You can suggest ways eye is that caused by exposure, re- plugs, although I wouldn’t use these as to try to help reduce exacerbation sulting from lagophthalmos, or partial a fi rst-line treatment in a patient with such as lowering the monitor, taking blink,” he continues. “This often gets pronounced blepharitis.”

34 | Review of Ophthalmology | November 2016

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RP1116_Icare.indd 1 10/10/16 11:55 AM Cover Dry Eye

REVIEW Focus

“If the problem looks like and potentially return them meibomian gland dysfunc- to 20/20. This started with tion, I may elect to use pre- the PROSE lens at the Bos- scription minocycline pills ton Foundation for Sight, instead of Restasis or Xiidra but now there are clinics all drops,” says Dr. Mah. “I usu- over the country fi tting scleral ally prescribe one 50-mg pill lenses. Other innovative pos- per day, unless the patient is Scleral lenses like the PROSE lens from the Boston Foundation sibilities for treating severe allergic to it, pregnant or a for Sight allow the cornea to bathe in fl uid all day. disease include compounded woman of childbearing age. drops such as albumin, topical I like minocycline because I currently Xiidra. We’ve gotten good results after hormones like medroxyprogesterone practice in San Diego where my pa- a single treatment 80 to 85 percent and dehydroepiandrosterone, better tients are exposed to a lot of sunlight. of the time. This is an out-of-pocket known as DHEA. These treatments Doxycycline, which I often prescribed cost for the patient, but the cost of the may work best for aqueous-defi cient when I practiced in Pittsburgh, can LipiFlow system is about half of what dry eye.” cause photosensitivity; minocycline it was a year ago.” If a patient has very bad mucus or isn’t usually associated with that side Dr. Rapuano says he often pre- fi laments, Dr. Rapuano suggests try- effect. If the problem still hasn’t di- scribes Medibeads, a microwavable ing Mucomyst (acetylcysteine), which minished after several months, I may pad you put on the eyes. “Commercial can be made up by a compounding consider using punctal plugs after lid scrubs often work quite well,” he pharmacy. “Usually I prescribe a 10% Restasis or Xiidra.” adds. “If the problem doesn’t improve, solution four times a day,” he says. “If the problem is anterior blephari- I have the patient use an antibiotic “That works well for many patients. tis, that tends to be mostly infectious, ointment at bedtime, either erythro- Also, in a few patients where dry eye is so you’d want to treat that with a topi- mycin, bacitracin or azithromycin. If severe, you can perform a small lateral cal antibiotic,” says Dr. Milner. “I like that’s not enough, then we may go to tarsorrhaphy, where the eyelid is sewn to use either a topical ointment like oral doxycycline or minocycline, or closed a little on the lateral side to erythromycin or bacitracin, or topi- use some mild topical steroids to get decrease the amount of evaporation. cal azithromycin, which I think works people over the hump. Omega-3 pills Patients don’t usually like it, but some- great. In addition to being an effec- can also be helpful, and LipiFlow can times it really helps.” tive antibiotic, azithromycin has anti- be benefi cial as well.” infl ammatory properties because it’s a Strategies for Success macrolide, which means it can also be When the Problem is Severe helpful for treating posterior blephari- Doctors suggest taking these steps: tis. A lot of us are also using cyclospo- Other treatment options can be tried • Always check your patients rine off-label for posterior blepharitis when the dry-eye problem is severe for dry eye. “Regardless of the rea- with great success, and there are stud- and doesn’t respond to these treat- son a patient comes in to see you, you ies supporting this use as well.”2 ments. “Moving up the ladder, you should be checking for dry eye,” says Dr. Milner uses the LipiFlow instru- can use autologous serum eye drops, Dr. Akpek. “Treating dry eye can do ment to treat some of his meibomian derived from the patient’s blood,” says a lot to improve your patient’s visual gland dysfunction patients. “LipiFlow Dr. Rapuano. “A laboratory removes acuity and quality of life, even if the is a low-risk, 12-minute procedure the red blood cells, dilutes it and sends patient isn’t complaining about it.” that heats the lids to exactly 108 de- the serum back frozen. The patient Dr. Rapuano adds that simply grees and then massages the glands defrosts little bottles of serum tears to downplaying dry-eye problems is a to express the oils,” he explains. “I use them, and some patients fi nd them disservice to both your patients and fi nd it especially useful when patients very helpful.” (For an in-depth look at your practice. “As Eric Donnenfeld aren’t getting enough benefit from the use of autologous serum, see the and others noted years ago,” he says, other treatments, or when a patient feature on p. 44.) “if you make a dry-eye patient happy, would rather not add more medica- Another option is scleral lenses. other family members and friends are tions. However, we also need to treat “Scleral lenses sit on the sclera and likely to come to your practice as a the glands so they start making healthy bathe the cornea with fl uid all day,” result. To see dry-eye treatment as oils again, so after using LipiFlow says Dr. Milner. “They can take dry- just a drain on your practice is a little we keep the patient on Restasis or eye patients who have 20/200 vision shortsighted.”

36 | Review of Ophthalmology | November 2016

028_rp1116_F1.indd 36 10/20/16 3:24 PM • Pay attention to the details of ment options, and you may want to re- patient complaints. Dr. Mah points fer the patient to a dry-eye specialist.” out that a patient’s complaint can of- • Remember that the problem is ten help with the diagnosis. “For ex- frequently multifactorial. “When ample, if the patient is experiencing diagnosing, you have to decide if the foreign body sensation in the morning, problem is primarily aqueous defi- I’ll lean more toward an evaporative ciency, or it’s more evaporative, which problem such as meibomian gland often goes along with meibomian dysfunction or blepharitis,” he says. gland and oil problems,” says Dr. “If the symptoms are appearing late in Rapuano. “The unfortunate reality is, the day or in the evening, I’m inclined most people have both problems. If to think the patient has more of an it’s 90/10 in favor of one cause, you aqueous defi ciency problem.” can treat the low-hanging fruit of the • Be sure to gauge the severity primary cause; but if it’s 50/50, then The of the problem. “At the minimum you really have to treat both causes or Series 3 you have to have some sort of marker you’re not going to make the patient of severity, both in terms of symp- feel better.” toms and signs,” notes Dr. Pfl ugfelder. • Never discount a patient’s com- RETINOMAX “You should always measure tear-fi lm plaint. “Even if the tests are negative, breakup time, because no matter what we should never discount the patient’s kind of dry eye or tear dysfunction you complaint,” says Dr. Mah. “The pa- HAND-HELD have, tear stability will be affected. tient knows what he or she is feeling. You should also perform corneal and It’s our job to fi nd out why they’re hav- Autorefractor conjunctival staining, because those ing the symptoms and then treat them are definitely valuable. Some clini- accordingly.” Precise measurements cians use osmolarity to gauge severity, • Read dry-eye studies as they’re Anywhere - Anytime but my experience has been that os- published. “There are multiple pub- molarity isn’t trustworthy for that pur- lications covering dry eye,” notes Dr. pose. Others, including myself, rely on Akpek. “Clinicians should read the tear volume as a marker. If you can’t results and discussion sections, not measure the tear meniscus height with just the abstract. Often the most im- •Accurate OCT or the keratograph, the Schirmer portant information isn’t found in the •Fast test is an OK fallback. abstract.” “It’s also important to gauge the se- •Portable verity of the symptoms the patient is Dr. Pflugfelder is a consultant for complaining about to act as a baseline Allergan, Shire, Santen and Senju. •Efficient so you can tell whether your treatment Dr. Rapuano is a consultant for Shire is [subjectively] causing improvement and TearLab. Dr. Mah is a consul- or not,” he continues. “You can do tant for TearLab, Allergan and Shire. this with a dry-eye questionnaire, or Dr. Milner is a speaker and consul- by asking basic questions about situ- tant for Allergan, Shire, TearScience ational triggers, symptoms, how often and Sun Pharmaceuticals and owns it’s a problem and how irritated the stock in RPS. Dr. Akpek has received eyes are.” institutional research support from • Get a sense of the impact the Allergan and is currently a consultant symptoms are having on the pa- with Shire.

tient’s quality of life. “In some cases, 1. Whitcher JP, Shiboski CH, Shiboski SC, et al. A simplifi ed the impact is signifi cant to the point at quantitative method for assessing keratoconjunctivitis sicca from the Sjögren’s Syndrome International Registry. Am J Ophthalmol which the patient is depressed and not 2010;149:3:405-15. functional,” says Dr. Pflugfelder. “If 2. Perry HD, Doshi-Carnevale S, Donnenfeld ED, Solomon R, Biser SA, Bloom AH. Effi cacy of commercially available topical the impact is that great, you’ll probably cyclosporine A 0.05% in the treatment of meibomian gland need to go beyond the simple treat- dysfunction. Cornea 2006;25:2:171-5. 250 Cooper Ave., Suite 100 Tonawanda NY 14150 www.s4optik.com I 888-224-6012 Sensible equiptment. Well made, well priced. For today’s modern office.

028_rp1116_F1.indd 37 10/20/16 3:24 PM Dry Eye REVIEW Cover Focus Treating Dry Eye: Beyond Drops

Michelle Stephenson, Contributing Editor

Ophthalmologists’ any ophthalmologists are on to a silicone, non-dissolvable plug opting not to use only artifi - afterwards. These are a wonderful op- armamentarium Mcial tears as a fi rst-line treat- tion, especially if the patient doesn’t ment for dry eye and are adding a va- have allergies or rosacea.” for treating dry eye riety of other treatments, as well, such Karl Stonecipher, MD, who is in as punctal plugs, nutraceuticals and private practice in Greensboro, N.C., continues to grow. moisture masks. “Some physicians are agrees. “Once the infl ammatory pro- still hesitant to use medications, much cess has been stopped, I am a huge to the chagrin of the pharmaceuti- fan of plugs,” he says. “They are re- cal companies,” says John Sheppard, versible, and they stay in permanently, MD, professor of ophthalmology, mi- without any swelling.” crobiology and molecular biology at Eastern Virginia Medical School and Nutritional Supplements president of Virginia Eye Consultants in Norfolk. “Many doctors favor or- Nutritional supplements are widely ganic therapies. Tear conservation is used and have also been found to be right at the top of the list of treatments an effective therapy for dry eye. “Nu- and so is nutrition. All patients should tritional supplements for dry eye have be treated using both modalities.” In been around for 10 or 15 years,” notes this article, dry-eye experts who think Dr. Latkany. “They are part of my similarly to Dr. Sheppard describe the regimen, and I usually start out with ways in which their treatment options 1,000 mg of fi sh oil a day. Some people are growing. are opposed to the fi sh component, so they use fl axseed oil instead. Patients Punctal Plugs can titrate upwards based on their response rate.” According to Robert Latkany, MD, A number of studies have demon- founder of the New York Eye and Ear strated that oral nutritional supple- Infi rmary’s Dry Eye Clinic, it can be ments are an effective treatment for argued that punctal plugs are a natural dry-eye symptoms. In one recent treatment because their sole purpose report, sponsored by nutraceutical- is to keep patients’ own tears on their maker Brudy Technology (Barcelona, eyes longer. “You can use a temporary Spain), a total of 1,419 patients with plug just to give it a shot and see if it dry-eye syndrome who were using works,” he says. “You can always move artificial tears participated in a 12-

38 | Review of Ophthalmology | November 2016 This article has no commercial sponsorship.

0038_rp1116_f2.indd38_rp1116_f2.indd 3838 110/20/160/20/16 3:393:39 PMPM ELITE SLIT Classic lissamine green staining LAMP two minutes after instillation. These staining patterns Karl Stonecipher, MD Karl Stonecipher, show both the patient’s lid wiper The H5 ELITE epitheliopathy and slit lamp features dry-eye disease. an innovative LED Some physicians illumination system are turning to providing brilliant organic treatments light spectrum, in addition to while increasing traditional tears patient comfort. and prescription medications to treat these patients.

An extensive power range, with Ƭ ve magniƬ cation settings week prospective study.1 Patients were cals) resulted in a statistically signifi - from 6x to 40x. Standard instructed to take three capsules/day cant improvement in tear osmolarity, on all ELITE slit lamps. (1.5 g) of the company’s nutraceutical as well as improvements in such sec- formulation Brudysec. The following ondary endpoints as corneal staining variables were assessed: dry-eye symp- and tear breakup time.2 (Several of the toms (scratchy and stinging sensation, study’s physicians received compensa- IMAGING eye redness, grittiness, painful and tion from PRN.) tired eyes, grating sensation and blurry It’s Dr. Sheppard’s belief that in- The S4OPTIK H5 ELITE slit vision); conjunctival hyperemia; tear flammation is the underlying cause lamp comes digital ready. breakup time; Schirmer I test; and of dry eye. “Essential fatty acids are Combine with the S4OPTIK Oxford grading scheme. a non-pharmaceutical way of produc- all-in-one digital camera to At 12 weeks, all dry-eye symptoms ing an anti-inflammatory effect,” he acquire exceptional still and improved significantly, and artificial says, noting that balanced essential video images. tear use decreased signifi cantly from fatty acid therapy has been found to 3.77 times per day at baseline to 3.45 signifi cantly improve signs and symp- times per day. In addition, the Schirm- toms of dry eye. “I’ve also found that er test scores and the TBUT increased gammalinoleic acid is very important signifi cantly, and there was an increase for the ocular surface and is univer- in patients grading 0 to I on the Oxford sally tolerated. It can be found in some scale and a decrease of those grading commercial preparations, but it is also IV to V. Additionally, signifi cant dif- readily available in supermarkets and ferences in improvements in dry-eye health-food stores as primrose, borage symptoms were found between com- or black currant seed oil.” pliant and noncompliant patients as A recent study sponsored by well as between those with moderate/ Taiwanese neutraceutical company severe and those with none/mild con- Acrobio Healthcare found that oral junctival hyperemia. In another study, antioxidant supplements may increase oral administration of re-esterified tear production and improve tear-fi lm omega-3 fatty acids (Dry Eye Omega, stability by reducing tear reactive oxy- Physician Recommended Nutraceuti- gen species.3 This study employed a 250 Cooper Ave., Suite 100 Tonawanda NY 14150 www.s4optik.com I 888-224-6012 Sensible equipment. Well made, well priced. For today’s modern oƯ ce.

038_rp1116_f2.indd 39 10/20/16 3:39 PM Cover Dry Eye

REVIEW Focus

vegetable-based antioxidant supple- recommend PRN, Nordic Naturals or patent pending on a goggle that closes ment that’s safe and can be used as HydroEye,” he states. “I give patients the eye. It is called Eye Shutters, and an adjuvant therapy to conventional a specifi c brand, and I send them to it should be out this fall. It will be the artifi cial tear therapy for patients with a specifi c website to order it online. fi rst eye mask that actually closes the dry-eye syndrome. You’ve got to make it easy. We used to eye.” This prospective, randomized, sell supplements in our offi ce to make double-blind study evaluated the ef- it more convenient, but we’ve found Warm Compresses & Lid Scrubs fects of an antioxidant supplement that ordering it online is even easier. (containing anthocyanosides, astax- Our office has a computer in every According to Dr. Sheppard, meibo- anthin, vitamins A, C and E, and sev- lane, and either I or the technician mian gland awareness and therapy has eral herbal extracts, including semen walk through how to order nutraceu- become a signifi cant area of interest Cassiae and Ophiopogonis japonicus) ticals. When you are recommending over the past few years. “Now, we are on patients with dry eye. The inves- an out-of-the-box product, it must be all imaging the meibomian gland and tigators assessed dry-eye symptoms, accessible.” producing more intelligent therapy visual acuity, Schirmer’s test, TBUT, “Our patients have welcomed ready than traditional baby shampoo,” he cornea and conjunctiva fluorescein access to all of our recommended dry- says. “When we understand that mei- staining, serum anti-SSA/anti-SSB eye products through our own prac- bomian gland physiology is subject to antibodies, and the level of reactive tice-specifi c retail website at myeye- geriatric and infl ammatory degrada- oxygen species in tears. Patients took store.com,” Dr. Sheppard notes. tion like everything else in the body, the supplements for eight weeks, and we can not only document morpholog- they were evaluated every four weeks Masks and Goggles ic changes in the meibomian glands, for 16 weeks. we can incorporate patients enthusi- Forty-three patients (20 in the treat- Dr. Latkany notes that masks and astically into the treatment paradigm, ment group and 23 in the placebo goggles are a great addition to the dry- especially when they see that there are group) completed the study. Patients’ eye armamentarium. “An enormous anatomical changes.” liver and renal functions were normal. number of patients suffer from noc- Several topical scrubs are now avail- Diastolic blood pressure decreased in turnal lagophthalmos, which is a major able that are not only antiseptic, but the treatment group; however, there contributor to dry eye, especially upon also anti-inflammatory. “We have were no signifi cant differences in sys- awakening,” he says. “My top recom- found this to be extremely benefi- tolic blood pressure, dry-eye symp- mendation for resolving dry-eye symp- cial, and we now recommend specifi c toms, serum anti-SSA and anti-SSB, toms is a good night’s sleep. Many pa- scrubs for all of our preoperative pa- visual acuity, intraocular pressure or tients with dry eye suffer from anxiety tients to sterilize the ocular surface fluorescein corneal staining among and stress, and it affects the quality or reduce the fl oral load and also to the groups. In the treatment group, of their sleep. Masks and goggles are improve meibomian gland function TBUT scores and Schirmer’s tests wonderful additions to improve their and, therefore, provide an alternative without topical anesthesia signifi cantly sleep pattern. Moisture chamber gog- therapy for ocular surface disease,” improved. Tear reactive oxygen spe- gles from Eye Eco form a seal around Dr. Sheppard adds. cies level differed between the groups the eye so no air gets to the eye while Dr. Stonecipher also recommends and decreased after treatment. Ad- the patient is sleeping. They come in the use of anti-dandruff shampoos and ditionally, patients’ overall subjective different varieties, shapes, and colors, lid scrubs. “I use three anti-dandruff impression revealed a signifi cant im- and I commonly recommend them shampoos: Head and Shoulders; Sel- provement with treatment compared in my practice. Additionally, I have a sun Blue; and T/Gel—specifi cally yel- with placebo. low T/Gel,” he avers. “A lot of people Dr. Stonecipher says that the key have a mixed-mechanism dry eye. to any therapy is making sure that pa- Sometimes, this can affect the natu- tients are compliant. If patients are ral bacteria that are on the face and going to take a nutritional supplement, around the eyes. It is simple to wash he says, it must be easy for them to your face with an anti-dandruff sham- purchase. He has also found that cer- poo while in the shower. Just make tain brands work better than others be- sure not to get it in your eyes. I am also cause they are more readily absorbed. Eyeseal 4.0 goggles from Eye Eco help a huge fan of lid scrubs like Avenova “For an over-the-counter omega-3, I protect patients’ eyes while they sleep. by NovaBay.”

40 | Review of Ophthalmology | November 2016

038_rp1116_f2.indd 40 10/20/16 3:40 PM Aim for Target IOP Consider Adding SIMBRINZA® Suspension to a PGA SIMBRINZA® Suspension should be taken at least fi ve (5) minutes apart from other topical ophthalmic drugs

Up to 7.1 mm Hg additional IOP 5.6 mm Hg* additional mean diurnal IOP lowering reduction from baseline when observed from baseline when added to a PGA1 added to a PGA1 * Treatment difference (mm Hg) and P value at Week 6 was -3.7, P<0.0001.

IOP Daily Time Points (mm Hg)1† Mean Diurnal IOP (mm Hg)1§

Treatment Arm 8 AM 10 AM 3 PM 5 PM Treatment Arm

PGA + SIMBRINZA® Baseline‡ 24.5 22.9 21.7 21.6 PGA + SIMBRINZA® Baseline|| 22.7 Suspension (N=88) Week 6 19.4 15.8 17.2 15.6 Suspension (N=83) Week 6 17.1

Baseline‡ 24.3 22.6 21.3 21.2 Baseline|| 22.4 PGA + Vehicle (N=94) PGA + Vehicle (N=92) Week 6 21.5 20.3 20.0 20.1 Week 6 20.5

† Differences (mm Hg) and P values at Week 6 time points between treatment groups §Difference (mm Hg) and P value at Week 6 between treatment groups were -2.14, P=0.0002; -4.56, P<0.0001; -2.84, P<0.0001; -4.42, P<0.0001. were -3.44, P<0.0001. ‡Baseline (PGA Monotherapy). ||Baseline (PGA Monotherapy).

Study Design: A prospective, randomized, multicenter, double-blind, parallel-group study of 189 patients with open-angle glaucoma and/or ocular hypertension receiving treatment with a PGA. PGA treatment consisted of either travoprost, latanoprost, or bimatoprost. Patients in the study were randomized to adjunctive treatment with SIMBRINZA® Suspension (N=88) or vehicle (N=94). The primary effi cacy endpoint was mean diurnal IOP (IOP averaged over all daily time points) at Week 6 between treatment groups. Key secondary endpoints included IOP at Week 6 for each daily time point (8 AM, 10 AM, 3 PM, and 5 PM) and mean diurnal IOP change from baseline to Week 6 between treatment groups.1 PGA=prostaglandin analog.

24-hour IOP-lowering coverage, including the night — nocturnal effi cacy established through an 8 AM time point2

Contact Lens Wear—The preservative in SIMBRINZA® Suspension, benzalkonium INDICATIONS AND USAGE chloride, may be absorbed by soft contact lenses. Contact lenses should SIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic suspension) be removed during instillation of SIMBRINZA® Suspension but may be reinserted 1%/0.2% is a fi xed combination indicated in the reduction of elevated intraocular 15 minutes after instillation. pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Severe Cardiovascular Disease—Brimonidine tartrate, a component of SIM- Dosage and Administration BRINZA® Suspension, had a less than 5% mean decrease in blood pressure 2 The recommended dose is one drop of SIMBRINZA® Suspension in the affected hours after dosing in clinical studies; caution should be exercised in treating patients eye(s) three times daily. Shake well before use. SIMBRINZA® Suspension may with severe cardiovascular disease. be used concomitantly with other topical ophthalmic drug products to lower intraoc- Adverse Reactions ular pressure. If more than one topical ophthalmic drug is being used, SIMBRINZA® Suspension the drugs should be administered at least fi ve (5) minutes apart. In two clinical trials of 3 months’ duration with SIMBRINZA® Suspension, the most frequent reactions associated with its use occurring in approximately 3-5% IMPORTANT SAFETY INFORMATION of patients in descending order of incidence included: blurred vision, eye irritation, Contraindications dysgeusia (bad taste), dry mouth, and eye allergy. Adverse reaction rates with SIMBRINZA® Suspension is contraindicated in patients who are hypersensitive SIMBRINZA® Suspension were comparable to those of the individual components. to any component of this product and neonates and infants under the age Treatment discontinuation, mainly due to adverse reactions, was reported of 2 years. in 11% of SIMBRINZA® Suspension patients. Warnings and Precautions Drug Interactions Sulfonamide Hypersensitivity Reactions—Brinzolamide is a sulfonamide, and al- Consider the following when prescribing SIMBRINZA® Suspension: though administered topically, is absorbed systemically. Sulfonamide attributable Concomitant administration with oral carbonic anhydrase inhibitors is not recom- adverse reactions may occur. Fatalities have occurred due to severe reactions mended due to the potential additive effect. Use with high-dose salicylate to sulfonamides. Sensitization may recur when a sulfonamide is readministered may result in acid-base and electrolyte alterations. Use with CNS depressants irrespective of the route of administration. If signs of serious reactions or hyper- may result in an additive or potentiating effect. Use with antihypertensives/cardiac sensitivity occur, discontinue the use of this preparation. glycosides may result in additive or potentiating effect on lowering blood Corneal Endothelium—There is an increased potential for developing corneal pressure. Use with tricyclic antidepressants may blunt the hypotensive effect edema in patients with low endothelial cell counts. of systemic clonidine and it is unknown if use with this class of drugs interferes Severe Hepatic or Renal Impairment (CrCl <30 mL/min)—SIMBRINZA® Suspension with IOP lowering. Use with monoamine oxidase inhibitors may result has not been specifi cally studied in these patients and is not recommended. in increased hypotension.

References: 1. Data on fi le, 2014. 2. SIMBRINZA® Suspension Package Insert. Learn more at myalcon.com/simbrinza For additional information about SIMBRINZA® Suspension, please refer © 2016 Novartis 4/16 US-SMB-16-E-1229 to the brief summary of the full Prescribing Information on the following page.

RRP1116_AlconP1116_Alcon SSimbrinza.inddimbrinza.indd 1 110/11/160/11/16 11:3011:30 AMAM BRIEF SUMMARY OF PRESCRIBING INFORMATION Tricyclic Antidepressants - Tricyclic antidepressants have been reported to blunt the hypotensive effect of INDICATIONS AND USAGE systemic clonidine. It is not known whether the concurrent use of these agents with SIMBRINZA® Suspension in SIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2% is a fixed combination of a carbonic humans can lead to resulting interference with the IOP lowering effect. Caution is advised in patients taking tricyclic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist indicated for the reduction of elevated intraocular antidepressants which can affect the metabolism and uptake of circulating amines. pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. Monoamine Oxidase Inhibitors - Monoamine oxidase (MAO) inhibitors may theoretically interfere with the DOSAGE AND ADMINISTRATION metabolism of brimonidine tartrate and potentially result in an increased systemic side-effect such as hypotension. ® Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating The recommended dose is one drop of SIMBRINZA Suspension in the affected eye(s) three times daily. Shake well amines. before use. SIMBRINZA® Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least USE IN SPECIFIC POPULATIONS five (5) minutes apart. Pregnancy - Pregnancy Category C: Developmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, DOSAGE FORMS AND STRENGTHS and 6 mg/kg/day (20, 60, and 120 times the recommended human ophthalmic dose) produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal variations, such as accessory skull bones, which was Suspension containing 10 mg/mL brinzolamide and 2 mg/mL brimonidine tartrate. only slightly higher than the historic value at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses CONTRAINDICATIONS from dams receiving oral doses of 18 mg/kg/day (180 times the recommended human ophthalmic dose) during Hypersensitivity - SIMBRINZA® Suspension is contraindicated in patients who are hypersensitive to any component gestation were proportional to the reduced maternal weight gain, with no statistically significant effects on organ of this product. or tissue development. Increases in unossified sternebrae, reduced ossification of the skull, and unossified hyoid Neonates and Infants (under the age of 2 years) - SIMBRINZA® Suspension is contraindicated in neonates and that occurred at 6 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. infants (under the age of 2 years) [see Use in Specific Populations]. Following oral administration of 14C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and WARNINGS AND PRECAUTIONS was present in the fetal tissues and blood. Sulfonamide Hypersensitivity Reactions - SIMBRINZA® Suspension contains brinzolamide, a sulfonamide, and Developmental toxicity studies performed in rats with oral doses of 0.66 mg brimonidine base/kg revealed no although administered topically is absorbed systemically. Therefore, the same types of adverse reactions that are evidence of harm to the fetus. Dosing at this level resulted in a plasma drug concentration approximately 100 times attributable to sulfonamides may occur with topical administration of SIMBRINZA® Suspension. Fatalities have higher than that seen in humans at the recommended human ophthalmic dose. In animal studies, brimonidine occurred due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, crossed the placenta and entered into the fetal circulation to a limited extent. fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur There are no adequate and well-controlled studies in pregnant women. SIMBRINZA® Suspension should be used when a sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or during pregnancy only if the potential benefit justifies the potential risk to the fetus. hypersensitivity occur, discontinue the use of this preparation [see Patient Counseling Information]. Nursing Mothers - In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral Corneal Endothelium - Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma dose of 15 mg/kg/day (150 times the recommended human ophthalmic dose) were observed during lactation. No membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients other effects were observed. However, following oral administration of 14C-brinzolamide to lactating rats, radioactivity with low endothelial cell counts. Caution should be used when prescribing SIMBRINZA® Suspension to this group of was found in milk at concentrations below those in the blood and plasma. In animal studies, brimonidine was excreted patients. in breast milk. Severe Renal Impairment - SIMBRINZA® Suspension has not been specifically studied in patients with severe renal It is not known whether brinzolamide and brimonidine tartrate are excreted in human milk following topical ocular impairment (CrCl < 30 mL/min). Since brinzolamide and its metabolite are excreted predominantly by the kidney, administration. Because many drugs are excreted in human milk and because of the potential for serious adverse SIMBRINZA® Suspension is not recommended in such patients. reactions in nursing infants from SIMBRINZA® (brinzolamide/brimonidine tartrate ophthalmic suspension) 1%/0.2%, Acute Angle-Closure Glaucoma - The management of patients with acute angle-closure glaucoma requires a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the therapeutic interventions in addition to ocular hypotensive agents. SIMBRINZA® Suspension has not been studied in importance of the drug to the mother. patients with acute angle-closure glaucoma. Pediatric Use - The individual component, brinzolamide, has been studied in pediatric glaucoma patients 4 weeks ® to 5 years of age. The individual component, brimonidine tartrate, has been studied in pediatric patients 2 to 7 years Contact Lens Wear - The preservative in SIMBRINZA Suspension, benzalkonium chloride, may be absorbed by ® ® old. Somnolence (50-83%) and decreased alertness was seen in patients 2 to 6 years old. SIMBRINZA Suspension is soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA Suspension but may be [see Contraindications] reinserted 15 minutes after instillation [see Patient Counseling Information]. contraindicated in children under the age of 2 years . Severe Cardiovascular Disease - Brimonidine tartrate, a component of SIMBRINZA® Suspension, has a less than Geriatric Use - No overall differences in safety or effectiveness have been observed between elderly and adult 5% mean decrease in blood pressure 2 hours after dosing in clinical studies; caution should be exercised in treating patients. patients with severe cardiovascular disease. OVERDOSAGE Severe Hepatic Impairment - Because brimonidine tartrate, a component of SIMBRINZA® Suspension, has not been Although no human data are available, electrolyte imbalance, development of an acidotic state, and possible nervous studied in patients with hepatic impairment, caution should be exercised in such patients. system effects may occur following an oral overdose of brinzolamide. Serum electrolyte levels (particularly potassium) Potentiation of Vascular Insufficiency - Brimonidine tartrate, a component of SIMBRINZA® Suspension, may and blood pH levels should be monitored. potentiate syndromes associated with vascular insufficiency. SIMBRINZA® Suspension should be used with caution Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse event reported to in patients with depression, cerebral or coronary insufficiency, Raynaud’s phenomenon, orthostatic hypotension, or date has been hypotension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children thromboangiitis obliterans. receiving brimonidine as part of medical treatment of congenital glaucoma or by accidental oral ingestion. Treatment Contamination of Topical Ophthalmic Products After Use - There have been reports of bacterial keratitis of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained. associated with the use of multiple-dose containers of topical ophthalmic products. These containers have been NONCLINICAL TOXICOLOGY inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the Carcinogenesis, Mutagenesis, Impairment of Fertility - Brinzolamide caused urinary bladder tumors in female ocular epithelial surface [see Patient Counseling Information]. mice at oral doses of 10 mg/kg/day and in male rats at oral doses of 8 mg/kg/day in 2 year studies. Brinzolamide was ADVERSE REACTIONS not carcinogenic in male mice or female rats dosed orally for up to 2 years. The carcinogenicity appears secondary Clinical Studies Experience - Because clinical studies are conducted under widely varying conditions, adverse to kidney and urinary bladder toxicity. These levels of exposure cannot be achieved with topical ophthalmic dosing in reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies humans. of another drug and may not reflect the rates observed in practice. The following tests for mutagenic potential of brinzolamide were negative: (1) in vivo mouse micronucleus assay; (2) in vivo E. coli in vitro SIMBRINZA® Suspension - In two clinical trials of 3 months duration 435 patients were treated with SIMBRINZA® sister chromatid exchange assay; and (3) Ames test. The mouse lymphoma forward mutation assay Suspension, and 915 were treated with the two individual components. The most frequently reported adverse was negative in the absence of activation, but positive in the presence of microsomal activation. In this assay, there reactions in patients treated with SIMBRINZA® Suspension occurring in approximately 3 to 5% of patients in was no consistent dose-response relationship to the increased mutation frequency and cytotoxicity likely contributed descending order of incidence were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. to the high mutation frequency. Carbonic anhydrase inhibitors, as a class, are not mutagenic and the weight of Rates of adverse reactions reported with the individual components were comparable. Treatment discontinuation, evidence supports that brinzolamide is consistent with the class. In reproduction studies of brinzolamide in rats, there mainly due to adverse reactions, was reported in 11% of SIMBRINZA® Suspension patients. were no adverse effects on the fertility or reproductive capacity of males or females at doses up to 18 mg/kg/day (180 times the recommended human ophthalmic dose). Other adverse reactions that have been reported with the individual components during clinical trials are listed below. Brimonidine tartrate was not carcinogenic in either a 21-month mouse or 24-month rat study. In these studies, dietary Brinzolamide 1% - In clinical studies of brinzolamide ophthalmic suspension 1%, the most frequently reported administration of brimonidine tartrate at doses up to 2.5 mg/kg/day in mice and 1 mg/kg/day in rats resulted in adverse reactions reported in 5 to 10% of patients were blurred vision and bitter, sour or unusual taste. Adverse plasma drug concentrations 80 and 120 times higher than the human plasma drug level at the recommended clinical reactions occurring in 1 to 5% of patients were blepharitis, dermatitis, dry eye, foreign body sensation, headache, dose, respectively. Brimonidine tartrate was not mutagenic or cytogenic in a series of in vitro and in vivo studies hyperemia, ocular discharge, ocular discomfort, ocular keratitis, ocular pain, ocular pruritus and rhinitis. including the Ames test, chromosomal aberration assay in Chinese Hamster Ovary (CHO) cells, a host-mediated assay The following adverse reactions were reported at an incidence below 1%: allergic reactions, alopecia, chest and cytogenic studies in mice, and a dominant lethal assay. In reproductive studies performed in rats with oral doses pain, conjunctivitis, diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye fatigue, hypertonia, of 0.66 mg brimonidine base/kg (approximately 100 times the plasma drug concentration level seen in humans keratoconjunctivitis, keratopathy, kidney pain, lid margin crusting or sticky sensation, nausea, pharyngitis, tearing and following multiple ophthalmic doses), fertility was not impaired. urticaria. PATIENT COUNSELING INFORMATION Brimonidine Tartrate 0.2% - In clinical studies of brimonidine tartrate 0.2%, adverse reactions occurring in Sulfonamide Reactions - Advise patients that if serious or unusual ocular or systemic reactions or signs of approximately 10 to 30% of the subjects, in descending order of incidence, included oral dryness, ocular hyperemia, hypersensitivity occur, they should discontinue the use of the product and consult their physician. burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular ® allergic reactions, and ocular pruritus. Temporary Blurred Vision - Vision may be temporarily blurred following dosing with SIMBRINZA Suspension. Care should be exercised in operating machinery or driving a motor vehicle. Reactions occurring in approximately 3 to 9% of the subjects, in descending order included corneal staining/ ® erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory symptoms, eyelid Effect on Ability to Drive and Use Machinery - As with other drugs in this class, SIMBRINZA Suspension may edema, conjunctival edema, dizziness, blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, conjunctival cause fatigue and/or drowsiness in some patients. Caution patients who engage in hazardous activities of the blanching, abnormal vision and muscular pain. potential for a decrease in mental alertness. The following adverse reactions were reported in less than 3% of the patients: lid crusting, conjunctival hemorrhage, Avoiding Contamination of the Product - Instruct patients that ocular solutions, if handled improperly or if the tip of abnormal taste, insomnia, conjunctival discharge, depression, hypertension, anxiety, palpitations/arrhythmias, nasal the dispensing container contacts the eye or surrounding structures, can become contaminated by common bacteria dryness and syncope. known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions [see Warnings and Precautions ]. Always replace the cap after using. If solution changes color Postmarketing Experience - The following reactions have been identified during postmarketing use of brimonidine or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle. tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their Intercurrent Ocular Conditions - Advise patients that if they have ocular surgery or develop an intercurrent ocular seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a condition (e.g., trauma or infection), they should immediately seek their physician’s advice concerning the continued combination of these factors, include: bradycardia, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, use of the present multidose container. skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), and tachycardia. Concomitant Topical Ocular Therapy - If more than one topical ophthalmic drug is being used, the drugs should be Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and administered at least five minutes apart. somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions [see Contraindications]. Contact Lens Wear - The preservative in SIMBRINZA® Suspension, benzalkonium chloride, may be absorbed by ® DRUG INTERACTIONS soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA Suspension, but may be reinserted 15 minutes after instillation. Oral Carbonic Anhydrase Inhibitors - There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide ophthalmic ©2013-2016 Novartis suspension 1%, a component of SIMBRINZA® Suspension. The concomitant administration of SIMBRINZA® U.S. Patent No: 6,316,441 Suspension and oral carbonic anhydrase inhibitors is not recommended. ALCON LABORATORIES, INC. High-Dose Salicylate Therapy - Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. Fort Worth, Texas 76134 These alterations were not reported in the clinical trials with brinzolamide ophthalmic suspension 1%. However, in USA1-800-757-9195 patients treated with oral carbonic anhydrase inhibitors, rare instances of acid-base alterations have occurred with [email protected] high-dose salicylate therapy. Therefore, the potential for such drug interactions should be considered in patients receiving SIMBRINZA® Suspension. CNS Depressants - Although specific drug interaction studies have not been conducted with SIMBRINZA® Suspension, the possibility of an additive or potentiating effect with CNS depressants (alcohol, opiates, barbiturates, sedatives, or anesthetics) should be considered. Antihypertensives/Cardiac Glycosides - Because brimonidine tartrate, a component of SIMBRINZA® Suspension, may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with SIMBRINZA® Suspension is advised. © 2016 Novartis 6/16 US-SMB-16-E-2215

RRP1116_AlconP1116_Alcon SSimbrinzaimbrinza PPI.inddI.indd 1 110/11/160/11/16 11:2811:28 AMAM Cover Dry Eye

REVIEW Focus

Warmth and Electricity of treatment in the left eye and in both evaporative dry eye disease. IPL has eyes at the 12-month evaluation. At the been used by dermatologists as a ro- Alternative therapies in this area, end of treatment and during the follow- sacea treatment for years, and now such as LipiFlow, are becoming popu- up period, there was a signifi cant reduc- it is being used to treat meibomian lar. “They are becoming a centerpiece tion of the use of tear substitutes. No gland disease and evaporative dry eye. for practice growth and patient aware- complications were reported. The treatment consists of delivering ness,” says Dr. Sheppard. “Addition- 10 to 15 treatment spots to the upper ally, in many cases, it is more readily cheek and lateral canthal area with an adopted by patients [than prescrip- intense pulsed-light handpiece. The tion therapy]. All of the alternative A novel intranasal physician usually makes two passes. In methods that we have discussed and neurostimulation a study of IPL, researchers reviewed the many others that are out there clinical data from 100 patients who are synergistic and complementary to therapy for dry eye may were diagnosed with evaporative dry prescription therapy, as well.” be approved as early eye.6 On average, patients underwent Also, a recent study found that four IPL sessions during the two-year the therapy known as transcutane- as the fi rst quarter of study period, and there was a signifi - ous electrical stimulation can improve 2017. cant decrease in scoring of lid margin patients’ dry eye, both subjectively edema, facial telangiectasia, lid mar- and objectively, without any adverse gin vascularity, meibum viscosity and effects, so it may be a potential addi- OSDI score. Additionally, there was tion to the ophthalmologist’s dry-eye “There is also excitement in the dry- a signifi cant increase in oil fl ow score armamentarium.4 eye community regarding neurostim- and TBUT. In this study, 27 patients with ulation therapy to stimulate natural As far as the future of alternative dry eye underwent transcutaneous tear production, which may be ap- dry-eye therapies, Dr. Sheppard says: electrostimulation. Electrodes were proved as early as the fi rst quarter of “The fact that the marketplace is ex- placed on the periorbital region of 2017,” Dr. Sheppard notes, referring panding tells us that these therapies both eyes along with manual stimu- to the Allergan/Oculeve intranasal tear are working.” lation with a hand-piece conductor neurostimulator device. moved by the operator. Each patient One study of intranasal neurostimu- Dr. Sheppard is a consultant for underwent 12 sessions that lasted 22 lation included 40 patients with mild Allergan, Alcon, Novartis, Abbvie, Sci- minutes each. Sessions were spread to severe dry eye disease who were ence Based Health, TearLab, Tear Sci- over two months, with two sessions provided with a nasal stimulation de- ence, Shire and Bausch + Lomb. Dr. per week in the fi rst month and one vice and instructed to use it at home Latkany has a licensing agreement session per week in the second month. four times daily.5 The study was spon- with Eye Eco for his eye mask. Dr. Ocular Surface Disease Index ques- sored by the device’s maker, Oculeve. Stonecipher is a consultant for AMO, tionnaire, TBUT, fl uorescein staining The nasal stimulation device is non- Alcon, Allergan, Bausch + Lomb, El- of the cornea, Schirmer I test and ad- invasive with probes that are placed lex, Nidek, Presbia, Refocus and Shire. verse events were assessed at baseline, in the nose to stimulate the lacrimal 1. Gatell-Tortajada J. Oral supplementation with a nutraceutical at the end of treatment, and at six and glands to produce tears. Patients were formulation containing omega-3 fatty acids, vitamins, minerals, 12 months after treatment. followed for up to 180 days. Schirmer and antioxidants in a large series of patients with dry eye symptoms: Results of a prospective study. Clin Interv Aging Patients’ OSDI improved from 43 scores were used to determine the 2016;19:11:571-578. ±19.2 at baseline to 25.3 ±22.1 at the difference between unstimulated 2. Epitropoulos A, Donnenfeld E, Shah Z. Effect of oral re-esterifi ed omega-3 nutritional supplementation on dry eyes. Cornea end of treatment, and this improve- and stimulated tear production. The 2016;35:9:1185-1191. ment was maintained at both six-month study found that the mean stimulated 3. Huang JY, Yeh PT, Hou YC. A randomized, double-blind, placebo- controlled study of oral antioxidant supplement therapy in patients and 12-month follow-up evaluations. Schirmer scores were significantly with dry eye syndrome. Clin Ophthalmol 2016;9:10:813-820. There was TBUT improvement in the higher than the unstimulated scores 4. Pedrotti E, Bosello F, Fasolo A, et al. Transcutaneous periorbital electrical stimulation in the treatment of dry eye. Br J Ophthalmol right eye at the end of treatment and at all visits. Additionally, corneal and 2016 Sept 22. Epub ahead of print. after 12 months in the left eye. The conjunctival staining and symptom 5. Friedman NJ, Butron K, Robledo N, Loudin J, Baba SN, Chayet A. A nonrandomized, open-label study to evaluate the effect of Oxford scores changed in both eyes scores from baseline to day 180 were nasal stimulation on tear production in subjects with dry eye at the end of treatment and at the six- signifi cantly reduced. disease. Clin Ophthalmol 2016;10:795-804. 6. Gupta PK, Vora GK, Matossian C, Kim M, Stinnett S. Outcomes month visit. Additionally, Schirmer I Also, a study has found that intense of intense pulsed light therapy for treatment of evaporative dye scores improved signifi cantly at the end pulsed light therapy effectively treats eye disease. Can J Ophthalmol 2016;51:4:249-253.

November 2016 | reviewofophthalmology.com | 43

0038_rp1116_f2.indd38_rp1116_f2.indd 4343 110/20/160/20/16 3:403:40 PMPM Dry Eye REVIEW Cover Focus Thicker than Water: Autologous Serum

Kristine Brennan, Senior Associate Editor

The benefi ts and utologous serum was one 100% serum drops. of the fluids used in a 1975 Darren G. Gregory, MD, associ- limitations of this Astudy testing the ability of a ate professor of ophthalmology at perfusion pump to keep chemically the University of Colorado School unique corneal burned eyes moist.1 The fi rst study of Medicine, spearheaded an ASED describing the benefi ts of serum eye program at the University of Colora- therapy. drops in Sjögren’s syndrome patients do Eye Center in Aurora, Colo., now with keratoconjunctivitis sicca was in its second decade. “The patient published in 1984.2 Eye drops de- gets blood drawn at the hospital’s out- rived from a patient’s own blood have patient blood-draw center, and then gained therapeutic standing over the the inpatient pharmacy centrifuges intervening decades, helping many and prepares the drops. Then the pa- dry-eye patients live better lives. Au- tient can pick up the drops from the tologous serum eye drops (ASED) hospital pharmacy,” he explains. The are many things: effective, well toler- pharmacy’s standard dilution is 25%, ated and full of substances that arti- but the strength can be titrated up to fi cial tears can’t replicate. They are 100% serum. also costly and not readily available Anat Galor, MD, MSPH, a staff to every patient who might benefi t physician at the Miami Veterans Af- from them. Here, three practitioners fairs Medical Center and associate discuss the benefi ts and challenges of professor of clinical ophthalmolo- using ASED to treat dry-eye patients. gy at Bascom Palmer Eye Institute University of Miami Miller School of How They’re Made Medicine, credits her colleague, Vic- tor L. Perez, MD, with setting up a Preparation protocols for ASED serum tears laboratory in the Bascom vary, but they all share these funda- Palmer Ocular Surface Center that mental steps: The patient donates makes procuring ASED easy for pa- blood; the blood coagulates and is tients. “I just write a prescription and centrifuged to extract the serum; and I send it to the lab, where it’s all done a quantity of serum is placed into for them,” she says. Dr. Galor says a dropper bottle, usually with dilu- that their standard dilution is 20%, ent—often a sterile saline solution. “but we can escalate the dosage up to Most drops are 20% serum, although 50% in our lab, based on effect.” some patients use 25%, 50%, or even Christopher J. Rapuano, MD,

44 | Review of Ophthalmology | November 2016 This article has no commercial sponsorship.

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REVIEW Focus Anat Galor, MD, MSPH chief of the cornea service at Wills Eye Hospital in Philadelphia, also typically starts his patients at 20% dilution. “We can go up to about 50%, but there’s no right or wrong on that,” he says. His patients currently get their drops made outside of Wills Eye. Dr. Rapuano calls a designated blood-draw facility to advise that a pa- tient is coming to donate. The blood then goes to a specialized compound- ing pharmacy in Maryland, which in turn ships the fi nished ASED to his patients.

The Benefi ts

To launch an ASED protocol at his hospital, Dr. Gregory had to pitch its Patients with limbal stem-cell defi ciency undergoing PK are at risk of developing dry eye. potential benefi ts. “I had to convince Autologous serum eye drops started preoperatively can help prevent this. a lot of committees that such a pro- gram was a viable option,” he recalls. who have a lot of signs of dry eye, universal protocol for preparing and ”We think that the various growth such as diffuse staining” that is refrac- storing the eye drops. Studies have, factors and nutrients that are con- tory to traditional therapies. “In those however, demonstrated instances of tained in the serum provide a lot of cases, it may be that the density of the ASED surpassing artifi cial drops in things for the surface of the eye that serum tears—the fact that they have a promoting comfort and improving may be missing when the eye is very lot of albumin—could be coating the the quality of the tear fi lm.3,4 dry, or if there is scarring or other ab- eye and driving the benefi cial effect,” Sjögren’s syndrome can cause normality on the surface of the eye. It she says. “Then again, it could be that severe dry eye stemming from can often alleviate dry-eye symptoms helping the nerves secondarily helps diminished basal and reflexive tear in patients who have not had good re- the epithelium, so that it all comes production.5 Dr. Galor says that lief from other available treatments. down to nerve health.” In addition patients with Sjögren’s and other It can also help non-healing corneal to using ASED before and after cer- autoimmune diseases can benefit epithelial defects,” he explains. tain high-risk corneal transplants from ASED. “There’s always a ques- “Dry eye is a huge category,” adds and SLET procedures, Dr. Galor tion regarding patients with autoim- Dr. Rapuano, “including patients with prescribes them for post-vitrectomy mune disease, because they have severe ocular surface disease, chemi- diabetics. “I also use them in patients circulating autoantibodies: Is their cal burns, Stevens-Johnson syndrome when I’m worried about their limbal blood going to be helpful for serum and ocular cicatricial pemphigoid.” stem-cell environment,” she explains. tears? But we have a very large group He tells his patients that ASED con- “That’s a very specifi c subtype of dry of patients with Sjögren’s syndrome tain “goodies” found in the body but eye that is not very common, but it’s and graft-versus-host disease, and unavailable in artifi cial tears, such as very diffi cult to keep the epithelium these patients seem to do well.” antibodies and growth factor. “It of- healthy in those patients.” A multifactorial condition with ten helps them feel better, see better, Serum contains bioactive agents numerous treatment options, dry and it helps the health of the ocular that may promote healthy cell growth eye sometimes proves recalcitrant surface.” and healing of the ocular surface, to measures such as artificial tears, “Whatever the underlying biology including albumin, vitamin A, and ointments, eyelid hygiene, moisture is, clinically, they work,” says Dr. Ga- nerve and epidermal growth factors. masks, glasses, goggles and punctal lor. “I’m a total believer in autologous Evaluating evidence regarding the plugs. When other therapies fail, serum tears.” She uses them in pa- effi cacy of ASED is not helped by the ASED can improve quality of life for tients with neuropathic eye pain, neu- fact that sample sizes tend to be small patients, either alone or with oth- rotrophic keratitis and for “patients with little follow-up; there is also no er modalities. Why, then, have they

November 2016 | reviewofophthalmology.com | 47

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REVIEW Focus

failed to become a standard part of Table 1. Possible Infections tal for preparing the drops,” he says. the dry-eye armamentarium? “We have a careful process. There are While Dr. Gregory counts himself certainly practices that will prepare fortunate to offer his patients ASED, Although infections are rare in the them in their own offi ces for patients, he has had to advocate for it. “We’ve literature surrounding the use of ASED, but I think that’s a little riskier.” squabbled with the hospital commit- studies of dropper bottles have shown While safe handling of blood prod- tee,” he acknowledges. “The pharma- positive microbiological cultures for fungi ucts during ASED formulation is cy was looking at all of their overhead and bacteria, including: critical, so is the safe handling of fi n- costs—factoring in the cost of light- ished eye drops. Patients must be ing in the lab, for example. They did Aspergillis spp7 counseled to store their unopened an analysis from start to fi nish: The Bacillus sp6 droppers in the freezer. A dropper blood-draw center had its charge; Candida sp6 in use should be refrigerated to pre- they fi gured in a charge for the in- Fonsecaea spp7 serve benefi cial agents and retard the hospital courier who walks the blood Klebsiella pnueumoniae6 growth of harmful microorganisms. from the blood-draw center up to the Micrococcus sp6,8 Although adverse events are rare in pharmacy lab where they mix it.” Dr. Psuedomonas aeruginosa6 the literature, dropper bottles can Gregory estimates that a three-month Staphylococcus aureus6,8 culture bacterial and fungal contami- supply of drops starts at $180 for his Staphylococcus epidermidis8 nation.6,7,8 “Theoretically, bacteria patients. “There were times when Streptococcus viridans6,8 could start to grow and patients could they tried to raise the price to nearly be giving themselves bacteria in the $300 for a batch, but the patients just eye,” notes Dr. Rapuano. “That’s why aren’t going to be able to pay that,” he ing is not an exclusion criterion at they have to take care of the drops continues. “We gave patient testimo- Bascom Palmer Eye Institute. “We and keep them in the freezer before nials to the various leadership folks in practice universal precautions, and use. We always tell patients there’s the hospital. We presented them with we do not test the blood prior,” Dr. a little bit of risk to this, but that a number of articles from the medical Galor says. “We’ve had good success we think there’s a bigger risk to the literature supporting the use of this with patients who have infectious se- current eye problem we’re trying to type of drop. Because we are a big rological markers. Our patients with treat.” academic center, we try to provide HIV, for example, seem to do well. care that is not readily available else- We haven’t found specifi c blood types Logistics and Costs where, so they recognized the impor- that are a contraindication to the clin- tance of that. Thankfully, we’ve been ical effect of serum tears; and again, Not only must patients comply able to maintain the program for over there are very strict universal precau- with safe storage and use guidelines 10 years now.” tions, no matter who the patient is.” to benefit from ASED; they must Prior to the protocol that Dr. also follow the steps it takes to obtain The Right Patients Rapuano currently uses for his pa- drops—several times per year, pos- tients, the lab that did blood draws sibly for years to come. Even though While ASED can and do help many required testing. “I’m told that’s not Dr. Gregory’s patients can get their patients, they aren’t for everyone. required anymore,” he says. “It was drops made on one campus, that lo- “About half of the patients we try it always a little bit funny to me as to cation is the only large academic eye on seem to benefi t and we continue; why that was required, because uni- facility in a 500-mile radius, so many but half don’t benefi t enough to want versal precautions are taken by the travel great distances. “The process to continue,” says Dr. Rapuano. “It’s a people who draw the blood and the is a bit cumbersome,” he says. “The hassle to get your blood drawn every people who treat the blood; so wheth- patient has to get the blood drawn, three, four, or six months, depending er or not there are infectious compo- and then there’s usually only one day on how much they draw, which de- nents in there, the people handling it per week that we have a technician pends on the percentage of the drops shouldn’t ever be exposed.” who’s assigned to prepare the drops.” you use.” Dr. Gregory’s ASED program Dr. Gregory adds that shipping is Some settings follow blood-donor does not require testing, either. “We available to patients in Colorado, but guidelines that disqualify certain pa- haven’t run into trouble. I guess that’s patients from Wyoming, Kansas, and tients from supplying their own blood part of the benefit of the rigorous Nebraska may need to come back a for the drops. Positive serology test- system that we have in our hospi- few days after blood donation to pick

48 | Review of Ophthalmology | November 2016

0044_rp1116_f3.indd44_rp1116_f3.indd 4848 110/20/160/20/16 3:163:16 PMPM RP1116_Paragon.indd 1 10/12/16 2:35 PM Cover Dry Eye

REVIEW Focus

up their eye drops. addition of other autologous blood glad to have them for our patients,” Last—but certainly not least—on components to increase their clinical he affi rms. the list of challenges to widespread effects. She cites a proprietary kit be- Doctors who want this option for use of autologous serum is the cost, ing developed by a company in Spain their patients need to screen those which is almost always borne by the that would simplify the production of patients carefully, candidly discussing patient. “It’s cash: Insurance generally serum tears. “I don’t have access to the financial and logistical burdens won’t cover it,” says Dr. Gregory. “It’s it, but I know that it’s being looked at that ASED treatment may impose. a couple of dollars a day when you as a way to get the technology out,” They can refer patients to appropri- add it all up, but when patients pay she says. “Another area of interest is ate phlebotomy and compounding it up front, it seems like an awful lot adding other blood products, such facilities to have the drops made, or of money for some drops.” Dr. Galor as making platelet-rich serum tears, face the formidable task of develop- estimates that a two-month supply to make the serum tears more effec- ing a safe in-house protocol. Educat- costs about $220. “It’s not cheap,” she tive. There is still a lot that’s unknown ing patients about the safe storage acknowledges, but her VA patients about the best percentages, formula- and handling of ASED is also impor- are spared out-of-pocket costs. “One tions, and other blood products you tant. Despite this lengthy to-do list, nice thing is that the veterans get it may want in there to enhance the autologous serum eye drops can offer paid for,” she notes. effect. Those are some of the things patients with recalcitrant dry eyes— Researchers have attempted to de- that people are talking about.” and the suffering that accompanies velop uniform preparation protocols Dr. Gregory notes that Regener- them—a good measure of bang for that would be accessible, affordable, Eyes, a Florida-based company, has the buck, provided they have the and replicable in most health-care made amniotic-fl uid eye drops com- money to spend. settings. A paper published in 2011 mercially available, and cites plasma “They help a lot of people,” says Dr. estimated that ASED cost U.S. pa- rich in growth factors as another po- Rapuano. “We tell patients that this is tients anywhere from $25 to more tential avenue of dry-eye therapy. His an unusual use, and we’re doing it to than $600 out of pocket for a two- hospital was involved in human trials address an unusual problem.” to three-month supply.9 Research- of an eye drop derived from recom- ers from Hamilton Eye Institute in binant bovine albumin. “I’m not sure Dr. Gregory, Dr. Galor, and Dr. Memphis, Tenn., proposed a protocol what became of it,” he says. “We had Rapuano report no fi nancial interest wherein blood-draw centers would just a handful of patients using it. We in any of the products mentioned in take the lead in serum preparation as didn’t know if they were getting pla- this article. well as blood collection. Factoring in cebo or the actual medication, so I 1.Ralph RA, Doane MG, Dohlman CH. Clinical experience with a the costs of materials and technician didn’t have a great sense of whether mobile ocular perfusion pump. Arch Ophthalmol 1975; 93:1039. time to produce one three-month or not it was helpful. But I think it 2.Fox RI, Chan R, Michelson J, et al. Benefi cial effect of artifi cial tears made with autologous serum in patients with supply of ASED, they posited an es- always comes down to the same prob- keratoconjunctivitis sicca. Arthritis Rheum 1984; 29: 577-83. timated cost of $80, which didn’t in- lem: None of these treatments, to 3.De Pascale MR, Lanza M, Sommese L, Napoli C. Human serum clude packaging or shipping. Another my knowledge, are currently covered eye drops in eye alterations: An insight and a critical analysis. J Ophthalmol 2015; 2015:396-410. estimated cost was $82 for annual under people’s insurance, so it’s all 4.Celebi AR, Ulusoy C, Mirza GE. The effi cacy of serum eye serological tests: The protocol exclud- out-of-pocket and expensive. Unfor- drops for severe dry eye syndrome: A randomized double- blind crossover study. Graefes Arch Clin Exp Ophthalmol ed patients with markers for HIV, tunately, nothing has really grabbed 2014;252:619-26. hepatitis or syphilis. hold or become logistically simple or 5.Tsubota K, Goto E, Fujita H, Ono M, Inoue H, Saito I, Shimmura S. Treatment of dry eye by autologous serum in Sjögren’s affordable.” syndrome. Br J Ophthalmol 1999; 83:390-395. Are Alternatives Coming? Refl ecting on his ASED program, 6.Leite SC, de Castro M, Alves M, Cunha DA, Correa MEP, da Silveira LA, Vigorito AC, de Souza CA, Rocha EM. Risk factors Dr. Gregory remains convinced of and characteristics of ocular complications, and effi cacy of Given the inherent challenges of its importance to his severe dry-eye autologous serum tears after haematopoietic progenitor cell transplantation. Bone Marrow Transplantation 2006;38:223-7. ASED use, are any other modalities patients. “The serum drops, with our 7.Thanathanee O, Phanphruk W, Anutarapongpan O, Romphruk in the pipeline that would confer preparation protocol, have shown A, Suwan-Apichon O. Contamination risk of 100% autologous serum eye drops in management of ocular surface diseases. their benefits without the hassles? themselves to be a reliable, safe treat- Cornea 2013; 32:1116-9 Dr. Galor sees two emerging tech- ment, that, despite the cost and some 8.Lagnado R, King AJ, Donald F, Dua HS. A protocol for a low contamination risk of autologous serum drops in the nologies, neither of which replaces of the hurdles, has proven very help- management of ocular surface disorders. Br J Ophthalmol 2004; 88: 464-5. autologous serum tears: a prepara- ful for those who haven’t gotten great 9.Partal A, Scott E. Low-cost protocol for the production of tion kit to make them more acces- benefi ts from the more readily avail- autologous serum eye drops by blood collection and processing centres for the treatment of ocular surface disease. Transfusion sible to patients; and the potential able treatment options. We’ve been Medicine 2011; 21:271-77.

50 | Review of Ophthalmology | November 2016

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RP1116_PRN.indd 1 10/4/16 2:14 PM of ers Su t rg s e a r y M Ten Things NOT To Do As a Surgeon

Go out and meet other practitioners in the area; communicate with refer- ring doctors and return patients to Bennie H. Jeng, MD them; be available to see their patients Baltimore any time; be nice to patients; and in- vest some time in making your prac- tice effi cient. Looking back, this was all true, and it’s advice that I continue phthalmology is the greatest to pass along to all of the trainees with O specialty in medicine, and studies whom I have the privilege of working. Sometimes, you have shown that we ophthalmologists While these are words to live by, are, in general, among the most sat- however, they’re rather general sug- can do what’s right isfied and content physicians when gestions, and I would like to provide compared to our colleagues in other more-specific ideas. Many times, just by knowing specialties. Before I knew these sta- when asked for advice, experts will tistics about satisfaction, though, I give you their top 10 reasons to do what’s wrong. sensed it, even as a medical student: something. Since my status as an ex- The cliché of ophthalmology being a pert is questionable, I thought I would nice blend of medicine and surgery change things up and give you my top was true, and I found it especially ap- 10 things NOT to do when you are pealing that I could be a transplant starting out as an ophthalmic surgeon. surgeon without dealing with blood These may seem obvious, but hav- (for the most part). As such, I was sure ing them in writing can be a useful that if I made it into ophthalmology, reminder: cornea would be my specialty, since 1) DON’T show off. Picture this: it’s the only part of the eye that can It’s your fi rst week at your practice’s be transplanted (for now). This no- ASC and you want everyone to know tion, coupled with the fact that I was that you’re a great surgeon. Even unable to see the retina in residency, though you probably are great, if made cornea the fi eld for me. your average phaco time is 10 min- utes, don’t try to push it and do a fi ve- Words to Live By minute phaco just to show everyone how awesome you are. If you push it, When I finished my fellowship bad things will happen—and then you training, I felt that I was well-trained won’t look so awesome. and had been armed with excellent Whether you feel it or not, when advice about how to build a practice: performing surgery, there’s a big jump

52 | Review of Ophthalmology | November 2016

052_rp1116_masters.indd 52 10/20/16 3:41 PM Edited by

Taliva D. Martin, MD Sara J. Haug, MD

from being a supervised trainee to being the one who is fully respon- sible. Let that sink in as you get back into the groove before turning it up a notch to achieve that five-minute case. 2) DON’T cut corners. During training, many residents and fellows have the luxury of not having to see every patient in a faculty practice. Trainees can spend their time with “interesting” patients who provide educational value, along with more mundane tasks such as suture remov- al and retinal injections. Then you hit the real world—and every patient that is scheduled to see you is yours. How- ever, we each see patients at a differ- The Argentinian Flag sign—it happens. Remember that you’re human (See tip #9), but just be prepared ahead of time and know what you will do when this occurs. ent pace. If 20 patients in a half day leads you to cut corners on patient care, then cut back the schedule until everyone and let them know how you should still seek out opportuni- you can increase your or your prac- much you appreciate them. Yes, ties to learn. This is especially true for tice’s effi ciency, but don’t cut corners you are inherently nice, but when you surgical procedures: as newer tech- on taking care of your patients. The realize that everything in your practice niques evolve, the techniques that extra time you spend with them in the and ASC is now your responsibility, you learned in training can become beginning will generate the word of sometimes the stress can build up un- obsolete, and you need to keep up mouth that’ll help build your practice til you’re short with—or lose it on—a with the times to be able to provide in the end. staff member. If that happens, apolo- the best care for your patients. I can The same idea goes for surgery. We gize, because saying you’re sorry can personally attest to this: The fi eld of just talked about not showing off in have a very positive effect on people. cornea has changed greatly in the past the OR, but we also inherently don’t Yes, you’re now the boss, but always decade. For instance, during my fel- want to look like we’re too slow, so we remember that you can’t do anything lowship, which was less than 15 years often feel the pull to cut corners here without your staff: It would take more ago, I only did full-thickness grafts, and there. You might instinctively feel than twice as long to do surgery if you as lamellar keratoplasty was not yet that that the wound is most likely wa- had to be both the scrub technician popularized or refi ned. Now, in most tertight, and so you don’t want to have and the surgeon. A little appreciation cases for certain indications, lamellar to ask for a 10-0 nylon suture to close goes a long way and can encourage keratoplasty is considered the stan- it and subsequently take an extra two your staff to go the extra mile for you dard of care. If I didn’t go out and minutes in the OR. Just remember and the practice. learn endothelial keratoplasty on my that those extra two minutes can save 4) DON’T stop learning. When own, I’d be in trouble, and I wouldn’t hours the next day if you have to take you complete your residency and fel- be providing the best care possible to the patient back to put a suture in—or lowship, it’s easy to think that you’ve my patients. worse, have to deal with an endoph- learned everything you need to know. 5) DON’T lose touch with your thalmitis. If you think you might want However, chances are there are things mentors. You chose your residency to do something in the OR so you’ll you didn’t have the opportunity to and fellowship for a number of rea- sleep better, just do it, and don’t cut learn in training, and there are defi - sons, including the clinical experience that corner. nitely things you haven’t seen in your you’d get, the faculty you’d interact 3) DON’T forget to be nice to office or done in the OR. As such, with and the research opportunities

November 2016 | reviewofophthalmology.com | 53

052_rp1116_masters.indd 53 10/20/16 3:41 PM that would be available tough situations that I think to you. But it doesn’t end in retrospect about how I there: Just because you’re might have handled differ- done with official training ently, or how I might have doesn’t mean that they can’t done something differently continue to help you clini- to avoid them. Thinking cally or surgically. Though about and replaying your you may worry that you are mistakes will help you be “bothering” them, or may- come a better surgeon. Just be you’re uncomfortable remember that we all make asking them a question that mistakes. might make them think 9) DON’T forget that you weren’t paying atten- under the drapes there’s tion in training, your men- a real, live patient. You tors should be fl attered that may be a super-slick sur- you’re still willing to ask geon who can perform 30 them for advice. I still love phacos per day from the it when my previous fellows If I only relied on what I learned in fellowship, I wouldn’t have been get-go (remembering #1 (sometimes from years ago) able to give this patient a great outcome with a short recovery period above), but don’t forget send me an email asking for with endothelial keratoplasty. Don’t stop learning (See tip #5). that you originally entered tips on how to handle an medicine to help people. upcoming surgical case. You can ask they’ll be more comfortable with you The people you help have names, and many different people, but your men- should they come back to have sur- aren’t just disembodied eyes, patient tors are the ones who most likely know gery with you. record numbers or “3+ PSC cata- you the best and know what you’re 7) DON’T forget that you were racts.” Though it may only be a fi ve- capable of doing. an amateur at one point. If you’re minute procedure to you, remember 6) DON’T be too proud to ask working in a training program, re- that the patient may be terrifi ed, and for help. As in #4 above, you will not member that you, too, were once a even just a few words of comfort will have encountered every clinical/sur- resident or fellow, and if you are read- go a long way toward reassuring him gical scenario during your training, ing this, you were likely one not too or her. and sometimes, you just don’t know long ago. There was a time when you 10) DON’T forget rules 1 the answer. Being able to admit that also made mistakes, so please remem- through 9. Lest you think that I just you need help can actually earn the ber to be patient with the trainees. ran out of ideas, I actually planned respect of patients and colleagues. Use your own mistakes to help teach for this particular suggestion. Sur- There are still occasions when I’ll tell your trainees. gery, ophthalmology and medicine patients that I have absolutely no idea 8) DON’T forget that you are all require a lifetime of learning, and what they have, and I’ll even do this in human. Though you are no longer learning requires repetition. So, con- front of the residents and fellows. The the “amateur,” you are still human, tinuously reminding yourself of rules patients have all appreciated my hon- and we humans all make mistakes. I 1 through 9 will help you be the best esty and my plan to ask my mentors was told in residency that if you have ophthalmologist, and person, that you for advice (See #5), and will eagerly never had a complication during sur- can be. come back during follow-up to ask gery, then you haven’t done enough what I’ve learned to help them. In surgery. This is totally true, as even Dr. Jeng is a professor and chair of addition, it’s also a good idea to freely the best cataract surgeons fi nd vitre- the Department of Ophthalmology offer patients the opportunity to see ous every now and again. The impor- and Visual Sciences at the University another provider for a second opinion; tant part of this is to recognize your of Maryland School of Medicine. He they always appreciate that, and they mistakes, then acknowledge them can be reached at (667) 214-1232 and respect you more for offering. And and learn from them. I still encounter [email protected].

54 | Review of Ophthalmology | November 2016

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REVIEW Edited by Carl Regillo, MD, and Emmett T. Cunningham, Jr., MD, PhD, MPH

Avoiding the Traps of Hydroxychloroquine Use Proper communication between specialties and using the correct formula for dosing can curb toxicity.

David J. Browning, MD, PhD, Charlotte, N.C.

atients who have a malady requir- based on height. However, in thin, as- ophthalmologists might be confused Ping the cooperation of physicians thenic patients in whom actual body about the importance of the daily dose from different specialties face risks due weight is less than ideal, dosing should and how it should be calculated. The to miscommunication, different per- be based on the actual body weight 2002 guidelines were potentially dan- ceived goals and variable knowledge (ABW), not IBW.4 Although a few cases gerous because of their lack of specifi c- bases across subspecialties. One ex- exist, it’s extremely rare to develop HR ity regarding how to use ABW or IBW ample concerns the prescription of if daily dose does not exceed 6.5 mg/kg in the calculation of the daily dose. The hydroxychloroquine by internists for based on using the lesser of ABW and 2011 guidelines were potentially dan- autoimmune diseases and the screen- IBW for the denominator.5 gerous for the person whose ABW is ing for toxic dosing and retinopathy Ophthalmic publications are partially less than IBW (See case 1). The 2016 by ophthalmologists. In this overview, responsible for the confusion that ex- guidelines are dangerous for the obese I’ll identify the gaps in understand- ists regarding the importance of daily person in whom IBW is less than ABW ing and communication between spe- dosing in preventing HR. Consider (See case 2). cialties that lead to avoidable cases of what three consecutive sets of guide- Safe prescribing of hydroxychloro- retinopathy, and discuss how you can lines from the American Academy of quine isn’t diffi cult. One takes the lesser bridge them. Ophthalmology have to say (Table 1): of the ABW and IBW based on height.4 The 2002 guidelines state that daily The daily dose shouldn’t exceed 6.5 A Persistent Problem dose is of “paramount importance,” mg/kg/d based on the lesser of ABW and advise the use of ABW except in and IBW. Which algorithm to use for Why do cases of hydroxychloroquine obese patients, in which case IBW is IBW is controversial, but as a practical retinopathy continue to develop, when recommended. In 2011, the guidelines concern, probably doesn’t matter. I its pathogenesis has been known since fl ipped, discounting the importance of prefer the National Heart, Lung, and the 1980s? Among several contribut- daily dose unless a patient is obese, in Blood Institute algorithm (Table 2).3 ing causes, the main one is that too which case dosing by IBW is advised. In the following sections, I’ll describe many patients are prescribed toxic daily In 2016, the guidelines fl opped, reaf- case reports involving HC and explain doses.1 Hydroxychloroquine is stored fi rming the importance of daily dose, the dosing issues involved. in lean tissues, and is largely excluded but discounting dosing by IBW while from fat.2 Therefore, dosing of HC stressing dosing by ABW and introduc- Case Report #1 should be based on the lean body mass.3 ing a different conversion factor. In most people this can be determined With such inconsistency, it’s easy to A 74-year-old woman with rheuma- from tables of ideal body weight (IBW) understand how rheumatologists and toid arthritis was started on hydroxy-

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Figure 1. Case report #1. A: Note the somatotype. In the short, obese patient, dosing based on ideal body weight, not actual body weight, is appropriate. B: Paracentral scotomata (red arrow) in her 10-2 visual fi eld test of 2012, missed by her ophthalmologist. C: Annulus of hyperautofl uorescence (green arrow) on blue fundus autofl uorescence imaging from 2014. D: Reduced paracentral wavelet amplitudes (blue arrow) on multifocal electroretinography. E: Paracentral loss of the ellipsoid line and thinning of the outer nuclear layer (yellow arrow) on spectral domain optical coherence tomography.

chloroquine 400 mg/d in 2004. She optical coherence tomography imaging • The rheumatologist prescribed was 5 ft. tall, weighed 198 pounds, and study of the macula showed loss of the a toxic dose of HC based on the had no renal or liver insuffi ciency (Fig- parafoveal ellipsoid zone and thinning patient’s height and weight. The ure 1). She was fi rst referred by her of the outer nuclear layer. patient was 5 ft. tall, with an ideal rheumatologist for screening for reti- This case illustrates the following body weight of 123 pounds (55.9 nopathy in 2012, and had lost the left avoidable, commonly seen traps in the kg, see Table 2) and a maximal daily eye to trauma as a child. multidisciplinary management of the safe dose of 55.9 x 6.5=363 mg/d of The ophthalmologist who screened patient taking HC: HC. To achieve this using the avail- her in 2012 found her to have a cor- able pill size of 200 mg, one con- rected visual acuity of 20/20 in her Table 2. An Algorithm for Ideal siders the fact that HC has a long right eye and interpreted her 10-2 vi- half-life (approximately 40 days1). sual fi eld and multifocal electroretino- Body Weight Thus, one can omit a day of dosing gram as normal, although they were Height (inches) Weight in a week and arrive at a suitable not. He didn’t recognize her toxic dos- average daily dose. Over a week’s ing and made no recommendation to (pounds) duration, this patient can take up to change it. She was asked to return in 60 123 7 x 363=2,543 mg of HC safely. If six months but never did. 61 127 she takes two tablets per day Mon- A different ophthalmologist exam- 62 131 day through Saturday and skips HC ined her in 2014. Her corrected visual 63 135 on Sunday, her weekly total dose acuity was 20/20 in the right eye and 64 140 will be 2,400 mg which averages her fundus examination was normal. A 65 144 out to 2,400/7=343 mg/d, which is 10-2 VF using a red test object showed less than a toxic dose. progression of an annular scotoma that 66 148 • The patient had no baseline was present in 2012. A spectral domain Source: Nat’l Heart, Lung, and Blood Institure ophthalmic screening examina-

November 2016 | reviewofophthalmology.com | 59

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Figure 2. Case report #2: A: Note the somatotype. In the asthenic patient, dosing based on actual body weight, not ideal body weight, is appropriate. B: Nonreproducible central scotoma (red arrow) in her 10-2 visual fi eld test isn’t typical of hydroxychloroquine retinopathy. C: Blue fundus autofl uorescence imaging is normal. D: Near infrared refl ectance imaging shows a hyperrefl ective annulus (yellow arrow) which has low sensitivity and specifi city for hydroxychloroquine retinopathy. E: The refl ectivity of the ellipsoid line in the parafovea is slightly less than in the fovea, a potentially early sign of retinopathy. F: Multifocal electroretinography is normal.

tion and wasn’t sent for screen- of HC. Toxic dosing is consistently clinical confidence in a diagnosis. ing by an ophthalmologist until found in 12.8 to 74.7 percent of The topic has been thoroughly ex- eight years into therapy. This patients taking HC.4,8-10 Correcting plored in multiple publications.1,12,13 occurred despite the patient hav- toxic daily dosing is the most com- Failure to properly interpret patient ing a high risk for toxicity based on mon action taken by the screening testing has formed the basis of large her daily dosing. AAO guidelines ophthalmologist, and is the main malpractice settlements in missed state that a baseline exam should be reason to screen patients taking cases of HR. obtained and then, for low-risk pa- HC. Where safe dosing is assumed, tients, yearly examinations should as in Great Britain, screening isn’t Case Report #2 begin fi ve years later. Ophthalmol- recommended because the rarity of ogists have regularly rejected these HR in these circumstances makes it In 2015, an ophthalmologist exam- recommendations.4,7 Rather than a wasteful use of scarce resources.11 ined a 63-year-old woman with rheu- continuing to recommend a gap in • The first ophthalmologist matoid arthritis who had been taking screening that’s rejected by those failed to recognize the evidence of HC 400 mg/d since 1990 (25 years, tasked with screening for retinopa- toxicity on the initial 10-2 VF. The 3,650 g cumulative dose). She was 5 ft. thy, it would be better if the guide- diagnosis of HR is based on ancillary 3 in. tall and weighed 112 pounds. She lines embraced the practical reality testing: 10-2 VF; SD-OCT; mfERG; had no renal or liver disease. Her cor- that annual screening is the norm, and fundus autofl uorescence imag- rected visual acuity was 20/20 and her which in the first years is mainly ing. Ophthalmologists who screen for fundus examination was normal bilat- aimed at detecting and correcting HR have an obligation to understand erally. Her 10-2 visual fi eld performed toxic daily dosing. what constitutes a positive test, what with a red test object showed a non- • The doctor failed to recog- the potential artifacts are, and how reproducible relative central scotoma nize and correct the toxic dosing to use multiple modalities to raise (Figure 2). Her fundus autofluores-

November 2016 | reviewofophthalmology.com | 61

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REVIEW Insider

Table 1. AAO Recommendations for Daily Dosing: Three Iterations Over 14 Years

2002: “The great majority of reports of hydroxychloroquine toxicity have occurred in individuals taking more than 6.5 mg/kg/d, which suggests that daily dosage is of paramount importance … Obesity is a risk factor because antimalarials are not retained in fatty tissues. Ingested amounts of the drug accumulate only in lean weight, and the “safe” dose for individuals with a high percentage of weight is less than 6.5 mg/kg …” 2011: “… recent surveys of patients taking hydroxychloroquine found that the risk of toxicity depended on cumulative exposure and was indepen- dent of daily dose or dose/kg … We suggest that daily doses be limited to 400 mg hydroxychloroquine and that lower doses (in the range of 6.5 mg/kg hydroxychloroquine … calculated on the basis of ideal body weight) be used for individuals who are of short stature. ...Obese individuals should be dosed on the basis of height, which allows estimation of an asthenic or ‘ideal’ body weight.” 2016: “… we recommend that all patients using hydroxychloroquine keep daily dosage < 5 mg/kg real weight. …Ideal weight formulas result in overdose in thin individuals…The most cited risk factor for the development of hydroxychloroquine toxicity is excessive daily dose by weight.”

cence imaging was normal. Her near and obese patients, for whom the AAO weight. This is a dangerous recom- infrared refl ectance imaging showed a advises calculating dosage based on mendation for the short, obese patient faint hyperrefl ective ring, which has in- ideal body weight for height.” This is as exemplifi ed in Case Report 1. consistently been associated with early not what the quoted reference states, In a rheumatologic review of HR HR.14 The SD-OCT showed a slightly however. Instead, it states, “The prior the authors wrote, “A French study less hyperrefl ective ellipsoid line and a recommendation [the 2002 guidelines] showed that whole-blood HC concen- suggestion of outer nuclear layer thin- emphasized dosing by weight. How- tration >1,000 ng/ml reduced risk of lu- ning. Multifocal electroretinography ever, most patients are routinely given pus fl ares. Measurement of HC blood was normal. 400 mg of HCQ daily. ...This dose is levels may suggest that some patients Because there was no defi nite reti- now considered acceptable, except for require >6.5 mg/kg/day to achieve the nopathy, she was cleared for continued individuals of short stature, for whom recommended level. These patients use of HC, but her toxic dosing was the dose should be determined on should not be at increased risk of tox- corrected. The lesser of her ABW and the basis of ideal body weight to avoid icity, providing levels are monitored, IBW was her ABW, which was 112 overdosage.”16 but it may be important to monitor pounds. Therefore, the upper limit of The author continues, “The sen- cumulative dose as well when assessing her safe daily dose was 330 mg. It was sitivity and specificity of these tests risk of ocular toxicity.”18 The statement recommended that she take no more are not yet known for hydroxychloro- erroneously suggests that there is a than 200 mg/d for the next six months quine-related retinal toxicity. There is known relationship between HC blood at which time repeat ancillary testing a high rate of baseline abnormalities, levels and HR, but this is not the case. was recommended to determine if in particular in those who are elderly If prescribing internists and screen- there was a signal for early retinopathy or have comorbid disease, which make ing ophthalmologists put a clearer given her large cumulative dose. the changes challenging to interpret. understanding of correct daily dosing Rheumatologic publications also Another issue is that systemic lupus into practice, the prevalence of HR contribute to confusion on dosing. In erythematosus itself associates with would fall. In most cases, the condition an April online article from the rheu- the presence of retinal abnormalities, is iatrogenic and can be avoided. Daily matology website RheumNow.com, adding further to the complexity of dosing is the only modifi able risk factor the author writes, “The known risk deciphering these tests.” These are and deserves the greatest attention in factors for the development of ocular incorrect statements. The relative sen- screening visits, especially in the fi rst deposition include duration of therapy, sitivity and specifi city of the tests are fi ve years of use of the drug, before the cumulative dose and renal function.”15 known (mfERG is most sensitive, 10-2 irreversible, cumulative load has built She doesn’t mention the most impor- VF next, and SD-OCT least; SD-OCT up and raises the retinopathy risk. The tant, and only modifi able, risk factor— is most specifi c, 10-2 VF is next, and recommendation that low-risk cases daily dosing. She goes on to write, “The mfERG is least).17 The rate of baseline have screening omitted for fi ve years American Academy of Ophthalmology abnormalities is high for 10-2 VF test- after a baseline examination has been (AAO) [citing the 2011 guidelines] ad- ing, but not for SD-OCT or mfERG. widely rejected by those who do the vises weight-based dosing of 6.5 mg/kg, SLE rarely affects any of the tests. screening, and is probably misguid- with an upper limit of 400 mg/day. Ex- Finally, the author advocates dos- ed given the high prevalence of toxic ceptions are individuals of short stature ing based on 6.5 mg/kg/actual body dosing. Detection and correction of

62 | Review of Ophthalmology | November 2016

0057_rp1116_rtinsider.indd57_rp1116_rtinsider.indd 6622 110/20/160/20/16 3:303:30 PMPM toxic dosing is of greatest value for the prevention of retinopathy in the early years of taking HC. The extremely rare cases that develop retinopathy despite safe dosing are more likely to be detected when a more sensitive and more specific ancillary test, for example, 10-2 VF and SD-OCT, are used together and when interpretation is competently done.

Dr. Browning is a retina specialist at Charlotte Eye, Ear, Nose, and Throat AW]¼ZM Associates. Contact Dr. Browning at 6035 Fairview Rd, Charlotte, NC TMI^QVOUM° 28210. He can be reached at (704)- 295-3180, or [email protected]. IZMV¼\aW]'

1. Browning DJ. Hydroxychloroquine and chloroquine retinopathy. New York: Springer, 2014. 2. McChesney EW, Banks WF Jr, Fabian RJ. Tissue distribution of chloroquine, hydroxychloroquine, and desethylchloroquine in the rat. Toxic App Pharm 1967;10:501-513. 3. Browning DJ, Lee C, Rotberg D. The impact of different algorithms for ideal body weight on screening for hydroxychloroquine retinopathy in women. Clinical Ophthalmology 2014;8:1401. 4. Browning DJ. Impact of the revised American Academy of Ophthalmology guidelines regarding hydroxychloroquine screening on actual practice. Am J Ophthalmol 2013;155:418.. 5. Falcone PM, Paolini L, Lou PL. Hydroxychloroquine toxicity despite normal dose therapy. Ann Ophthalmol 1993;25:385-388. 6. Browning DJ. Reply to Defi ning Ideal Body Weight. Am J Ophthalmol 2002;134:935-936. 7. Blomquist PH, Chundru RK. Screening for hydroxychloroquine toxicity by Texas ophthalmologists. J Rheumatol 2002;29:1665. 8. Wolfe F, Marmor MF. Rates and predictors of hydroxychloroquine retinal toxicity in patients with rheumatoid arthritis and systemic Parasol® lupus erythematosus. Arthritis Care Res 2010;62:775-784. 9. Cukras C, Huynh N, vitale S, Wong WT, Ferris III FL, Sieving PA. Subjective and objective screening tests for hydroxychloroquine toxicity. Ophthalmology 2015;122:356-366. 10. Lee MG, Kim SJ, Ham DI, Kang SW, Kee C, Lee J, Cha HS, Koh Trust us. We’re not like the others. EM. Macular retinal ganglion cell-inner plexiform layer thickness in patients on hydroxychloroquine therapy. Invest Ophthalmol Vis Sci 2015;56:396-402. Patients shouldn’t fear their tears will disappear 11. FielderA, Graham E, Jones S, et al. Royal college of ophthalmologists guidelines: Ocular toxicity and hydroxy- because their plugs up and left. Help them face chloroquine. Eye 1998;12:907-909. 12. Marmor MF, Melles RB. Disparity between visual fi elds and life with eyes wide open and comfortably moist. optical coherence tomography in hydroxychloroquine retinopathy. Ophthalmology 2014;121:1257-1262. Trust the Parasol Punctal Occluder; it’s the perfect 13. Mititelu M, Wong BJ, Brenner M, et al. Progression of fi t for your patients — and guaranteed to stay put. hydroxychloroquine toxic effects after drug therapy cessation. New evidence from multimodal imaging. Arch Ophthalmol 2013;131:1187-1197. TO ORDER: 14. Wong KL, Pautler SE, Browning DJ. Near-infrared refl ectance 866-906-8080 bull’s eye maculopathy as an early indicator of hydroxychloroquine toxicity. Clin Ophthalmol 2015; 9:521-5. [email protected] 15. Petrie M, Durcan L. “The role of hydroxychloroquine blood levels in SLE” found at http://rheumnow.com/blog/role- odysseymed.com or beaver-visitec.com hydroxychloroquine-blood-levels-sle#.VvaKbIfbwMQ.mailto. Accessed 28 September 2016. 16. Marmor MF, Kellner U, Lai TYY, Lyons JS, Mieler WF. Revised recommendations on screening for chloroquine and hydroxychloroquine retinopathy. Ophthalmology 2011;118:415. 17. Browning DJ, Lee C. The relative sensitivity and specifi city of 10-2 visual fi elds, multifocal electroretinography, and spectral domain optical coherence tomography in detecting hydroxychloroquine and chloroquine retinopathy. Clinical Ophthalmology 2014;8:1389-1399. 18. Ding HJ, Denniston AK, Rao VK, Gordon C. Hydroxychloroquine- related retinopathy. Rheumatology (Oxford) 2016;55:6:957-67. Beaver-Visitec International, Inc., 411 Waverley Oaks Road, Waltham, MA 02452. BVI, BVI Logo and all other trademarks (unless noted otherwise) are property of Beaver-Visitec International (“BVI”) © 2016 BVI

0057_rp1116_rtinsider.indd57_rp1116_rtinsider.indd 6633 110/20/160/20/16 3:303:30 PMPM An interdisciplinary faculty of ophthalmic subspecialists will review the continuing progress in Cataract and Refractive Surgery, Save the Date Glaucoma, Retina, Neuro-Ophthalmology, Pediatric Ophthalmology, Ocular Surface Disease, Cornea and Oculoplastics. OphthalmologyUpdate LOCATION Hilton Torrey Pines NEW San Diego, CA THIS YEAR Hands-on PROGRAM CHAIRS Workshops Don O. Kikkawa, MD Robert N. Weinreb, MD

FOR MORE INFORMATION www.ReviewofOphthalmology.com/Update2017 Email: [email protected] Phone: 855-306-2474

PROGRAM TIMES* Saturday, February 18 8:00am — 5:00pm Reception to follow Sunday, February 19 8:00am — 12:15pm

*Subject to change

Accreditation Statement This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of Amedco and Postgraduate Health Education, LLC (PHE). Amedco is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Statement ©iStock.com/uschools This meeting is approved for AMA PRA Category 1 Credits™

Jointly provided by Shiley Eye Institute Review of Ophthalmology® UC San Diego Plastic Pointers

REVIEW Edited by Ann P. Murchison, MD, MPH

Periocular Peels And Potions A look at the chemical agents patients can use topically in an effort to fi ght the effects of aging. Teri Kleinberg, MD, Worcester, Mass.

search for “crow’s feet cream” used for peels can be used at much Vitamin C A on Amazon.com revealed more lower concentration with daily appli- than 3,000 products, one of which cation. As discussed in the fi rst part of Vitamin C, or ascorbic acid, is a well- costs nearly $1,000 for less than 1 oz. this series, “Chemical Peels Demysti- studied antioxidant for the treatment of cream and claims to be an “effec- fi ed,” in the October issue of Review, of photodamaged skin. The effects are tive anti-wrinkle serum which acts alpha hydroxy acids (See Table 1), thought to occur via transcriptional up- on all types of facial lines, thanks to including glycolic acid derived from regulation of collagen synthesis, scav- an exclusive combination of four tar- sugarcane, cause superfi cial exfolia- enging of reactive oxygen species, and geted active ingredients ... expression tion by keratinocyte discohesion at inhibition of elastin biosynthesis and lines are immediately smoothed and the level of the stratum granulosum in tyrosinase to reduce elastin accumula- relaxed, dehydration lines are erased the epidermis with resulting improve- tion and pigment synthesis, respective- and plumped, and deep wrinkles are ment in skin texture.1 AHAs can be ly.2,3 Unlike most plants and animals, plumped from the inside with spec- combined with retinoids to accelerate humans cannot synthesize ascorbic tacular results after four weeks of use.” skin turnover from 28 days to 10 to acid; it must be obtained via diet or When facing this avalanche of mar- 12 days in preparation for subsequent topical application.3 However, oral in- keting lingo, unless you’ve had cos- chemical peels.1 Glycolic acid prod- gestion of ascorbic acid doesn’t pro- metics plastics training or have spent ucts can be used as daily skin-care vide adequate replenishment of skin time sifting through the literature, it’s products at concentrations as low as ascorbic acid stores. Due to diffi culty hard to know which claims are based 5 to 15%. in stabilization, a topically absorbed on good data and which version of L-ascorbic acid are just hype. The follow- Table 1. Common Alpha Hydroxy Acid Products has only recently been avail- ing article, the second in able.4 Topical L-ascorbic a two-part series, reveals Brand Name Product (concentration) acid can be used to allevi- chemical agents that have ate skin infl ammation from Obagi Nu-Derm Exfoderm Forte (6% glycolic acid, strong evidence to sup- 4% lactic acid) ultraviolet light exposure, as port their use in periocu- well as erythema from laser lar anti-aging. NeoStrata Foaming Glycolic Wash (18% glycolic acid) resurfacing procedures.4 A Daily Antioxidant Peel (10% citric acid) porcine study demonstrated Alpha Hydroxy Acids SkinCeuticals Retexturing Activator (20% glycolic acid) that best skin absorption of SkinMedica Glypro products (proprietary % glycolic acid) L-ascorbic acid occurs at a Chemicals that can be pH less than 3.5 and a con-

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REVIEW Pointers

at least two weeks prior to chemical Table 2. Commercially Available L-Ascorbic Acid Preparations peels can reduce post-peel infl amma- tion, improve peel uniformity and ac- Brand Product Name % L-Ascorbic Acid pH celerate re-epithelialization.7 Topically SkinCeuticals C+AHA 15 Unknown applied retinol (vitamin A, all-trans- SkinCeuticals AOX+ Eye Gel 5 Unknown retinol) is converted into retinaldehyde SkinCeuticals C E Ferulic 15 Unknown and subsequently into the active me- SkinCeuticals AOX+ 10, 15 or 20 Unknown tabolite retinoic acid (tretinoin) by de- hydrogenases in human keratinocytes.9 Cellex-C High Potency Serum 10 2.2 Active stereoisomers 9-cis-retinoic Cellex-C Sensitive Skin Serum Unknown 3.3 acid (alitretinoin) and 13-cis-retinoic Cellex-C Eye Contour Gel Unknown Unknown acid (isotretinoin) as well as adapalene, tazarotene and seletinoid G are ap- Cellex-C Advanced C Serum 17.5 Unknown plied in their active form.7 Obagi Professional-C 10, 15 or 20 Unknown Tretinoin and tazarotene are ap- proved for photodamage treatment. Table 3. Forms of Retinoids Available Topically The typical protocol is 0.05% tretinoin Form Brand Names (concentration) cream applied nightly, with improve- Retinol Multiple brands including: ment in epidermal thickness and fi ne Jan Marini Skin Research Age Intervention Enlighten, wrinkles at three months (based on Luminate, Luminate Eye, Retinol Plus (all proprietary Level II Evidence, and well-designed percentages) case-controlled, cohort or non-ran- Obagi (0.5%, 1%) SkinMedical Lytera (proprietary percentage), Retinol domized trials) and improvements in Complex (0.25%, 0.5%, 1%) fi ne and coarse wrinkling, sallowness, SkinCeuticals (0.5%, 1%) dyschromias, roughness and laxity at Retinaldehyde (Retinal) Multiple brands including: six months (based on Level I Evidence Avene RetrinAL Eyes (proprietary percentage), and evidence from at least one ran- Retrinal Plus (0.05%, 0.1%) 7 Glytone Enhance (0.05%) domized, controlled trial). Tretinoin Atralin (0.05%), Avita (0.025%), Retin-A (0.025%, 0.05%, Optimized dosing consists of bal- 0.1%), Retin-A Micro (0.04%, 0.1%), Renova (0.02%) ancing effi cacy and side effects. The Isotretinoin Isotrexin (0.05%) dose-dependent retinoid reaction that usually occurs early in the treatment Tazarotene Avage (0.1%), Tazorac (0.05%, 0.1%) course consists of erythema, scaling, Adapalene Differin (0.1%) xerosis and pruritis.7 The most impor- tant predictive feature of those likely to centration of 20%, with minimal ab- A-related compounds that have been suffer the retinoid reaction is sensitive sorption of L-ascorbic acid derivatives used topically and orally since the skin, such as Fitzpatrick type 1; histori- such as magnesium ascorbyl phos- 1940s for a multitude of skin condi- cal intolerance of other topical agents; phate, ascorbyl-6-palmitate and dehy- tions, primarily acne.7 Their ability to those with a tendency for skin fl ushing, droascorbic acid. Higher percentages rejuvenate photoaged skin was popu- exposure to large amounts of cosmet- of L-ascorbic acid failed to increase larized in the 1980s.7 They are thought ics; or skin with other conditions such absorption.5 The mean time to clinical to reduce wrinkles by increasing type I as eczema, rosacea or seborrheic der- improvement of skin texture is one procollagen expression and inhibiting matitis.7 Although the retinoid reaction month of daily application, and the dermal collagen degradation in the subsides, it’s seen in the majority of pa- mean time to improvement of coarse upper papillary dermis.7,8 Skin texture tients using 0.05% tretinoin and in ap- rhytids, telangiectasias, pigmentation, is improved by increasing epidermal proximately 90 percent of patients us- keratoses, sallowness and histological proliferation and differentiation, com- ing 0.1% tretinoin.7 Long-term use of collagen deposition is three months.4,6 pacting stratum corneum, thickening tretinoin (over 11 months) has shown of the granular layer, and increasing no difference in outcomes between Retinoids epidermal and dermal glycosamino- higher (0.05%) and lower (0.01% or glycan deposition.7,8 There is evidence 0.02%) concentrations.7,10 Retinoids are a family of vitamin that pretreatment with a retinoid for Given the topical instability of reti-

66 | Review of Ophthalmology | November 2016

0065_rp1116_plastics.indd65_rp1116_plastics.indd 6666 110/20/160/20/16 3:353:35 PMPM Classic retinoid reaction with erythema, scaling and xerosis from use of topical retinol daily for a week. This was treated by stopping the cream and starting 1% hydrocortisone until symptoms resolved. nol and the side-effect profi le of tretinoin, there are a slew of retinol esters and derivatives. Of these, retinaldehyde (0.05% to 0.1%) may have comparable performance to tretinoin (0.5%) with more limited side effects.7,8 There is no evidence at this point to support the use of other retinoids, including retinyl-palmitate, retinyl-propionate and retinyl-acetate.7 Photosensitivity is a known side effect of topical retinoid therapy, so avoidance of excessive sun exposure and daily sunscreen use are mandatory when using retinoids. Make sure to accompany these measures with good moisturizers such as hyaluronic acid or ceramides to limit the scaling and fl aking seen with the retinoid reaction. Although there have been no systemic side effects or reported teratogenicity in over three decades of topical use, pregnant and lactating females should be advised to avoid use due to lack of safety data.7,8

Dr. Kleinberg practices comprehensive ophthalmology and oculoplastics at Worcester Ophthalmology Associates in Mas- sachusetts. She can be reached at 25 Oak Ave., Worcester, MA 01605; Tel: (508) 521-2010; e-mail: [email protected].

1. Clark E, Scerri L. Superfi cial and medium-depth chemical peels. Clin Dermatol 2008;26:2:209. 2. Pinnell S. Cutaneous photodamage, oxidative stress, and topical antioxidant protection. J Am Acad Dermatol 2003;48:1:1-22. 3. Farris P. Topical vitamin C: A useful agent for treating photoaging and other dermatologic conditions. Dermatol Surg 2005;31:S1:814-818. 4. Traikovich S. Use of topical ascorbic acid and its effects on photodamaged skin topography. Arch Otolaryngol–Head & Neck Surgery 1999;125:10:1091-1098. 5. Pinnell S, Yang H, Omar M, et al. Topical L-ascorbic acid: Percutaneous absorption studies. Dermatologic Surgery 2001;27:2:137-142. 6. Fitzpatrick R, Rostan E. Double-blind, half-face study comparing topical vitamin c and vehicle for rejuvenation of photodamage. Dermatol Surg 2002;28:3:231-236. 7. Hubbard B, Unger J, Rohrich R. Reversal of skin aging with topical retinoids. Plast Reconstr Surg 2014;133:4:481e-490e. 8. Fathi R, Pfeiffer ML, Tsoukas M. Minimally invasive eyelid care in dermatology: Medical, laser, and cosmetic therapies. Clin Dermatol 2015;33.2:207-216. 9. Pilkington S, Belden S, Miller R. The Tricky Tear Trough: A Review of Topical Cosmeceuticals for Periorbital Skin Rejuvenation. J Clin Aesthetic Dermatol 2015;8:9:39. 10. Manaloto RM, Alster T. Periorbital rejuvenation: a review of dermatologic treatments. Dermatol Surg 1999;25:1:1-9.

Suggested Reading: Chen L, Hu J, Wang S. The role of antioxidants in photoprotection: A critical review. J Am Acad Dermatol 2012;67:5:1013-1024. Clark C, Rohrich R. Skin care in an aesthetic plastic surgery practice: Indications and scientifi c rationale. Perspect Plast Surg 1994;8:01:159-169.

065_rp1116_plastics.indd 67 10/20/16 3:36 PM Therapeutic Topics REVIEW

Accommodation For the Aging Eye

Mark B. Abelson, MD, CM, FRCSC, FARVO, David A. Hollander, MD, MBA, and Connie Slocum, PhD Andover, Mass.

ike death and taxes, presbyopia is Americans will be older than 65. Glob- ing treatment options for presbyopia Lone of life’s certainties, an inevi- ally, data collected from 228 countries that include contact lenses, LASIK table companion to the aging process: in 2005 estimated that presbyopia af- and other approaches.5 A number of Sometime between your 35th and fected more than 1 billion people. By surgical options are also available, but 45th birthday, you wake up to the real- 2050, this number is projected to in- results can be variable, and some pro- ity that your arms are no longer long crease to almost 1.8 billion.1 cedures are contraindicated in certain enough to hold the medicine bottle at Although the incidence rates of pres- patient populations. The limitations of a proper reading distance. While not byopia are very high, public awareness current treatment options, together pathological, this condition requires of this condition, its origins and what with the growing numbers of affected some form of treatment to correct the can be done to correct it are surpris- individuals, have driven increased sci- failing near vision. The change in visu- ingly low. A 1996 study reported that entifi c and clinical interest in presby- al function patients experience at mid- more than half of patients queried did opia in recent years. life is particularly impactful in today’s not know the meaning of the word,2 age of electronic devices used both at while a more recent survey found that The Physiology of Presbyopia home and in the workplace. And while more than eight in 10 American con- the process of accommodation may be sumers couldn’t provide a definition The process of accommodation, or the single most studied physiological for presbyopia; of those that could, focusing on near objects, occurs by a process in the visual system, we still more than six in 10 mistakenly be- concerted action of the ciliary muscle do not fully understand its intricacies. lieved that it could lead to blindness.3 on the zonule fibers which hold the This month, we survey some of the lat- Typically, a patient learns of pres- lens in place. The ciliary muscle is a est research and consider the growing byopia at an age when more frequent ring of smooth muscle that, upon con- interest in the development of alter- ocular health examinations are recom- traction, relaxes the tension on the zo- native therapies for this harbinger of mended because of the increased risk nular fi bers and allows the lens to be- advancing age. of age-related ocular diseases such as come more spherical. This increase in glaucoma, cataracts and macular de- axial thickness results in an increase in Presbyopia by the Numbers generation.4 This timing can have the the dioptric power, facilitating accom- effect of downplaying the signifi cance modation for improved near vision. Presbyopia’s incidence and impact and impact of the condition. Once di- With ciliary muscle relaxation, the ten- are rising in conjunction with the aging agnosed, many patients resist seeking sion on the zonules increases, resulting of the population, both in the United treatment due to the stigma associated in lens flattening and a reduction in States and around the world. Now, as with aging. Most grudgingly accept the dioptric power. All of these structures the baby boomers transition into their inevitability of reading glasses, but a are modified by the aging process, 60s, our aging population continues growing contingent want more infor- but it is the reduction in lens fl exibil- to expand: By 2030, about one in fi ve mation and are interested in explor- ity that’s most associated with loss of

68 | Review of Ophthalmology | November 2016 This article has no commercial sponsorship.

0068_rp1116_ttops68_rp1116_ttops 2.indd2.indd 6868 110/21/160/21/16 2:262:26 PMPM accommodation.6-8 De- neal inlays has become creased lens fl exibility possible through major limits the lens round- advancements made in ing and thickening biomaterials as well as needed for near focus. surgical devices such as Models of the process the femtosecond laser.5 suggest that as the lens Femtosecond laser becomes less flexible technology has numer- with age, ciliary mus- ous advantages over cles apply greater ten- traditional surgical sion to zonules, causing techniques and can be ligament fatigue. Mus- applied to a variety of cular atrophy is also a different ophthalmic contributing factor.9 procedures. Still, this These paired changes is a relatively new tech- in the physical proper- nology and is limited ties of the focal appara- by training and cost tus collectively result in issues.13 Examples of the presbyopic condi- corneal inlays employ- tion. The end effect is ing femtosecond laser loss of near focus, ac- technology include the A look at our current understanding of presbyopia’s physiology. companied by blurred KAMRA inlay (Acu- vision, eye strain and Focus), which is an headaches in many individuals. For to limited success for individual ap- opaque polymer ring that employs the some, these secondary effects are ex- proaches including bifocal or progres- pinhole concept to expand the depth acerbated after reading or computer sive lenses, monovision lenses (one eye of focus and allow for improvement use.6 for distance, one eye for near vision), in near visual acuity.5 In one study of Much of what we know about ac- and reduced-aperture (pinhole) lenses. 223 presbyopes who fi rst underwent commodation comes from research on Development of predictive algorithms LASIK to correct their pre-existing non-human primates. Studies in the may be the key to making progress refractive error, subsequent KAMRA rhesus monkey have shown that cili- with this treatment modality.11 implantation increased their average ary body displacement plays a key role uncorrected near vision from J8 to in the accommodation process. The Inlays and Surgeries J2.14 Another recently approved in- force of contraction moves the muscle lay, the Raindrop Near Vision Inlay in an anterior direction, and this dis- In recent years, surgery has been the (ReVision Optics), is a clear hydrogel placement is attenuated in aging ani- new frontier for presbyopia therapy, by implant that increases the anterior cor- mals. One study confi rmed the roles either direct intraocular replacement neal curvature to add optical power, of both muscle atrophy and decline in of the lens or by modifi cation of extra- with a refractive index approximating ligament elasticity in the development ocular structures such as the cornea or that of the cornea.12 Other devices are of presbyopia,9 and another recently sclera.12 Modifi cation involves the use in development, such as the Presbia showed that similar movement occurs of corneal inlays, devices that are surgi- Flexivue Microlens (PresbiBio).15 in the human eye.10 Hopefully, these cally placed within the corneal stroma Although the safety of corneal inlays fi ndings can provide clues to pharma- of the non-dominant eye to change is well-established, the use of some, cological strategies to reverse or re- the optical properties of the cornea.12 such as the KAMRA inlay, has been duce accommodative loss. Inlays serve as an attractive option for associated with the development of The use of contact lenses to address correction of presbyopia, since they corneal changes.5 The improvement visual changes associated with presby- are an additive, removable technol- of uncorrected near vision may be ac- opia has been an area of great promise ogy. Unlike laser refractive surgery, companied by decreased distance vi- but only modest success. The limita- which ablates corneal tissue, the inlay sion, increased glare or halos, reduced tion to this approach may be that the can easily be removed if the patient is contrast sensitivity, and the develop- great diversity of visual tasking and unable to adapt to this type of vision ment of dry-eye symptoms second- visual activity among patients has led correction. The development of cor- ary to the creation of the corneal fl ap/

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REVIEW Topics

channel for inlay insertion.12 Despite ing vision for presbyopes.17 Many of life of many more individuals. While these issues the frequency of explants of these drugs have the benefit of a surgical and device-based treatments has been reasonably low. well-established safety profi le due to for this condition hold promise, it’s also Another approach to presbyopia is a long history of usage in diagnostics. exciting to see the innovations provided excimer laser surgery, which remod- Another study, evaluating a cocktail of by pharmaceutical approaches. els the corneal curvature to improve topical agents that included pilocar- uncorrected vision and reduce depen- pine and phenylephrine, showed an Dr. Abelson is a clinical professor of dence on glasses or contacts. Approved improvement in near vision without a ophthalmology at Harvard Medical in 2001, one of the most popular tech- signifi cant effect on distance vision.18 School. Dr. Hollander is chief medi- niques, LASIK, has seen tremendous Other research efforts have reached cal offi cer at the ophthalmic consulting improvements in technology, which the clinic for study: The California- firm Ora, and assistant clinical pro- now includes correction of presby- based startup Presbyopia Therapies fessor of ophthalmology at the Jules opia, or “presbyLASIK.” While con- is evaluating the efficacy and safety Stein Eye Institute at the University of ventional monovision LASIK corrects of their proprietary drop PRX-100 California, Los Angeles. Dr. Slocum is the dominant eye for distance and the in presbyopes.19 PRX-100 has been a medical writer at Ora. Dr. Abelson non-dominant eye for near, presby- formulated to induce miosis without may be reached at MarkAbelsonMD@ LASIK involves a number of different stimulation of accommodation, and has gmail.com. approaches.12 Nevertheless, there is been shown to be safe and effective in 1. Holden BA, Fricke TR, Ho SM, et al. Global vision impairment no “one size fits all” for presbyopia; increasing near vision for up to eight due to uncorrected presbyopia. Archives of Ophthalmology 2008;126:12:1731-1739. each surgical strategy presents its own hours. Presbyopia Therapies hopes that 2. Walline JJ, Zadnik K, Mutti DO. Validity of surveys reporting myopia, astigmatism, and presbyopia. Optom Vis Sci 1996; 73:376- unique benefi ts and limitations that in- PRX-100 will supplement current pres- 81. volve some degree of compromise be- byopia treatments by providing short- 3. Wakefi eld survey on behalf of Transitions Optical, among a representative sample of more than 2,200 Americans ages 18+. tween distant and near visual acuities.16 term, self-administered correction for April 2011. Available at: http://pro.transitions.com/NewsEvents/ Press%20Releases/nr_Multicultural%20Research.pdf For example, crystalline lens removal daytime near vision. 4. Mancil GL, Bailey IL, Brookman KE, et al. Optometric clinical practice guideline care of the patient with presbyopia. American and replacement with an IOL may not An interesting alternative to phar- Optometric Association 2011. Available at: http://www.aoa.org/ documents/optometrists/CPG-17.pdf be preferable in a young patient with macological modulation of the ciliary 5. Naroo SA and Bilkhu PS. Clinical utility of the KAMRA corneal presbyopia without refractive error.16 apparatus is being pursued by another inlay. Clinical Ophthalmology 2016;10:913-919. 6. Truscott RJ. Presbyopia. Emerging from a blur towards an Similarly, treatment of the crystalline emerging biotech fi rm, Encore Vision. understanding of the molecular basis for this most common eye condition. Experimental Eye Research 2009;88:241-247. lens may not be a suitable choice for a Their approach is aimed at directly in- 7. Scarcelli G, Kim P, Yun SH. In vivo measurement of age-related stiffening in the crystalline lens by brillouin optical microscopy. patient with early cataract. Thus, there creasing flexibility of the aging lens. Biophysical Journal 2011;101:1539-1545. 8. Ostrin LA, Glasser A. Edinger-Westphal and pharmacologically are a number of considerations that A key aspect of lens rigidity involves stimulated accommodative refractive changes and lens and have limited the widespread accep- formation of disulfide crosslinks be- ciliary process movements in rhesus monkeys. Exp Eye Res 2007;84:302-313. tance of surgical correction, keeping tween lens protein fi bers, and studies 9. Kaufman PL. Enhancing trabecular outfl ow by disrupting the actin cytoskeleton, increasing uveoscleral outfl ow with prostaglandins, the correction of presbyopia a signifi - have shown a strong positive correla- and understanding the pathophysiology of presbyopia. Exp Eye Res 2008;86:1:3-17. cant challenge for refractive surgeons. tion between lens age and the number 10. Croft MA, McDonald JP, Katz A, et al. Extralenticular and 20 lenticular aspects of accommodation and presbyopia in human of disulfi de bonds in lenses. In pre- versus monkey eyes. Invest Ophthalmol Vis Sci 2013;54:5035. clinical studies, researchers have shown 11. Sivardeen A, Laughton D, Wolffsohn JS. Investigating the utility Pharmacotherapy of clinical assessments to predict success with presbyopic contact that treatment of isolated lenses with a lens correction. Cont Lens Anterior Eye 2016;39:5:322. 12. Paley GL, Chuck RS, Tsai LM. Corneal-based surgical presbyopic Pharmacotherapy for presbyopia is lipoic-acid reducing agent can reduce therapies and their application in pseudophakic patients. Journal of Ophthalmology 2016;doi:http://dx.doi.org/10.1155/2016/5263870 on the rise, as many patients seek free- disulfide bonds and increase elastic- 13. Callou TP, Garcia R, Mukai A, et al. Advances in femtosecond dom from spectacle use without the ity.21 This approach holds real promise, laser technology. Clinical Ophthalmology 2016;10:697-703. 14. Tomita M, Kanamori T, Waring GO, et al. Small-aperture risk and cost of surgical approaches. especially if the prevailing wisdom that corneal inlay implantation to treat presbyopia after laser in situ keratomileusis. J Cataract Refract Surg 2013;39:898-905. For some time, there has been inter- lens infl exibility is the most signifi cant 15. https://clinicaltrials.gov/ct2/show/NCT02110472?term=Presbi a&rank=1. Accessed 12 Sept 2016 est in a topical drop that can provide contributing factor in the development 16. Gil-Cazorla R, Shah S, Naroo SA. A review of the surgical options for the correction of presbyopia. Br J Ophthalmol. 2016; 100: 62- a safe, albeit transient, improvement of presbyopia proves to be true. 70. in accommodation, even if it reduc- The aging population represents a 17. Abdelkader A. Improved presbyopic vision with miotics. Eye & Contact Lens 2015;41:323-7. es distance vision. In a recent study, impending explosion of unmet medical 18. Renna A, Vejarano LF, De la Cruz E, Alió JL Pharmacological treatment of presbyopia by novel binocularly instilled eye drops: A use of miotic parasympathomimetic need. Though sight-threatening condi- pilot study. Ophthalmol Ther 2016;5:1:63–73. 19. https://clinicaltrials.gov/ct2/show/NCT02554396?term=PRX- drugs such as carbachol, alone or in tions such as AMD often dominate the 100&rank=1. Accessed 13 Sept 2016. 20. Lou MF, Dickerson JE. Protein-thiol mixed disulfi des in human combination with alpha-adrenergic conversation of age-related diseases, it’s lens. Exp Eye Res 1992;55:889-896. agonists such as brimonidine, was important to remember that conditions 21. Garner WH, Garner MH. Protein disulfi de levels and lens elasticity modulation: Applications for presbyopia. Invest Ophthalmol Vis Sci shown to provide acceptable read- such as presbyopia impact the quality 2016;57:2851–2863.

70 | Review of Ophthalmology | November 2016

0068_rp1116_ttops68_rp1116_ttops 2.indd2.indd 7070 110/21/160/21/16 2:262:26 PMPM RRP1116_HAIP1116_HAI LLabs.inddabs.indd 1 110/18/160/18/16 10:3210:32 AMAM Research Review REVIEW

Chronic Prostaglandins Associated with MGD

n early July, researchers from the type of MGD was detected in the Fifty-seven percent of eyes with- Idepartment of ophthalmology at majority of patients treated with out ocular comorbidities reached Hacettepe University Faculty of PGAs (95.7 percent). Grade two ≥20/25 at fi ve years after DMEK. Medicine, Ankara, Turkey, pub- and three MGD was noted in 80.5 Endothelial cell density was stable lished fi ndings from a study look- percent of patients using PGAs. after the initial post-surgical de- ing at the association of long-term Patients on PGAs had worse ocular crease, from 2,602 ±243 cells/mm2 prostaglandin analog use with mei- surface disease index scores and oc- before DMEK to 1,460 ±179 cells/ bomian gland dysfunction in medi- ular surface test results than those mm2 at fi ve years. Central corneal cally treated glaucoma patients. of control subjects (p<0.001). thickness decreased from 644 ±67 Researchers determined that long- J Glaucoma 2016;25:770-774 µm before DMEK to 557 ±49 µm at term administration of PGA is as- Mehmet M, Enes, U, Sibel K, Jale K, Murat I. fi ve years, with a minimum of 530 sociated with an obstructive type ±54 µm at three months. Cumula- of MGD. Long-term Outcomes of DMEK tive probability of five-year graft In their prospective, cross-sec- n this retrospective, consecutive survival was 95 percent. tional study (conducted in an aca- Icase series, researchers sought Visual acuity and endothelial cell demic setting), researchers looked to evaluate the long-term clinical loss remained stable between three at 70 eyes of 70 patients with a med- outcomes (up to five years) after months and fi ve years after DMEK. ical diagnosis of glaucoma that were Descemet’s membrane endothe- Notwithstanding the limitations on long-term (>12 months) topical lial keratoplasty. They found that of the study’s retrospective nature hypotensive medications. Patients DMEK not only provides fast vi- and the relatively high proportion were classified based on whether sual rehabilitation but maintains of patients lost to long-term follow- they were on PGA or non-PGA its clinical outcome over a fi ve-year up, the investigators say these data classes of medications. Forty-five follow-up period. support the implication that for pa- age-matched, healthy control sub- The researchers reviewed 310 tients meeting the characteristics jects who were not on any topical DMEK operations for endothelial of those in this study, the three- to medications were also included. decompensation. Ninety-seven eyes fi ve-year clinical results of DMEK In total, 25 patients (35.7 percent) of 84 patients met the inclusion are at least comparable to those were on PGA monotherapy, 21 (30 criterion of a minimum three-year previously reported for DSEK/ percent) were treated with fixed follow-up. Retrospective evaluation DSAEK. The researchers add that or unfi xed PGA combination regi- of clinical examinations occurred at these findings further strengthen mens and 24 (34.3 percent) were one and three months and annually DMEK as a fi rst choice in the treat- on non-PGA medications. MGD up to fi ve years after DMEK. ment of corneal endothelial dys- prevalence was higher in patients Mean follow-up was 53 ±13 function, and that further studies treated with PGA monotherapy months. Corrected distance visual may demonstrate better long-term (92 percent) compared with those acuity improved from 0.62 ±0.42 results. receiving non-PGA therapy (58.6 logMAR before DMEK to 0.13 J Ophthalmol 2016;69:218-226 percent, p<0.02). The obstructive ±0.12 logMAR (p<0.001) postop. Andreas S, Theofi los T, Friedrich K, Julia W.

72 | Review of Ophthalmology | November 2016 This article has no commercial sponsorship.

0072_rp1116_rr.indd72_rp1116_rr.indd 7272 110/20/160/20/16 3:473:47 PMPM Anterior Uveitis’ Effect on the or panuveitis). uveitis (54 percent) than in contralat- Endothelium They found that central ECD was eral eyes (58.8 percent). There was n a cross-sectional, observational lower among eyes that had under- no significant difference in central Istudy, researchers investigated a gone cataract or glaucoma surgery corneal thickness between eyes with possible effect of intraocular in- or both (n=28, p=0.0004). After and without uveitis (p=0.27). No eyes flammation on corneal endothe- exclusion of eyes with surgery, vari- had clinically apparent central corneal lium by measuring corneal endo- ables for eyes with uveitis (n=56) edema. thelial cell density and morphologic were compared with two histori- Relationships remained un- variables in eyes with anterior uve- cal populations of normal, age- changed after exclusion of eyes itis. They also looked at factors that matched controls and with con- with herpetic anterior uveitis, the may infl uence these fi ndings. They tralateral eyes in individuals with researchers say. Host and disease- found that the observed relation- unilateral uveitis. Central ECD was related characteristics were evalu- ships suggest that anterior segment lower in eyes with uveitis than in ated as risk factors for variations infl ammation adversely affects the control eyes for all age groups (p≤ in outcome measures, and central corneal endothelium, but note that 0.01 for four of six 10-year age in- ECD was correlated with the du- longitudinal studies are warranted tervals, compared with the primary ration of active uveitis (r=−0.41; to determine whether longstanding control group). p<0.0001), maximum intraocular anterior uveitis increases the risk of Among patients with unilateral uve- pressure during the course of dis- endothelial dysfunction, especially itis who had not undergone surgery ease (r=−0.40, p=0.0002), and maxi- in the setting of intraocular surgery. in either eye (n=12), central ECD mum laser flare photometry value Researchers looked at 52 patients was lower in eyes with uveitis (2,324 (r=−0.26, p=0.020). (84 eyes) with histories of unilateral cells/mm2) than in contralateral eyes Ophthalmology 2016;123:1637- or bilateral anterior segment in- (2,812.5 cells/mm2), and percentage 1645 fl ammation (anterior, intermediate of hexagonality was lower in eyes with Abdullah A, Gary H, Fei Y, Mathew M, JoAnn G, Anthony A.

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072_rp1116_rr.indd 73 10/20/16 3:46 PM REVIEW Product News Keeler’s Z Series Slit Lamp

ith a focus on doctor preferences vitreoretinal surgeons, Alcon recently system is an excellent teaching and col- Wand practice needs, Keeler re- launched its NGENUITY 3-D visual- laborative tool, since the system uses cently introduced its new Z Series slit ization system (a platform for digitally a wide-screen monitor that allows the lamp, which the company says is highly assisted vitreoretinal surgery). operating team to see what the sur- customizable to user preference. The The new visualization system allows geon is seeing, in real time. new slit lamp is equipped with either surgeons to operate while looking at For more information on Alcon’s converging or parallel oculars and is a high-defi nition, 3-D screen, instead NGENUITY 3D system, visit novartis. available with either a three-step rotat- of through an operating microscope. com. ing drum (10x to 25x magnification) Because of the duration of vitrectomy or a fi ve-step rotating drum (6x to 40x surgeries (ranging anywhere from 30 Bausch + Lomb ORBSCAN3 magnification). It also includes two minutes to three hours), Alcon says the or surgeons performing the latest mounting options: a refraction arm microscope-free viewing design may Frefractive procedures, Bausch + table mount or a rolling table mount improve the surgeon’s experience and Lomb has introduced a new anterior confi guration. comfort during the procedure, adding segment analyzer, the ORBSCAN3. The slit lamp is the first available that the system’s high dynamic range The new device provides data regard- with a 1 mm square aperture and 14- camera creates an image with excellent ing corneal biomechanics and stability mm variable slit width. Keeler says resolution, depth, clarity and contrast. by examining anterior and posterior that the customization available for the With this new view, the surgeon may astigmatism and optical pachymetry. Z Series may appeal to doctors with now have access to depth perception Using these results, surgeons can make specifi c or specialized clinical interests, not previously available on standard informed choices and identify appro- such as intraocular infl ammation. For monitors. priate candidates instance, the preset apertures include Surgeons can for their proce- 0.2, 2, 3, 5 and 9 mm, a 14-mm circle, also magnify dures. The ORB- and a 1-mm square specifically de- the 3-D image SCAN3 also allows signed for assessing uveitis. It also in- while maintain- surgeons to provide cludes space for additional preset aper- ing a wide field high-quality refrac- tures. The slit angle can be adjusted a of view. The new tive care through full 360 degrees. The Z Series includes system provides its ability to assess a shutter trigger on the joystick and digital fi lters that the size, shape and camera exposure controls on its base. allow surgeons extent of surface ab- For more information, call 1-800- to highlight ocu- normalities. 523-5620 or visit keelerusa.com. lar structures and tissue layers crucial The ORBSCAN3 features a touch- in visualizing the back of the eye. This screen that’s user-friendly, with new Alcon’s NGENUITY 3D visualization also minimizes light ex- software which allows for the analysis Visualization posure to the patient’s eye, while still of the elevation and curvature on both n an effort to enhance the visualiza- allowing surgeons to operate. the anterior and posterior surfaces Ition of the posterior segment for Alcon claims that the NGENUITY of the cornea. It is also able to mea-

74 | Review of Ophthalmology | November 2016 This article has no commercial sponsorship.

074_rp1116_products 2.indd 74 10/21/16 2:25 PM sure full corneal pachymetry, white- the CTS can be fully customized to test results via an XML or CSV fi le. to-white distance, anterior chamber fi t the specifi c trial’s needs. Through These fi les can then be reviewed for depth and angle kappa. It accomplish- visual acuity and contrast sensitiv- immediate analysis on-site or secure- es all of this through a contact-free ity protocols, CTS guides the user ly transferred to a reading center. analysis of the eye’s anterior segment through eye charts step by stem For more information, visit using slit scanning. and responds to user input. mstech-eyes.com. For more information on Bausch + The module exports the data and Lomb’s ORBSCAN3, visit bausch.com. Eschenbach’s Visolux HD Magnifi er n September, with a focus on provid- Iing reading comfort to patients with vision loss, Eschenbach released Vi- solux Digital HD, a 7-in. hand-held video magnifi er. The Visolux has mag- nifi cation capabilities of 2x to 22x, in- cluding an HD camera and HDMI/ USB connectivity, allowing it to con- nect to both computers and televisions. At the higher magnifi cation levels, its dynamic line-scrolling capability allows the user to scroll through the image selection without moving the device. The Visolux also includes 14 color contrast modes, three brightness settings and optional underlineline and blinds function, allowing users to un- derline or highlight text. Eschenbach says the device’s fold-out stand creates a comfortable and effective reading level, and that the Visolux’s orientation marks, found on the outside of the device, provide guidance for the HD camera’s positioning. For more information on the Vi- solux, visit eschenbach.com. M&S Tech Clinical Trial Suite n early October, M&S Technologies Iintroduced its clinical trial suite, a customizable set of protocols designed for use in research and clinical trials. In conjunction with the M&S DataRight module, the CTS allows doctors and researchers to retrieve raw data and test results immediately. DataRight’s encrypted data transfer also ensures the security of any clinical trial data, M&S says. Coming equipped with a full range of hardware options, M&S says that

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76 | Review of Ophthalmology | November 2016

ROPH1116.indd 76 10/19/16 7:51 AM REVIEW Classifi eds

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ĂƐƐĞƩ ,ĞĂůƚŚĐĂƌĞ EĞƚǁŽƌŬ͕ Ă ƉƌŽŐƌĞƐƐŝǀĞ ŚĞĂůƚŚ ĐĂƌĞ ŶĞƚǁŽƌŬ ŝŶ Charlotte Eye Ear Nose and Throat Associates, PA ĐĞŶƚƌĂůEĞǁzŽƌŬĂŶĚŵĂũŽƌƚĞĂĐŚŝŶŐĂĸůŝĂƚĞŽĨŽůƵŵďŝĂhŶŝǀĞƌƐŝƚLJŝƐƐĞĞŬŝŶŐ (CEENTA), established in 1923, is a physician-owned OPHTHALMOLOGY and operated multi-specialty private practice of ĂGeneral OphthalmologistƚŽũŽŝŶĂďƵƐLJŽƉŚƚŚĂůŵŽůŽŐLJĚĞƉĂƌƚŵĞŶƚďĂƐĞĚŝŶƚŚĞ Ophthalmology and Otolaryngology with over 100 ůŽǀĞůLJǀŝůůĂŐĞŽĨŽŽƉĞƌƐƚŽǁŶ͘'ůĂƵĐŽŵĂĞdžƉĞƌŝĞŶĐĞĂƉůƵƐ͊ providers and 19 offices spread over a geographic area ĂƐƐĞƩ ,ĞĂůƚŚĐĂƌĞ EĞƚǁŽƌŬ ŝƐ ĂŶ ŝŶƚĞŐƌĂƚĞĚ ŚĞĂůƚŚ ĐĂƌĞ ƐLJƐƚĞŵ ƚŚĂƚ ƉƌŽǀŝĚĞƐ ĐĂƌĞ ĂŶĚ of approximately 50 miles centered on Charlotte, NC. ƐĞƌǀŝĐĞƐƚŽƉĞŽƉůĞůŝǀŝŶŐŝŶĂŶĞŝŐŚƚĐŽƵŶƚLJƌĞŐŝŽŶĐŽǀĞƌŝŶŐϱ͕ϲϬϬƐƋƵĂƌĞŵŝůĞƐŝŶƵƉƐƚĂƚĞEĞǁ Due to continued expansion, CEENTA has the zŽƌŬ͘dŚĞŽƌŐĂŶŝnjĂƟŽŶŝŶĐůƵĚĞƐƐŝdžĐŽƌƉŽƌĂƚĞůLJĂĸůŝĂƚĞĚŚŽƐƉŝƚĂůƐ͕ ĂƐ ǁĞůů ĂƐ ƐŬŝůůĞĚ ŶƵƌƐŝŶŐ following physician ophthalmology positions available: ĨĂĐŝůŝƟĞƐ͕ĐŽŵŵƵŶŝƚLJĂŶĚƐĐŚŽŽůͲďĂƐĞĚŚĞĂůƚŚĐĞŶƚĞƌƐ͕ĂŶĚŚĞĂůƚŚƉĂƌƚŶĞƌƐŝŶƌĞůĂƚĞĚĮĞůĚƐ͘ Neuro-Ophthalmologist and Retina Specialist <›ù›Ä›¥®ãÝʥ㫮ÝWÊÝ®ã®ÊÄ͗ The group has all subspecialties represented, an ͻ KƉƉŽƌƚƵŶŝƟĞƐĞdžŝƐƚĨŽƌďŽƚŚƌĞƐĞĂƌĐŚĂŶĚƚĞĂĐŚŝŶŐŝĨŝŶƚĞƌĞƐƚĞĚ͘ established referral base, and an in-house contract ͻ ƵƌƌĞŶƚůLJƚŚĞƌĞĂƌĞƐƉĞĐŝĂůŝƐƚƐŝŶƌĞƟŶĂ͕ĐŽƌŶĞĂ͕ƉĞĚŝĂƚƌŝĐƐĂŶĚŽĐƵůŽƉůĂƐƟĐƐ͘ research organization. Charlotte is two hours east of the Appalachian ͻ dŚĞƐƵƉƉŽƌƚƐƚĂīŝƐǁĞůůƚƌĂŝŶĞĚĂŶĚĞdžƉĞƌŝĞŶĐĞĚŝŶďŽƚŚƚŚĞĐůŝŶŝĐĂŶĚŽƉĞƌĂƟŶŐƌŽŽŵ͘ Mountains and 3 1/2 hours west of the Atlantic Ocean. ͻ 'ƌŽƵƉĞŵƉůŽLJĞĚŵŽĚĞůǁŝƚŚĐŽŵƉĞƟƟǀĞƐĂůĂƌLJ It is home to the University of North Carolina, Charlotte, ͻ ŽŵƉƌĞŚĞŶƐŝǀĞ ďĞŶĞĮƚ ƉĂĐŬĂŐĞ͕ ŝŶĐůƵĚŝŶŐ ďƵƚ ŶŽƚ ůŝŵŝƚĞĚ ƚŽ ŵĞĚŝĐĂů͕ ĚĞŶƚĂů͕ D͕ the NFL Panthers, the NBA Hornets and a variety of ƌĞůŽĐĂƟŽŶĂƐƐŝƐƚĂŶĐĞĂŶĚƉĂŝĚŵĂůƉƌĂĐƟĐĞŝŶƐƵƌĂŶĐĞ cultural venues. Charlotte and its metropolitan area  have one of the fastest growing populations of ĂƐƐĞƩ DĞĚŝĐĂů ĞŶƚĞƌ ŝƐ ůŽĐĂƚĞĚ ŝŶ ŽŽƉĞƌƐƚŽǁŶ͕ EĞǁ zŽƌŬ͕ Ă ďĞĂƵƟĨƵů ƌĞƐŽƌƚ ǀŝůůĂŐĞ ŽŶ mid-sized metropolitan areas in the United States. KƚƐĞŐŽ >ĂŬĞ͘ ,ŽŵĞ ƚŽ ƚŚĞ EĂƟŽŶĂů ĂƐĞďĂůů ,Ăůů ŽĨ &ĂŵĞ ĂŶĚ DƵƐĞƵŵ͕ ƚŚĞ 'ůŝŵŵĞƌŐůĂƐƐ These positions include an excellent salary with part- KƉĞƌĂŽŵƉĂŶLJ͕ĂŶĚƚŚĞ&ĞŶŝŵŽƌĞƌƚDƵƐĞƵŵ͕ƚŚĞĂƌĞĂĂůƐŽďŽĂƐƚƐŵĂŶLJĐƵůƚƵƌĂůĂŶĚĨŽƵƌƐĞĂͲ nership anticipated, potential commercial real estate ƐŽŶƌĞĐƌĞĂƟŽŶĂůĂĚǀĂŶƚĂŐĞƐŝŶĐůƵĚŝŶŐƚŚĞĂƚĞƌ͕ŵƵƐŝĐ͕ŵƵƐĞƵŵƐ͕ŐŽůĨ͕ƐĂŝůŝŶŐ͕ŚŝŬŝŶŐ͕ĂŶĚƐŬŝŝŶŐ͘ and ASC ownership, an attractive 401(k) match and profit sharing, professional liability insurance, health, EEO Employer dental and life insurance, as well as short and long term disability insurance. &ÊÙ‘ÊÄ¥®—›Ä㮃½‘ÊÄÝ®—›Ùƒã®ÊÄ͕Ö½›ƒÝ›‘ÊÄパã͗ For immediate consideration, contact: ĞďƌĂ&ĞƌƌĂƌŝ͕DĂŶĂŐĞƌ͕DĞĚŝĐĂů^ƚĂīZĞĐƌƵŝƚŵĞŶƚ͕ Annette Nash ĂƐƐĞƩDĞĚŝĐĂůĞŶƚĞƌ͕KŶĞƚǁĞůůZŽĂĚ͕ŽŽƉĞƌƐƚŽǁŶ͕Ez͕ϭϯϯϮϲ Charlotte Eye Ear Nose and Throat Associates, PA ƉŚŽŶĞ͗ϲϬϳͲϱϰϳͲϲϵϴϮ͖ĨĂdž͗ϲϬϳͲϱϰϳͲϯϲϱϭ͗ĞŵĂŝů͗ĚĞďƌĂ͘ĨĞƌƌĂƌŝΛďĂƐƐĞƩ͘ŽƌŐ 6035 Fairview Road, Charlotte, NC 28210 ŽƌǀŝƐŝƚŽƵƌǁĞďͲƐŝƚĞĂƚǁǁǁ͘ďĂƐƐĞƩŽƉƉŽƌƚƵŶŝƟĞƐ͘ŽƌŐ [email protected] • Fax: 704.295.3415 Interviewing opportunities may be available at 2016 AAO Annual meeting. www.ceenta.com EOE Products and Services We are a large, well-established and growing multispecialty practice in Practice For Sale South Florida. The team is comprised of  SUB SPECIALISTS CORNEA REFRACTIVE GLAUCOMA RETINA AND PLASTICS  WZd/&KZ^>͗ZE͕t general ophthalmologists, and 12 KƉŚƚŚĂůŵŽůŽŐLJͬŽƉƚŽŵĞƚƌLJŽĸĐĞĂŶĚƉƌĂĐƟĐĞĨŽƌƐĂůĞ optometrists. ;ŝŶĐůƵĚŝŶŐ ƌŽĂĚǁĂLJ KƉƟĐĂů ƐŚŽƉͿ ŝŶ ďĞƌĚĞĞŶ͕t͘ Before After ƉƉƌĂŝƐĞĚǀĂůƵĞĨŽƌƉƌĂĐƟĐĞĂŶĚĞƋƵŝƉŵĞŶƚΨϯϬϬ͕ϬϬϬ͘ Interviewing for: KĸĐĞďƵŝůĚŝŶŐƐĞƉĂƌĂƚĞůLJĂƉƉƌĂŝƐĞĚΨϯϱϴ͕ϬϬϬ͘ŽƚŚ DIAMOND KNIFE REPAIR/RESIZE ƚŽŐĞƚŚĞƌ ĂƌĞ ŽīĞƌĞĚ Ψϰϵϵ͕ϬϬϬ͘  WƌĂĐƟĐĞ ĂŶĚ ĞƋƵŝƉ- Comprehensive Ophthalmologist ŵĞŶƚĐĂŶďĞƉƵƌĐŚĂƐĞĚƐĞƉĂƌĂƚĞůLJ͕ǁŝƚŚƌĞŶƚĂůůĞĂƐĞ • Repair any make or style diamond blade ŽŶƚŚĞďƵŝůĚŝŶŐ͘ďĞƌĚĞĞŶŝƐƚŚĞǁĞƐƚĞƌŶŐĂƚĞǁĂLJƚŽ • Changing to a smaller incision? We can Cornea/Anterior Segment KůLJŵƉŝĐ EW͕Ă ƉĂƌĂĚŝƐĞ ĨŽƌ ƚŚĞ ŽƵƚĚŽŽƌƐŵĂŶͬƐƉŽƌƚƐ- resize or reshape any style diamond blade ŵĂŶ͘ĚĚƌĞƐƐ͗ďĞƌĚĞĞŶĂƚĂƌĂĐƚΘ>ĂƐĞƌ͕ϭϭϴt͘ϭƐƚ • Free annual cleaning and inspection of Glaucoma Specialist ^ƚ͕͘ďĞƌĚĞĞŶ͕tϵϴϱϮϬ͘ Pelion/Metico diamond blades • Over 30 years experience in diamond knives Contact owner Dr. William Hoot (817) 925-6918 Oculo-plastics (ǁƌŚŽŽƚΛĂƩ͘ŶĞƚͿ Žƌ ŽĸĐĞ ŵĂŶĂŐĞƌ :ŽĂŶŶĞ We also repair any make surgical tĂƩĞƌƐĂƚ;ϯϲϬͿϱϵϬͲϰϲϯϲ͕;ũŬǁƩƌƐΛĐŽŵĐĂƐƚ͘ŶĞƚ) or instrument, including phaco, Overall practice growth has and will ĂƚŽĸĐĞƉŚŽŶĞ;ϯϲϬͿϱϯϯͲϱϴϬϬDŽŶĚĂLJŽƌdƵĞƐĚĂLJ I/A handpieces and tips continually provide ample opportunities for new physicians to grow with the practice.

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2014_opg_ad_fullpge_rp.indd 1 6/17/15 11:22 AM 079_rp1116_wills.indd 79 Medical History Eye Hospitalforfurtherevaluationandmanagement. was referredtotheOcularOncologyServiceatWills heterogeneous masswithcrispmargins.Thepatient hancement. the T1serieswithfat-suppresionandgadoliniumen- signal onT1anddemonstratedheterogenous measuring 30mmanteroposteriorly. Themasswaslow the leftsuperonasalorbit,compressingglobeand which revealedalarge,well-circumscribedmassin pursued magneticresonanceimagingoftheorbit, of theleftupperlid. for thepastfourmonths,andnotedassociatedswelling diplopia. Shehadbeenhavingprogressivesymptoms a leftchoroidalnevus,withnewcomplaintsofpainless retina specialist,withwhomshehadbeenfollowingfor Presentation Lucas Bonafede, MD OcularOncologyService. swelling thatresultsinareferraltoWills’ A middle-agedwomanpresentswithpainlessdoublevisionandlid was 14mmHginbotheyes.Therenoafferentpupillary defect,andIshiharacolorplateswerefull(8/8)OU.Hertelex- Examination smoking orexcessivealcoholintake.Thereviewofsystemswasunremarkable. ditional ocularhistoryorchronicmedications.Therewasnopersonalfamilyofcancer. Shehadnohistoryoftobacc A 53-year-old Caucasianfemalepresentedtoher On ocular examination, her best corrected visual acuity was 20/20 in the right eye and 20/40 in the left. Intraocular pressure On ocularexamination,herbestcorrectedvisualacuitywas20/20intherighteyeand20/40left.Intraocularpressure The patienthadapastmedicalhistoryofseasonalallergiesforwhichshetookloratadineasneeded.Shedidnothaveanyad- REVIEW . The T2 series revealed a slightly (Figure 1).TheT2seriesrevealedaslightly . The retina specialist (Figure 1).Theretinaspecialist Wills Eye Wills Eye and retinal pigmentepithelialmottling. prominent chorioretinal folds, tortuous retinal vessels, bluntedfoveal reflex fiotherwise normal ndings. The lefteye (B)revealed atilteddiscwith Figure 2.Fundusphotography oftherighteye (A)showing atilted discand retinal folds, a tilted disc, tortuous retinal vessels and a blunted foveal retinal folds,atilteddisc,tortuousvesselsandblunted foveal (Figure 2).FunduscopicexaminationOSrevealedprominentchorio- scopic examinationODwasonlyremarkableforaslightlytilted disc by 50percentinelevation,adductionanddepressionOS. the leftuppereyelid.ExtraocularmotilitywasfullODandreduced a 3-cm,fi ophthalmometry demonstrated5mmofrelativeproptosison the left. slightly heterogeneoussignalwithcrispmargins on T2 imaging. (C) heterogeneoussignalon T1 withgadoliniumenhancementand(D) compressing theglobewith(B)low signalonaxial T1 imaging, resonance imagingrevealed awell-circumscribed orbitalmass exotropia andproptosisfromanorbitalmasssuperomedially. Magnetic Figure 1. A 53-year-old woman was notedtohave (A)lefthypoglobus, Anterior segmentslitlampexaminationwasnormalOU.Fundu- An externalexamrevealedadownwardlydisplacedglobeOS with Resident CaseSeries Edited by Alison Huggins, MD rm, palpable orbital mass underlying the medial portion of rm,palpableorbitalmassunderlyingthemedialportionof November 2016 | reviewofophthalmology.com |

79 10/20/16 4:11 PM o 079_rp1116_wills.indd 80 ly, theearlyphasewasnotcaptured,butFA at23seconds the clinicallyevidentchorioretinalfoldsOS.Unfortunate- outer retinallayers(Figure3). additional intraretinalcystoidedemaanddisruptionofthe concentrated inthepapillomacularregion.Therewas ure 3).OCTOSrevealedprominentchorioretinalfolds refl linear hyper- andhypo-autofluorescence corresponding tothechoroidal folds. focal areas ofdeepstaining. Fundusautofluorescence ofthelefteye (D)showed bandsofhyper-23 secondsshowed alternating andhypofluorescence, and disruption oftheouterretinal layers. Angiography ofthelefteye (C)at7minutes concentrated inthepapillomacularregion, intraretinal cystoid edemaand macula. showed anormal The lefteye (B)showed prominentchorioretinal folds Figure 3.Inthispatient’s case, opticalcoherence tomography oftherighteye (A) 80 vascular mass removal ofa30mmx26 x19mmcircumscribed gioma, givenitsrathercharacteristicradiologicalfi in makingapresumptivediagnosisofcavernousheman- fi chorioretinal foldsseenonfundoscopicassessment. secondary globecompressionresultinginthenotable MRI. Itisnotuncommonforanintraconalmasstocause was inlinewithanorbitalprocess,asconfi Diagnosis, Workup andTreatment What isyourdifferentialdiagnosis?furtherworkupwouldyoupursue? nitive diagnosis.Fortunately, theMRIwasveryhelpful REVIEW Fluorescein angiography was normal OD, and displayed Fluorescein angiographywasnormalOD,anddisplayed Optical coherencetomographyODwasnormal The patientunderwentleftorbitotomy withcomplete Therefore, thenextstepwastoobtaintissueforade- The patient’s presentationofproptosisanddiplopia ex | ReviewofOphthalmology Resident CaseSeries . The cup-to-disc ratio was 0.2 OU. (Figure 2).Thecup-to-discratiowas0.2OU. (Figure 4).Microscopicpathologydem- | November2016 rmed with rmed ndings. (Fig- folds, withliopofuscinshowingabrightsignal tofl similar confi guration ofalternatinghyper- andhypo-au- folds withnoobviousleakage(Figure3). OS. FA atsevenminutesshowed asimilarpatternforthe corresponding totheobliquelyorientedchorioretinalfolds showed alternatingbandsofhyper- andhypofl folds. tent RPEchangeswithresolution ofthechorioretinal diplopia. Funduscopically, thelefteyerevealedpersis- lar musclesurgeryallowedforresolutionofmyogenic with visualacuityof20/20ODand20/25OS.Extraocu- ernous hemangioma. features wereconsistentwithadiagnosisoforbitalcav- (Figure 4).Therewasnoevidenceofmalignancy. The areas ofsmoothmuscleaswellchronicinfl lium-lined vascularchannelsseparatedbyseptae,with onstrated anencapsulatedtumorcomposedofendothe- Fundus autofluorescenceOSclearlydemonstrateda At threeyears’follow-up,thepatienthasdonewell uorescence representing shifting of the RPE along the uorescencerepresentingshiftingoftheRPEalong demonstrate thelarge vascular channels in themass. High-magnification microscopicimages(CandD) and containingthick septaeandsmoothmuscle. large vascular channels linedwithendothelialcells Low-magnification microscopicimage(B)showed purple tumormeasuring30mmx2619mm. Figure specimen(A)showed 4.Imageofgross alarge C A D B (Figure 3). uorescence uorescence ammation 10/20/16 4:12 PM Discussion sitated surgical removal.1 If surgical re- was noted in 70 to 77 percent of folds.13 moval is indicated due to tumor size or Another report described the biome- Orbital cavernous hemangioma is a symptoms, various techniques can be chanical forces that lead to chorioretinal benign, slowly progressive tumor that used depending on tumor location and folds in different etiologies, including typically manifests as a unilateral mass, size. The two main surgical approaches orbital tumors.11 The author explained most often located within the muscle include the transconjunctival technique that intraconal orbital tumors lead to cone.1-4 In 2004, Jerry Shields, MD and for tumors located anteriorly and the optic nerve displacement and cause the co-workers conducted a survey of 1,264 lateral orbitotomy for tumors in the mid choroidal folds to originate from the patients who were referred to their clin- and posterior orbit.2 A transcranial ap- nerve and radiate outwards.13 On the ic for evaluation of space-occupying le- proach and an endoscopic approach other hand, he found that extraconal sions, and found that orbital cavernous have been described for posterior tu- tumors will lead to compression of the hemangioma was the third most com- mors located near the orbital apex.2 sclera and choroid, causing the folds.13 monly diagnosed orbital mass.1 Orbital Chorioretinal folds are relatively One notable fi nding was that an inves- cavernous hemangioma accounted for common in patients with orbital tumors. tigation of the pattern of the folds can 6 percent of the total cases and 36 per- The patient in this case had unilateral help determine the tumor location.13 cent of vasculogenic lesions.1 oblique chorioretinal folds. These folds In conclusion, orbital cavernous hem- Patients with orbital cavernous hem- are seen as linear alterations at the level angioma is a benign, slowly progressive angiomas typically present with painless of the retina, retinal pigment epitheli- vascular tumor that generally manifests proptosis.2-5 Other signs include globe um and choroid, which represent undu- in middle-aged patients. This mass can compression with choroidal/chorioreti- lations of the tissue, often causing shift- cause painless proptosis as well as com- nal folds, optic nerve compression with ing of the RPE.9-12 Such folds generate pressive features such as chorioretinal decreased vision, visual fi eld changes, a broad differential diagnosis, including folds accompanied by vision loss. Surgi- acquired hyperopia and diplopia.1-5 The hyperopia, hypotony, AMD, thyroid eye cal removal of the tumor can resolve characteristic MRI fi ndings of orbital disease, scleritis, uveitis, orbital or cho- vision loss in some cases. cavernous hemangiomas include a well- roidal tumor, postop changes, uveal ef- defined mass that is hypointense on fusion syndrome and optic nerve head The author would like to thank Carol T1-weighted imaging and hyperintense swelling.9-13 One study noted that the Shields, MD, and Sara Lally, MD, of on T2-weighted imaging.3,6-7 Contrast rate of diagnosis of idiopathic chorio- the Wills Eye Ocular Oncology Service, enhancement shows initial heteroge- retinal folds has been decreasing, likely and Ralph Eagle, MD, of Wills’ Oph- neous enhancement, which progresses due to more accurate diagnostic tests.10 thalmic Pathology Department for their to homogeneous enhancement.3,6-7 One The laterality of the chorioretinal assistance with this report. study of 214 cases of orbital cavernous folds can provide a diagnostic clue to 1. Shields JA, Shields CL, Scartozzi R. Survey of 1264 patients hemangiomas found that imaging using help narrow the diagnosis. Two recent with orbital tumors and simulating lesions: The 2002 Montgomery Lecture, part 1. Ophthalmology. 2004 May;111:5:997-1008. echography and computed tomography studies found that 42 to 44 percent of 2. Shields JA, Shields CL. Eyelid, Conjunctival, and Orbital Tumors: or MRI could correctly diagnose 93 chorioretinal folds were bilateral and An Atlas and Textbook. 3rd ed. Philadelphia: Wolters Kluwer, 2016. 516-23. 8 11,13 percent of cases prior to surgery. that the rest were unilateral. In one 3. Herter T, Bennefeld H, Brandt M. Orbital cavernous hemangiomas. Neurosurg Rev 1988;11:2:143-7. The differential diagnosis for a round, study, researchers compared 54 cases 4. Shields JA, Hogan RN, Shields CL, et al. Bilateral cavernous haemangiomas of the orbit. Br J Ophthalmol 2000;84:8:928. well-circumscribed, solid mass includes of bilateral and unilateral chorioretinal 5. Shields JA, Shields CL, Eagle RC. Cavernous hemangioma of the cavernous hemangioma, hemangioper- folds and found that, in addition to id- orbit. Arch Ophthalmol 1987;105:6:853. 6. Héran F, Bergès O, Blustajn J, Boucenna M, Charbonneau ictyoma, schwannoma, solitary fi brous iopathic, the most common causes of F, Koskas P, Lafi tte F, Nau E, Roux P, Sadik JC, Savatovsky J, 2 Williams M. Tumor pathology of the orbit. Diagn Interv Imaging tumor, neurofi broma and melanoma. bilateral chorioretinal folds were AMD 2014;95:10:933-44. Other conditions to consider in the dif- and hypotony, while unilateral cases 7. Bagheri N, Wajda B. The Wills Eye Manual: Offi ce and Emergency Room; Diagnosis and Treatment of Eye Disease. 7th ed. Philadelphia: ferential diagnosis include lymphoma, were most commonly due to scleritis, Wolters Kluwer, 2017. 8. Yan J, Wu Z. Cavernous hemangioma of the orbit: Analysis of 214 fibrous histiocytoma, lymphangioma, ocular tumors, retinal vascular occlu- cases. Orbit 2004;23:1:33-40. 1-6 13 9. Cangemi FE, Trempe CL, Walsh JB. Choroidal folds. Am J Ophthal- metastasis and infl ammatory lesions. sion and hypotony. The characteris- mol 1978;86:3:380-7. Management of orbital cavernous tics and orientation of the chorioretinal 10. Olsen TW, Palejwala NV, Lee LB, Bergstrom CS, Yeh S. Chorio- retinal folds: Associated disorders and a related maculopathy. Am J hemangioma varies depending on the folds can also provide useful informa- Ophthalmol 2014;157:5:1038-47. 11. Friberg TR. The etiology of choroidal folds. A biomechanical clinical presentation. Small, asymptom- tion about the underlying cause. In this explanation. Graefes Arch Clin Exp Ophthalmol 1989;227:5:459-64. atic orbital cavernous hemangiomas study, researchers described fi ve unique 12. Fine HF, Cunningham ET Jr, Kim E, Smith RT, Chang S. Autofl uo- rescence imaging fi ndings in long-standing chorioretinal folds. Retin 2 can be monitored for progression. Dr. orientations for chorioretinal folds: hori- Cases Brief Rep 2009;3:2:137-9. 13. Leahey AB, Brucker AJ, Wyszynski RE, Shaman P. Chorioretinal Shields noted that only 52 percent of zontal; oblique; vertical; radiating; and folds. A comparison of unilateral and bilateral cases. Arch Ophthal- orbital cavernous hemangiomas neces- concentric.13 The horizontal orientation mol 1993;111:3:357-9.

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