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Glaucoma Management and OSD 2015 Disclosure: Glaucoma Management and Ocular Surface Disease • Michael Chaglasian, O.D. is a paid advisor, consultant and researcher for the following commercial/industry groups: – 1. Advisory Boards: Michael Chaglasian, O.D. Illinois Eye Institute Illinois College of Optometry [email protected] • Allergan, Alcon Labs, Carl Zeiss Meditec • The content of this presentation is in no manner influenced by any of the aforementioned parties or companies COPE # 40918-GL 1 Objectives 2 OSD is Just Like Glaucoma • A chronic disease the increases with age • Definitions of the disease vary • Signs of the disease rarely match the symptoms and vice versa • Diagnostic tests are variable, not repeatable and often inconclusive • Treatment regimens are variable and often not effective • Majority of patients are non-compliant 1. Understand the prevalence, severity and impact of OSD and glaucoma in the population. 2. Understand the clinical signs of OSD and glaucoma. 3. Understand the histological effects of BAK on the ocular surface. 4. Be familiar with recent studies examining the effects of topical glaucoma agents on patients. 5. Be familiar with all options for treating glaucoma patient with medications that do not include BAK. 3 4 A Very Current Topic Glaucoma Management and Ocular Surface Disease Why should we care? 5 M. Chaglasian, O.D. 6 1 Glaucoma Management and OSD 2015 Glaucoma Care for the Future • New Ophthalmic Drug Delivery Systems are Coming for Glaucoma. Will there be something to replace topical therapy in glaucoma in the near future? – The future therapy for glaucoma remains pharmacologically based (vs. laser/surgery). – Some new therapeutic agents will arrive. – But more importantly new drug delivery systems will significantly alter how we start therapy for our glaucoma patients. 7 New Delivery Systems 8 QLT's punctal plug drug delivery technology http://www.qltinc.com/development/technologies/punctalPlugDelivery.htm Iluvien (Alimera) • Iluvien – extended release intravitreal • delivers fluocinolone acetonide, to the retina for up to three years for treatment of DME – Completed Phase III Clinical Trial – Medidur™ Technology is a miniaturized, injectable, sustained-release drug delivery system Subconjunctival Injection • Anecortave acetate – angiostatic, initially for wet AMD – posterior juxtascleral injection – initial success of 3 month IOP reduction, then failure in large scale studies • Latanoprost – Encapulated in poly-glycolide micro particles – Animal studies showed up to 30 days IOP reduction post injection 13 M. Chaglasian, O.D. 2 Glaucoma Management and OSD 2015 Clinical Trial Completed DURASERT™ 15 A nanomedicine approach for ocular neuroprotection in glaucoma. The Helios Insert Jeun, M et al. Engineered superparamagnetic nanoparticles as a heat shock protein induction agent for ocular neuroprotection in glaucoma Biomaterials :10.1016/j.biomaterials.2010.09.016 http://forsightvision5.com/products/helios-insert/ Look and sound familiar? • 75y/o female with primary open angle glaucoma • Controlled IOP, moderate field loss but STABLE. • On Xalatan, Cosopt and Brimonidine • You pat yourself on the back, ready to conquer the next challenging patient but wait… A new medical/topical option for glaucoma is coming….. CAI? PGA? Combination? New Class?? “that’s nice that my glaucoma is doing well, but doctor, my eyes are tearing” 21 M. Chaglasian, O.D. 3 Glaucoma Management and OSD 2015 We Are Treating the Whole Patient • Goals of Glaucoma Management Glaucoma and Ocular Surface Disease (OSD) – Treatment • Lower IOP to Target • Preserve Vision – Quality of Life Considerations Overview • Long Term Impact of Medications • Balance of Efficacy and Side Effects • Do No Harm – Primum non noceru 24 OSD in the Elderly OSD in the Elderly 2,520 residents of Salisbury, MD. 65 years or older as of 1993. Standardized questionnaire (6 questions). Exam: Age % Reporting 1 or more symptoms often or all the time • • • • – Schirmer – Rose bengal – Assessment of meibomian glands » Gender 50% 50% 40% 40% 30% 20% 30% 14.20% 14.90% 13.70% 16.30% 10% 20% 15.60% 13.30% 10% 0% 0% 65-69 70-74 75-79 80+ Male Female Years Schein OD, et al. Prevalence of Dry Eye Among the Elderly. Am J Ophthalmol. 1997:124:723-728 . Schein OD, et al. Prevalence of Dry Eye Among the Elderly. Am J Ophthalmol. 1997:124:723-728. 26 Age and OSD OSD in the Elderly OSD in the Women’s Health Study 12 14.6% reported one or more dry eye symptom “often” or “all the time.” 12 10 10 8 6 4 2 55-59 1. 2. 3. 4. M. Chaglasian, O.D. 28 8 6 4 2 0 N = 36,995 OSD in the Public Health Study (Men) 14 Prevalence of Dry Eye (%) Prevalence of Dry Eye (%) 14 Schein OD, et al. Prevalence of Dry Eye Among the Elderly. Am J Ophthalmol. 1997:124:723-728. 27 60-64 65-69 70-74 Age Group (Years) 75+ 0 55-59 N ≈25,000 60-64 65-69 70-74 Age Group (Years) 75+ Schaumberg DA et al. Adv Exp Med Biol. 2002;506(Pt B):989-998. Schaumberg DA et al. Ophthalmol. 2003;136:317-326. Schaumberg DA et al. Epidemiology of Dry Eye Syndrome. Cornea 2000:19;S120. Miljanovic R et al. Prevalence and Risk Factors for Dry Eye Syndrome Among Older Men in the United States. IOVS. 2007;48:4293. 29 4 Glaucoma Management and OSD 2015 OSD and Glaucoma Cornea 2006 Review of Literature: 1. Moderate OSD in 20-60% 2. Severe OSD in 14-66% Curr Eye Res. 2011 May;36(5):391-8 30 31 Quality of Life How do we study/measure and quantify this? Important for documenting any claims of improvement in response to treatment options. 33 32 Ocular Surface Disease Index “OSDI” OSDI Severity Grading Severe • Developed by Outcomes Research Group at Allergan, Inc. • 12 item questionnaire. • Provide rapid assessment of symptoms of ocular irritation consistent with dry eye disease. • Designed as endpoint in clinical trial testing of treatment for dry eye disease. 00-12 0 10 13 -22 23 -32 20 33-100 30 40 Normal 50 Score Mild 60 Moderate 70 80 90 100 Severe Total OSDI Score= (Sum of Score for All Questions Answered) X (25) (Total # of Questions Answered) 34 M. Chaglasian, O.D. Miller, K.L., Mink, D.R., Mathias, S.D, & Walt, J.G. (2006). Estimating the minimal clinical important difference of the Ocular Surface Disease Index®: Preliminary findings [Abstract]. Abstract obtained from www.isoqol.org/2006AbstractsBook.pdf. 35 5 Glaucoma Management and OSD 2015 OSDI Results: 630 Glc Patients Impact of Multiple Medications 25 60% 51.6% 48.4% 40% 30% 21.3% 20% † * 16.7 20 OSDI Score Percentage 50% 13.3% 13.8% Moderate Severe 15 19.4 12.9 10 5 10% 0 0% Normal n=325 Mild n=84 n=134 OSD Severity n=87 36 Additional Prevalence Data: Leung Evaluation Schirmer 61% decreased tear production in 1 eye 35% severe deficiency Lissamine Green 22% positive staining TBUT 78% abnormal tear quality 65% severe decrease in tear quality Fechtner, R, Budenz, D, Godfrey D. Prevalence of ocular surface disease symptoms in glaucoma patients on IOPlowering medications. Cornea. 2010 Jun;29(6):618-21.. 37 “A large proportion of patients with open-angle glaucoma or ocular hypertension had signs and/or symptoms of OSD in at least 1 eye. Each additional BAKcontaining eye drop = ~2x higher odds of an abnormal lissamine green result. (OR =2.03; 95% CI: 1.06 to 3.89; P=0.034) Leung E, et al. Prevalence of Ocular Surface Disease in Glaucoma Patients. J Glaucoma 2008;17:350–355. 38 OSD in Glaucoma Prevalence: Summary 1. Fechtner, R, Budenz, D, Godfrey D. Prevalence of ocular surface disease symptoms in glaucoma patients on IOP-lowering medications. Presented at: Annual Meeting of the American Glaucoma Society ; March 2008; Washington DC. 2. Leung E, et al. Prevalence of Ocular Surface Disease in Glaucoma Patients. J Glaucoma 2008;17:350–355. 3. Schein OD, et al. Prevalence of dry eye among the elderly. AJO 1997 124;723-728. 4. Ghosh S, Crowston JG, et al. Assessment of Prevalence of Ocular Toxicity in Glaucomatous Patients Presented as paper during the 2008 American Academy of Ophthalmology. Nov. 2008. PA046. The co-existence of OSD and the use of BAK-containing medications may impact vision-related quality of life in this patient population.” Leung E, et al. Prevalence of Ocular Surface Disease in Glaucoma Patients. J Glaucoma 2008;17:350–355. 39 OSD (Glaucoma Today ’08) • Ocular Surface Disease is a Significant Problem For Many Glaucoma Patients. • Prevalence is High, ranging from 48.4% to 60%.1,2 • Previously Reported in a Population Based Study of Elderly (~15%).3 • OSD Severity Increases With The Number of Medications Used.2,4 M. Chaglasian, O.D. 3 N=114 Leung: Key Learnings Observation 59% symptoms in 1 eye 27% reported severe symptoms 2 N=227 Number of Medications * P=0.007 (1 Med vs. 2 Meds) † P=0.001 (1 Med vs. 3 Meds) Fechtner, R, Budenz, D, Godfrey D. Prevalence of ocular surface disease symptoms in glaucoma patients on IOPlowering medications. Cornea. 2010 Jun;29(6):618-21.. OSDI 1 N= 253 • Any condition that adversely affects the stability and function of the tear film. • Common causes dry eye syndrome, blepharitis, meibomian gland dysfunction, and preservative toxicity. • Pathology involves corneal epithelial cell changes, decreased goblet cell density, and increased inflammatory mediators. 40 Kahook MY, Springs CL. Treating the ocular surface in glaucoma. Glaucoma Today Nov 2008. http://bmctoday.net/glaucomatoday/2008/11/article.asp?f=GT1108_11.php 41 6 Glaucoma Management and OSD 2015 Detecting OSD Signs and Symptoms • Signs do not always match symptoms. “The lack of concordance between signs and symptoms presents a problem to the diagnosis of the disease and assessment of severity.” • Multiple approaches possible. • Should be validated. -M. Lemp, MD • Need a better system! 48 Lemp MA, Advances in understanding and managing dry eye disease. Am J Ophthalmol 2008; 146(3): 350-356. 49 Why Are Preservatives Needed? • FDA requires multi-dose ophthalmic preparations to contain a preservative to reduce contamination. The Effects of Benzylalkonium Chloride (BAK) • Decrease the risk of microbial contamination in the bottle. Abelson MB, et al. Rev Ophthalmol. 2002;9(12). 55 Preservative Systems Preservative Preservative Affect on Cornea Example • Directly: Detergents Benzalkonium chloride (BAK) Xalatan, Timoptic, Lumigan Benzododecinium bromide (BDD) Timoptic XE Cetrimonium chloride Civigel Clorobutanol TobraDex Ointment Polyquaternium-1 (Polyquad) Tears Naturale II, Opti-free Express Disinfecting solution – Modifying anatomical and physiological the epithelium which affects optical properties and epithelial barrier function. • Indirectly: Oxidative Agents sofZia Travatan Z Sodium perborate (GenAqua) Genteal Stabilized oxychloro complex (SOC/Purite) Alphagan-P, Refresh Tears Freeman DP, Kahook MY. Expert Rev Ophthalmol 2009. 4(1):59-64 M. Chaglasian, O.D. 56 – Modifying tear film leading to ocular non-wetting tear disorders 57 59 7 Glaucoma Management and OSD 2015 When is BAK Use Most Problematic? Preservatives in PGA’s: 2014 XALATAN • High BAK Concentration: Cell Death is Dose-Dependent.1,2,3 0.02% BAK LUMIGAN 0.01% – High Concentration in a Single Drop or Due to The Accumulation of Dose With Multiple Drops. 0.02% BAK 0.0001% BAK Growth Arrest LUMIGAN 0.03% 0.005% BAK TRAVATAN Z® BAK Free sofZia™ 0.05–0.1% BAK Necrosis – Longer Duration of BAK Exposure Increased Corneal Epithelial Cell Lysis.3 1. 2. LUMIGAN* package insert. 2. 3. 3. TRAVATAN® solution and Travatan Z® package inserts 62 BAK Impact on Ocular Surface Health Noecker R. Ophthalmic preservatives: Considerations for long-term use in glaucoma patients with dry eye or glaucoma. Review of Ophthalmology [serial online] 2001 June. Available from: http://www.revophth.com/2001/june/cme0601_article.htm Accessed June 5, 2006. De Saint Jean M, et al. Expression of CD40 and CD 40 ligand in the human conjunctival epitheliumCurrent Eye Res. 2000;20:85-94. Cha SH, et al. Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro Clin Experimental Ophthalmology 2004;32:180184. 63 Effects of BAK on the Ocular Surface • Cornea: • Decreases Epithelial Cell Integrity.1 – Accelerates superficial desquamation. – Disrupts permeability barrier. – Triggers apoptosis by 0.01% and necrosis by 0.05%. – Epithelial Barrier is Compromised. – Healing is Impaired. • Increases Conjunctival Inflammatory Cells.1 • Loss of Goblet Cells.1 • Conjunctiva: • Reduction in Tear Function.2 – Increases expression of HLA-DR antigen and chemokine receptors. – Promotes inflammatory cell infiltration. – Goblet cell loss. • Decreases Tear Film Break-up Time (TBUT).2 1. Broadway DC, I. Grierson I, O'Brien C; Hitchings RA. Adverse effects of topical antiglaucoma medication. Arch Ophthalmol. 1994;112:1437-1445. 2. Baudouin C, de Lunardo C. Short term comparative study of topical 2% cartelol with and without benzalkonium chloride in healthy volunteers. Br J Ophthalmol. 1998;82:39–42. Abelson MB, et al. Rev Ophthalmol. 2002;9(12). 65 64 BAK Effect on Cornea Dry Eye Work Shop 2007 BAK on Corneal Epithelial Surface “The single most critical advance in the treatment of dry eye came from the elimination of preservatives, such as benzalkonium chloride, from OTC lubricants.” Tear Film Instability Epithelial Damage Epithelial Cell Apoptosis Decrease MUC5A 0.01% BAK Apoptosis • Treatment of Chronic Ophthalmic Diseases, such as Glaucoma, with BAK Containing Medications. 1. XALATAN* package insert *Trademarks are the property of their respective owners. Photo Courtesy of H Edelhauser,PhD (gel forming mucin secreted by the goblet cells of the ocular surface) Increase ICAM (intracellular adhesion molecule for cell to cell adhesion: a marker for inflammation) Lemp M, et al. 2007 Report of the International Dry Eye Workshop (DEWS). The Ocular Surface 2007; 5:75-200, 2007. M. Chaglasian, O.D. 66 DEWS Report. Ocul Surf. 2007;5(2):65-204. 67 8 Glaucoma Management and OSD 2015 Factors Contributing to Preservative Toxicity Chronic Effect of Preservatives • Patients treated >1 year with preserved latanoprost (21), preserved timolol (15) or unpreserved timolol (17) were compared to normals. • Concentration. • Frequency and duration of use. • Tear production and clearance (blink rate and corneal sensitivity). • Contact lens use. • Number and type of concurrent medications. • Type of preservative. • Unpreserved timolol was similar to controls. • Preserved latanoprost and preserved timolol with 0.02% BAK showed pro-inflamatory and pro-apoptotic effects but less than 0.02% BAK alone. Pisella PJ ,et al, IOVS 2004 S. Pflugfelder, MD 69 71 Summary Implications for Glaucoma Therapy • Do preserved glaucoma medications have a deleterious • Chronic therapy with BAK preserved medications may: effect on superficial eye tissues? Yes • Are preservatives like BAK deleterious? – Promote development of dry eye and OSD – Increase risk of: Yes • Are the changes dose/time dependent? • Corneal complications: haze, infiltrates, ulcers. • Irritation symptoms. • Decreased functional vision. • Are the changes reversible? • Is it clinically important? Yes Probably In many patients S. Pflugfelder, MD 72 74 Human Clinical Data • Purpose: Examine The Safety, Tolerability and Efficacy of Travoprost BAK-free Compared to Latanoprost or Bimatoprost. • Methods: Experience with BAK-Free Glaucoma Medications – 694 POAG or OH Patients Treated With Latanoprost or Bimatoprost Monotherapy Who Demonstrate a Need For Greater Tolerability, and Judged by The Physician to be a Good Candidate, Were Changed to Travoprost BAK Free Ophthalmic Solution and Returned for a Second Visit 3 Months Later – Prospective, Multi-center, Open-label, 3 Month Study With 2 Visits (Baseline And Month 3) Human Clinical Data – Variables Measured: Patient Global Preference • IOP Slit-Lamp Biomicroscopy • Ocular Hyperemia Grading Adverse Events • Global OSDI Score • Visual Acuity 75 M. Chaglasian, O.D. Henry JC, Peace J, et al. Efficacy, safety, and improved tolerability of travoprost BAK-free ophthalmic solution compared to prior prostaglandin therapy. Clin Ophth 2008; (2):613-621. 76 9 Glaucoma Management and OSD 2015 Compliance Component Conclusions • In this evaluation of 691 POAG or OH patients treated with Latanoprost or Bimatoprost monotherapy who demonstrated a need for greater tolerability, change to BAK-free travoprost resulted in significant improvements in OSDI, hyperemia, and patient preference at 3 months. • “A major cause of intolerance or poor tolerance to glaucoma medication is the ocular surface changes created by treatment.” • Patient preference may have been driven by improved functionality including driving at night, reading, sensitivity to light, grittiness, pain, blurred vision, and computer work. Henry JC, Peace J, et al. Efficacy, safety, and improved tolerability of travoprost BAK-free ophthalmic solution compared to prior prostaglandin therapy. Clin Ophth 2008; (2):613-621. – Detry-Morel M. Side effects of glaucoma medications. Bull Soc Delge Ophtalmol. 2006;27-40. 79 80 Bitmatoprost Non BAK PGA Options • Travatan Z Unique Ionic Buffer System – SofZia Preservative Borate Polyols Zinc T M • Lumigan – 0.01 • 0.02% BAK – 0.03% • 0.005% BAK When TRAVATAN® Z solution comes in contact with the positively charged ions in the tear film, the ionic buffered preservative system becomes inactive, providing a solution that is safe and gentle on the eye. Lumigan.com Latanoprost Generic • Latanoprost ophthalmic solution is supplied as a sterile, isotonic, buffered aqueous solution of latanoprost with a pH of approximately 6.7 and an osmolality of approximately 267 mOsmol/kg. • Each mL of latanoprost contains 50 micrograms of latanoprost. Benzalkonium chloride, 0.02% is added as a preservative. • M. Chaglasian, O.D. The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, and water for injection. Other Non-BAK Options for Glaucoma Patients with OSD • Alphagan P – Brimonidine PURITE® 0.1% • PURITE® (stabilized oxychloro complex) is a preservative that is effective at low concentrations. – Way WA, Matsumoto S, Apel LJ, Wiese A, Tarlo K, Vehige J. PURITE® as a nondisruptive preservative for lubricating eye drop solutions in comparison to alternative preservatives. Invest Ophthalmol Vis Sci. 2001;42(4):S39. 10 Glaucoma Management and OSD The Only: Preservative Free PGA 2015 Zioptan • A Preservative Free prostaglandin analog – Introduced in 2003 – Tafluprost 0.015% – Single use vial delivery • Same PGA side effects: – Iris/Periorbital Pigmenation, Hyperemia, Deepening Orbital Sulcus, etc. http://www.zioptan.com/zioptan/consumer/secure/index.html Zioptan: Efficacy • Clinical Trial: – IOP reduced by 6.4 – 7.5 mmHg @ 12 weeks • Baseline 23-26 mmHg • n=618 – AJO June 2012 Zioptan Non-Clinical Data • Tafluprost: less toxic than travoprost, latanoprost, or unoprostone. • Ayaki M, Iwasawa A. Cytotoxicity of prostaglandin analog eye drops preserved with benzalkonium chloride in multiple corneoconjunctival cell lines. Clin Ophthalmol. 2010;4:919–924. • Application of PF tafluprost at 5-minute intervals on 15 occasions had no toxic effects on the rabbit corneoconjunctival surface • Liang H, Baudouin C, Pauly A, Brignole-Baudouin F. Conjunctival and corneal reactions in rabbits following short- and repeated exposure to preservative-free tafluprost, commercially available latanoprost and 0.02% benzalkonium chloride. Br J Ophthalmol. 2008;92:1275–1282 90 Zioptan vs. Latanoprost No Difference in OSD for 3 PGAs (3 months) • “Both treatments had a substantial IOPlowering effect which persisted throughout the study.” • Xalatan – 0.02% BAK • Lumigan 0.03% – 0.005% BAK • Travatan Z • 7.1 mmHg for tafluprost • 7.7 mmHg for latanoprost – Sofzia • Graded: – Ocular Tolerability – TBUT – Hyperemia – at 24 months JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 26, Number 3, 2010 M. Chaglasian, O.D. 97 11 Glaucoma Management and OSD Cosopt PF 2015 Recent Cosopt PF articles • dorzolamide HCL - timolol maleate 2%/0.5% • Preservative Free • BID dosing • 25-30% IOP reduction when used as monotherapy • Role: – COPD and other beta blocker contraindications • Similar indications for OSD patients where BAK toxicity is a concer http://akorn.com/prod_detail.php?ndc=17478-604-30 BAK in Other Meds Another PF Option • Simbrinza • TIMOPTIC® in OCUDOSE® — – 0.003% • Combigan – 0.005% – 0.01% • Trusopt – 0.0075% • Cosopt – Valeant Pharmacueticals – 0.0075% • Patient Care Program Other Non-BAK Options for Glaucoma Patients with OSD • Alphagan P • Timolol sol – 0.01% My Typical Approach • Glaucoma Patient – New or established • History – Brimonidine PURITE® 0.1% – Higher pH 7.8 – Lower Concenration – Specific for dry eye symptoms – Questionnaire if necessary • Thorough slit lamp • PURITE® – TBUT and Lissamine green – stabilized oxychloro complex) is a preservative that is effective at low concentrations. PURITE® Way WA, Matsumoto S, Apel LJ, Wiese A, Tarlo K, Vehige J. as a nondisruptive preservative for lubricating eye drop solutions in comparison to alternative preservatives. Invest Ophthalmol Vis Sci. 2001;42(4):S39. 102 M. Chaglasian, O.D. – 0.015% • Azopt – Preservative-free Sterile Ophthalmic Solution TIMOPTIC® is supplied in OCUDOSE®, a clear, individual, unit dose container – • Rescula • With Positive Findings or Risk Factors – Review Medications and Treatment Options – Patient Education – Reduce the Preservative Load 104 12 Glaucoma Management and OSD 2015 Summary Questions • Do preserved glaucoma medications have a deleterious effect on superficial eye tissues? • Are preservatives like BAK deleterious? • Are the changes dose/time dependent? • Are the changes reversible? Yes Yes Yes Probably • Is it clinically important? In many patients, especially those with OSD. 109 M. Chaglasian, O.D. [email protected] 13