Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Glaucoma Management and OSD MOA 2014 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 2 1 Objectives 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 MOA 2014 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 MOA 2014 Clinical Trial Completed Mini Drug Pump • MEMS – pump that is refillable, enables long-term use, and possesses broad drug compatibility • The pumping mechanism is based on electrolysis and the pump includes a drug refill port as well as a check valve to control drug delivery – Current Eye Research, 35(3), 192–201, 2010 Replenish MicroPump Iontophoresis • Replenish, Inc. is developing a small, refillable, implantable ocular drug pump. • The pump can be programmed to dispense precise nanoliter-sized doses (a drug flow sensor gives closed-feedback) of drugs every hour, day or month as needed over six to nine months before the next refill. Not Available in US • Iontophoresis uses an electrical current to drive drugs in the form of ions through a tissue or membrane. http://www.replenishinc.com/ 16 http://www.drugdeliverytech.com/ME2 A nanomedicine approach for ocular neuroprotection in glaucoma. A new medical/topical option for glaucoma is coming….. CAI? PGA? Combination? New Class?? 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 M. Chaglasian, O.D. 19 3 Glaucoma Management and OSD MOA 2014 We Are Treating the Whole Patient 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… • Goals of Glaucoma Management – Treatment • Lower IOP to Target • Preserve Vision – Quality of Life Considerations • Long Term Impact of Medications • Balance of Efficacy and Side Effects • Do No Harm “that’s nice that my glaucoma is doing well, but doctor, my eyes are tearing” – Primum non noceru Age and Glaucoma 25.0% Caucasians African Americans Glaucoma and Ocular Surface Disease (OSD) 20.0% 15.0% 10.0% Overview 5.0% 0.0% 40 50 60 70 80 Sommer A. Glaucoma risk factors observed in the Baltimore Eye Survey. Curr Opin Ophthalmol. 1996 Apr;7(2):93-8. • 22 23 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% 13.30% 15.60% 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 . M. Chaglasian, O.D. 24 Schein OD, et al. Prevalence of Dry Eye Among the Elderly. Am J Ophthalmol. 1997:124:723-728. 25 4 Glaucoma Management and OSD MOA 2014 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. Schein OD, et al. Prevalence of Dry Eye Among the Elderly. Am J Ophthalmol. 1997:124:723-728. 26 OSD and Glaucoma 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 60-64 65-69 70-74 Age Group (Years) 75+ 0 55-59 60-64 N ≈25,000 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. 27 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 28 29 Quality of Life How do we study/measure and quantify this? Important for documenting any claims of improvement in response to treatment options. 30 M. Chaglasian, O.D. 31 5 Glaucoma Management and OSD MOA 2014 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) 32 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. 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 33 15 19.4 12.9 10 5 10% 0 0% Normal n=325 Mild n=84 n=134 OSD Severity n=87 34 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.. 35 “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. 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 36 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. 37 6 Glaucoma Management and OSD MOA 2014 OSD in Glaucoma Prevalence: Summary 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 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. • 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. 38 Dry Eye Cascade OBSERVABLE PATHOPHYSIOLOGIES 39 Aqueous Deficient Dry Eye ABNORMAL TEAR FILM CAUSES & CONTRIBUTORS 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 Aging Dry Environment Hormonal Changes Contact Lens Blepharitis LASIK Auto-immune Disease Alcohol Use Pollution Computer Use Anti-depressants Quaternary Ammoniums (i.e. BAK) Courtesy R. Yee, MD 41 42 Perry H. Dry eye diagnosis and management in 2004. Curr Opin Ophthal. 2004;15:299-304. OSD Affects Quality of Life Evaporative Dry Eye • Impact on patients’ day-to-day lives comparable to that of moderate-to-severe angina.1 Lid Margin neovascularization • % of Patients reporting interference with daily life functions:2 • Night time driving • Reading • Computer work • Watching TV Squamous metaplasia of meibomian gland orifices Meibomian gland dysfunction results in a decrease in lipid volume and is a leading cause of evaporative dry eye disease1 Photos Courtesy of Richard Yee, MD Perry H. Dry eye diagnosis and management in 2004. Curr Opin Ophthal. 2004;15:299-304. M. Chaglasian, O.D. 32.3% 27.5% 25.7% 17.9% 1. Schiffman RM, Walt JC, Jacobsen G, et al. Utility assessment among patients with dry eye disease. Ophthalmology. 2003; 110:1412-1419. 2. Hirsch J. Pharmacoeconomic of Dry Eye. Suppl P & T 2003; 28(12) 1-45 43 44 7 Glaucoma Management and OSD MOA 2014 OSD Affects Quality of Vision Detecting OSD Unfortunately, Just Can’t Feel Vision • Signs do not always match symptoms. • Multiple approaches possible. • Should be validated. • Need a better system! Courtesy C Springs, MD 46 45 Diagnostic Tools Signs and Symptoms “The lack of concordance between signs and symptoms presents a problem to the diagnosis of the disease and assessment of severity.” Tear Film Break-Up Time Injection Rose Bengal Staining Lissamine Green Staining -M. Lemp, MD Fluorescein Staining Lemp MA, Advances in understanding and managing dry eye disease. Am J Ophthalmol 2008; 146(3): 350-356. 47 Schirmer Testing Osmolarity 48 Clinician Ratings for Diagnostic Tests DTS Study Group Most Commonly Used Diagnostic Tests 100% Blink Rate Sutphin JE, et al. External disease and cornea. Basic and clinical science course Section 8 2006-2007. American Academy of Ophthalmology. P 20-22,56,61,62,80. 100% 94% 71% 65% 60% 41% 40% 24% 24% 18% TEST OSDI NEIVFQ-25 Tear Flourscein Clearance Corneal Topography Impression Cytololgy Schirmer TBUT Fluorescein Rose Bengal 6% 0% 6% Tear Osmolarity 20% 6% Conjunctival Biopsy Percent (%) Reporting Regular Use of Test 80% DTS=Dysfunctional Tear Syndrome NEIVFQ+National Eye Institute Vision Function Questionnaire Behrens A, et al. Dysfunctional Tear Syndrome: A Delphi Approach to Treatment Recommendations. Cornea 2006; 25(8): 900-907. M. Chaglasian, O.D. 49 Turner AW, Layton CJ, Bron AJ. Survey of eye practitioners’ attitudes towards diagnostic tests and therapies for dry eye disease. Clin Exp Ophthalmol. 2005;33:351-5 50 8 Glaucoma Management and OSD MOA 2014 Sequence of Testing Lissamine Green Staining Lissamine green is a dye, used for staining cells which are devitalized or have lost their normal mucin surface.. Wratten 25 filter. The lissamine green staining appears black. Milton Hom, OD Photos Courtesy of Terrence P. O’Brien, MD 51 Lemp MA, Baudouin C, Baum J, et al. Methodologies to Diagnose and Monitor Dry Eye Disease: Report of the Diagnostic Methodology Subcommittee of the International Dry Eye WorkShop (2007). Ocular Surface 2007;5:108-=151. 52 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). 53 BAK is a Common Preservative Preservative Systems Preservative • Quaternary ammonium compound. Example • Cationic surfactant properties (a detergent). 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 • In majority of ophthalmic medications (72%), ranging in concentrations from 0.004-0.02%. Travatan Z Sodium perborate (GenAqua) Genteal Stabilized oxychloro complex (SOC/Purite) Alphagan-P, Refresh Tears + N CI- • Preserves multi-dose containers from microbial contamination. Oxidative Agents sofZia 54 • Enhances corneal penetration of some drugs by causing epithelial separation. • Efficacy impact on some drugs. Freeman DP, Kahook MY. Expert Rev Ophthalmol 2009. 4(1):59-64 M. Chaglasian, O.D. 55 Abelson MB, et al. Rev Ophthalmol. 2002;9(12). 56 9 Glaucoma Management and OSD MOA 2014 Percent of Eye Drops Preserved with BAK Preservative Affect on Cornea • Directly: – Modifying anatomical and physiological the epithelium which affects optical properties and epithelial barrier function. 28% BAK Preserved Non BAK Preserved 72% Contain BAK • Indirectly: – Modifying tear film leading to ocular non-wetting tear disorders Abelson MB, Fink K. Review of Ophthalmology [serial online] 2002;9(12). Available from: http://www.revophth.com/index.asp?page=1_247.htm Accessed June 5, 2006. 57 Preservatives in IOP-Lowering Medications Generic (Trade Name) Brimonidine (Alphagan1) 0.005% BAK 0.005% SOC Brinzolamide (Azopt 1) 0.01% BAK Levobunolol (Betagan1) 0.005% BAK Betaxolol (Betoptic S Suspension1) Dorzolamide/Timolol 1. 2. 3. Preservatives in PGA’s: 2014 Concentration Preservative Brimonidine with Purite (Alphagan P1) (Cosopt1) 0.01% BAK 0.005% BAK Unoprostone (Rescula1) 0.015% BAK Timolol (Timoptic1) 0.01% BAK Timolol (Timoptic-XE1) 0.012% BDD Travoprost (Travatan3) 0.015% BAK Dorzolamide (Trusopt1) 0.0075% BAK Latanoprost (Xalatan1) 0.02% BAK 0.005% BAK TRAVATAN Z® BAK Free sofZia™ 0.01% BAK Apoptosis *Trademarks are the property of their respective owners. 60 • Decreases Epithelial Cell Integrity.1 – Epithelial Barrier is Compromised. 0.05–0.1% BAK Necrosis – Healing is Impaired. • Treatment of Chronic Ophthalmic Diseases, such as Glaucoma, with BAK Containing Medications. – Longer Duration of BAK Exposure Increased Corneal Epithelial Cell Lysis.3 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. 61 M. Chaglasian, O.D. LUMIGAN 0.03% BAK Impact on Ocular Surface Health – High Concentration in a Single Drop or Due to The Accumulation of Dose With Multiple Drops. 1. 0.02% BAK 3. TRAVATAN® solution and Travatan Z® package inserts 59 • High BAK Concentration: Cell Death is Dose-Dependent.1,2,3 2. 3. LUMIGAN 0.01% 1. XALATAN* package insert BAK: Benzalkonium chloride BDD: Benzododecinium bromide SOC: Stabilized Oxychloro Complex When is BAK Use Most Problematic? 0.02% BAK 2. LUMIGAN* package insert. Noecker R. Rev Ophthalmol. 2001(6). Lumigan package insert. Travatan package insert. Growth Arrest XALATAN 0.0075% BAK Bimatoprost (Lumigan2) 0.0001% BAK 58 • Increases Conjunctival Inflammatory Cells.1 • Loss of Goblet Cells.1 • Reduction in Tear Function.2 • 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. 62 10 Glaucoma Management and OSD MOA 2014 Effects of BAK on the Ocular Surface BAK Effect on Cornea • Cornea: BAK on Corneal Epithelial Surface – Accelerates superficial desquamation. – Disrupts permeability barrier. – Triggers apoptosis by 0.01% and necrosis by 0.05%. Tear Film Instability Epithelial Damage Epithelial Cell Apoptosis • Conjunctiva: – Increases expression of HLA-DR antigen and chemokine receptors. – Promotes inflammatory cell infiltration. – Goblet cell loss. Photo Courtesy of H Edelhauser,PhD Decrease MUC5A (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) Abelson MB, et al. Rev Ophthalmol. 2002;9(12). 63 Lemp M, et al. 2007 Report of the International Dry Eye Workshop (DEWS). The Ocular Surface 2007; 5:75-200, 2007. 64 BAK Adversely Affects TBUT in 30 Healthy Volunteers Dry Eye Work Shop 2007 “The single most critical advance in the treatment of dry eye came from the elimination of preservatives, such as benzalkonium chloride, from OTC lubricants.” TBUT Pre/Post Single Drop 12 TBUT (Secs) Cartelol with BAK 9 8.1 7.9 8 Decrease from Baseline Cartelol without BAK 10.4 10 7.3 7.4 0 7.9† -1 6.1 6 -1.1 -2 4 -3 2 -4 Cartelol without BAK Cartelol with BAK 0 Baseline 30 mins 1 Hr 3 Hrs* -4.3* -5 *Decrease in TBUT at 3 hours from baseline was significantly lower in the BAK-free group than in the preserved carteolol (P=.04). †Significantly lowered compared with baseline (P=.001). Baudouin C et al. Br J Ophthalmol. 1998;82(1):39-42. DEWS Report. Ocul Surf. 2007;5(2):65-204. 66 65 Is Chronic Exposure to BAK a Big Deal? Chronic Effect of Preservatives • Patients treated >1 year with preserved latanoprost (21), preserved timolol (15) or unpreserved timolol (17) were compared to normals. “The Single Most Critical Advance in the Treatment of Dry Eye Came with The Elimination of Preservatives, such as BAK from OTC Lubricants.”1 Stephen Pflugfelder, MD • 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. “BAK is Largely Responsible for the Ocular Toxicities and Inflammation Associated with the Chronic Use of Many Ophthalmic Solutions.”2 Christoph Baudouin, MD, PhD 1. Pflugfelder SC, et al. Management and therapy of dry eye disease: Report of the management and therapy subcommittee of the international dry eye workshop (2007). The Ocular Surface. 2007;5:163-178. Pisella PJ ,et al, IOVS 2004 67 M. Chaglasian, O.D. 2. Baudouin C, Riancho L. In vitro Studies of antiglaucomatous prostaglandin analogues: travoprost with and without benzalkonium chloride and preserved latanoprost. IOVS. 2007;48:41234128. 68 11 Glaucoma Management and OSD MOA 2014 Factors Contributing to Preservative Toxicity Implications for Glaucoma Therapy • 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. • Chronic therapy with BAK preserved medications may: – Promote development of dry eye and OSD – Increase risk of: • Corneal complications: haze, infiltrates, ulcers. • Irritation symptoms. • Decreased functional vision. S. Pflugfelder, MD S. Pflugfelder, MD 69 70 Other Clinical Effects on Chronic Glaucoma Medications Summary • Decreased mucus layer of the tear film.1 • Reduced tear secretion, basal Schirmers and TBUT.2,3 • Increased Rose-Bengal staining of cornea.4 • Foreshortening of the inferior conjunctival fornix.5 • Inflammatory cell infiltration in trabecular meshwork.6 • Do preserved glaucoma medications have a deleterious 1 Herreras JM et al Ophthalmol 1992 2 Nuzzi R. et al Int. Ophthalmol, 1998, 3 Ariei MK et al Clin Experimental Ophthalmol 2000 4 Thygesen J et al Acta Ophthalmol Scand 2000 5 Schwab IR et al, Ophthalmol 1992 6 Baudouin C et al, Ophthalmol 1999 effect on superficial eye tissues? Yes • Are preservatives like BAK deleterious? Yes • Are the changes dose/time dependent? • Are the changes reversible? • Is it clinically important? Yes Probably In many patients 71 72 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 73 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. 74 12 Glaucoma Management and OSD MOA 2014 Study Results Patient Preference OSDI Severity Grading Product Severe 00-12 0 10 13 -22 23 -32 20 33-100 30 40 Normal 50 Score Mild 60 70 Moderate 80 90 100 191 (28%) 500 (72%) P-Value < 0.0001 Symptoms Improved: Severe Photophobia, pain, grittiness, blurred vision Total OSDI Score= (Sum of Score for All Questions Answered) X (25) Functional Improvements: Driving at night, reading, and computer use. (Total # of Questions Answered) 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. 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. 75 *Trademarks are the property of their respective owners 76 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. 77 78 Bitmatoprost Non BAK PGA Options • Travatan Z N (%) XALATAN*/ LUMIGAN* TRAVATAN Z Solution 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. M. Chaglasian, O.D. Lumigan.com 13 Glaucoma Management and OSD 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. • The inactive ingredients are: sodium chloride, sodium dihydrogen phosphate monohydrate, disodium hydrogen phosphate anhydrous, and water for injection. MOA 2014 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. PURITE® Is a Gentle Preservative SEM of rabbit corneal epithelium (800X) New to USA (March 2012) Preservative Free PGA Zioptan Tafluprost 0.015% Untreated PURITE® QID 7 days The clinical significance of these data is unknown. 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. M. Chaglasian, O.D. Merck BAK QID 7 days Way et al. Invest Ophthalmol Vis Sci. 2001. Zioptan: Efficacy • Clinical Trial: – IOP reduced by 6.4 – 7.5 mmHg @ 12 weeks • Baseline 23-26 mmHg • n=618 – AJO June 2012 14 Glaucoma Management and OSD MOA 2014 Multiple Clinical Trials 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 Liu, Mao Clinical Ophthalmology 2013:7 7–14 88 Patients’ Dry Eye Complaints, Mean TBUT, and Abnormal Corneal Fluorescein Staining at Baseline (Latanoprost With BAK), and at 2, 6, and 12 Weeks After Changing to Preservative-free Tafluprost in a Prospective, Observer-masked Study Involving 30 Patients (60 Eyes) Zioptan vs. Latanoprost • “Both treatments had a substantial IOPlowering effect which persisted throughout the study.” Result/Finding: Decreased dry eye complaints • 7.1 mmHg for tafluprost • 7.7 mmHg for latanoprost – at 24 months 93 No Difference in OSD for 3 PGAs (3 months) Cosopt PF • dorzolamide HCL - timolol maleate 2%/0.5% • Preservative Free • BID dosing • 25-30% IOP reduction when used as monotherapy • Role: • Xalatan – 0.02% BAK • Lumigan 0.03% – 0.005% BAK • Travatan Z – Sofzia – COPD and other beta blocker contraindications • Graded: • Similar indications for OSD patients where BAK toxicity is a concer – Ocular Tolerability – TBUT – Hyperemia JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICS Volume 26, Number 3, 2010 M. Chaglasian, O.D. 95 http://cosoptpf.com/consumer/index.html 15 Glaucoma Management and OSD MOA 2014 Recent Cosopt PF articles Another PF Option • TIMOPTIC® in OCUDOSE® — – Preservative-free Sterile Ophthalmic Solution TIMOPTIC® is supplied in OCUDOSE®, a clear, individual, unit dose container – Valeant Pharmacueticals • Patient Care Program BAK in Other Meds • Simbrinza • Rescula – 0.003% • Alphagan P – 0.015% – Brimonidine PURITE® 0.1% – Higher pH 7.8 – Lower Concenration • Azopt • Combigan – 0.01% – 0.005% • Trusopt – 0.0075% • Cosopt • Timolol sol – 0.0075% Other Non-BAK Options for Glaucoma Patients with OSD – 0.01% • PURITE® – stabilized oxychloro complex) is a preservative that is effective at low concentrations. – PURITE® Is a Gentle Preservative SEM of rabbit corneal epithelium (800X) Way WA, Matsumoto S, Apel LJ, Wiese A, Tarlo K, Vehige J. PURITE® as a non-disruptive preservative for lubricating eye drop solutions in comparison to alternative preservatives. Invest Ophthalmol Vis Sci. 2001;42(4):S39. 100 My Typical Approach • Glaucoma Patient – New or established • History – Specific for dry eye symptoms – Questionnaire if necessary • Thorough slit lamp – TBUT and Lissamine green • With Positive Findings or Risk Factors Untreated PURITE® QID 7 days The clinical significance of these data is unknown. M. Chaglasian, O.D. BAK QID 7 days Way et al. Invest Ophthalmol Vis Sci. 2001. – Review Medications and Treatment Options – Patient Education – Reduce the Preservative Load 102 16 Glaucoma Management and OSD MOA 2014 Clinical Evaluation EJO 2013: Who?,When?,Why? Eur J Ophthalmol 2013; DOI: 10.5301/ejo.5000270 103 104 105 106 Summary Summary • Do preserved glaucoma medications have a deleterious effect on superficial eye tissues? Yes • Are preservatives like BAK deleterious? Yes • Are the changes dose/time dependent? Yes • Are the changes reversible? Probably • Is it clinically important? In many patients, especially those with OSD. 107 M. Chaglasian, O.D. 108 17 Glaucoma Management and OSD MOA 2014 Questions [email protected] M. Chaglasian, O.D. 18