Glaucoma Management and OSD Management and ... Moderate OSD in 20-60% 2. Severe OSD in 14-66% ......

Glaucoma Management and OSD MOA 2014

M. Chaglasian, O.D. 1

1

Glaucoma Management and Ocular Surface Disease

Michael Chaglasian, O.D.

Illinois Eye Institute

Illinois College of Optometry

[email protected]

COPE # 40918-GL

Disclosure:

• Michael Chaglasian, O.D. is a paid advisor, consultant and researcher for the following commercial/industry groups:– 1. Advisory Boards:

• Allergan, Alcon Labs, Carl Zeiss Meditec

• The content of this presentation is in no manner influenced by any of the aforementioned parties or companies

2

Objectives

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

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-compliant4

Why should we care?

5

Glaucoma Management and Ocular Surface Disease

A Very Current Topic

6



Will there be something to replace topical therapy in

glaucoma in the near future?

7

Glaucoma Care for the Future

8

• New Ophthalmic Drug Delivery Systems are Coming for Glaucoma.– 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.

New Delivery SystemsQLT'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 IOPreduction post injection

13



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

• 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.

16Not Available in US http://www.replenishinc.com/

Iontophoresis

• Iontophoresis uses an electrical current to drive drugs in the form of ions through a tissue or membrane.

http://www.drugdeliverytech.com/ME2

A nanomedicine approach for ocular neuroprotection in glaucoma.

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

A new medical/topical option for glaucoma is coming…..

CAI? PGA? Combination?

New Class??

19



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… “that’s nice that my glaucoma is

doing well, but doctor, my eyes are tearing”

We Are Treating theWhole Patient

• 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– Primum non noceru

22

Glaucoma and Ocular Surface Disease (OSD)

Overview

Age and Glaucoma

23

• Sommer A. Glaucoma risk factors observed in the Baltimore Eye Survey. Curr Opin Ophthalmol. 1996 Apr;7(2):93-8.

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

40 50 60 70 80

CaucasiansAfrican Americans

24

OSD in the Elderly

• 2,520 residents of Salisbury, MD.

• 65 years or older as of 1993.

• Standardized questionnaire (6 questions).

• Exam:– Schirmer

– Rose bengal

– Assessment of meibomian glands» Schein OD, et al. Prevalence of Dry Eye Among the Elderly. Am J

Ophthalmol. 1997:124:723-728

.. 25

OSD in the Elderly

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.

14.20% 14.90% 13.70%16.30%

0%

10%

20%

30%

40%

50%

65-69 70-74 75-79 80+

% R

epor

tin

g 1

or m

ore

sym

ptom

s of

ten

or

all t

he

tim

e

Years

Age

13.30%15.60%

0%

10%

20%

30%

40%

50%

Male Female

Gender



26

OSD in the Elderly

14.6% reported one or more dry eye symptom “often” or

“all the time.”

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.

1. Schaumberg DA et al. Adv Exp Med Biol. 2002;506(Pt B):989-998.2. Schaumberg DA et al. Ophthalmol. 2003;136:317-326.3. Schaumberg DA et al. Epidemiology of Dry Eye Syndrome. Cornea 2000:19;S120.4. Miljanovic R et al. Prevalence and Risk Factors for Dry Eye Syndrome Among Older Men in the United States.

IOVS. 2007;48:4293. 27

Age and OSD

0

2

4

6

8

10

12

14

55-59 60-64 65-69 70-74 75+Age Group (Years)

Pre

vale

nce

of

Dry

Eye

(%

)

N = 36,995

0

2

4

6

8

10

12

14

55-59 60-64 65-69 70-74 75+Age Group (Years)

Pre

vale

nce

of

Dry

Eye

(%

)

N ≈25,000

OSD in the Women’s Health Study

OSD in the Public Health Study

(Men)

OSD and Glaucoma

28

Review of Literature:1. Moderate OSD in 20-60%2. Severe OSD in 14-66%

Curr Eye Res. 2011 May;36(5):391-8

Cornea 2006

29

Quality of Life

30

How do we study/measure and quantify this?

Important for documenting any claims of improvement in

response to treatment options.

31



32

Ocular Surface Disease Index “OSDI”

• 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.

33

OSDI Severity GradingOSDI Severity Grading

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.

Severe

Total OSDI Score=(Sum of Score for All Questions Answered) X (25)

(Total # of Questions Answered)



Mild ModerateNormal Severe

0 10 20 30 40 50 60 70 80 90 100Score

0-12 23-3213-220 33-100

34

OSDI Results: 630 Glc Patients

51.6%

21.3%

13.3% 13.8%

0%

10%

20%

30%

40%

50%

60%

Normal Mild Moderate Severe

n=325 n=134 n=84 n=87

Per

cen

tage

OSD Severity

48.4%

Fechtner, R, Budenz, D, Godfrey D. Prevalence of ocular surface disease symptoms in glaucoma patients on IOP-lowering medications. Cornea. 2010 Jun;29(6):618-21.. 35

Impact of Multiple Medications

12.9

16.7

19.4

0

5

10

15

20

25

1 2 3

Number of Medications

*

†

* P=0.007 (1 Med vs. 2 Meds) † P=0.001 (1 Med vs. 3 Meds)

N= 253 N=227 N=114

OSD

I Sc

ore

Fechtner, R, Budenz, D, Godfrey D. Prevalence of ocular surface disease symptoms in glaucoma patients on IOP-lowering medications. Cornea. 2010 Jun;29(6):618-21..

36Leung E, et al. Prevalence of Ocular Surface Disease in Glaucoma Patients. J Glaucoma 2008;17:350–355.

Evaluation Observation

OSDI 59% symptoms in 1 eye

27% reported severe symptoms

Schirmer 61% decreased tear production in

1 eye 35% severe deficiency

LissamineGreen

22% positive staining

TBUT 78% abnormal tear quality

65% severe decrease in tear quality

Additional Prevalence Data: Leung

Each additional BAK-containing eye drop =

~2x higher odds of an abnormal lissamine green result.

(OR =2.03;

95% CI: 1.06 to

3.89; P=0.034)

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.

The co-existence of OSD and theuse 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.

Leung: Key Learnings



38

OSD in Glaucoma Prevalence: Summary

• 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. 39

OSD (Glaucoma Today ’08)

• 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.

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

Aging

Dry Environment

Hormonal Changes

Contact Lens

Blepharitis

LASIK

Auto-immune Disease

Alcohol Use

Pollution

Computer Use

Anti-depressants

Quaternary Ammoniums(i.e. BAK)

Dry Eye CascadeDry Eye CascadeABNORMAL TEAR FILM CAUSES

& CONTRIBUTORSABNORMAL TEAR FILM CAUSES

& CONTRIBUTORS

OBSERVABLEPATHOPHYSIOLOGIES

OBSERVABLEPATHOPHYSIOLOGIES

Courtesy R. Yee, MD42

Aqueous Deficient Dry Eye

Perry H. Dry eye diagnosis and management in 2004. Curr Opin Ophthal. 2004;15:299-304.

43

Evaporative Dry Eye

Meibomian gland dysfunction results in a decrease in lipid volume and is a leading cause of evaporative dry eye disease1

Squamous metaplasia ofmeibomian gland orifices

Lid Margin neovascularization

Photos Courtesy of Richard Yee, MDPerry H. Dry eye diagnosis and management in 2004. Curr Opin Ophthal. 2004;15:299-304. 44

OSD Affects Quality of Life

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

• Impact on patients’ day-to-day lives comparable to that of moderate-to-severe angina.1

• % of Patients reporting interference with daily life functions:2

• Night time driving 32.3%• Reading 27.5%• Computer work 25.7%• Watching TV 17.9%



45Courtesy C Springs, MD

OSD Affects Quality of VisionUnfortunately, Just Can’t Feel Vision

46

Detecting OSD

• Signs do not always match symptoms.

• Multiple approaches possible.

• Should be validated.

• Need a better system!

47

Signs and Symptoms

“The lack of concordance between signs and symptoms presents a problem to the diagnosis of the

disease and assessment of severity.”

Lemp MA, Advances in understanding and managing dry eye disease. Am J Ophthalmol 2008; 146(3): 350-356.

-M. Lemp, MD

48

Tear Film Break-Up Time

Injection Lissamine Green Staining

Fluorescein Staining OsmolarityBlink Rate Schirmer Testing

Diagnostic Tools

Rose BengalStaining

OsmolarityBlink Rate Schirmer Testing

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.

49

DTS Study Group Most Commonly Used Diagnostic Tests

Behrens A, et al. Dysfunctional Tear Syndrome: A Delphi Approach to Treatment Recommendations. Cornea 2006; 25(8): 900-907.

DTS=Dysfunctional Tear Syndrome NEIVFQ+National Eye Institute Vision Function Questionnaire

100%

94%

71%

65%

41%

24% 24%

18%

6% 6% 6%

0%

20%

40%

60%

80%

100%

Per

cen

t (%

) R

epor

tin

gR

egu

lar

Use

of

Test

Flu

ores

cein

TBU

T

Sch

irm

er

Ros

e B

enga

l

Cor

nea

lTo

pog

raph

y

Impr

essi

onC

ytol

olgy

Tear

Flo

ursc

ein

Cle

aran

ce

NEI

VFQ

-25

OSD

I

Tear

O

smol

arit

y

Con

junc

tiva

lB

iops

y

TEST

50

Clinician Ratings for Diagnostic Tests

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



51

Lissamine Green Staining

Photos Courtesy of Terrence P. O’Brien, MD Milton Hom, OD

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.

52

Sequence of Testing

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.

53

The Effects of BenzylalkoniumChloride (BAK)

54

• FDA requires multi-dose ophthalmic preparations to contain a preservative to reduce contamination.

• Decrease the risk of microbial contamination in the bottle.

Abelson MB, et al. Rev Ophthalmol. 2002;9(12).

Why Are Preservatives Needed?

55

Preservative Systems

Preservative Example

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

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 56

BAK is a Common Preservative

• Quaternary ammonium compound.

• Cationic surfactant properties (a detergent).

• In majority of ophthalmic medications (72%), ranging in concentrations from 0.004-0.02%.

• Preserves multi-dose containers from microbial contamination.

• Enhances corneal penetration of some drugs by causing epithelial separation.

• Efficacy impact on some drugs.

N+

CI-

Abelson MB, et al. Rev Ophthalmol. 2002;9(12).



57

Preservative Affect on Cornea

• Directly: – Modifying anatomical and physiological the

epithelium which affects optical properties and epithelial barrier function.

• Indirectly: – Modifying tear film leading to ocular non-wetting

tear disorders

58

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.

Percent of Eye Drops Preserved with BAK

BAK Preserved

Non BAKPreserved

28%

72%Contain BAK

59

Preservatives in IOP-Lowering Medications

1. Noecker R. Rev Ophthalmol. 2001(6). 2. Lumigan package insert. 3. Travatan package insert.

Generic (Trade Name)Concentration Preservative

Brimonidine (Alphagan1) 0.005% BAK

Brimonidine with Purite (Alphagan P1) 0.005% SOC

Brinzolamide (Azopt 1) 0.01% BAK

Levobunolol (Betagan1) 0.005% BAK

Betaxolol (Betoptic S Suspension1) 0.01% BAK

Dorzolamide/Timolol (Cosopt1) 0.0075% BAK

Bimatoprost (Lumigan2) 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

BAK: Benzalkonium chlorideBDD: Benzododecinium bromide SOC: Stabilized Oxychloro Complex 60

Preservatives in PGA’s: 2014

XALATAN 0.02% BAK

LUMIGAN 0.01% 0.02% BAK

LUMIGAN 0.03% 0.005% BAK

TRAVATAN Z® BAK Free sofZia™

1. XALATAN* package insert

2. LUMIGAN* package insert.

3. TRAVATAN® solution and Travatan Z® package inserts

*Trademarks are the property of their respective owners.

61

When is BAK Use Most Problematic?

Growth Arrest NecrosisApoptosis

0.0001% BAK 0.05–0.1% BAK0.01% BAK

1. 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.

2. De Saint Jean M, et al. Expression of CD40 and CD 40 ligand in the human conjunctival epitheliumCurrent Eye Res. 2000;20:85-94.3. Cha SH, et al. Corneal epithelial cellular dysfunction from benzalkonium chloride (BAC) in vitro Clin Experimental Ophthalmology 2004;32:180-

184.

• High BAK Concentration: Cell Death is Dose-Dependent.1,2,3

– High Concentration in a Single Drop or Due to The Accumulation of Dose With Multiple Drops.

• Treatment of Chronic Ophthalmic Diseases, such as Glaucoma, with BAK Containing Medications.– Longer Duration of BAK Exposure Increased Corneal

Epithelial Cell Lysis.3

62

BAK Impact onOcular Surface Health

• Decreases Epithelial Cell Integrity.1

– Epithelial Barrier is Compromised.

– Healing is Impaired.

• 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.



63Abelson MB, et al. Rev Ophthalmol. 2002;9(12).

Effects of BAK on theOcular Surface

• Cornea:– Accelerates superficial desquamation. – Disrupts permeability barrier.– Triggers apoptosis by 0.01% and necrosis by

0.05%.

• Conjunctiva:– Increases expression of HLA-DR antigen and

chemokine receptors.– Promotes inflammatory cell infiltration.– Goblet cell loss.

64

BAK Effect on Cornea

BAK on Corneal Epithelial Surface

Tear Film Instability

Epithelial Damage

Epithelial Cell Apoptosis

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)

Lemp M, et al. 2007 Report of the International Dry Eye Workshop (DEWS). The Ocular Surface 2007; 5:75-200, 2007.

Photo Courtesy ofH Edelhauser,PhD

65

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.”

DEWS Report. Ocul Surf. 2007;5(2):65-204. 66

BAK Adversely Affects TBUT in 30 Healthy Volunteers

*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.

98.1

7.37.9

10.4

7.97.4

6.1

0

2

4

6

8

10

12

Baseline 30 mins 1 Hr 3 Hrs

Cartelol without BAK

Cartelol with BAK

-1.1

-4.3-5

-4

-3

-2

-1

0

Decrease from Baseline

Cartelol without BAK

Cartelol with BAK

TB

UT

(S

ecs)

*

†

TBUT Pre/Post Single Drop

*

67

Chronic Effect of Preservatives

• Patients treated >1 year with preserved latanoprost (21), preserved timolol (15) or unpreserved timolol (17) were compared to normals.

• 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

68

Is Chronic Exposure to BAK a Big Deal?

“The Single Most Critical Advance in the Treatment of Dry Eye Came with The Elimination of Preservatives,

such as BAK from OTC Lubricants.”1

“BAK is Largely Responsible for the Ocular Toxicities and Inflammation Associated with the Chronic Use of

Many Ophthalmic Solutions.”2

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.

2. Baudouin C, Riancho L. In vitro Studies of antiglaucomatous prostaglandin analogues: travoprost with and without benzalkoniumchloride and preserved latanoprost. IOVS. 2007;48:41234128.

Stephen Pflugfelder, MD

Christoph Baudouin, MD, PhD



69

• 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.

Factors Contributing to Preservative Toxicity

S. Pflugfelder, MD70

Implications for Glaucoma Therapy

S. Pflugfelder, MD

• 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.

71

Other Clinical Effects on Chronic Glaucoma Medications

• 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

1 Herreras JM et al Ophthalmol 19922 Nuzzi R. et al Int. Ophthalmol, 1998, 3 Ariei MK et al Clin Experimental Ophthalmol 20004 Thygesen J et al Acta Ophthalmol Scand 20005 Schwab IR et al, Ophthalmol 19926 Baudouin C et al, Ophthalmol 1999

72

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

Human Clinical Data

73

Experience with BAK-FreeGlaucoma Medications

74

Human Clinical Data• Purpose: Examine The Safety, Tolerability and Efficacy of Travoprost

BAK-free Compared to Latanoprost or Bimatoprost.

• Methods:

– 694 POAG or OH Patients Treated With Latanoprost or BimatoprostMonotherapy 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)

– Variables Measured:

• IOP

• Ocular Hyperemia Grading

• Global OSDI Score

• Visual Acuity

Patient Global Preference

Slit-Lamp Biomicroscopy

Adverse Events

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

OSDI Severity GradingOSDI Severity Grading

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.

Severe





Mild ModerateNormal Severe

0 10 20 30 40 50 60 70 80 90 100Score

0-12 23-3213-220 33-100

76

Study ResultsPatient Preference

Product N (%) P-Value

XALATAN*/LUMIGAN*

191 (28%)< 0.0001TRAVATAN Z

Solution500 (72%)

Symptoms Improved:

Photophobia, pain, grittiness, blurred vision

Functional Improvements:

Driving at night, reading, and computer use.

*Trademarks are the property of their respective owners


77

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.

• Patient preference may have been driven by improved functionality including driving at night, reading, sensitivity to light, grittiness, pain, blurred vision, and computer work.


Compliance Component

• “A major cause of intolerance or poor tolerance to glaucoma medication is the ocular surface changes created by treatment.”

– Detry-Morel M. Side effects of glaucoma medications. Bull Soc Delge Ophtalmol. 2006;27-40.

78

Non BAK PGA Options

Unique Ionic Buffer SystemTMPolyolsBorate Zinc

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.

• Travatan Z– SofZia

Preservative

Bitmatoprost

Lumigan.com

• Lumigan– 0.01

• 0.02% BAK

– 0.03%• 0.005% BAK



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 latanoprostcontains 50 micrograms of latanoprost. Benzalkoniumchloride, 0.02% is added as a preservative.

• The inactive ingredients are: sodium chloride, sodium dihydrogenphosphate 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 non-disruptive 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)

Untreated PURITE® QID 7 days BAK QID 7 days

Way et al. Invest OphthalmolVis Sci. 2001.The clinical significance of these data is unknown.

New to USA(March 2012)

Preservative Free PGA

ZioptanTafluprost 0.015%

Merck

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.

Zioptan: Efficacy

• Clinical Trial:– IOP reduced by

6.4 – 7.5 mmHg @ 12 weeks

• Baseline 23-26 mmHg

• n=618

– AJO June 2012



Multiple Clinical Trials

Liu, Mao Clinical Ophthalmology 2013:7 7–14

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

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Zioptan vs. Latanoprost

• “Both treatments had a substantial IOP-lowering effect which persisted throughout the study.”

• 7.1 mmHg for tafluprost

• 7.7 mmHg for latanoprost– at 24 months

Patients’ Dry Eye Complaints, Mean TBUT, and Abnormal CornealFluorescein 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)

Result/Finding: Decreased dry eye complaints

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No Difference in OSD for 3 PGAs (3 months)

• Xalatan– 0.02% BAK

• Lumigan 0.03%– 0.005% BAK

• Travatan Z– Sofzia

• Graded:– Ocular Tolerability

– TBUT

– Hyperemia

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JOURNAL OF OCULAR PHARMACOLOGY AND THERAPEUTICSVolume 26, Number 3, 2010

Cosopt PF

• dorzolamide HCL - timololmaleate 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://cosoptpf.com/consumer/index.html



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– 0.003%

• Combigan– 0.005%

• Cosopt– 0.0075%

• Rescula– 0.015%

• Azopt– 0.01%

• Trusopt– 0.0075%

• Timolol sol– 0.01%

Other Non-BAK Options for Glaucoma Patients with OSD

• Alphagan P– Brimonidine PURITE® 0.1%

– Higher pH 7.8

– Lower Concenration

• 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 non-disruptive preservative for lubricating eye drop solutions in comparison to alternative preservatives. Invest Ophthalmol Vis Sci. 2001;42(4):S39. 100

PURITE® Is a Gentle Preservative

SEM of rabbit corneal epithelium (800X)

Untreated PURITE® QID 7 days BAK QID 7 days

Way et al. Invest OphthalmolVis Sci. 2001.The clinical significance of these data is unknown.

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– Review Medications and Treatment Options

– Patient Education

– Reduce the Preservative Load102



Clinical Evaluation

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EJO 2013: Who?,When?,Why?

104

105Eur J Ophthalmol 2013; DOI: 10.5301/ejo.5000270

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107

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.

Summary

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Questions

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Glaucoma Management and OSD Management and ... Moderate OSD in 20-60% 2. Severe OSD in 14-66% ......

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