Download Glaucoma Management and Ocular Surface Disease Disclosure

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.
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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.
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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.
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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
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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.
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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
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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.
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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
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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
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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
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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.
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Glaucoma Management and OSD
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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.
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Glaucoma Management and OSD
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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
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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
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Glaucoma Management and OSD
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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
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Glaucoma Management and OSD
MOA 2014
Questions
[email protected]
M. Chaglasian, O.D.
18