Download Glaucoma Management and Ocular Surface Disease Disclosure

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