The Role of The Role of Benzalkonium Chloride in Benzalkonium Chloride in

the Occurrence of the Occurrence of Punctate Keratitis: A Punctate Keratitis: A

Meta-Analysis of Meta-Analysis of Randomized, Controlled Randomized, Controlled

Clinical TrialsClinical TrialsS Trocme, MD,S Trocme, MD,11 L-J Hwang, PhD, L-J Hwang, PhD,22 G W Bean, G W Bean,

BS,BS,3 3 M B Sultan, MD, MBAM B Sultan, MD, MBA2,42,4

11Department of Ophthalmology and Visual Sciences, Case Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Western Reserve University and University Hospitals Eye

Institute, Cleveland, Ohio; Institute, Cleveland, Ohio; 22Pfizer Inc, New York, New York; Pfizer Inc, New York, New York; 33Independent Consultant, Burkett, Texas; Independent Consultant, Burkett, Texas; 44New York Eye & New York Eye &

Ear Infirmary, New York, New YorkEar Infirmary, New York, New York

Dr. Trocme declares no financial interest; Drs. Hwang and Sultan are employees of Pfizer Inc; Mr. Bean is a paid consultant to Pfizer Inc. This study was supported by Pfizer Inc.

Introduction / Introduction / BackgroundBackground Although benzalkonium chloride (BAK) is the most Although benzalkonium chloride (BAK) is the most

commonly used preservative, it has undergone commonly used preservative, it has undergone considerable criticism based on in vitro and in vivo considerable criticism based on in vitro and in vivo studiesstudies1-51-5

Evidence of dose-dependent BAK-induced epithelial cell Evidence of dose-dependent BAK-induced epithelial cell damage has been confirmed in cultured cornealdamage has been confirmed in cultured corneal66 and and conjunctival cellsconjunctival cells77 and in cat and rabbit studies and in cat and rabbit studies3,4,8,93,4,8,9

At common clinical concentrations, however, not all At common clinical concentrations, however, not all preclinical studies demonstrate toxicitypreclinical studies demonstrate toxicity10,1110,11 and their and their relevance has not been confirmed in large clinical trialsrelevance has not been confirmed in large clinical trials

Clinically, BAK has been associated with corneal Clinically, BAK has been associated with corneal epithelial cell injury manifesting as punctate keratitisepithelial cell injury manifesting as punctate keratitis12-12-

1919

If punctate keratitis is caused by BAK at common If punctate keratitis is caused by BAK at common concentrations in IOP-lowering drugs then increasing concentrations in IOP-lowering drugs then increasing the amount of BAK exposure daily should cause more the amount of BAK exposure daily should cause more pathologypathology

References on notes page

BAK Concentrations in IOP-BAK Concentrations in IOP-Lowering Ophthalmic Solutions Lowering Ophthalmic Solutions by Daily Doseby Daily Dose

DrugDrugBAK/BAK/

mL (%)mL (%)Drops/Drops/

mLmLBAK BAK

µgµg/drop/dropDosing Dosing per PIper PI

Daily Daily BAK BAK µgµg

ApraclonidinApraclonidinee

0.010.01 32.932.9 3.03.0 3-6/day3-6/day 9.0-9.0-18.018.0

BetaxololBetaxolol 0.010.01 28.528.5 3.53.5 1-4/day1-4/day 3.5-3.5-14.014.0

BimatoprostBimatoprost 0.0050.005 35.235.2 1.41.4 1/day1/day 1.41.4

BrimonidineBrimonidine 0.0050.005 22.222.2 2.32.3 3/day3/day 6.96.9

BrinzolamidBrinzolamidee

0.010.01 25.125.1 4.04.0 3/day3/day 12.012.0

DorzolamideDorzolamide 0.00750.0075 27.127.1 2.82.8 3/day3/day 8.48.4

LatanoprostLatanoprost 0.020.02 28.028.0 7.17.1 1/day1/day 7.17.1

PilocarpinePilocarpine 0.010.01 23.023.0 4.34.3 2-8/day2-8/day 8.6-8.6-34.434.4

TimololTimolol 0.010.01 32.532.5 3.13.1 2/day2/day 6.26.2

TravoprostTravoprost 0.0150.015 34.534.5 4.34.3 1/day1/day 4.34.3

PurposePurpose To determine the incidence of To determine the incidence of punctate keratitis reported in punctate keratitis reported in double-masked trials comparing double-masked trials comparing latanoprost and timolol latanoprost and timolol ophthalmic solutions in which the ophthalmic solutions in which the amount of BAK was twice as much amount of BAK was twice as much in the latanoprost arm as in the in the latanoprost arm as in the timolol armtimolol arm

A PubMed search of prospective, A PubMed search of prospective, randomized, double-masked clinical randomized, double-masked clinical trials comparing the efficacy and safety trials comparing the efficacy and safety of latanoprost and timolol ophthalmic of latanoprost and timolol ophthalmic solutions in glaucoma or ocular solutions in glaucoma or ocular hypertension for ≥6 months duration hypertension for ≥6 months duration

The number of reports of punctate The number of reports of punctate keratitis either as a finding or an keratitis either as a finding or an adverse event were identified in each adverse event were identified in each trial and were meta-analyzed trial and were meta-analyzed

Incidence was calculated and forest Incidence was calculated and forest plots generated to summarize risk plots generated to summarize risk difference and odds ratiosdifference and odds ratios

MethodsMethods

ResultsResults7 Studies Identified in PubMed 7 Studies Identified in PubMed SearchSearch

No. of Patients and No. of Patients and Dosing FrequencyDosing Frequency

StudyStudy DurationDuration Latanoprost/Latanoprost/VehicleVehicle

TimololTimolol

AlmAlm 6 months6 months 183 QD/QD183 QD/QD 84 BID84 BID

CamrasCamras 6 months6 months 128 QD/QD128 QD/QD 140 BID140 BID

WatsonWatson 6 months6 months 149 QD/QD149 QD/QD 145 BID145 BID

LassLass 12 12 monthsmonths

127 QD/none127 QD/none 126 QD126 QD

PfeifferPfeiffer 6 months6 months 147 QD/QD147 QD/QD 149 BID149 BID

HigginbothamHigginbotham 6 months6 months 140 QD/QD140 QD/QD 140 BID140 BID

MastropasquaMastropasqua 12 12 monthsmonths

18 QD/QD18 QD/QD 18 BID18 BIDAlm A, et al. Ophthalmology 1995;102:1743-52; Camras CB. Ophthalmology 1996;103:138-47; Watson PG, et al. Ophthalmology 1996;103:126-37; Lass JH, et al. 2001;108:264-71; Pfeiffer N, et al. Graefes Arch Clin Exp Ophthalmol 2002;240:893-9; Higginbotham EJ, et al. Arch Ophthalmol 2002;120:915-22; Mastropasqua L, et al. Ophthalmology 1999;106:550-5.

Results Results (cont’d)(cont’d) Timolol maleate (0.01% BAK) was given Timolol maleate (0.01% BAK) was given

twice daily and latanoprost (0.02% BAK) was twice daily and latanoprost (0.02% BAK) was given once daily with vehicle (0.01% [in 2 given once daily with vehicle (0.01% [in 2 studies] or 0.02% BAK) given once daily in 6 studies] or 0.02% BAK) given once daily in 6 of the 7 trials; 1 study dosed both drugs once of the 7 trials; 1 study dosed both drugs once daily daily

Of the 1694 patients enrolled in the double-Of the 1694 patients enrolled in the double-masked portion of the trials (latanoprost, masked portion of the trials (latanoprost, N=892; timolol, N=802) the overall N=892; timolol, N=802) the overall incidence of punctate keratitis was 6.3% incidence of punctate keratitis was 6.3% (106/1694) (106/1694)

The incidence of punctate keratitis was 6.5% The incidence of punctate keratitis was 6.5% and 6.0% in latanoprost- and timolol-treated and 6.0% in latanoprost- and timolol-treated patients, respectively, similar to rates patients, respectively, similar to rates reported in glaucoma and ocular reported in glaucoma and ocular hypertension patients treated with hypertension patients treated with preservative-free eye drops preservative-free eye drops

Incidence of Punctate Keratitis Incidence of Punctate Keratitis (PK) and Amount of BAK(PK) and Amount of BAK

StudyStudy

LatanoprosLatanoprost: t:

Incidence Incidence (PK/Total)(PK/Total)

Timolol:Timolol:IncidenceIncidence(PK/Total)(PK/Total)

Amount of BAK Amount of BAK ((µg/day): µg/day):

Latanoprost/Vehicle vs Latanoprost/Vehicle vs Timolol Twice DailyTimolol Twice Daily

AlmAlm 6.6% 6.6% (12/183)(12/183)

2.4% (2/84)2.4% (2/84) 14.2 vs 6.214.2 vs 6.2

CamrasCamras 13.3% 13.3% (17/128)(17/128)

17.9% 17.9% (25/140)(25/140)

14.2 vs 6.214.2 vs 6.2

WatsonWatson 12.8% 12.8% (19/149)(19/149)

6.9% 6.9% (10/145)(10/145)

14.2 vs 6.214.2 vs 6.2

LassLass 3.9% 3.9% (5/127)(5/127)

5.6% (7/126)5.6% (7/126) 7.1 vs 3.1*7.1 vs 3.1*

PfeifferPfeiffer 0.7% 0.7% (1/147)(1/147)

1.3% (2/149)1.3% (2/149) 10.2 vs 6.210.2 vs 6.2

HigginbothaHigginbothamm

2.9% 2.9% (4/140)(4/140)

1.4% (2/140)1.4% (2/140) 10.2 vs 6.210.2 vs 6.2

MastropasquMastropasquaa

0% (0/18)0% (0/18) 0% (0/18)0% (0/18) 14.2 vs 6.214.2 vs 6.2

TotalTotal 6.5% 6.5% (58/892)(58/892)

6.0% 6.0% (48/802)(48/802)

~2 vs 1~2 vs 1

*Latanoprost and timolol were dosed once daily

Combined Risk Difference for Combined Risk Difference for Punctate Keratitis: Latanoprost Punctate Keratitis: Latanoprost – Timolol– Timolol

Alm

Camras

Watson

Lass

Pfeiffer

Higginbotham

0.042 0.025 0.001 -0.007 0.090 1.689 0.091

0.300-1.037-0.132-0.046 0.044 0.002 0.041

0.059 0.034 0.001 0.126 1.698 0.090-0.009

-0.016 -0.069 -0.606

-0.007 -0.029 -0.570

-0.020

-0.013

0.027 0.001 0.036 0.545

0.012 0.000 0.016 0.569

0.014 0.017 0.000 0.048 0.826 0.409

0.007 0.010 0.000 0.027 0.675 0.500

RiskDifference

StandardError Variance

LowerLimit

UpperLimit Z-Value P-Value

Favors latanoprost Favors timolol

Study Statistics for Each Study

Combined

ME TA - A NA L Y S I S

Risk Difference and 95% CI

-1.00 -0.50 0.00 0.50 1.00

-0.1020.000 0.052 0.003 0.102 0.000 1.000Mastropassqua

Combined Odds Ratio for Combined Odds Ratio for Punctate Keratitis: Latanoprost Punctate Keratitis: Latanoprost Versus TimololVersus Timolol

Statistics for Each StudyStudy

Alm

Camras

Watson

Lass

Pfeiffer

Higginbotham

ME TA - ANA LY S I S

Odds Ratio and 95% CI

Favors latanoprost Favors timolol

LowerLimit

UpperLimit Z-Value P-Value

OddsRatio

2.877

0.705

13.154 1.363 0.173

0.361 1.375 -1.026 0.305

1.973 0.884 4.403 1.659 0.097

0.697 0.215 2.256 -0.603 0.547

0.503 0.045 5.613 -0.558 0.577

2.029 0.366 11.263 0.809 0.418

1.114 0.726 1.710 0.496 0.620Combined

0.629

0.01 0.1 1 10 100

ConclusionsConclusions To our knowledge, this meta-analysis is To our knowledge, this meta-analysis is

the first to evaluate the corneal effects of the first to evaluate the corneal effects of variable BAK concentrations in variable BAK concentrations in ophthalmic solutions ophthalmic solutions

Although containing a higher Although containing a higher concentration of BAK, latanoprost concentration of BAK, latanoprost ophthalmic solution was not associated ophthalmic solution was not associated with a significantly increased risk of with a significantly increased risk of punctate keratitis vs timolol ophthalmic punctate keratitis vs timolol ophthalmic solutionsolution

The incidence of punctate keratitis found The incidence of punctate keratitis found in this study (6%) was similar to that in this study (6%) was similar to that (8.9%) reported in patients treated with (8.9%) reported in patients treated with preservative-free eye dropspreservative-free eye drops11

11Jaenen N, et al. Eur J Ophthalmol 2007:17:341-9.

ConclusionsConclusions (cont’d)(cont’d) Study limitations Study limitations

evaluation of punctate keratitis was not evaluation of punctate keratitis was not pre-specified in any of the trialspre-specified in any of the trials

standardized grading for lesion severity standardized grading for lesion severity was not usedwas not used

patients with severe corneal pathology patients with severe corneal pathology were not enrolled in the included studieswere not enrolled in the included studies

These results indicate that BAK does These results indicate that BAK does not produce significant corneal not produce significant corneal toxicity in the vast majority of toxicity in the vast majority of patients with glaucoma or ocular patients with glaucoma or ocular hypertension at the concentrations hypertension at the concentrations used in these studiesused in these studies