-
Effect of Nepafenac Eye DroA Randomized Pr
A
present in ocular tissues such as the cornea, iris, ciliarybody,
retina, and choroid, with their highest concentra-
have 80% power to demonstrate this effect. The primary
authors (B.R.). We used a random number table toInquiries to
Paaraj Dave, Dr T. V. Patel Eye Institute, Vinoba Bhavetions being
in the retina and choroid. Nepafenac has excel-lent penetration of
the cornea and scleral tissues and rapidbioactivation by the iris,
ciliary body, retina, and choroid.2
randomize 1 eye of each patient to the treatment groupwhile the
other eye acted as control. The allocationconcealment was done with
a sealed envelope technique.The envelope was received and opened
(by P.D.) just afterthe first examination of the patient and the
treatment eyewas noted, with the same being explained to the
patient. Ifthe envelope seal was broken, the patient was
excludedfrom the study.
Accepted for publication Dec 5, 2013.From Dr T. V. Patel Eye
Institute, Vadodara, India.
Road, Salatwada, Vadodara, India-390001; e-mail:
[email protected] DAVE, KUNTAL SHAH, BHAR
PURPOSE: To report the effect of nepafenac (0.1%) eyedrops on
intraocular pressure in eyes with cataract. DESIGN: Prospective
randomized clinical trial. METHODS: Three hundred and twenty-seven
patientswith bilateral cataracts in an institutional setting
wereincluded. All patients had a baseline intraocular pressure(IOP)
21 mm Hg without a history of intraocular sur-gery in the past 3
months. One eye of each individualwas randomized to the treatment
group, with the othereye acting as a control. Nepafenac (0.1%) eye
dropswere instilled 3 times a day in the eye that received
treat-ment. Intraocular pressure (IOP) with Goldmann appla-nation
tonometer (GAT) was measured at baseline andat 4 and 8 weeks.
Proportion of eyes with an IOP eleva-tion of>4 mm Hg was the
main outcome measure. RESULTS: The mean age of the participants was
45.7 4.4 years. Participants included 192 female and 135
malepatients. Themean IOP at baseline in the treated and con-trol
eyes was, respectively, 13.8 2.5 mmHg and 13.4 3.0 mm Hg, which
reduced to 12.0 2.0 mm Hg and12.1 1.5 mm Hg, respectively, at the
end of 8 weeks. Thisreduction in IOP in both groups was significant
(P 4 mm Hg. CONCLUSION: Nepafenac eye drops do not increase theIOP.
They can possibly be used as an alternative to ste-roid medications
where steroid responsiveness is aconcern. (Am J Ophthalmol
2014;157:735738. 2014 by Elsevier Inc. All rights reserved.)
NEPAFENAC 0.1% (NEVANAC; ALCON LABS, FORT
Worth, Texas, USA) is an ocular nonsteroidalanti-inflammatory
drug (NSAID) with a prodrug
structure. Intraocular hydrolases convert nepafenac to themore
active metabolite amfenac.1 These hydrolases
are0002-9394/$36.00http://dx.doi.org/10.1016/j.ajo.2013.12.015
2014 BY ELSEVIER INC.outcome measure was proportion of eyes with
IOP eleva-tion more than 4 mm Hg from baseline. The minimumlevel of
significance was set at P < .05. From December3, 2012 to
February 28, 2013, 2 authors (P.D. and K.S.)initially enrolled 500
consecutive bilateral cataract pa-tients with best-corrected visual
acuity better than 20/80in both eyes, who were otherwise normal for
the study,from the outpatient department of a tertiary care
hospital.We excluded 100 patients who either did not fit the
inclu-sion criteria or declined to take part in the study.
Random-ization and allocation concealment was done by one of theps
on Intraocular Pressure:ospective Study
T RAMCHANDANI, AND RUPA JAIN
Topical nepafenac has been used previously to treatcystoid
macular edema in steroid-responsive patientswithout its causing a
rise in the intraocular pressure(IOP).3 The nepafenac product
information insert saysthat it can cause increase in IOP in 5%-10%
of patients.4
There is very little published literature on the effect
oftopical nepafenac eye drops on IOP in normal eyes. Thepurpose of
our study is to report its effect on the IOP inotherwise normal
eyes with a working hypothesis that thereis no increase in IOP
following use of nepafenac eye drops.
METHODS
THIS WAS A PROSPECTIVE, OPEN-LABEL, SINGLE-CENTER,
single-masked randomized controlled study, and aninformed
consent was obtained from all subjects. The studyprotocol was
prospectively approved by the institutionalreview board and health
research ethics committee(Dr TV Patel Eye Institute Ethics
Committee). The trialwas registered with http://www.clinical
trials.gov (identi-fier: NCT01995890, registration location:
Vadodara,Gujarat, India). The rise in IOP with nepafenac eye
dropsis reported in up to 10 in 100 patients. Keeping a confi-dence
interval of 95% and an alpha error of 5%, a samplesize of 276 in
each group was thought to be adequate to735ALL RIGHTS RESERVED.
-
re: the study protocol.
TABLE. Effect of Nepafenac Eye Drops onIntraocular Pressure
Treated Eye Control Eye P Value
IOP at baseline (mm Hg) 13.8 6 2.5 13.4 6 3.0 .07Inclusion
criteria were best-corrected visual acuity betterthan 20/80 in both
eyes, IOP (measured with Goldmannapplanation tonometer [GAT],mean
of 4 daytime readings)
-
Table. Three hundred and twenty-seven patients werefinally
included in the study. The mean age of the partici-
onpants was 45.76 4.4 years; 192 female and 135male subjectswere
included. None of the patients had hypertension,diabetes mellitus,
or a family history of glaucoma. Thesetreated and the control eyes.
A 2-tailed t test was used tocompare the IOP between the treated
and the control eyes.
RESULTS
PATIENTS IOP MEASUREMENTS ARE SUMMARIZED IN THE
FIGURE 2. Box plot showing the effect of nepafenac eye
dropspatients were not on any systemic medications during thecourse
of the study. The mean IOP at baseline in the treatedand control
eyes was 13.86 2.5 mmHg and 13.46 3.0 mmHg, respectively, which
reduced to 12.0 6 2.0 mm Hg and12.1 6 1.5 mm Hg, respectively, at
the end of 8 weeks.This reduction in the IOP from baseline to 8
weeks was sig-nificant for both the treated and the control eyes (P
< .01).However, the difference between the IOP in the treated
andcontrol eyes at 8 weeks was not statistically significant(P .34)
(Figure 2).One eye in the treatment group had an IOP elevation
of
>4 mm Hg. The IOP increased from 11 mm Hg at baselineto 16 mm
Hg at 4 weeks, then came back to 13 mm Hg at8 weeks. Two eyes in
the control group had an IOP eleva-tion>4 mmHg. One eye had a
baseline IOP of 10 mmHg,which increased to 15 mm Hg at 4 weeks
before comingdown to 12mmHg at 8 weeks. The other eye had a
baselineIOP of 10 mmHg, which increased to 16 mmHg at 4 weeksand
remained so until the final check at 8 weeks. Thirty outof the 327
patients (10%) reported to have missed at least1 dose of the
medication during the course of the study.
VOL. 157, NO. 3 EFFECT OF NEPAFENAC EYE DROPDISCUSSION
THIS STUDY PROVIDES EVIDENCE THAT THERE IS NO
increase in the IOP following the use of topical nepafenaceye
drops. The mean IOP at baseline in the treated and con-trol eyes
was 13.8 6 2.5 mm Hg and 13.4 6 3.0 mm Hg,respectively, which
reduced to 12.0 6 2.0 mm Hg and12.1 6 1.5 mm Hg, respectively, at
the end of 8 weeks.The reduction in the IOP from baseline to 8
weeks was sta-tistically significant for both the treated and the
control eyes(P < .01). This reduction, though statistically
significant, isnot clinically significant as it is within the
test-retest vari-ability of the GAT.5 It is unlikely that this
reduction isthe result of a direct effect of nepafenac medication
since
intraocular pressure after 8 weeks from baseline.the reduction
in IOP is quite similar in both the groups(13% in the treated group
and 9.7% in the control group).Only 1 eye in the treated group and
2 eyes in the controlgroup had an IOP elevation of >4 mm Hg from
baseline.The study by Warren and Fox3 showed that nepafenac
eyedrops were successfully used to treat patients with
cystoidmacular edema in steroid-responsive patients. They
alsoshowed that during the course when nepafenac eye dropswere
used, the IOP did not increase. This is in agreementwith our
present study. Chiba and associates6 reported thatconcurrent use of
topical NSAID reduced the IOP-lowering effect of prostaglandin
latanoprost. This effect isprobably attributable to its inhibitory
effect on the exter-nally administered prostaglandins and not its
direct action.Also, the reduction in the IOP-lowering capability
was quitemodest (1.08 mm Hg). The product insert warns of
increasein IOP in 5%-10% of the patients. This, however, is basedon
studies following cataract surgery. It is quite possiblethat these
effects on the IOP are attributable to the alter-ations in the
dynamics of the eye following the cataract sur-gery and not a
direct consequence of the medication.
737S ON INTRAOCULAR PRESSURE
-
The strength of our study is its large sample size. In our
studyonly the examiner was masked and not the patient. Since
ouroutcomemeasurewas IOP,which is an objectivemeasure, thiswould
not have affected our results in any way. Forty-threepatients in
our study were lost to follow-up. Considering thelow incidence of
IOP rise reported, we do not think this losswould have impacted the
study results in any way. Our studydesign is limited by its short
follow-up. Also, it is possible tohave missed IOP spikes in between
the follow-up visits aswell as at different time points on that
day. The adherencerate in our study was very good (90%), but this
couldhave been falsely high as the adherence was self-reported.
A
crossover effect of nepafenac eye drops is also a
possibility.However in our study, the 1 treated eye that had a
significantIOP elevation of >4 mm Hg did not show a
correspondingincrease in the fellow control eye. Also, the overall
rate ofeyes showing this significant IOP elevation was very low
inour study. The obvious next step would be to note the IOPchanges
in patients known to be steroid responders.To conclude, nepafenac
eye drops do not increase the
IOP. This result allows them to be used as an alternativeto
steroid medications in patients in whom steroid respon-siveness is
a major concern and a strong anti-inflammatoryeffect is not
needed.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR
DISCLOSURE OF POTENTIAL CONFLICTS OF INTERESTand none were
reported. The authors indicate no funding support. Contributions of
authors: design and conduct of the study (P.D., B.R., R.J.);
collection,management, analysis, and interpretation of the data
(P.D., K.S., B.R.); preparation and review of manuscript (P.D.,
K.S., B.R., R.J.); approval of themanu-script (R.J.).
REFERENCES
1. Gamache DA, Graff G, Brady MT, Spellman JM, Yanni
JM.Nepafenac, a unique nonsteroidal prodrug with potential
util-
3. Warren KA, Fox JE. Topical nepafenac as an alternate
treat-ment for cystoid macular edema in steroid responsive
patients.Retina 2008;28(10):14271434.
4. Nevanac product information. Available at
http://www.rxlist.com/nevanac-drug/side-effects-interactions.htm.
Accessed June 8, 2013.738 AMERICAN JOURNAL OFAssessment of
anti-inflammatory efficacy. Inflammation 2000;24(4):357370.
2. Ke TL, Graff G, Spellman JM, Yanni JM. Nepafenac, a
uniquenonsteroidal prodrug with potential utility in the treatment
oftrauma-induced ocular inflammation. II. In vitro bioactivationand
permeation of external ocular barriers. Inflammation
2000;24(4):371384.5.
TonnuPA,HoT,SharmaK,WhiteE,BunceC,Garway-HeathD.A comparison of
four methods of tonometry: method agreementand interobserver
variability. Br JOphthalmol 2005;89(7):847850.
6. ChibaT,Kashiwagi K,ChibaN,Tsukahara S. Effect of
non-steroidalanti-inflammatory ophthalmic solution on intraocular
pressurereduction by latanoprost in patients with primary open
angle glau-coma or ocular hypertension. Br J Ophthalmol
2006;90(3):314317.ity in the treatment of trauma-induced ocular
inflammation. I.MARCH 2014OPHTHALMOLOGY
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Biosketch
Dr Paaraj Dave finished his Masters in Ophthalmology from P.S.
Medical College, Gujarat. He later joined the L.V. Prasad
Eye Institute, Hyderabad as a long term Glaucoma Fellow. He
currently heads the Glaucoma Services at Dr T.V. Patel Eye
Institute in Vadodara, Gujarat, India. His research interests
include clinical research on management of secondary
glaucomas and outcomes.VOL. 157, NO. 3 738.e1EFFECT OF NEPAFENAC
EYE DROPS ON INTRAOCULAR PRESSURE
-
Biosketch
Dr Kuntal Shah finished his Masters in Ophthalmology from Dr
T.V. Patel Eye Institute, Vadodara, Gujarat, India. His
research interests include clinical research on glaucoma
management and patient outcomes.738.e2 MARCH 2014AMERICAN JOURNAL
OF OPHTHALMOLOGY
Effect of Nepafenac Eye Drops on Intraocular Pressure: A
Randomized Prospective StudyMethodsStatistical Analysis
ResultsDiscussionReferences
