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Nepafenac: An Ophthalmic Nonsteroidal

Antiinflammatory Drug for Pain After Cataract
Surgery (July/August).

ARTICLE in ANNALS OF PHARMACOTHERAPY MAY 2013

Impact Factor: 2.06 DOI: 10.1345/aph.1R757 Source: PubMed

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Formulary Forum
Nepafenac: An Ophthalmic Nonsteroidal Antiinflammatory
Drug for Pain After Cataract Surgery
Benjamin M Jones, Michael W Neville
C ataract surgery is an invasive proce-
dure that involves manipulation and
incision of ocular tissue, including the
retina, sclera, aqueous and vitreous hu-
mor, iris, cornea, ciliary body, choroid,
and conjunctiva. Surgical manipulation
results in the production of prostaglandins
by the phospholipase and cyclooxygenase
(COX) 1 and 2 enzymes. As a result, mio-
sis, hyperemia, pain, photophobia, and
cystoid macular edema, the most com-
mon and potentially the most worrisome
complication of the surgery, may devel-
op.1 Topical corticosteroids and topical
nonsteroidal antiinflammatory drugs
(NSAIDs) have been used to manage
these complications and evidence sug-
gests that the combination therapy of
corticosteroids and NSAIDs is synergis-
tic in reducing postoperative inflamma-
tion.2,3
Topical NSAID use following cataract
surgery began in the 1970s when re-
searchers discovered that topical prod-
ucts were more effective than systemic
agents to penetrate the intraocular envi-
ronment.1 Most NSAID preparations are
weakly acidic and ionize in the more ba-
Author information provided at end of text.
1967-2013 Harvey Whitney Books Co. All
rights reserved. No part of this document may
be reproduced or transmitted in any form or by
any means without prior written permission of
Harvey Whitney Books Co. For reprints of any
article appearing in The Annals, please contact
415sales@hwbooks.com
892 The Annals of Pharmacotherapy
Downloaded from aop.sagepub.com by guest on October 11, 2013
OBJECTIVE: To examine the efficacy of nepafenac in the treatment of pain and
inflammation in patients after cataract surgery using evidence from controlled clinical
studies.
DATA SOURCES: Citations in Google Scholar, PubMed, and Web of Science from
January 1, 2005, to March 25, 2013, were identified using nepafenac and cataract
as search terms.
STUDY SELECTION AND DATA EXTRACTION:
The literature search was limited to
human studies published in English. Three trials that compared nepafenac with
other nonsteroidal antiinflammatory drugs (NSAIDs) were included.
DATA SYNTHESIS:
The pharmacokinetics and pharmacodynamics of nepafenac
0.1% suspension (and its active metabolite, amfenac) were compared with
bromfenac 0.09% solution and ketorolac 0.4% solution with respect to aqueous
humor concentrations and ability to reduce cyclooxygenase 1 and 2 (COX-1 and
COX-2) enzymes. The maximum concentration (Cmax) values of ketorolac and
amfenac were statistically similar, while the Cmax of bromfenac was significantly
lower than that of amfenac. Ketorolac most effectively inhibited COX-1 enzymes;
COX-2 enzymes were most effectively reduced by amfenac. When nepafenac 0.1%
suspension was compared with placebo and ketorolac 0.5% solution, nepafenac
achieved a higher percentage cure rate than placebo at day 14 (p = 0.0241).
Significant differences in cure rates between nepafenac and ketorolac were not
observed. Nepafenac 0.1%, bromfenac 0.09%, and ketorolac 0.45% were
compared to determine which most effectively reduced prostaglandin E2 (PGE2)
following surgery. PGE2 concentrations were significantly lowest in the ketorolac
group, followed by the bromfenac and nepafenac groups, respectively. Topical
nepafenac 0.1% suspension was approved in 2005. A 0.3% suspension was
approved in October 2012. The 0.3% product may have some advantages over its
predecessor: it is dosed once rather than thrice daily, which may increase patient
adherence and improve outcomes. The price and dosing frequency of the 0.3%
product are comparable to those of bromfenac 0.09% solution.
CONCLUSIONS: The 2 nepafenac products appear to be equally efficacious, with a
slightly increased adverse event rate in patients using the 0.3% versus 0.1%
formulation. Head-to-head clinical trials that compare the 0.3% product with the
0.1% product or other commercially available NSAIDs are unavailable.
Ann Pharmacother 2013;47:892-6.
Published Online, 28 May 2013, theannals.com, doi: 10.1345/aph.1R757
2013 June, Volume 47 theannals.com

sic lachrymal fluid, which limits corneal penetration. As
the pH of the preparations is adjusted to improve corneal
permeability, the incidence of ocular irritation may also in-
crease. The delicate balance of permeability and patient
tolerability presents a great challenge to drug manufactur-
ers who seek to develop these agents.
Five topical NSAID preparations are available on the
US market for use in cataract surgery: bromfenac 0.09%
solution; diclofenac 0.1% solution; flurbiprofen 0.03% so-
lution; ketorolac 0.4%, 0.45%, and 0.5% solutions; and
nepafenac 0.1% suspension.4
A new drug application submitted by Alcon Laborato-
ries for nepafenac 0.3% ophthalmic suspension was ap-
proved by the FDA October 2012.5 The formulation of the
0.3% strength has been changed to modify the preserva-
tives and improve the pharmacokinetics of the active in-
gredient to permit once daily versus the 3 times daily dos-
ing required with the 0.1% product.6
Although nepafenac is approved to treat postoperative
ocular inflammation and pain following cataract surgery, it
also has been used off-label to reduce pathologic ocular an-
giogenesis, treat exudative age-related macular degenera-
tion, prevent post pars-plana vitrectomy macular edema,
during epiretinal membrane surgery, and to maintain intra-
operative mydriasis.4,7-11
Topical NSAIDs may offer an advantage in the postopera-
tive setting as they effectively reduce pain and inflammation,
photophobia, intraocular pressure, pruritus, and intraoperative
miosis without the adverse effects that occur with cortico-
steroids.1 However, this class of medications is not without
risk. Systemic inflammatory disease, epithelial keratopathy,
and concurrent topical steroid use appear to increase the risk
of ulceration, keratitis, and perforation with topical NSAID
administration.12 These adverse events have been reported
more often with older topical NSAIDs: bromfenac, ketorolac,
and diclofenac. However, Wolf and colleagues reported a
case of full thickness corneal melt in a patient with graft-ver-
sus-host disease who received topical nepafenac.12 Alcon
Laboratories advises against the use of nepafenac more than
1 day prior to surgery or use beyond 14 days after surgery to
reduce the risk of severe corneal adverse events.13
Pharmacology
Corticosteroids and NSAIDs have been used successfully
to reduce pain and inflammation in the postoperative setting.
Corticosteroids prevent prostaglandin production in the early
stages of the arachidonic acid cascade by inhibiting phospho-
lipases while NSAIDs block COX-1 and COX-2 enzymes in
the latter stages of the cascade. Although both drug classes
are beneficial in the postoperative setting, the adverse effect
profile of corticosteroids, including increased intraocular
pressure, impaired wound healing, immune system suppres-
sion, and increased infection risk, makes this class less favor-
theannals.com The Annals of Pharmacotherapy
v
able.1 As newer NSAIDs emerge, use of corticosteroids in the
perioperative setting will likely decrease.
Pharmacokinetics
Nepafenac differs from other topical NSAIDs because it is
administered as a prodrug. The more neutral, less polarized
prodrug structure facilitates penetration into the cornea where
conversion to the active form, amfenac, by intraocular hydro-
lases occurs.2 The prodrug mechanism may support im-
proved activity of amfenac in the anterior and posterior eye
segments, with activation in specific areas such as the ciliary
body, choroid, retina, iris, and cornea.14 The rapid distribution
of nepafenac into the anterior chamber and posterior seg-
ments minimizes surface accumulation and the associated
surface complications often observed with topical NSAIDs.14
The benefits of increased permeability include a decrease in
adverse events on the eye surface, decreased time to maxi-
mum concentration (Cmax) of the drug, and increased patient
comfort during administration.15
Nepafenac 0.1% suspension must be administered 3
times daily for cataract surgery, but the newer 0.3%
nepafenac suspension requires dosing only once daily. The
mean steady-state Cmax observed for nepafenac and am-
fenac SD when the 0.1% suspension was administered
bilaterally 3 times daily was 0.310 0.104 ng/mL and
0.422 0.121 ng/mL, respectively.16 When the 0.3% sus-
pension was administered bilaterally once daily, the mean
steady-state Cmax for nepafenac and amfenac was 0.847
0.269 ng/mL and 1.13 0.491 ng/mL, respectively.13
The drug-drug interaction risk with nepafenac and am-
fenac administration with other agents is low; in vitro
metabolism of CYP1A2, 2C9, 3A4, 2C19, 2D6, and 2E1
was not inhibited by either drug. Other topical agents, such
as carbonic anhydrase inhibitors, -agonists, -blockers,
mydriatics, and cycloplegics, may be given with topical
nepafenac if the administration is separated by 5 minutes.
Clinical Trials
There is much debate in the literature regarding
nepafenac 0.1% in clinical trials.17-25 Some authors insisted
that trials had design flaws that compromised study integri-
ty. The flaws discussed included inappropriate masking,
nonrandomization, lack of power to support the conclu-
sions, and faulty interpretation of patient-reported out-
comes. Other authors insisted that the conflict of interest
between industry sponsors and trial investigators resulted
in conclusions that were misleading.
NEPAFENAC 0.1% OPHTHALMIC SUSPENSION
Walters and colleagues compared the pharmacokinetics
and pharmacodynamics of nepafenac 0.1% suspension,
amfenac, ketorolac 0.4% solution, and bromfenac 0.09%
2013 June, Volume 47 893
BM Jones, MW Neville
solution in a study including 75 subjects.26 The primary ob-
jective of this study was to compare aqueous humor con-
centrations of each agent. Subjects were randomized in a
1:1:1 ratio of treatment groups. Participants received 1 drop
of study medication prior to surgery and 1 sample per patient
was obtained using the sparse-sampling methodology at 5
time points (30, 60, 120, 180, and 240 minutes) . COX-1 in-
hibition was most powerful with ketorolac, followed by
bromfenac, amfenac, and nepafenac, and COX-2 enzymes
were inhibited to the greatest extent by amfenac, followed by
bromfenac, and ketorolac; nepafenac had no effect on COX-
2. Nepafenac achieved significantly greater ocular bioavail-
ability than the other medications. Alcon Laboratories, the
manufacturer of nepafenac, funded this study.
A 2007 study compared nepafenac 0.1% suspension with
placebo and ketorolac 0.5% solution in 227 subjects in a mul-
ticenter, randomized, placebo- and active-controlled, double-
masked design.2 The primary objective of the study was to
compare the effects of nepafenac 0.1% with placebo on ante-
rior segment inflammation (presence of aqueous cells and
flare) at day 14. Other comparisons between nepafenac 0.1%
and ketorolac 0.5% for the treatment and prevention of post-
operative pain (ocular pain score) and inflammation were
also made. Subjects instilled 1 drop 3 times daily beginning
on day 1 before surgery, the day of surgery, and for 21 days
thereafter. Evaluations occurred on days 1, 3, 7, 14, 21, and
28. Inflammation and cure rates were determined using 2 pa-
rameters: presence of aqueous cells on a 5-point scale (0
[none] to 4 [>30 cells]) and aqueous flare on a 4-point scale
(0 [no flare] to 3 [very dense flare]). Cure rates (absence of
cells and flare) were significantly better with nepafenac
(76.3%) versus placebo (59.2%) (p = 0.0241). Clinical suc-
cess rates of nepafenac 0.1% were greater than those ob-
served with ketorolac 0.5% at day 14 (p = 0.0319), but were
not significantly different at other time points. More subjects
receiving nepafenac 0.1% reported no ocular pain compared
to those receiving ketorolac 0.5% at day 3 (p = 0.0366), but
the percentages were not statistically significant at other time
points. Rates of ocular discomfort were significantly statisti-
cally lower in the nepafenac 0.1% versus ketorolac 0.5%
groups. Researchers hypothesized that molecule or formula-
tion (nepafenac is a suspension, ketorolac is a solution) varia-
tions might account for the different rates of reported ocular
discomfort. The researchers noted that this study was not
powered to detect the superiority of nepafenac 0.1% over ke-
torolac 0.5%. Alcon Laboratories supported this study.
A study completed in 2011 by Bucci and Waterbury com-
pared the prostaglandin E2 (PGE2) inhibition efficacy of
nepafenac 0.1% suspension, bromfenac 0.09% solution, and
ketorolac 0.45% solution in a cataract surgery model.27 The
primary outcome was to evaluate the PGE2 inhibition effica-
cy for each agent in the aqueous humor for each drug. This
single-center, double-masked study was completed in 121
subjects scheduled to undergo phacoemulsification and in-
894 The Annals of Pharmacotherapy 2013 June, Volume 47
traocular lens implantation. Participants were randomized to
receive bromfenac 0.09% twice daily, ketorolac 0.45% twice
daily, and nepafenac 0.1% 3 times daily 1 day prior to
surgery. Each patient received 4 additional doses 1 hour prior
to surgery. Mean (SD) reductions (224.8 [164.87] pg/mL) in
PGE2 were significant in the ketorolac 0.45% group. Howev-
er, PGE2 inhibition was not significant for bromfenac or
nepafenac. Although a significant difference favoring ketoro-
lac was observed, no other significant differences between
products emerged. Investigators concluded that evidence sug-
gests that a reduction in prostaglandin synthesis and cy-
clooxygenase activity improves patient outcomes; nepafenac
was least able among the 3 to accomplish this. Allergan,
manufacturers of ketorolac, funded this study.
NEPAFENAC 0.3% OPHTHALMIC SUSPENSION
In June 2010, Alcon Laboratories enrolled 2022 individ-
uals (intent to treat) in a Phase 3 randomized, double-
masked, parallel assignment clinical trial to assess the safe-
ty and efficacy of nepafenac 0.3% suspension for the pre-
vention and treatment of ocular inflammation and pain
after cataract surgery.28 The primary outcome of this study
was the percentage of patients cured. This trial used the 5-
point aqueous cell presence and 4-point scale for aqueous
flare, as described in the Nardi et al. trial.2 Investigators
also examined ocular pain (0 [no pain] to 5 [severe pain])
as a secondary outcome measure. Subjects were random-
ized to 1 of 4 parallel groups: nepafenac 0.3% (n = 851) 1
drop in the affected eye daily for 16 days beginning 1 day
prior to surgery with an additional dose just prior to
surgery, nepafenac 0.1% (n = 845) 1 drop in the affected
eye 3 times daily for 16 days beginning 1 day preopera-
tively, nepafenac 0.3% vehicle (n = 211) 1 drop in affected
eye daily for 16 days beginning 1 day prior to surgery with
an additional dose just prior to surgery, or nepafenac 0.1%
vehicle (n = 213) 1 drop in the affected eye 3 times daily
for 16 days beginning 1 day preoperatively. The results
summarized in Table 1 demonstrated similarity between
the 0.1% and 0.3% nepafenac suspensions with respect to
cure rates and percentage of pain-free subjects at day 14.
The adverse event rate in the 0.3% versus 0.1% group was
0.96% and 0.79%, respectively. Data collection for the pri-
mary outcome measure was discontinued in September
2011. Statistical analyses of the final results are pending.
In April 2011, investigators began enrolling subjects in a
randomized, Phase 2, double-masked, parallel assignment
trial to assess the safety and efficacy of nepafenac 0.3%
suspension for the prevention and treatment of pain and in-
flammation in the eye following cataract surgery.29 Data
collection was completed for the primary end point in
September 2011. Subjects were randomized to receive
nepafenac 0.3%, nepafenac 0.1%, or nepafenac 0.3% vehi-
cle once daily beginning 1 day preoperatively and continu-
theannals.com
 Nepafenac: An Ophthalmic NSAID for Pain After Cataract Surgery

ing for 14 days after surgery. The primary outcome of this
trial was the presence of inflammatory cells and flare (us-
ing the 5-point and 4-point scales described above). The
secondary outcome measure was the presence of inflam-
matory cells 7 days postoperatively. The study has been
completed and the results are pending.
Dosage Recommendations
Patients should be advised to shake the nepafenac oph-
thalmic suspension prior to administration. The 0.1% suspen-
sion is administered 3 times daily, and the 0.3% suspension is
administered once daily. Patients should begin therapy 1 day
before the cataract removal procedure, and then continue dur-
ing the day of the procedure and for 2 weeks following the
procedure. Those receiving the 0.3% product should admin-
ister an additional drop (ie, total of 2 drops) on the day of
surgery, 30-120 minutes before the procedure. Nepafenac
may be given with other ophthalmic agents if the administra-
tion is separated by at least 5 minutes. Contact lenses should
be removed before instilling drops. No studies have been
completed in children younger than 10 years. No significant
changes in safety or efficacy have been found in geriatric pa-
tients.13
Table 1. Results of Confirmatory Study
Nepafenac 0.3% (NCT 01109173)a
Nepafenac
Adverse Effects
Nepafenac 0.1% suspension is contraindicated in pa-
tients with hypersensitivity to the other ingredients in the
formulation or to other NSAIDs. Nepafenac is a pregnancy
category C medication, and its benefits must outweigh any
potential risks to the fetus. Whether nepafenac is excreted
in breast milk remains unclear. As with other NSAIDs,
nepafenac should be avoided in late pregnancy because of
cardiovascular risks to the fetus. Because of its interference
with platelet actions, nepafenac should be used cautiously
in patients with increased bleeding tendencies or in those
taking medications that prolong bleeding time. Nepafenac
has also been known to delay wound healing following
cataract surgeries, especially when combined with other
topical steroid medications.13,16
Formulary Considerations
Table 2 summarizes the dosing regimens and average
wholesale prices for each ocular NSAID.30 The least ex-
pensive is ketorolac 0.5% solution; bromfenac 0.09% is
the most costly. The prices for nepafenac 0.1% and 0.3%
suspensions are similar and slightly lower than that of the
bromfenac 0.09% solution.
NSAID dosing regimens for cataract surgery require 16
days, beginning the day before surgery and continuing for
14 days postoperatively, for optimal results based on pub-
lished findings. The dosing frequencies between products
vary. As researchers have demonstrated that dosing fre-

quency is inversely related to medication adherence, the

0.3% 0.1% 0.3%
Suspension Suspension Vehicle
Characteristic (n = 512) (n = 493) (n = 252) potential cost of nonadherence and increased postoperative
Cure rates at day 14, % 64.6 65.3 25.0 complications must be considered. Regimens that require
Pts. pain free at day 14, % 89.1 89.0 40.1 once- or twice-daily dosing have an advantage in this re-
Serious adverse event rate,% 0.96 0.79 0 gard.31-33
a
Adapted from Nepafenac 0.3% Two Study.29

Table 2. Ophthalmic Nonsteroidal Antiinflammatory Drugs30

AWP, $
Drug Dose (container size)

Bromfenac 0.09% solution 1 drop in affected eye daily 204.76 (1.7 mL)
Bromday, Xibrom
Bromfenac 0.09% solution 1 drop in affected eye 2 times daily 144.54 (2.5 mL)
generic
Ketorolac 0.45% solution 1 drop in affected eye 2 times daily 206.02 (0.4 mL)
Acuvail
Ketorolac 0.5% solution 1 drop in affected eye 4 times daily 48.73 (3 mL)
generic
Nepafenac 0.1% suspension 1 drop in affected eye 3 times daily 173.40 (3 mL)
Nevanac
Nepafenac 0.3% suspension 1 drop in affected eye 1 time daily 173.40 (1.7 mL)
Ilevro

AWP = average wholesale price.

theannals.com The Annals of Pharmacotherapy 2013 June, Volume 47 895

BM Jones, MW Neville
Summary
Nepafenac 0.3% ophthalmic suspension was approved
in October 2012. A more neutral pH and slightly lower os-
molality may increase its tolerability profile compared with
that of the 0.1% suspension. The major advantage of the
0.3% suspension over the 0.1% product is once-daily ver-
sus thrice-daily dosing. No head-to-head trials have com-
pared nepafenac 0.3% with other topical NSAIDS. Since
the 0.3% suspension and bromfenac 0.09% solution are
administered once daily, a head-to-head trial comparing the
2 would be useful in determining the preferred agent. At
the time of writing, preliminary data from 2 clinical trials
that compared nepafenac 0.1% and 0.3% suspensions were
available. The 2 products appear to be equally efficacious,
with a slightly increased adverse event rate with the 0.3%
versus 0.1% formulation.
Benjamin M Jones, PharmD student, College of Pharmacy, Uni-
versity of Georgia, Athens
Michael W Neville PharmD BCPS FASHP, Clinical Associate Pro-
fessor, College of Pharmacy, University of Georgia
Correspondence: Dr. Neville, neville@uga.edu
Reprints/Online Access: www.theannals.com/cgi/reprint/aph.1R757
Conflict of interest: Authors reported none
1967-2013 Harvey Whitney Books Co. All rights reserved. No part
of this document may be reproduced or transmitted in any form or
by any means without prior written permission of Harvey Whitney
Books Co. For reprints of any article appearing in The Annals, please
contact 415sales@hwbooks.com
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