Treatment of postoperative ocular inflammation following cataract extraction in adults.

Posology
Use in adults, including the elderly
For the treatment of postoperative inflammation in patients who have undergone cataract extraction, one
drop of Bromfenac™ should be applied to the affected eye(s) once daily beginning 1 day prior to cataract
surgery, continued on the day of surgery, and through the first 14 days of the postoperative period.
Paediatric population
The safety and efficacy of bromfenac in paediatric patients has not been established. No data are available.
Hepatic and renal impairment
Bromfenac has not been studied in patients with hepatic disease or renal impairment.
Method of administration
For ocular use.
If more than one topical ophtalmic medicinal product is being used, each one should be administered at
least 5 minutes apart.
To prevent contamination of the dropper-tip and solution, care must be taken not to touch the eyelids,
surrounding areas or other surfaces with the dropper-tip of the bottle. Instruct patient to keep the bottle
tightly closed when not in use. Contact lenses should not be worn during treatment with Bromfenac
(see section 4.4).

Bromfenac must not be used in patients with known hypersensitivity to bromfenac, to any of the excipients, or to other non-steroidal anti-inflammatory medicinal products (NSAIDs). Bromfenac is contraindicated in patients in whom attacks of asthma, urticaria or acute rhinitis are precipitated by acetylsalicylic acid or by other medicinal products with prostaglandin synthetase inhibiting activity.

All topical NSAIDs may slow or delay healing like topical corticosteroids. Concomitant use of NSAIDs
and topical steroids may increase the potential for healing problems.
Bromfenac contains sodium sulphite which may cause allergic-type reactions including anaphylactic
symptoms and life-threatening or less severe asthmatic episodes in susceptible patients.
Cross-sensitivity
There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other
NSAIDs. Therefore, caution should be used when treating individuals who have previously exhibited
sensitivities to these medicinal products and potential risks and benefit should be carefully evaluated.
Susceptible persons
In susceptible patients, continued use of topical NSAIDs, including Bromfenac may result in epithelial
breakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These events may
be sight threatening. Patients with evidence of corneal epithelial breakdown should immediately
discontinue use of topical NSAIDs and should be closely monitored for corneal health. Consequently in at
risk patients concomitant use of ophthalmic corticosteroids with NSAIDs may lead to a higher risk of
corneal adverse events.
Postmarketing experience
Postmarketing experience with topical NSAIDs suggests that patients with complicated ocular surgeries,
corneal denervation, corneal epithelial defects, diabetes mellitus and ocular surface diseases e.g. dry eye
syndrome, rheumatoid arthritis or repeat ocular surgeries within a short period of time may be at increased
risk for corneal adverse reactions which may become sight threatening. Topical NSAIDs should be used
with caution in these patients.
There have been reports that ophthalmic NSAIDs may cause increased bleeding of ocular tissues
(including hyphaema) in conjunction with ocular surgery. Bromfenac should be used with caution in
patients with known bleeding tendencies or who are receiving other medicinal products which may prolong
bleeding time.
Ocular infection
An acute ocular infection may be masked by the topical use of anti-inflammatory medicinal products.
Use of contact lenses
In general, contact lens wear is not recommended during the postoperative period following cataract
surgery. Therefore, patients should be advised not to wear contact lenses during treatment with Bromfenac.
Excipients
Since Bromfenac contains benzalkonium chloride, close monitoring is required with frequent or prolonged
use.
Benzalkonium chloride is known to discolour soft contact lenses. Contact with soft contact lenses must be
avoided.
Benzalkonium chloride has been reported to cause eye irritation, punctuate keratopathy and/or toxic
ulcerative keratopathy.

Formal interaction studies have not been performed, but no interactions with antibiotic eye drops used in
conjunction with surgery have been reported.

Pregnancy Category C.

There are no adequate data from the use of bromfenac in pregnant women. Studies in animals have shown
reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Since the systemic
exposure in non-pregnant women is negligible after treatment with Bromfenac, the risk during pregnancy
could be considered low.
However, because of the known effects of prostaglandin biosynthesis-inhibiting medicinal products on the
foetal cardiovascular system (closure of ductus arteriosus), the use of Bromfenac during third trimester
pregnancy should be avoided. The use of Bromfenac is in general not recommended during pregnancy
unless the benefit outweighs the potential risk.
Breast-feeding
It is unknown whether bromfenac or its metabolites are excreted in human milk. Animal studies have
shown excretion of bromfenac in the milk of rats following very high oral doses (see section 5.3). No
effects on the breastfed newborn/infant are anticipated since the systemic exposure of the breastfeeding
woman to bromfenac is negligible. Bromfenac can be used during breast-feeding.
Fertility
No effects of bromfenac on the fertility were observed in animal studies. In addition the systemic exposure
to bromfenac is negligible; for this reason no pregnancy testing or contraceptive measures are required.

Transient blurring of vision may occur on instillation. If blurred vision occurs at instillation refrain from
driving or using machines until vision is clear.

Summary of the safety profile
Based on an analysis of all patients receiving Bromfenac in a clinical trial for treatment of post-operative
inflammation following cataract surgery (n = 973, whereof n=356 in studies performed in the U.S and
n=617 in studies performed in Japan), a total of 3.4% of patients (6.7% in U.S. studies and 1.3% in
Japanese studies) experienced one or more adverse reactions. The most common or most important
reactions in the pooled studies were abnormal sensation in eye (0.5%), corneal erosion (mild or moderate)
(0.4%), eye pruritus (0.4%), eye pain (0.3%) and eye redness (0.3%). Corneal adverse reactions were only
observed in the Japanese population. Adverse reactions rarely led to withdrawal, with a total of 8 (0.8%)
patients who prematurely discontinued treatment in a study due to an adverse reaction. These comprised 3
(0.3%) patients with mild corneal erosion, 2 (0.2%) patients with eyelid oedema and 1 (0.1%) patient each
with abnormal sensation in eye, corneal oedema, or eye pruritus.
Tabulated list of adverse reactions
The following adverse reactions were classified according to the following convention: very common
(≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000), or
very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of
decreasing seriousness.

Patients with evidence of corneal epithelial breakdown should immediately discontinue use of Bromfenac
and should be monitored closely for corneal health (see section 4.4).

If Bromfenac is accidentally ingested, fluids should be taken to dilute the medicinal product.

Pharmacotherapeutic group: Ophtalmologics, Antiinflammatory agents, non-steroids, ATC code: S01BC11
Mechanism of action
Bromfenac is a non-steroidal anti-inflammatory drug (NSAID) that has anti-inflammatory activity which is
thought to be due to its ability to block prostaglandin synthesis by inhibiting primarily cyclooxygenase 2
(COX-2). Cyclooxygenase 1 (COX-1) is only inhibited to a small extent.
In vitro, bromfenac inhibited the synthesis of prostaglandins in the rabbit iris ciliary body. The IC50-values
were lower for Bromfenac (1.1 μM) than for indometacin (4.2 μM) and pranoprofen (11.9 μM)
Bromfenac at concentrations of 0.02%, 0.05%, 0.1% and 0.2% inhibited almost all signs of ocular
inflammation in an experimental uveitis model in rabbits.
Clinical efficacy
Two Phase II multicentre, randomised, double-masked, parallel group studies were conducted in Japan, and
two Phase III multicentre, randomised (2:1), double-masked, parallel group, placebo-controlled studies
were conducted in the US to assess the clinical safety and efficacy of Bromfenac dosed twice daily in the
treatment of post-operative inflammation in patients undergoing cataract surgery. In these studies, study
substance was administered approximately 24 hours after cataract surgery and continued for up to 14 days.
Treatment effect was evaluated up to 29 days.
A significantly greater proportion of patients in the Bromfenac group 64.0% vs. 43.3% in the placebo
group (p<0.0001) experienced complete clearance of ocular inflammation at study day 15. There was
significantly less anterior chamber cells and flare within the first 2 weeks post-surgery (85.1% of patients
with flare score of ≤1) vs. placebo (52%). The difference in the rate of inflammation clearance showed as
early as day 3.
In a large, well controlled study that was conducted in Japan, Bromfenac was shown to be as effective as
pranoprofen ophthalmic solution.
Paediatric population
The European Medicines Agency has waived the obligation to submit the results of studies with Bromfenac
in all subsets of the paediatric population in postoperative ocular inflammation (see section 4.2 for
information on paediatric use)

 

Absorption
Bromfenac efficiently permeates the cornea of cataract patients: A single dose resulted in a mean peak
aqueous humour concentrations of 79±68 ng/ml at 150-180 minutes after dosing. Concentrations were
maintained for 12 hours in aqueous humour with measurable levels up to 24 hours in major ocular tissues
including the retina. Following twice daily dosing with bromfenac eye drops plasma concentrations were
not quantifiable.
Distribution
Bromfenac shows high binding to plasma proteins. In vitro, the 99.8% were bound to proteins in human
plasma.
No biological relevant melanin binding was observed in vitro.
Studies in rabbits using radio-labelled bromfenac have demonstrated that highest concentrations after
topical administration are observed in the cornea followed by the conjunctiva and the aqueous humour.
Only low concentrations were observed in the lens and vitreous.
Biotransformation
In vitro studies indicate that bromfenac is mainly metabolised by CYP2C9, which is absent in both irisciliary
body and retina/choroid and the level of this enzyme in the cornea is less than 1% compared to the
corresponding hepatic level.
In orally treated humans unchanged parent compound is the major component in plasma. Several
conjugated and unconjugated metabolites have been identified with the cyclic amide being the major
urinary metabolite.
Excretion
After ocular administration the half-life of bromfenac in aqueous humour is 1.4 h indicating rapid
elimination.
After oral administration of 14C-bromfenac to healthy volunteers, urinary excretion was found to be the
major route of radioactive excretions, accounting for approximately 82% while faecal excretion
represented approximately 13% of the dose.

Non-clinical data reveal no special hazard for humans based on conventional studies of safety,
pharmacology, 'repeated-dose' toxicity, genotoxicity and carcinogenic potential. However, 0.9 mg/kg/day
in rats at oral doses (900 times the recommended ophthalmic dose) caused embryo-foetal lethality,
increased neonatal mortality, and reduced postnatal growth. Pregnant rabbits treated orally with 7.5
mg/kg/day (7500 times the recommended ophthalmic dose) caused increased post-implantation loss (see
section 4.6).
Animal studies have shown excretion of bromfenac in breast milk when applied orally at doses of 2.35
mg/kg which is 2350 times the recommended ophthalmic dose. However, following ocular administration
plasma levels were not detectable (see section 5.2).

Benzalkonium Chloride
Boric acid
Sodium tetraborate
Disodium Edetate
Polysorbate 80
Sodium Sulfite Anhydrous
Povidone K29 32
Sodium Hyroxide 1N
Water

Not applicable.

Unopened: 24 months Discard after 30 days of opening.

Do not store above 30°C.

5 ml ophthalmic solution, packed in 10 ml LDPE opaque bottle

No special requirements.
Any unused medicinal product or waste material should be disposed of in accordance with local
requirements.