Summary of Product Characteristics Updated 30-Aug-2016 | Bausch & Lomb U.K Limited
Use in adults, including the elderlyThe dose is one drop of Yellox in the affected eye(s) twice daily, beginning the next day after cataract surgery and continuing through the first 2 weeks of the postoperative period. The treatment should not exceed 2 weeks as safety data beyond this is not available.
Hepatic and renal impairmentYellox has not been studied in patients with hepatic disease or renal impairment.
Paediatric populationThe safety and efficacy of bromfenac in paediatric patients has not been established. No data are available.
Method of administrationFor 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
Cross-sensitivityThere is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, and other NSAIDs. Therefore, treating individuals who have previously exhibited sensitivities to these medicinal products has to be avoided (see section 4.3).
Susceptible personsIn 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 experiencePostmarketing 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. Yellox should be used with caution in patients with known bleeding tendencies or who are receiving other medicinal products which may prolong bleeding time.It has been observed in rare cases that upon withdrawal of Yellox, a flare-up of the inflammatory response, e.g. in the form of macular oedema, due to the cataract operation may occur.
Ocular infectionAn acute ocular infection may be masked by the topical use of anti-inflammatory medicinal products.
Use of contact lensesIn 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 Yellox.
ExcipientsSince Yellox 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. Yellox contains sodium sulphite which may cause allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in susceptible patients.
PregnancyThere 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 Yellox, 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 Yellox during third trimester pregnancy should be avoided. The use of Yellox is in general not recommended during pregnancy unless the benefit outweighs the potential risk.
Breast-feedingIt 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. Yellox can be used during breast-feeding.
FertilityNo 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.
Summary of the safety profileBased on clinical data available, a total of 3.4% of patients 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 reactionsThe 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); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.The table below describes adverse reactions by system organ class and frequency.
|MedDRA system organ class||Frequency||Adverse reactions|
|Eye disorders||Uncommon||Visual acuity reduced Haemorrhagic retinopathy Corneal epithelium defect** Corneal erosion (mild or moderate) Corneal epithelium disorder Corneal oedema Retinal exudates Eye pain Eyelid bleeding Vision blurred Photophobia Eyelid oedema Eye discharge Eye pruritus Eye irritation Eye redness Conjunctival hyperaemia Abnormal sensation in eye Ocular discomfort|
|Rare||Corneal perforation* Corneal ulcer* Corneal erosion, serious* Scleromalacia* Corneal infiltrates* Corneal disorder * Corneal scar*|
|Respiratory, thoracic and mediastinal disorders||Uncommon||Epistaxis Cough Nasal sinus drainage|
|General disorders and administrative site conditions||Uncommon||Face swelling|
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via: Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard
Mechanism of actionBromfenac 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 efficacyTwo 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 Yellox 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 Yellox 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, Yellox was shown to be as effective as pranoprofen ophthalmic solution.
Paediatric populationThe European Medicines Agency has waived the obligation to submit the results of studies with Yellox in all subsets of the paediatric population in postoperative ocular inflammation (see section 4.2 for information on paediatric use)
AbsorptionBromfenac 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.
DistributionBromfenac 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.
BiotransformationIn vitro studies indicate that bromfenac is mainly metabolised by CYP2C9, which is absent in both iris-ciliary 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.
EliminationAfter 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.
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