Contents of the package leaflet for the medicine YELLOX 0.9mg / ml ophthalmic drops solution

1. NAME OF THE MEDICINAL PRODUCT

Yellox 0.9 mg/ml eye drops solution

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml of solution contains 0.9 mg bromfenac (as sodium sesquihydrate).

One drop contains approximately 33 micrograms bromfenac.

Excipient(s) with known effect:

Each ml of solution contains 50 micrograms of benzalkonium chloride.

For the full list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Eye drops, solution.

Clear yellow solution.pH: 8.0-8.5; osmolality: 270-310 mOsmol/kg

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Yellox is indicated in adults for the treatment of postoperative ocular inflammation following cataractextraction .

4.2 Posology and method of administration

Posology
Use in adults, including the elderly

The dose is one drop of Yellox in the affected eye(s) twice daily, beginning the next day after cataractsurgery 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 impairment

Yellox has not been studied in patients with hepatic disease or renal impairment.

Paediatric population

The safety and efficacy of bromfenac in paediatric patients has not been established. No data areavailable.

Method of administration

For ocular use.

If more than one topical ophtalmic medicinal product is being used, each one should be administeredat 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

4.3 Contraindications

Hypersensitivity to bromfenac or to any of the excipients listed in section 6.1, or to other non-steroidal anti-inflammatory medicinal products (NSAIDs).

Yellox is contraindicated in patients in whom attacks of asthma, urticaria or acute rhinitis areprecipitated by acetylsalicylic acid or by other medicinal products with prostaglandin synthetaseinhibiting activity.

4.4 Special warnings and precautions for use

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.

Cross-sensitivity

There is the potential for cross-sensitivity to acetylsalicylic acid, phenylacetic acid derivatives, andother NSAIDs. Therefore, treating individuals who have previously exhibited sensitivities to thesemedicinal products has to be avoided (see section 4.3).

Susceptible persons

In susceptible patients, continued use of topical NSAIDs, including bromfenac may result in epithelialbreakdown, corneal thinning, corneal erosion, corneal ulceration or corneal perforation. These eventsmay be sight threatening. Patients with evidence of corneal epithelial breakdown should immediatelydiscontinue use of topical NSAIDs and should be closely monitored for corneal health. Consequentlyin at risk patients concomitant use of ophthalmic corticosteroids with NSAIDs may lead to a higherrisk of corneal adverse events.

Postmarketing experience

Postmarketing experience with topical NSAIDs suggests that patients with complicated ocularsurgeries, corneal denervation, corneal epithelial defects, diabetes mellitus and ocular surface diseasese.g. dry eye syndrome, rheumatoid arthritis or repeat ocular surgeries within a short period of timemay 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 inpatients with known bleeding tendencies or who are receiving other medicinal products which mayprolong bleeding time.

It has been observed in rare cases that upon withdrawal of Yellox, a flare-up of the inflammatoryresponse, e.g. in the form of macular oedema, due to the cataract operation may occur.

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 cataractsurgery. Therefore, patients should be advised not to wear contact lenses during treatment with Yellox.

Excipients
Benzalkonium chloride

This medicinal product contains 0.00185 mg benzalkonium chloride in each drop which is equivalentto 0.05 mg/ml.

Benzalkonium chloride may be absorbed by soft contact lenses and may change the colour of thecontact lenses. Patients should remove contact lenses before using this medicinal product and put themback 15 minutes afterwards.

Benzalkonium chloride has been reported to cause eye irritation, symptoms of dry eyes and may affectthe tear film and corneal surface. Should be used with caution in dry eye patients and in patients wherethe cornea may be compromised.

Patients should be monitored in case of prolonged use.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed. No interactions with antibiotic eye drops used inconjunction with surgery have been reported.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of bromfenac in pregnant women. Studies in animals haveshown reproductive toxicity (see section 5.3). Even if systemic exposure is very low after treatmentwith Yellox, it is not known if the systemic Yellox exposure reached after ophthalmic administrationcan be harmful to an embryo/foetus. During the first and second trimester of pregnancy, Yellox shouldnot be used unless clearly necessary. If used, the dose should be kept as low and duration of treatmentas short as possible.

During the third trimester of pregnancy, systemic use of prostaglandin synthetase inhibitors mayinduce cardiopulmonary and renal toxicity in the foetus. At the end of the pregnancy prolongedbleeding time in both mother and child may occur, and labour can be delayed. Therefore, Yellox is notrecommended during the last trimester of pregnancy.

Breast-feeding

It is unknown whether bromfenac or its metabolites are excreted in human milk. Animal studies haveshown excretion of bromfenac in the milk of rats following very high oral doses (see section 5.3). Noeffects on the breastfed newborn/infant are anticipated since the systemic exposure of thebreastfeeding woman to bromfenac is negligible. Yellox can be used during breast-feeding.

Fertility

No effects of bromfenac on the fertility were observed in animal studies. In addition the systemicexposure to bromfenac is negligible; for this reason no pregnancy testing or contraceptive measuresare required.

4.7 Effects on ability to drive and use machines

Yellox has minor influence on the ability to drive and use machines. Transient blurring of vision mayoccur on instillation. If blurred vision occurs at instillation patients should be advised to refrain fromdriving or using machines until vision is clear.

4.8 Undesirable effects

Summary of the safety profile

Based 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 eyeredness (0.3%). Corneal adverse reactions were only observed in the Japanese population. Adversereactions rarely led to withdrawal, with a total of 8 (0.8%) patients who prematurely discontinuedtreatment in a study due to an adverse reaction. These comprised 3 (0.3%) patients with mild cornealerosion, 2 (0.2%) patients with eyelid oedema and 1 (0.1%) patient each with abnormal sensation ineye, 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);very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order ofdecreasing seriousness.

The table below describes adverse reactions by system organ class and frequency.

MedDRA system organ Frequency Adverse reactionsclass

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 Uncommon Epistaxismediastinal disorders Cough

Nasal sinus drainage

Rare Asthma*

General disorders and Uncommon Face swellingadministrative siteconditions

*Serious reports from post-marketing experience of more than 20 million patients

** Observed with four times daily dose

Patients with evidence of corneal epithelial breakdown should be instructed to immediatelydiscontinue use of Yellox and should be monitored closely for corneal health (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

4.9 Overdose

No abnormal findings or adverse reactions of clinical concern were noted upon administration of twodrops 2mg/ml solution four times a day for the period of up to 28 days. Accidental administration ofmore than one drop should not result in increased topical exposure as excessive volume would rinseout of the eye due to limited conjunctival sac capacity.

There is practically no risk of adverse effects due to accidental oral ingestion. Ingestion of the 5 mlbottle content corresponds to an oral dose of less than 5 mg bromfenac, which is 30 times lower thandaily dose of bromfenac oral formulation formerly used.

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

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Ophtalmologicals, Antiinflammatory agents, non-steroids, ATC code:

S01BC11.

Mechanism of action

Bromfenac is a non-steroidal anti-inflammatory drug (NSAID) that has anti-inflammatory activitywhich is thought to be due to its ability to block prostaglandin synthesis by inhibiting primarilycyclooxygenase 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 ocularinflammation 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 Yellox dosedtwice daily in the treatment of post-operative inflammation in patients undergoing cataract surgery. Inthese studies, study substance was administered approximately 24 hours after cataract surgery andcontinued 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 placebogroup (p<0.0001) experienced complete clearance of ocular inflammation at study day 15. There wassignificantly less anterior chamber cells and flare within the first 2 weeks post-surgery (85.1% ofpatients with flare score of ≤1) vs. placebo (52%). The difference in the rate of inflammation clearanceshowed as early as day 3.

In a large, well-controlled study that was conducted in Japan, Yellox was shown to be as effective aspranoprofen ophthalmic solution.

Paediatric population

The 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 4.2for information on paediatric use)

5.2 Pharmacokinetic properties

Absorption

Bromfenac efficiently permeates the cornea of cataract patients: A single dose resulted in a mean peakaqueous humour concentrations of 79±68 ng/ml at 150-180 minutes after dosing. Concentrations weremaintained for 12 hours in aqueous humour with measurable levels up to 24 hours in major oculartissues including the retina. Following twice daily dosing with bromfenac eye drops plasmaconcentrations were not quantifiable.

Distribution

Bromfenac shows high binding to plasma proteins. In vitro, the 99.8% were bound to proteins inhuman plasma.

No biological relevant melanin binding was observed in vitro.

Studies in rabbits using radio-labelled bromfenac have demonstrated that highest concentrations aftertopical administration are observed in the cornea followed by the conjunctiva and the aqueoushumour. 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 bothiris-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. Severalconjugated and unconjugated metabolites have been identified with the cyclic amide being the majorurinary metabolite.

Elimination

After ocular administration the half-life of bromfenac in aqueous humour is 1.4 h indicating rapidelimination.

After oral administration of 14C-bromfenac to healthy volunteers, urinary excretion was found to bethe major route of radioactive excretions, accounting for approximately 82% while faecal excretionrepresented approximately 13% of the dose.

5.3 Preclinical safety data

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 treatedorally 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 of2.35 mg/kg which is 2350 times the recommended ophthalmic dose. However, following ocularadministration plasma levels were not detectable (see section 5.2).

6. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Boric acid

Borax

Sodium sulphite, anhydrous (E221)

Tyloxapol

Povidone (K30)

Benzalkonium chloride

Disodium edetate

Water for injections

Sodium hydroxide (for pH adjustment)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

2 years.

After first opening: 4 weeks.

6.4 Special precautions for storage

Do not store above 25°C.

Patients should be instructed to keep the bottle tightly closed when not in use.

6.5 Nature and contents of container

5 ml solution in a polyethylene squeeze bottle with a dropper-tip and a polyethylene screw cap.

Pack of 1 bottle.

6.6 Special precautions for disposal and other handling

No special requirements.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

7. MARKETING AUTHORISATION HOLDER

BAUSCH + LOMB IRELAND LIMITED3013 Lake Drive

Citywest Business Campus

Dublin 24, D24PPT3

Ireland

8. MARKETING AUTHORISATION NUMBER(S)

EU/1/11/692/001

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation: 18.05.2011

Date of latest renewal: 11.01.2016

10. DATE OF REVISION OF THE TEXT

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu

Leaflet YELLOX 0.9mg / ml ophthalmic drops solution

General data about YELLOX 0.9mg / ml

Marketing authorisation