DUOTRAV 40mcg / 5mg / ml ophthalmic drops solution medication leaflet

DuoTrav 40 micrograms/mL + 5 mg/mL eye drops, solution

Each mL of solution contains 40 micrograms of travoprost and 5 mg of timolol (as timolol maleate).

Each mL of solution contains polyquaternium-1 (POLYQUAD) 10 microgram, propylene glycol7.5 mg and polyoxyethylene hydrogenated castor oil 40 1 mg (see section 4.4).

For the full list of excipients, see section 6.1.

Eye drops, solution (eye drops).

Clear, colourless solution.

DuoTrav is indicated in adults for the decrease of intraocular pressure (IOP) in patients withopen-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta blockersor prostaglandin analogues (see section 5.1).

The dose is one drop of DuoTrav in the conjunctival sac of the affected eye(s) once daily, in themorning or evening. It should be administered at the same time each day.

If a dose is missed, treatment should be continued with the next dose as planned. The dose should notexceed one drop in the affected eye(s) daily.

No studies have been conducted with DuoTrav or with timolol 5 mg/mL eye drops in patients withhepatic or renal impairment.

Travoprost has been studied in patients with mild to severe hepatic impairment and in patients withmild to severe renal impairment (creatinine clearance as low as 14 mL/min). No dose adjustment wasnecessary in these patients.

Patients with hepatic or renal impairment are unlikely to require dose adjustment with DuoTrav (seesection 5.2).

The safety and efficacy of DuoTrav in children and adolescents below the age of 18 years have notbeen established. No data are available.

For ocular use.

The patient should remove the protective overwrap immediately prior to initial use. To preventcontamination of the dropper tip and solution, care must be taken not to touch the eyelids, surroundingareas or other surfaces with the dropper tip of the bottle.

When nasolacrimal occlusion is used or the eyelids are closed for 2 minutes, systemic absorption isreduced. This may result in a decrease in systemic side effects and an increase in local activity (seesection 4.4).

If more than one topical ophthalmic medicinal product is being used, the medicinal products must beadministered at least 5 minutes apart (see section 4.5).

When substituting another ophthalmic antiglaucoma medicinal product with DuoTrav, the othermedicinal product should be discontinued and DuoTrav should be started the following day.

Patients must be instructed to remove soft contact lenses prior to application of DuoTrav and wait15 minutes after instillation of the dose before reinsertion (see section 4.4).

Hypersensitivity to the active substances, or to any of the excipients listed in section 6.1.

Hypersensitivity to other beta blockers.

Reactive airway disease including bronchial asthma, or a history of bronchial asthma, severe chronicobstructive pulmonary disease.

Sinus bradycardia, sick sinus syndrome, including sino-atrial block, second- or third-degreeatrioventricular block not controlled with pacemaker. Overt cardiac failure, cardiogenic shock. Severeallergic rhinitis and corneal dystrophies.

Like other topically applied ophthalmic agents, travoprost and timolol are absorbed systemically. Dueto the beta-adrenergic component, timolol, the same types of cardiovascular, pulmonary and otheradverse reactions seen with systemic beta-adrenergic blocking medicinal products may occur. Theincidence of systemic ADRs after topical ophthalmic administration is lower than for systemicadministration. For information on how to reduce systemic absorption, see section 4.2.

In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal’s angina and cardiacfailure) and hypotension, therapy with beta blockers should be critically assessed and therapy withother active substances should be considered. Patients with cardiovascular diseases should be watchedfor signs of deterioration of these diseases and of adverse reactions.

Due to their negative effect on conduction time, beta blockers should only be given with caution topatients with first-degree heart block.

Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’sdisease or Raynaud’s syndrome) should be treated with caution.

Respiratory reactions, including death due to bronchospasm in patients with asthma, have beenreported following administration of some ophthalmic beta blockers.

DuoTrav should be used with caution in patients with mild/moderate chronic obstructive pulmonarydisease (COPD) and only if the potential benefit outweighs the potential risk.

Hypoglycaemia/diabetes

Beta blockers should be administered with caution in patients subject to spontaneous hypoglycaemiaor in patients with labile diabetes, as beta blockers may mask the signs and symptoms of acutehypoglycaemia.

Muscle weakness

Beta-adrenergic blocking medicinal products have been reported to potentiate muscle weaknessconsistent with certain myasthenic symptoms (e.g. diplopia, ptosis and generalised weakness).

Corneal diseases

Ophthalmic beta blockers may induce dryness of eyes. Patients with corneal diseases should be treatedwith caution.

Choroidal detachment

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g.timolol, acetazolamide) after filtration procedures.

Other beta-blocking agents

The effect on intra-ocular pressure or the known effects of systemic beta blockade may be potentiatedwhen timolol is given to patients already receiving a systemic beta-blocking medicinal product. Theresponse of these patients should be closely observed. The use of two topical beta-adrenergic blockingagents is not recommended (see section 4.5).

Surgical anaesthesia

Beta-blocking ophthalmological preparations may block systemic beta-agonist effects, e.g. ofadrenaline. The anaesthetist should be informed when the patient is receiving timolol.

Beta blockers may mask the signs of hyperthyroidism.

Skin contact

Prostaglandins and prostaglandin analogues are biologically active substances that may be absorbedthrough the skin. Women who are pregnant or attempting to become pregnant should exerciseappropriate precautions to avoid direct exposure to the contents of the bottle. In the unlikely event ofcoming in contact with a substantial portion of the contents of the bottle, thoroughly cleanse theexposed area immediately.

Anaphylactic reactions

While taking beta blockers, patients with a history of atopy or a history of severe anaphylactic reactionto a variety of allergens may be more reactive to repeated challenge with such allergens andunresponsive to the usual dose of adrenaline used to treat anaphylactic reactions.

Concomitant therapy

Timolol may interact with other medicinal products (see section 4.5).

The use of two local prostaglandins is not recommended.

Travoprost may gradually change the eye colour by increasing the number of melanosomes (pigmentgranules) in melanocytes. Before treatment is instituted, patients must be informed of the possibility ofa permanent change in eye colour. Unilateral treatment can result in permanent heterochromia. Thelong-term effects on the melanocytes and any consequences thereof are currently unknown. Thechange in iris colour occurs slowly and may not be noticeable for months to years. The change in eyecolour has predominantly been seen in patients with mixed coloured irides, i.e. blue-brown,grey-brown, yellow-brown and green-brown; however, it has also been observed in patients withbrown eyes. Typically, the brown pigmentation around the pupil spreads concentrically towards theperiphery in affected eyes, but the entire iris or parts of it may become more brownish. Afterdiscontinuation of therapy, no further increase in brown iris pigment has been observed.

In controlled clinical trials, periorbital and/or eyelid skin darkening in association with the use oftravoprost has been reported.

Periorbital and lid changes, including deepening of the eyelid sulcus, have been observed withprostaglandin analogues.

Travoprost may gradually change eyelashes in the treated eye(s); these changes were observed inabout half of the patients in clinical trials and include: increased length, thickness, pigmentation,and/or number of lashes. The mechanism of eyelash changes and their long-term consequences arecurrently unknown.

Travoprost has been shown to cause slight enlargement of the palpebral fissure in studies in themonkey. However, this effect was not observed during the clinical trials and is considered to bespecies specific.

There is no experience of DuoTrav in inflammatory ocular conditions, nor in neovascular,angle-closure, narrow-angle or congenital glaucoma, and only limited experience in thyroid eyedisease, in open-angle glaucoma of pseudophakic patients and in pigmentary or pseudoexfoliativeglaucoma.

Macular oedema has been reported during treatment with prostaglandin F2 analogues. Caution isrecommended when using DuoTrav in aphakic patients, pseudophakic patients with a torn posteriorlens capsule or anterior chamber lenses, or in patients with known risk factors for cystoid macularoedema.

In patients with known predisposing risk factors for iritis/uveitis, and in patients with activeintraocular inflammation, DuoTrav can be used with caution.

DuoTrav contains propylene glycol which may cause skin irritation.

DuoTrav contains polyoxyethylene hydrogenated castor oil 40 which may cause skin reactions.

Patients must be instructed to remove contact lenses prior to application of DuoTrav and wait15 minutes after instillation of the dose before reinsertion (see section 4.2).

No specific drug interaction studies have been performed with travoprost or timolol.

There is a potential for additive effects resulting in hypotension and/or marked bradycardia whenophthalmic beta-blocker solution is administered concomitantly with oral calcium channel blockers,beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides,parasympathomimetics or guanethidine.

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking betablockers.

Potentiated systemic beta blockade (e.g. decreased heart rate, depression) has been reported duringcombined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol.

Mydriasis resulting from concomitant use of ophthalmic beta blockers and adrenaline (epinephrine)has been reported occasionally.

Beta blockers may increase the hypoglycaemic effect of antidiabetic medicinal products. Beta blockerscan mask the signs and symptoms of hypoglycaemia (see section 4.4).

DuoTrav must not be used in women of child-bearing age/potential unless adequate contraceptivemeasures are in place (see section 5.3).

Travoprost has harmful pharmacological effects on pregnancy and/or the foetus/newborn child.

There are no or limited amount of data from the use of DuoTrav or the individual components inpregnant women. Timolol should not be used during pregnancy unless clearly necessary.

Epidemiological studies have not revealed malformative effects but show a risk for intrauterine growthretardation when beta blockers are administered by the oral route. In addition, signs and symptoms ofbeta blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have beenobserved in the neonate when beta blockers have been administered until delivery. If DuoTrav isadministered until delivery, the neonate should be carefully monitored during the first days of life.

DuoTrav should not be used during pregnancy unless clearly necessary. For information on how toreduce systemic absorption, see section 4.2.

It is unknown whether travoprost from eye drops is excreted in human breast milk. Animal studieshave shown excretion of travoprost and metabolites in breast milk. Timolol is excreted in breast milkand has the potential to cause serious adverse reactions in the breast-fed infant. However, attherapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present inbreast milk to produce clinical symptoms of beta blockade in the infant. For information on how toreduce systemic absorption, see section 4.2.

The use of DuoTrav by breast-feeding women is not recommended.

There are no data on the effects of DuoTrav on human fertility. Animal studies showed no effect oftravoprost on fertility at doses up to 75 times the maximum recommended human ocular dose, whereasno relevant effect of timolol was noted at this dose level.

DuoTrav has minor influence on the ability to drive and use machines. As with any eye drops,temporary blurred vision or other visual disturbances may occur. If blurred vision occurs atinstillation, the patient must wait until the vision clears before driving or using machines. DuoTravmay also cause hallucinations, dizziness, nervousness and/or fatigue (see section 4.8) which mayaffect the ability to drive and use machines. Patients should be advised not to drive and use machinesif these symptoms occur.

In clinical studies involving 2,170 patients treated with DuoTrav the most frequently reportedtreatment-related adverse reaction was ocular hyperaemia (12.0%).

The adverse reactions listed in the table below were observed in clinical studies or with post-marketingexperience. They are ranked according to system organ class and classified according to the followingconvention: 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), or not known (cannot be estimated from the availabledata). Within each frequency grouping, adverse reactions are presented in decreasing order ofseriousness.

System organ class Frequency Adverse reactions

Immune system disorders Uncommon Hypersensitivity

Psychiatric disorders Rare Nervousness

Not known Hallucinations*, Depression

Nervous system disorders Uncommon Dizziness, headache

Not known Cerebrovascular accident, syncope, paraesthesia

Eye disorders Very common Ocular hyperaemia

Common Punctate keratitis, eye pain, visual disturbance,vision blurred, dry eye, eye pruritus, oculardiscomfort, eye irritation

Uncommon Keratitis, iritis, conjunctivitis, anterior chamberinflammation, blepharitis, photophobia, visual acuityreduced, asthenopia, eye swelling, lacrimationincreased, erythema of eyelid, growth of eyelashes,eye allergy, conjunctival oedema, eyelid oedema

Rare Corneal erosion, meibomianitis, conjunctivalhaemorrhage, eyelid margin crusting, trichiasis,distichiasis

Not known Macular oedema, eyelid ptosis, lid sulcus deepened,iris hyperpigmentation, corneal disorder

Cardiac disorders Uncommon Bradycardia

Rare Arrhythmia, heart rate irregular

Not known Cardiac failure, tachycardia, chest pain, palpitations

Vascular disorders Uncommon Hypertension, hypotension

Not known Oedema peripheral

Respiratory, thoracic and Uncommon Dyspnoea, postnasal dripmediastinal disorders Rare Dysphonia, bronchospasm, cough, throat irritation,oropharyngeal pain, nasal discomfort

Not known Asthma

Gastrointestinal disorders Not known Dysgeusia

Hepatobiliary disorders Rare Alanine aminotransferase increased, aspartateaminotransferase increased

Skin and subcutaneous tissue Uncommon Dermatitis contact, hypertrichosis, skindisorders hyperpigmentation (periocular)

Rare Urticaria, skin discolouration, alopecia

Not known Rash

Musculoskeletal and Rare Pain in extremityconnective tissue disorders

Renal and urinary disorders Rare Chromaturia

General disorders and Rare Thirst, fatigueadministration site conditions

* adverse reactions observed with timolol.

Additional adverse reactions that have been seen with one of the active substances and may potentiallyoccur with DuoTrav:

Travoprost

System organ class MedDRA preferred term

Immune system disorders Seasonal allergy

Psychiatric disorders Anxiety, insomnia

Eye disorders Uveitis, conjunctival follicles, eye discharge,periorbital oedema, eyelids pruritus, ectropion,cataract, iridocyclitis, ophthalmic herpessimplex, eye inflammation, photopsia, eczemaeyelids, halo vision, hypoaesthesia eye, anteriorchamber pigmentation, mydriasis, eyelashhyperpigmentation, eyelash thickening, visualfield defect

Ear and labyrinth disorders Vertigo, tinnitus

Vascular disorders Blood pressure diastolic decreased, bloodpressure systolic increased

Respiratory, thoracic and mediastinal disorders Asthma aggravated, rhinitis allergic, epistaxis,respiratory disorder, nasal congestion, nasaldryness

Gastrointestinal disorders Peptic ulcer reactivated, gastrointestinaldisorder, diarrhoea, constipation, dry mouth,abdominal pain, nausea, vomiting

Skin and subcutaneous tissue disorders Skin exfoliation, hair texture abnormal,dermatitis allergic, hair colour changes,madarosis, pruritus, hair growth abnormal,erythema

Musculoskeletal and connective tissue disorders Musculoskeletal pain, arthralgia

Renal and urinary disorders Dysuria, urinary incontinence

General disorders and administration site Astheniaconditions

Investigations Prostatic specific antigen increased

Timolol

Like other topically applied ophthalmic medicinal products, timolol is absorbed into the systemiccirculation. This may cause undesirable effects similar to those seen with systemic beta-blockingagents. Additional listed adverse reactions include reactions seen within the class of ophthalmic betablockers. The incidence of systemic ADRs after topical ophthalmic administration is lower than forsystemic administration. For information on how to reduce systemic absorption, see section 4.2.

System organ class MedDRA preferred term

Immune system disorders Systemic allergic reactions includingangioedema, urticaria, localised and generalisedrash, pruritus, anaphylaxis

Metabolism and nutrition disorders Hypoglycaemia

Psychiatric disorders Hallucinations, insomnia, nightmares, memoryloss

Nervous system disorders Cerebral ischaemia, increases in signs andsymptoms of myasthenia gravis

Eye disorders Signs and symptoms of ocular irritation (e.g.burning, stinging, itching, tearing, redness),choroidal detachment following filtrationsurgery (see section 4.4), decreased cornealsensitivity, diplopia

Cardiac disorders Oedema, congestive heart failure,atrioventricular block, cardiac arrest

Vascular disorders Raynaud’s phenomenon, cold hands and feet

Gastrointestinal disorders Nausea, dyspepsia, diarrhoea, dry mouth,abdominal pain, vomiting

Skin and subcutaneous tissue disorders Psoriasiform rash or exacerbation of psoriasis

Musculoskeletal and connective tissue disorders Myalgia

Reproductive system and breast disorders Sexual dysfunction, decreased libido

General disorders and administration site Astheniaconditions

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.

A topical overdose with DuoTrav is not likely to occur or to be associated with toxicity.

In case of accidental ingestion, symptoms of overdose from systemic beta blockade may includebradycardia, hypotension, bronchospasm and heart failure.

If overdose with DuoTrav occurs, treatment should be symptomatic and supportive. Timolol does notdialyse readily.

Pharmacotherapeutic group: Ophthalmologicals; Antiglaucoma preparations and miotics, ATC code:

S01ED51.

DuoTrav contains two active substances: travoprost and timolol maleate. These two components lowerintraocular pressure by complementary mechanisms of action and the combined effect results inadditional IOP reduction compared to either compound alone.

Travoprost, a prostaglandin F2α analogue, is a full agonist which is highly selective and has a highaffinity for the prostaglandin FP receptor, and reduces the intraocular pressure by increasing theoutflow of aqueous humour via trabecular meshwork and uveoscleral pathways. Reduction of IOP inman starts within approximately 2 hours after administration and maximum effect is reached after12 hours. Significant lowering of intraocular pressure can be maintained for periods exceeding24 hours with a single dose.

Timolol is a non-selective adrenergic blocking agent that has no intrinsic sympathomimetic, directmyocardial depressant or membrane-stabilising activity. Tonography and fluorophotometry studies inman suggest that its predominant action is related to reduced aqueous humour formation and a slightincrease in outflow facility.

Secondary pharmacology

Travoprost significantly increased optic nerve head blood flow in rabbits following 7 days of topicalocular administration (1.4 micrograms once daily).

Clinical effects

In a twelve-month controlled clinical study in patients with open-angle glaucoma or ocularhypertension and baseline mean IOP of 25 to 27 mmHg, the mean IOP-lowering effect of DuoTravdosed once daily in the morning was 8 to 10 mmHg. The non-inferiority of DuoTrav as compared tolatanoprost 50 micrograms/mL + timolol 5 mg/mL in the mean IOP reduction was demonstratedacross all time-points at all visits.

In a three-month controlled clinical study in patients with open-angle glaucoma or ocular hypertensionand baseline mean IOP of 27 to 30 mmHg, the mean IOP-lowering effect of DuoTrav dosed once dailyin the morning was 9 to 12 mmHg, and was up to 2 mmHg greater than that of travoprost40 micrograms/mL dosed once daily in the evening and 2 to 3 mmHg greater than that of timolol5 mg/mL dosed twice daily. A statistically superior reduction in morning mean IOP (08:00, 24 hoursafter the last dose of DuoTrav) was observed compared to travoprost at all visits throughout the study.

In two three-month controlled clinical studies in patients with open-angle glaucoma or ocularhypertension and baseline mean IOP of 23 to 26 mmHg, the mean IOP-lowering effect of DuoTravdosed once daily in the morning was 7 to 9 mmHg. Mean IOP reductions were non-inferior, althoughnumerically lower, to those achieved by concomitant therapy with travoprost 40 micrograms/mLdosed once daily in the evening and timolol 5 mg/mL dosed once daily in the morning.

In a 6-week controlled clinical study in patients with open-angle glaucoma or ocular hypertension andbaseline mean IOP of 24 to 26 mmHg, the mean IOP-lowering effect of DuoTrav(polyquaternium-1-preserved) dosed once daily in the morning was 8 mmHg and equivalent to that of

DuoTrav (benzalkonium chloride-preserved).

Inclusion criteria were common across the studies, with the exception of the IOP entry criteria andresponse to previous IOP therapy. The clinical development of DuoTrav included both patients naiveand on therapy. Insufficient responsiveness to monotherapy was not an inclusion criterion.

Existing data suggest that evening dosing might have some advantages as regards mean IOP reduction.

Consideration should be given to patient convenience and their likely compliance whenrecommending morning vs. evening dosing.

Travoprost and timolol are absorbed through the cornea. Travoprost is a prodrug that undergoes rapidester hydrolysis in the cornea to the active free acid. Following once-daily administration of DuoTrav

PQ in healthy subjects (N=22) for 5 days, travoprost free acid was not quantifiable in plasma samplesfrom the majority of subjects (94.4%) and generally was not detectable one hour after dosing. Whenmeasurable (0.01 ng/mL, the assay limit of quantitation), concentrations ranged from0.01 to 0.03 ng/mL. The mean timolol steady-state Cmax was 1.34 ng/ml and Tmax was approximately0.69 hours after once-daily administration of DuoTrav.

Travoprost free acid can be measured in the aqueous humour during the first few hours in animals andin human plasma only during the first hour after ocular administration of DuoTrav. Timolol can bemeasured in human aqueous humour after ocular administration of timolol and in plasma for up to12 hours after ocular administration of DuoTrav.

Metabolism is the major route of elimination of both travoprost and the active free acid. The systemicmetabolic pathways parallel those of endogenous prostaglandin F2 which are characterised byreduction of the 13-14 double bond, oxidation of the 15-hydroxyl and -oxidative cleavages of theupper side chain.

Timolol is metabolised by two pathways. One route yields an ethanolamine side chain on thethiadiazole ring and the other gives an ethanolic side chain on the morpholine nitrogen and a secondsimilar side chain with a carbonyl group adjacent to the nitrogen. The plasma t1/2 of timolol is 4 hoursafter ocular administration of DuoTrav.

Travoprost free acid and its metabolites are mainly excreted by the kidneys. Less than 2% of an oculardose of travoprost was recovered in urine as free acid. Timolol and its metabolites are primarilyexcreted by the kidneys. Approximately 20% of a timolol dose is excreted in the urine unchanged andthe remainder excreted in urine as metabolites.

In monkeys, administration of DuoTrav twice daily was shown to induce increased palpebral fissureand to increase iris pigmentation similar to that observed with ocular administration of prostanoids.

DuoTrav preserved with polyquaternium-1 induced minimal ocular surface toxicity, compared to eyedrops preserved with benzalkonium chloride, on cultured human corneal cells and following topicalocular administration in rabbits.

Travoprost

Topical ocular administration of travoprost to monkeys at concentrations of up to 0.012% to the righteye, twice daily for one year resulted in no systemic toxicity.

Reproduction toxicity studies with travoprost have been undertaken in rats, mice and rabbits using thesystemic route. Findings are related to FP receptor agonist activity in uterus with earlyembryolethality, post-implantation loss and foetotoxicity. In pregnant rats, systemic administration oftravoprost at doses more than 200 times the clinical dose during the period of organogenesis resultedin an increased incidence of malformations. Low levels of radioactivity were measured in amnioticfluid and foetal tissues of pregnant rats administered 3H-travoprost. Reproduction and developmentstudies have demonstrated a potent effect on foetal loss with a high rate observed in rats and mice(180 pg/mL and 30 pg/mL plasma, respectively) at exposures 1.2 to 6 times the clinical exposure (upto 25 pg/mL).

Timolol

Non-clinical data revealed no special hazard for humans with timolol based on conventional studies ofsafety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential. Reproductiontoxicity studies with timolol showed delayed foetal ossification in rats with no adverse effects onpostnatal development (7000 times the clinical dose) and increased foetal resorptions in rabbits(14000 times the clinical dose).

Polyquaternium-1

Mannitol (E421)

Propylene glycol (E1520)

Polyoxyethylene hydrogenated castor oil 40 (HCO-40)

Boric acid

Sodium chloride

Sodium hydroxide and/ or hydrochloric acid (for pH adjustment)

Purified water

Not applicable.

2 years.

Discard 4 weeks after first opening.

Do not store above 30°C.

2.5 mL oval polypropylene (PP) or low-density polyethylene (LDPE) bottle and PP or LDPEdispensing plug with PP screw cap, presented in an overwrap.

Pack sizes of 1, 3 or 6 bottles.

Not all pack sizes may be marketed.

No special requirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/06/338/001-6

Date of first authorisation: 24 April 2006

Date of last renewal: 07 October 2010

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

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