AZARGA 10mg / 5mg / ml ophthalmic drops suspension medication leaflet

AZARGA 10 mg/ml + 5 mg/ml eye drops, suspension

One ml of suspension contains 10 mg brinzolamide and 5 mg timolol (as timolol maleate).

One ml of suspension contains 0.10 mg benzalkonium chloride.

For the full list of excipients, see section 6.1.

Eye drops, suspension (eye drops)

White to off-white uniform suspension, pH 7.2 (approximately).

Decrease of intraocular pressure (IOP) in adult patients with open-angle glaucoma or ocularhypertension for whom monotherapy provides insufficient IOP reduction (see section 5.1).

The dose is one drop of AZARGA in the conjunctival sac of the affected eye(s) twice daily.

When using nasolacrimal occlusion or closing the eyelids, the systemic absorption is reduced. Thismay result in a decrease in systemic side effects and an increase in local activity (see section 4.4).

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) twice daily.

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

The safety and efficacy of AZARGA in children and adolescents aged 0 to 18 years have not yet beenestablished. No data are available.

No studies have been conducted with AZARGA or with timolol 5 mg/ml eye drops in patients withhepatic or renal impairment. No dosage adjustment is necessary in patients with hepatic impairment orin patients with mild to moderate renal impairment.

AZARGA has not been studied in patients with severe renal impairment (creatinineclearance <30 ml/min) or in patients with hyperchloraemic acidosis (see section 4.3). Sincebrinzolamide and its main metabolite are excreted predominantly by the kidney, AZARGA is thereforecontraindicated in patients with severe renal impairment (see section 4.3).

AZARGA should be used with caution in patients with severe hepatic impairment (see section 4.4).

For ocular use.

Patients should be instructed to shake the bottle well before use. After cap is removed, if tamperevident snap collar is loose, remove before using product.

To prevent contamination of the dropper tip and the suspension, care must be taken not to touch theeyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Instruct patients to keepthe bottle tightly closed when not in use.

If more than one topical ophthalmic medicinal product is being used, the medicinal products must beadministered at least 5 minutes apart. Eye ointments should be administered last.

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

* Hypersensitivity to other beta-blockers.

* Hypersensitivity to sulphonamides (see section 4.4).

* Reactive airway disease including bronchial asthma or a history of bronchial asthma, or severechronic obstructive pulmonary disease.

* Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degreeatrioventricular block not controlled with pace-maker. Overt cardiac failure, cardiogenic shock.

* Severe allergic rhinitis

* Hyperchloraemic acidosis (see section 4.2).

* Severe renal impairment.

* Brinzolamide and timolol are absorbed systemically. Due to the beta-adrenergic blockingcomponent, timolol, the same types of cardiovascular, pulmonary and other adverse reactionsseen with systemic beta-adrenergic blocking agents may occur. The incidence of systemicadverse reactions after topical ophthalmic administration is lower than for systemicadministration. To reduce the systemic absorption, see section 4.2.

* Hypersensitivity reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermalnecrolysis (TEN) reported with sulphonamide derivates can occur in patients receiving

AZARGA as it is absorbed systemically. At the time of prescription, patients should be advisedof the signs and symptoms and monitored closely for skin reactions. If signs of serious reactionsor hypersensitivity occur, AZARGA should be withdrawn immediately.

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 the 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 its 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.

Beta-blockers may also mask the signs of hyperthyroidism.

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).

Respiratory reactions, including death due to bronchospasm in patients with asthma have beenreported following administration of some ophthalmic beta-blockers. AZARGA should be used withcaution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if thepotential benefit outweighs the potential risk.

Hypoglycaemia/diabetes

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

AZARGA contains brinzolamide, a sulphonamide. The same types of adverse reactions that areattributable to sulphonamides may occur with topical administration. Acid-base disturbances havebeen reported with oral carbonic anhydrase inhibitors. This medicinal product should be used withcaution in patients with risk of renal impairment because of the possible risk of metabolic acidosis. Ifsigns of serious reactions or hypersensitivity occur, discontinue the use of this medicinal product.

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertnessand/or physical coordination. AZARGA is absorbed systemically and therefore this may occur withtopical administration.

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 doses of adrenaline used to treat anaphylactic reactions.

Choroidal detachment

Choroidal detachment has been reported with administration of aqueous suppressant therapy (e.g.

timolol, acetazolamide) after filtration procedures.

Surgical anaesthesia

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

Concomitant therapy

The effect on intra-ocular pressure or the known effects of systemic beta-blockade may be potentiatedwhen timolol is given to the patients already receiving a systemic beta-blocking agent. The response ofthese patients should be closely observed. The use of two topical beta-adrenergic blocking agents ortwo local carbonic anhydrase inhibitors is not recommended (see section 4.5).

There is potential for an additive effect on the known systemic effects of carbonic anhydrase inhibitionin patients receiving an oral carbonic anhydrase inhibitor and AZARGA. The concomitantadministration of AZARGA and oral carbonic anhydrase inhibitors has not been studied and is notrecommended (see section 4.5).

There is limited experience with AZARGA in the treatment of patients with pseudoexfoliativeglaucoma or pigmentary glaucoma. Caution should be utilised in treating these patients and closemonitoring of IOP is recommended.

AZARGA has not been studied in patients with narrow-angle glaucoma and its use is notrecommended in these patients.

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

The possible role of brinzolamide on corneal endothelial function has not been investigated in patientswith compromised corneas (particularly in patients with low endothelial cell count). Specifically,patients wearing contact lenses have not been studied and careful monitoring of these patients whenusing brinzolamide is recommended, since carbonic anhydrase inhibitors may affect corneal hydration.

This may lead to a corneal decompensation and oedema and wearing contact lenses might increase therisk for the cornea. Careful monitoring of patients with compromised corneas, such as patients withdiabetes mellitus or corneal dystrophies, is recommended.

AZARGA may be used while wearing contact lenses with careful monitoring (see below under‘Benzalkonium chloride’).

AZARGA contains benzalkonium chloride which may cause eye irritation and is known to discoloursoft contact lenses. Contact with soft contact lenses should be avoided. Patients must be instructed toremove contact lenses prior to the application of AZARGA and wait 15 minutes after instillation of thedose before reinsertion.

Benzalkonium chloride has also been reported to cause punctate keratopathy and/or toxic ulcerativekeratopathy. Close monitoring is required with frequent or prolonged use.

AZARGA should be used with caution in patients with severe hepatic impairment.

No specific drug interaction studies have been performed with AZARGA.

AZARGA contains brinzolamide, a carbonic anhydrase inhibitor and, although administered topically,is absorbed systemically. Acid-base disturbances have been reported with oral carbonic anhydraseinhibitors. The potential for interactions must be considered in patients receiving AZARGA.

There is a potential for an additive effect on the known systemic effects of carbonic anhydraseinhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide eye drops. Theconcomitant administration of eye drops containing brinzolamide and oral carbonic anhydraseinhibitors is not recommended.

The cytochrome P-450 isozymes responsible for metabolism of brinzolamide include CYP3A4 (main),

CYP2A6, CYP2B6, CYP2C8 and CYP2C9. It is expected that inhibitors of CYP3A4 such asketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin will inhibit the metabolism ofbrinzolamide by CYP3A4. Caution is advised if CYP3A4 inhibitors are given concomitantly.

However, accumulation of brinzolamide is unlikely as renal elimination is the major route.

Brinzolamide is not an inhibitor of cytochrome P-450 isozymes.

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

Beta blockers can decrease the response to adrenaline used to treat anaphylactic reactions. Specialcaution should be exercised in patients with a history of atopy or anaphylaxis (see section 4.4).

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers. Caution is recommended in the concomitant use of this medicinal product with clonidine.

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.

Caution is recommended.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can maskthe signs and symptoms of hypoglycaemia (see section 4.4).

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

There are no adequate data regarding the use of ophthalmic brinzolamide and timolol in pregnantwomen. Studies in animals with brinzolamide have shown reproductive toxicity following systemicadministration, see section 5.3. AZARGA should not be used during pregnancy unless clearlynecessary. To reduce the systemic absorption, see section 4.2.

Epidemiological studies have not revealed malformative effects but show a risk for intra uterinegrowth retardation when beta-blockers are administered by the oral route. In addition, signs andsymptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia)have been observed in the neonate when beta-blockers have been administered until delivery. If

AZARGA is administered until delivery, the neonate should be carefully monitored during the firstdays of life.

It is not known whether ophthalmic brinzolamide is excreted in human breast milk. Studies in animalshave shown that following oral administration brinzolamide is excreted in breast milk, see section 5.3.

Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it isnot likely that sufficient amounts would be present in breast milk to produce clinical symptoms ofbeta-blockade in the infant. To reduce the systemic absorption, see section 4.2.

However, a risk to the suckling child cannot be excluded. A decision must be made whether todiscontinue breast-feeding or to discontinue/abstain from AZARGA therapy taking into account thebenefit of breast-feeding for the child and the benefit of therapy for the woman.

Studies have not been performed to evaluate the effect of topical ocular administration of Azarga onhuman fertility.

Non-clinical data do not show any effects of either brinzolamide or timolol on male or female fertilityfollowing oral dosing. No effects on male or female fertility are anticipated from the use of AZARGA.

AZARGA has minor influence on the ability to drive and use machines.

Temporary blurred vision or other visual disturbances may affect the ability to drive or use machines.

If blurred vision occurs at instillation, the patient must wait until the vision clears before driving orusing machines.

Carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertnessand/or physical coordination (see section 4.4).

In clinical trials, the most common adverse reactions were blurred vision, eye irritation and eye pain,occurring in approximately 2% to 7% of patients.

The following adverse reactions have been reported during clinical studies and post-marketingsurveillance with AZARGA and the individual components brinzolamide and timolol. They areclassified 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), or not known(cannot be estimated from the available data). Within each frequency grouping, adverse reactions arepresented in order of decreasing seriousness.

System Organ MedDRA Preferred Term (v. 18.0)

Classification

Infections and infestations Not known: nasopharyngitis3, pharyngitis3, sinusitis3, rhinitis3

Blood and lymphatic Uncommon: white blood cell count decreased1system disorders Not known: decreased red blood cell count3, increased bloodchloride3

Immune system disorders Not known: anaphylaxis2, anaphylactic shock1, systemic allergicreactions including angioedema, 2 localised and generalised rash2,hypersensitivity1, urticaria2, pruritus2

Metabolism and nutrition Not known: hypoglycaemia2disorders

Psychiatric disorders Rare: insomnia1

Not known: hallucinations2, depression1, memory loss2, apathy3,depressed mood3, decreased libido3, nightmare2,3, nervousness3

Nervous system disorders Common: dysgeusia1

Not known: cerebral ischaemia2, cerebrovascular accident2,syncope2, increases in the signs and symptoms of myastheniagravis2, somnolence3, motor dysfunction3, amnesia3, memoryimpairment3, paraesthesia2,3, tremor3, hypoaesthesia3, ageusia3,dizziness1, headache1

Eye disorders Common: punctate keratitis1, blurred vision1, eye pain1, eyeirritation1

Uncommon: keratitis1,2,3, dry eye1, vital dye staining corneapresent1, eye discharge1, eye pruritus1, foreign body sensation ineyes1, ocular hyperaemia1, conjunctival hyperaemia1

Rare: corneal erosion1, anterior chamber flare1, photophobia1,lacrimation increased1, scleral hyperaemia1, erythema of eyelid1,eyelid margin crusting1

Not known: increased optic nerve cup/disc ratio3, choroidaldetachment following filtration surgery2 (see section 4.4 Specialwarnings and precautions for use), keratopathy3, corneal epitheliumdefect3, corneal epithelium disorder3, increased intraocularpressure3, eye deposit3, corneal staining3, corneal oedema3,decreased corneal sensitivity2, conjunctivitis3, meibomianitis3,diplopia2, 3, glare3, photopsia3, reduced visual acuity3, visualimpairment1, pterygium3, ocular discomfort3, keratoconjunctivitissicca3, hypoaesthesia of the eye3, scleral pigmentation3,subconjunctival cyst3, visual disturbance3, eye swelling3, eyeallergy3, madarosis3, eyelid disorder3, eyelid oedema1, ptosis2

Ear and labyrinth disorders Not known: vertigo3, tinnitus3

Cardiac disorders Common: heart rate decreased1

Not known: cardiac arrest2, cardiac failure2, congestive heartfailure2, atrioventricular block2, cardio-respiratory distress3, anginapectoris3, bradycardia2,3, irregular heart rate3, arrhythmia2,3,palpitations2,3, tachycardia3, increased heart rate3, chest pain2,oedema2

Vascular disorders Uncommon: decreased blood pressure1

Not known: hypotension2, hypertension3, blood pressure increased1,

Raynaud’s phenomenon2, cold hands and feet2

Respiratory, thoracic and Uncommon: cough1mediastinal disorders Rare: oropharyngeal pain1, rhinorrhoea1

Not known: bronchospasm2 (predominantly in patients with pre-existing bronchospastic disease), dyspnoea1, asthma3, epistaxis1,bronchial hyperactivity3, throat irritation3, nasal congestion3, upperrespiratory tract congestion3, postnasal drip3, sneezing3, nasaldryness3

Gastrointestinal disorders Not known: vomiting2,3, abdominal pain upper1, abdominal pain2,diarrhoea1, dry mouth1, nausea1, oesophagitis3, dyspepsia2,3,abdominal discomfort3, stomach discomfort3, frequent bowelmovements3, gastrointestinal disorder3, oral hypoaesthesia3, oralparaesthesia3, flatulence3

Hepatobiliary disorders Not known: abnormal liver function test3

Skin and subcutaneous Not known: Stevens-Johnson syndrome (SJS)/toxic epidermaltissue disorders necrolysis (TEN) (see section 4.4), urticaria3, maculo-papular rash3,generalised pruritus3, skin tightness3, dermatitis3, alopecia1,psoriasiform rash or exacerbation of psoriasis2, rash1, erythema1

Musculoskeletal and Not known: myalgia1, muscle spasms3, arthralgia3, back pain3, painconnective tissue disorders in extremity3

Renal and urinary disorders Uncommon: blood urine present1

Not known: renal pain3, pollakiuria3

Reproductive system and Not known: erectile dysfunction3, sexual dysfunction2, decreasedbreast disorders libido2

General disorders and Uncommon: malaise1,3administration site Not known: chest pain1, pain3, fatigue1, asthenia2,3, chestconditions discomfort3, feeling jittery3, irritability3, peripheral oedema3,medication residue3

Investigations Uncommon: blood potassium increase1, blood lactatedehydrogenase increased11 adverse reactions observed for Azarga2 additional adverse reactions observed with timolol monotherapy3 additional adverse reactions observed with brinzolamide monotherapy

Dysgeusia (bitter or unusual taste in the mouth following instillation) was a frequently reportedsystemic adverse reaction associated with the use of AZARGA during clinical trials. It is likely to becaused by passage of the eye drops in the nasopharynx via the nasolacrimal canal and is attributable tobrinzolamide. Nasolacrimal occlusion or gently closing the eyelid after instillation may help reducethe occurrence of this effect (see section 4.2).

AZARGA contains brinzolamide which is a sulphonamide inhibitor of carbonic anhydrase withsystemic absorption. Gastrointestinal, nervous system, haematological, renal and metabolic effects aregenerally associated with systemic carbonic anhydrase inhibitors. The same type of adverse reactionsattributable to oral carbonic anhydrase inhibitors may occur with topical administration.

Timolol is absorbed into the systemic circulation. This may cause similar adverse reactions as seenwith systemic beta-blocking medicinal products. Listed adverse reactions include reactions seen withinthe class of ophthalmic beta-blockers. Additional adverse reactions associated with the use of theindividual components that may potentially occur with AZARGA are included in the table above. Theincidence of systemic adverse reactions after topical ophthalmic administration is lower than forsystemic administration. To reduce the systemic absorption, see section 4.2.

AZARGA is not recommended for use in children and adolescents below 18 years due to a lack ofdata on safety and efficacy.

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.

In case of accidental ingestion, symptoms of overdose from beta blockade may include bradycardia,hypotension, cardiac failure and bronchospasm.

If overdose with AZARGA eye drops occurs, treatment should be symptomatic and supportive. Due tobrinzolamide, electrolyte imbalance, development of an acidotic state, and possibly central nervoussystem effects may occur. Serum electrolyte levels (particularly potassium) and blood pH levelsshould be monitored. Studies have shown that timolol does not dialyse readily.

Pharmacotherapeutic group: Ophthalmologicals, Antiglaucoma preparation and miotics, ATC code:

S01ED51

AZARGA contains two active substances: brinzolamide and timolol maleate. These two componentsdecrease elevated IOP primarily by reducing aqueous humour secretion, but do so by differentmechanisms of action. The combined effect of these two active substances results in additional IOPreduction compared to either compound alone.

Brinzolamide is a potent inhibitor of human carbonic anhydrase II (CA-II), the predominant iso-enzyme in the eye. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreasesaqueous humour secretion, presumably by slowing the formation of bicarbonate ions with subsequentreduction in sodium and fluid transport.

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.

Clinical effects

In a twelve-month, controlled clinical trial in patients with open-angle glaucoma or ocularhypertension who, in the investigator’s opinion could benefit from a combination therapy, and whohad baseline mean IOP of 25 to 27 mmHg, the mean IOP-lowering effect of AZARGA dosed twicedaily was 7 to 9 mmHg. The non-inferiority of AZARGA as compared to dorzolamide20 mg/ml + timolol 5 mg/ml in the mean IOP reduction was demonstrated across all time-points at allvisits.

In a six-month, controlled clinical study in patients with open-angle glaucoma or ocular hypertensionand baseline mean IOP of 25 to 27 mmHg, the mean IOP-lowering effect of AZARGA dosed twicedaily was 8 to 9 mmHg, and was up to 3 mmHg greater than that of brinzolamide 10 mg/ml dosedtwice daily and up to 2 mmHg greater than that of timolol 5 mg/ml dosed twice daily. A statisticallysuperior reduction in mean IOP was observed compared to both brinzolamide and timolol at all time-points and visits throughout the study.

In three controlled clinical trials, the ocular discomfort upon instillation of AZARGA was significantlylower than that of dorzolamide 20 mg/ml + timolol 5 mg/ml.

Following topical ocular administration, brinzolamide and timolol are absorbed through the corneaand into the systemic circulation. In a pharmacokinetic study, healthy subjects received oralbrinzolamide (1 mg) twice daily for 2 weeks to shorten the time to reach steady-state prior to starting

AZARGA administration. Following twice daily dosing of AZARGA for 13 weeks, red blood cell(RBC) concentrations of brinzolamide averaged 18.8  3.29 µM, 18.1  2.68 µM and 18.4  3.01 µMat weeks 4, 10 and 15, respectively, indicating that steady-state RBC concentrations of brinzolamidewere maintained

At steady state, following administration of AZARGA, the mean plasma Cmax and AUC0-12h of timololwere 27% and 28% lower (Cmax: 0.824 ± 0.453 ng/ml; AUC0-12h: 4.71 ± 4.29 ng·h/ml), respectively, incomparison to the administration of timolol 5 mg/ml (Cmax: 1.13 ± 0.494 ng/ml;

AUC0-12h: 6.58 ± 3.18 ng·h/ml). The lower systemic exposure to timolol following AZARGAadministration is not clinically relevant. Following administration of AZARGA, mean Cmax of timololwas reached at 0.79 ± 0.45 hours.

Plasma protein binding of brinzolamide is moderate (about 60%). Brinzolamide is sequestered in

RBCs due to its high affinity binding to CA-II and to a lesser extent to CA-I. Its active N-desethylmetabolite also accumulates in RBCs where it binds primarily to CA-I. The affinity of brinzolamideand metabolite to RBC and tissue CA results in low plasma concentrations.

Ocular tissue distribution data in rabbits showed that timolol can be measured in aqueous humour upto 48 hours after administration of AZARGA. At steady-state, timolol is detected in human plasma forup to 12 hours after administration of AZARGA.

The metabolic pathways for the metabolism of brinzolamide involve N-dealkylation, O-dealkylationand oxidation of its N-propyl side chain. N-desethyl brinzolamide is a major metabolite ofbrinzolamide formed in humans, which also binds to CA-I in the presence of brinzolamide andaccumulates in RBCs. In vitro studies show that the metabolism of brinzolamide mainly involves

CYP3A4 as well as at least four other isozymes (CYP2A6, CYP2B6, CYP2C8 and CYP2C9).

Timolol is metabolised by two pathways. One route yields an ethanolamine side chain on thethiadiazole ring and the other giving an ethanolic side chain on the morpholine nitrogen and a secondsimilar side chain with a carbonyl group adjacent to the nitrogen. Timolol metabolism is mediatedprimarily by CYP2D6.

Brinzolamide is eliminated primarily by renal excretion (approximately 60%). About 20% of the dosehas been accounted for in urine as metabolite. Brinzolamide and N-desethyl-brinzolamide are thepredominant components found in the urine along with trace levels (<1%) of the N-desmethoxypropyland O-desmethyl metabolites.

Timolol and its metabolites are primarily excreted by the kidneys. Approximately 20% of a timololdose is excreted in the urine unchanged and the remainder excreted in urine as metabolites. Theplasma t1/2 of timolol is 4.8 hours after administration of AZARGA.

Non-clinical data reveal no special hazard for humans with brinzolamide based on single-dosetoxicity, repeated dose toxicity, genotoxicity, carcinogenic potential, and topical ocular irritationstudies.

Developmental toxicity studies in rabbits with oral doses of brinzolamide of up to 6 mg/kg/day(214 times the recommended daily clinical dose of 28 µg/kg/day) revealed no effect on foetaldevelopment despite significant maternal toxicity. Similar studies in rats resulted in slightly reducedossification of skull and sternebrae of foetuses of dams receiving brinzolamide at dosesof 18 mg/kg/day (642 times the recommended daily clinical dose), but not 6 mg/kg/day. Thesefindings occurred at doses that caused metabolic acidosis with decreased body weight gain in damsand decreased foetal weights. Dose-related decreases in foetal weights were observed in pups of damsreceiving brinzolamide orally ranging from a slight decrease (about 5-6%) at 2 mg/kg/day tonearly 14% at 18 mg/kg/day. During lactation, the no adverse effect level in the offspring was5 mg/kg/day.

Timolol

Non-clinical data reveal no special hazard for humans with timolol based on single-dose toxicity,repeated dose toxicity, genotoxicity, carcinogenic potential, and topical ocular irritation studies.

Reproduction toxicity studies with timolol showed delayed foetal ossification in rats with no adverseeffects on postnatal development (at 50 mg/kg/day or 3 500 times the daily clinical dose of14 g/kg/day) and increased foetal resorptions in rabbits (at 90 mg/kg/day or 6 400 times the dailyclinical dose).

Mannitol (E421)

Carbopol 974P

Tyloxapol

Disodium edetate

Sodium chloride

Hydrochloric acid and/or sodium hydroxide (for pH adjustment)

Purified water

Not applicable.

2 years4 weeks after first opening.

This medicinal product does not require any special storage conditions.

5 ml round opaque low density polyethylene bottles with a dispensing plug and white polypropylenescrew cap containing 5 ml suspension.

Cartons containing 1 or 3 bottles. Not all pack sizes may be marketed.

No special requirements.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/08/482/001-002

Date of first Authorisation: 25 November 2008

Date of latest renewal: 26 August 2013

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

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