SIMBRINZA 10mg / 2mg / ml ophthalmic drops suspension medication leaflet

SIMBRINZA 10 mg/mL + 2 mg/mL eye drops, suspension

1 mL of suspension contains 10 mg of brinzolamide and 2 mg of brimonidine tartrate equivalent to1.3 mg of brimonidine.

Each mL of suspension contains 0.03 mg of benzalkonium chloride.

For the full list of excipients, see section 6.1.

Eye drops, suspension (eye drops).

White-to-off-white uniform suspension, pH 6.5 (approximately).

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

The recommended dose is one drop of SIMBRINZA in the affected eye(s) two times daily.

If a dose is missed, treatment should be continued with the next dose as planned.

SIMBRINZA has not been studied in patients with hepatic impairment and caution is thereforerecommended in this population (see section 4.4).

SIMBRINZA has not been studied in patients with severe renal impairment (CrCl <30 mL/min) or inpatients with hyperchloraemic acidosis. Since the brinzolamide component of SIMBRINZA and itsmetabolite are excreted predominantly by the kidney, SIMBRINZA is contraindicated in such patients(see section 4.3).

The safety and efficacy of SIMBRINZA in children and adolescents aged 2 to 17 years have not beenestablished. No data are available.

SIMBRINZA is contraindicated in neonates and infants aged less than 2 years in the decrease ofelevated intraocular pressure (IOP) with open-angle glaucoma or ocular hypertension for whommonotherapy provides insufficient IOP reduction because of safety concerns (see section 4.3).

For ocular use.

Patients should be instructed to shake the bottle well before use.

When nasolacrimal occlusion is used and 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).

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

SIMBRINZA may be used concomitantly with other topical ophthalmic medicinal products to lowerintraocular pressure. If more than one topical ophthalmic medicinal product is being used, themedicinal products must be administered at least 5 minutes apart.

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Hypersensitivity to sulphonamides (see section 4.4).

Patients receiving monoamine oxidase (MAO) inhibitor therapy (see section 4.5).

Patients on antidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants andmianserin) (see section 4.5).

Patients with severe renal impairment (see section 4.4).

Patients with hyperchloraemic acidosis.

Neonates and infants under the age of 2 years (see section 4.4).

The medicinal product should not be injected. Patients should be instructed not to swallow

SIMBRINZA.

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

The possible effect of brinzolamide on corneal endothelial function has not been investigated inpatients with compromised corneas (particularly in patients with low endothelial cell count).

Specifically, patients wearing contact lenses have not been studied and careful monitoring of thesepatients when using brinzolamide is recommended, since carbonic anhydrase inhibitors may affectcorneal hydration and wearing contact lenses might increase the risk for the cornea (for furtherinstructions on wearing contact lenses, see below under “Benzalkonium chloride”). Carefulmonitoring of patients with compromised corneas, such as patients with diabetes mellitus or cornealdystrophies, is recommended.

Brimonidine tartrate may cause ocular allergic reactions. If allergic reactions are observed, treatmentshould be discontinued. Delayed ocular hypersensitivity reactions have been reported withbrimonidine tartrate, with some reported to be associated with an increase in IOP.

The potential effects following cessation of treatment with SIMBRINZA have not been studied. Whilethe duration of IOP-lowering effect for SIMBRINZA has not been studied, the IOP-lowering effect ofbrinzolamide is expected to last for 5-7 days. The IOP-lowering effect of brimonidine may be longer.

SIMBRINZA contains brinzolamide, a sulphonamide inhibitor of carbonic anhydrase and, althoughadministered topically, is absorbed systemically. The same types of adverse reactions that areattributable to sulphonamides may occur with topical administration. If signs of serious reactions orhypersensitivity occur, the use of this medicinal product should be discontinued.

Following administration of SIMBRINZA, small decreases in blood pressure were observed in somepatients. Caution is advised when using medicinal products such as antihypertensives and/or cardiacglycosides concomitantly with SIMBRINZA or in patients with severe or unstable and uncontrolledcardiovascular disease (see section 4.5).

SIMBRINZA should be used with caution in patients with depression, cerebral or coronaryinsufficiency, Raynaud's phenomenon, orthostatic hypotension or thromboangiitis obliterans.

Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. SIMBRINZAcontains brinzolamide, an inhibitor of carbonic anhydrase, and although administered topically, isabsorbed systemically. The same types of adverse reactions that are attributable to oral carbonicinhibitors (i.e. acid-base disturbances) may occur with topical administration (see section 4.5).

SIMBRINZA should be used with caution in patients with risk of renal impairment because of thepossible risk of metabolic acidosis. SIMBRINZA is contraindicated in patients with severe renalimpairment (see section 4.3).

SIMBRINZA has not been studied in patients with hepatic impairment; caution should be used intreating such patients (see section 4.2).

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertnessand/or physical coordination in elderly patients. SIMBRINZA is absorbed systemically and this maytherefore occur with topical administration (see section 4.7).

The safety and efficacy of SIMBRINZA in children and adolescents aged 2 to 17 years have not beenestablished. Symptoms of brimonidine overdose (including loss of consciousness, hypotension,hypotonia, bradycardia, hypothermia, cyanosis and apnoea) have been reported in neonates and infantsreceiving brimonidine eye drops as part of medical treatment of congenital glaucoma. SIMBRINZA istherefore contraindicated in children below 2 years of age (see section 4.3).

Treatment of children 2 years and above (especially those in the 2-7 age range and/or weighing<20 kg) is not recommended because of the potential for central nervous system-related side effects(see section 4.9).

SIMBRINZA contains benzalkonium chloride which may cause eye irritation and is known todiscolour soft contact lenses. Contact with soft contact lenses should be avoided. Patients must beinstructed to remove contact lens prior to application of SIMBRINZA and wait at least 15 minutesbefore reinsertion.

Benzalkonium chloride has been reported to cause eye irritation and symptoms of dry eyes and mayaffect the tear film and corneal surface. It should be used with caution in dry eye patients and inpatients whose cornea may be compromised. Patients should be monitored in case of prolonged use.

No specific drug interaction studies have been performed with SIMBRINZA.

SIMBRINZA is contraindicated in patients receiving monoamine oxidase inhibitors and in patients onantidepressants which affect noradrenergic transmission (e.g. tricyclic antidepressants and mianserin),(see section 4.3). Tricyclic antidepressants may blunt the ocular hypotensive response of

SIMBRINZA.

Caution is advised due to the possibility of an additive or potentiating effect with CNS depressants(e.g. alcohol, barbiturates, opiates, sedatives or anaesthetics).

No data on the level of circulating catecholamines after SIMBRINZA administration are available.

However, caution is advised in patients taking medicinal products which can affect the metabolismand uptake of circulating amines (e.g. chlorpromazine, methylphenidate, reserpine, serotonin-norepinephrine reuptake inhibitors).

Alpha adrenergic agonists (e.g. brimonidine tartrate), as a class, may reduce pulse and blood pressure.

Following administration of SIMBRINZA, small decreases in blood pressure were observed in somepatients. Caution is advised when using medicinal products such as antihypertensives and/or cardiacglycosides concomitantly with SIMBRINZA.

Caution is advised when initiating (or changing the dose of) concomitant systemic medicinal products(irrespective of pharmaceutical form) which may interact with α-adrenergic agonists or interfere withtheir activity, i.e. agonists or antagonists of the adrenergic receptor (e.g. isoprenaline, prazosin).

Brinzolamide is a carbonic anhydrase inhibitor and, although administered topically, is absorbedsystemically. Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. Thepotential for interactions must be considered in patients receiving SIMBRINZA.

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 topical brinzolamide. Theconcomitant administration of SIMBRINZA and oral carbonic anhydrase inhibitors is notrecommended.

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 are no or limited amount of data from the use of SIMBRINZA in pregnant women.

Brinzolamide was not teratogenic in rats and rabbits, following systemic administration (oral gavage).

Animal studies with oral brimonidine do not indicate direct harmful effects with respect toreproductive toxicity. In animal studies, brimonidine crossed the placenta and entered into the foetalcirculation to a limited extent (see section 5.3). SIMBRINZA is not recommended during pregnancyand in women of childbearing potential not using contraception.

It is unknown whether topical SIMBRINZA is excreted in human milk. Availablepharmacodynamic/toxicological data in animals have shown that following oral administration,minimal levels of brinzolamide are excreted in breast milk. Brimonidine administered orally isexcreted in breast milk. SIMBRINZA should not be used by women who are breast-feeding.

Non-clinical data do not show any effects of brinzolamide or brimonidine on fertility. There are nodata on the effect of topical ocular administration of SIMBRINZA on human fertility.

SIMBRINZA has a moderate influence on the ability to drive and use machines.

SIMBRINZA may cause dizziness, fatigue and/or drowsiness, which may impair the ability to drive oruse 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.

Oral carbonic anhydrase inhibitors may impair the ability of elderly patients to perform tasks requiringmental alertness and/or physical coordination (see section 4.4).

In clinical trials involving SIMBRINZA dosed twice daily the most common adverse reactions wereocular hyperaemia and ocular allergic type reactions occurring in approximately 6-7% of patients, anddysgeusia (bitter or unusual taste in the mouth following instillation) occurring in approximately 3%of patients.

The following adverse reactions have been reported during clinical studies with SIMBRINZA twice-daily dosing and during clinical studies and post-marketing surveillance with the individualcomponents brinzolamide and brimonidine. They are classified according to the subsequentconvention: 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 order of decreasingseriousness.

System Organ Adverse reactions

Classification

Infections and Uncommon: nasopharyngitis2, pharyngitis2, sinusitis2infestations Not known: rhinitis2

Blood and lymphatic Uncommon: red blood cells decreased2, blood chloride increased2system disorders

Immune system disorders Uncommon: hypersensitivity3

Psychiatric disorders Uncommon: apathy2, depression2,3, depressed mood2, insomnia1, libidodecreased2, nightmares2, nervousness2

Nervous system disorders Common: somnolence1, dizziness3, dysgeusia1

Uncommon: headache1, motor dysfunction2, amnesia2, memoryimpairment2, paraesthesia2

Very rare: syncope3

Not known: tremor2, hypoaesthesia2, ageusia2

Eye disorders Common: eye allergy1, keratitis1, eye pain1, ocular discomfort1, blurredvision1, abnormal vision3, ocular hyperaemia1, conjunctival blanching3

Uncommon: corneal erosion1, corneal oedema2, blepharitis1, cornealdeposits (keratic precipitates)1, conjunctival disorder (papillae)1,photophobia1, photopsia2, eye swelling2, eyelid oedema1, conjunctivaloedema1, dry eye1, eye discharge1, visual acuity reduced2, lacrimationincreased1, pterygium2, erythema of eyelid1, meibomianitis2, diplopia2,glare2, hypoaesthesia eye2, scleral pigmentation2, subconjunctivalcyst2,abnormal sensation in eye1, asthenopia1

Very rare: uveitis3, miosis3

Not known: visual disturbances2, madarosis2

Ear and labyrinth Uncommon: vertigo1, tinnitus2disorders

Cardiac disorders Uncommon: cardio-respiratory distress2, angina pectoris2, arrhythmia3,palpitations2,3, heart rate irregular2, bradycardia2,3, tachycardia3

Vascular disorders Uncommon: hypotension1

Very rare: hypertension3

Respiratory, thoracic and Uncommon: dyspnoea2, bronchial hyperactivity2, pharyngolaryngealmediastinal disorders pain2, dry throat1, cough2, epistaxis2, upper respiratory tract congestion2,nasal congestion1, rhinorrhoea2, throat irritation2, nasal dryness1,postnasal drip1, sneezing2

Not known: asthma2

Gastrointestinal disorders Common: dry mouth1

Uncommon: dyspepsia1, oesophagitis2, abdominal discomfort1,diarrhoea2, vomiting2, nausea2, frequent bowel movements2, flatulence2,hypoaesthesia oral2, paraesthesia oral1

Hepatobiliary disorders Not known: liver function test abnormal2

Skin and subcutaneous Uncommon: dermatitis contact1, urticaria2, rash2, rash maculopapular2,tissue disorders pruritus generalised2, alopecia2, skin tightness2

Not known: face oedema3, dermatitis2,3, erythema2,3

Musculoskeletal and Uncommon: back pain2, muscle spasms2, myalgia2connective tissue Not known: arthralgia2, pain in extremity2disorders

Renal and urinary Uncommon: renal pain2disorders Not known: pollakiuria2

Reproductive system and Uncommon: erectile dysfunction2breast disorders

General disorders and Uncommon: pain2, chest discomfort2, feeling abnormal2, feeling jittery2,administration site irritability2, medication residue1conditions Not known: chest pain2, peripheral oedema2,31 adverse reaction observed with SIMBRINZA2 additional adverse reaction observed with brinzolamide monotherapy3 additional adverse reaction observed with brimonidine monotherapy

Dysgeusia was the most common systemic adverse reaction associated with the use of SIMBRINZA(3.4%). It is likely to be caused by passage of the eye drops in the nasopharynx via the nasolacrimalcanal and is mainly attributable to the brinzolamide component of SIMBRINZA. Nasolacrimalocclusion or gently closing the eyelid after instillation may help reduce the occurrence of this effect(see section 4.2).

SIMBRINZA 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.

Adverse reactions commonly associated with the brimonidine component of SIMBRINZA include thedevelopment of ocular allergic type reactions, fatigue and/or drowsiness, and dry mouth. The use ofbrimonidine has been associated with minimal decreases in blood pressure. Some patients who dosedwith SIMBRINZA experienced decreases in blood pressure similar to those observed with the use ofbrimonidine as monotherapy.

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.

If overdose with SIMBRINZA occurs treatment should be symptomatic and supportive. The patient’sairway should be maintained.

Due to the brinzolamide component of SIMBRINZA, electrolyte imbalance, development of anacidotic state, and possible nervous system effects may occur. Serum electrolyte levels (particularlypotassium) and blood pH levels must be monitored.

There is very limited information regarding accidental ingestion with the brimonidine component of

SIMBRINZA in adults. The only adverse reaction reported to date was hypotension. It was reportedthat the hypotensive episode was followed by rebound hypertension.

Oral overdoses of other alpha-2-agonists have been reported to cause symptoms such as hypotension,asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnoea, hypotonia,hypothermia, respiratory depression and seizure.

Serious adverse reactions following inadvertent ingestion with the brimonidine component of

SIMBRINZA by paediatric subjects have been reported. The subjects experienced symptoms of CNSdepression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia,bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission tointensive care with intubation if indicated. All subjects were reported to have made a full recovery,usually within 6-24 hours.

Pharmacotherapeutic group: Ophthalmologicals, Antiglaucoma preparations and miotics, ATCcode: S01EC54

SIMBRINZA contains two active substances: brinzolamide and brimonidine tartrate. These twocomponents lower intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) and ocularhypertension (OHT) by suppressing the formation of aqueous humour from the ciliary process in theeye. Although both brinzolamide and brimonidine lower IOP by suppressing aqueous humourformation, their mechanisms of action are different.

Brinzolamide acts by inhibiting the enzyme carbonic anhydrase (CA-II) in the ciliary epithelium thatreduces the formation of bicarbonate ions with subsequent reduction in sodium and fluid transportacross the ciliary epithelium, resulting in decreased aqueous humour formation. Brimonidine, analpha-2 adrenergic agonist, inhibits the enzyme adenylate cyclase and suppresses the cAMP-dependentformation of aqueous humour. Additionally, administration of brimonidine results in an increase inuveoscleral outflow.

In a 6-month, controlled, contribution of elements clinical study enrolling 560 patients with open-angle glaucoma (including pseudoexfoliation or pigment dispersion component) and/or ocularhypertension who, in the investigator’s opinion, were insufficiently controlled on monotherapy oralready on multiple IOP-lowering medicinal products, and who had mean baseline diurnal IOP of26 mmHg, the mean diurnal IOP-lowering effect of SIMBRINZA dosed twice daily wasapproximately 8 mmHg. Statistically superior reductions in the mean diurnal IOP were observed with

SIMBRINZA compared to brinzolamide 10 mg/ml or brimonidine 2 mg/ml dosed twice daily at allvisits throughout the study (Figure 1).

a

Figure 1 Mean diurnal (9 AM, +2 hrs, +7 hrs) IOP change from baseline (mmHg) —

Contribution of elements studyaLeast squares means derived from a statistical model that accounts for study site, 9 AM baseline IOP stratum,and correlated IOP measurements within patient.

All treatment differences (SIMBRINZA versus individual components) were statistically significant withp=0.0001 or less.

Mean IOP reductions from baseline at each time point at each visit were greater with SIMBRINZA (6to 9 mmHg) than monotherapy with either brinzolamide (5 to 7 mmHg) or brimonidine (4 to7 mmHg). Mean percent IOP reductions from baseline with SIMBRINZA ranged from 23 to 34%. Thepercentages of patients with an IOP measurement less than 18 mmHg were greater in the

SIMBRINZA group than in the Brinzolamide group at 9 of 12 assessments through Month 6 and weregreater in the SIMBRINZA group than in the Brimonidine group at all 12 assessments through

Month 6. At the +2 h time point (the time corresponding to the morning efficacy peak) for the primaryefficacy visit at Month 3, the percentage of patients with an IOP less than 18 mmHg was 61.7% in the

SIMBRINZA group, 40.1% in the Brinzolamide group, and 40.0% in the Brimonidine group.

In a 6-month, controlled, non-inferiority clinical study enrolling 890 patients with open-angleglaucoma (including pseudoexfoliation or pigment dispersion component) and/or ocular hypertensionwho, in the investigator’s opinion, were insufficiently controlled on monotherapy or already onmultiple IOP-lowering medicinal products, and who had mean baseline diurnal IOP of 26 to27 mmHg, non-inferiority of SIMBRINZA compared to brinzolamide 10 mg/mL + brimonidine2 mg/mL dosed concomitantly was demonstrated at all visits throughout the study with respect tomean diurnal IOP reduction from baseline (Table 1).

Table 1 Comparison of mean diurnal IOP (mmHg) change from baseline - Non-inferioritystudy

Visit SIMBRINZA Brinzolamide + Brimonidine Difference

Meana Meana Meana (95% CI)

Week 2 -8.4 (n=394) -8.4 (n=384) -0.0 (-0.4, 0.3)

Week 6 -8.5 (n=384) -8.4 (n=377) -0.1 (-0.4, 0.2)

Month 3 -8.5 (n=384) -8.3 (n=373) -0.1 (-0.5, 0.2)

Month 6 -8.1 (n=346) -8.2 (n=330) 0.1 (-0.3, 0.4)a Least squares means derived from a statistical model that accounts for study site, 9 AMbaseline IOP stratum, and correlated IOP measurements within patient

Mean IOP reductions from baseline at each time point at each visit with SIMBRINZA or theindividual components administered concomitantly were similar (7 to 10 mmHg). Mean percent IOPreductions from baseline with SIMBRINZA ranged from 25 to 37%.The percentages of patients withan IOP measurement less than 18 mmHg were similar across study visits for the same time pointthrough Month 6 in the SIMBRINZA and Brinzolamide + Brimonidine groups. At the +2 h time point(the time corresponding to the morning efficacy peak) for the primary efficacy visit at Month 3, thepercentage of patients with an IOP less than 18 mmHg was 65.6% in the SIMBRINZA group and63.7% in the Brinzolamide + Brimonidine groups.

Clinical data on the use of SIMBRINZA adjunctive to prostaglandin analogues (PGA) also showedsuperior IOP-lowering efficacy of SIMBRINZA + PGA compared with the PGA alone. In study

CQVJ499A2401, SIMBRINZA + PGA (i.e. travoprost, latanoprost, or bimatoprost) demonstratedsuperior IOP-lowering efficacy from baseline compared to Vehicle + PGA after 6 weeks of treatment,with between-treatment difference in model-adjusted mean change from baseline in diurnal IOPof -3.44 mmHg (95% CI, -4.2, -2.7; p-value <0.001).

Clinical data on the use of SIMBRINZA adjunctive to travoprost-timolol maleate fixed dosecombination eye drops, solution also showed superior IOP-lowering efficacy of SIMBRINZA +travoprost-timolol maleate eye drops compared with the travoprost-timolol maleate alone. In study

CQVJ499A2402, SIMBRINZA + travoprost-timolol maleate eye drops demonstrated superior IOP-lowering efficacy from baseline compared to Vehicle + travoprost-timolol maleate eye drops after6 weeks of treatment, with between-treatment difference in model-adjusted mean change frombaseline in diurnal IOP of -2.15 mmHg (95% CI, -2.8, -1.5; p-value <0.001).

The safety profile of SIMBRINZA in adjunct therapy was similar to that observed with SIMBRINZAmonotherapy.

There are no efficacy and safety data for adjunct therapy beyond 6 weeks.

The European Medicines Agency has waived the obligation to submit the results of studies with

SIMBRINZA in all subsets of the paediatric population in the treatment of glaucoma and ocularhypertension (see section 4.2 for information on paediatric use).

Brinzolamide is absorbed through the cornea following topical ocular administration. The substance isalso absorbed into the systemic circulation, where it binds strongly to carbonic anhydrase in red bloodcells (RBCs). Plasma concentrations are very low. Whole blood elimination half-life is prolonged(>100 days) in humans due to RBC carbonic anhydrase binding.

Brimonidine is rapidly absorbed into the eye following topical administration. In rabbits, maximumocular concentrations were achieved in less than one hour in most cases. Maximum human plasmaconcentrations are <1 ng/mL and achieved within <1 hour. Plasma levels decline with a half-life ofapproximately 2-3 hours. No accumulation occurs during chronic administration.

In a topical ocular clinical study comparing the systemic pharmacokinetics of SIMBRINZAadministered two or three times daily to brinzolamide and brimonidine administered individually usingthe same two posologies, the steady-state whole blood brinzolamide and N-desethylbrinzolamidepharmacokinetics were similar between the combination product and brinzolamide administered alone.

Likewise, the steady-state plasma pharmacokinetics of brimonidine from the combination were similarto those observed for brimonidine administered alone, with the exception of the twice daily

SIMBRINZA treatment group, for which the mean AUC0-12 hours was about 25% lower than that forbrimonidine alone administered twice daily.

Studies in rabbits showed that maximum brinzolamide ocular concentrations following topicaladministration are in the anterior tissues such as cornea, conjunctiva, aqueous humour and iris-ciliarybody. Retention in ocular tissues is prolonged due to binding to carbonic anhydrase. Brinzolamide ismoderately (about 60%) bound to human plasma proteins.

Brimonidine exhibits affinity for pigmented ocular tissues, particularly iris-ciliary body, due to itsknown melanin binding properties. However, clinical and non-clinical safety data show it to be well-tolerated and safe during chronic administration.

Brinzolamide is metabolised by hepatic cytochrome P450 isozymes, specifically CYP3A4, CYP2A6,

CYP2B6, CYP2C8 and CYP2C9. The primary metabolite is N-desethylbrinzolamide, followed by the

N-desmethoxypropyl and O-desmethyl metabolites, as well as an N-propionic acid analogue formedby oxidation of the N-propyl side chain of O-desmethyl brinzolamide. Brinzolamide and N-desethylbrinzolamide do not inhibit cytochrome P450 isozymes at concentrations at least 100-foldabove maximum systemic levels.

Brimonidine is extensively metabolised by hepatic aldehyde oxidase, with formation of 2-oxobrimonidine, 3-oxobrimonidine and 2,3-dioxobrimonidine being the major metabolites. Oxidativecleavage of the imidazoline ring to 5-bromo-6-guanidinoquinoxaline is also observed.

Brinzolamide is primarily eliminated in urine unchanged. In humans, urinary brinzolamide and N-desethylbrinzolamide accounted for about 60 and 6% of the dose, respectively. Data in rats showedsome biliary excretion (about 30%), primarily as metabolites.

Brimonidine is primarily eliminated in the urine as metabolites. In rats and monkeys, urinarymetabolites accounted for 60 to 75% of oral or intravenous doses.

Brinzolamide pharmacokinetics are inherently non-linear due to saturable binding to carbonicanhydrase in whole blood and various tissues. Steady-state exposure does not increase in a dose-proportional manner.

In contrast, brimonidine exhibits linear pharmacokinetics over the clinically therapeutic dose range.

SIMBRINZA is intended for local action within the eye. Assessment of human ocular exposure atefficacious doses is not feasible. The pharmacokinetic/pharmacodynamic relationship in humans for

IOP-lowering has not been established.

Studies to determine the effects of age, race, and renal or hepatic impairment have not been conductedwith SIMBRINZA. A study of brinzolamide in Japanese versus non-Japanese subjects showed similarsystemic pharmacokinetics between the two groups. In a study of brinzolamide in subjects with renalimpairment, a 1.6- to 2.8-fold increase in the systemic exposure to brinzolamide and N-desethylbrinzolamide between normal and moderately renally-impaired subjects was demonstrated.

This increase in steady-state RBC concentrations of substance-related material did not inhibit RBCcarbonic anhydrase activity to levels that are associated with systemic side effects. However, thecombination product is not recommended for patients with severe renal impairment (creatinineclearance <30 mL/minute).

The Cmax, AUC and elimination half-life of brimonidine are similar in elderly (>65 years of age)subjects compared to young adults. The effects of renal and hepatic impairment on the systemicpharmacokinetics of brimonidine have not been evaluated. Given the low systemic exposure tobrimonidine following topical ocular administration, it is expected that changes in plasma exposurewould not be clinically relevant.

The systemic pharmacokinetics of brinzolamide and brimonidine, alone or in combination, inpaediatric patients have not been studied.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.

Effects in non-clinical reproduction and development toxicity studies were observed only at exposuresconsidered sufficiently in excess of the maximum human exposure indicating little relevance toclinical use. In rabbits oral, maternally toxic doses of brinzolamide of up to 6 mg/kg/day (261 timesthe recommended daily clinical dose of 23 µg/kg/day) revealed no effect on foetal development. Inrats doses of 18 mg/kg/day (783 times the recommended daily clinical dose), but not 6 mg/kg/day,resulted in slightly reduced ossification of skull and sternebrae of foetuses. These findings wereassociated with metabolic acidosis with decreased body weight gain in dams and decreased foetalweights. Dose related decreases in foetal weights were observed in pups of dams given 2 to18 mg/kg/day. During lactation, the no adverse effect level in the offspring was 5 mg/kg/day.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproductionand development.

Carbomer 974P

Boric acid

Mannitol

Sodium chloride

Tyloxapol

Hydrochloric acid and/or sodium hydroxide (to adjust pH)

Purified water

Not applicable.

2 years.

4 weeks after first opening.

This medicinal product does not require any special storage conditions.

8 mL round, opaque, low density polyethylene (LDPE) bottles with a LDPE dropper tip and whitepolypropylene screw cap (Drop-Tainer) containing 5 mL suspension.

Carton containing 1 or 3 bottles.

Not all pack sizes may be marketed.

No special requirements for disposal.

Novartis Europharm Limited

Vista Building

Elm Park, Merrion Road

Dublin 4

Ireland

EU/1/14/933/001-002

Date of first authorisation: 18 July 2014

Date of last renewal: 20 February 2019

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

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