4.1. Therapeutic indications

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

4.2. Posology and method of administration

Posology

Use in adults, including the elderly

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

Missed dose

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

Hepatic and/or renal impairment

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

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

Paediatric population

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

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

Method of administration

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 is reduced. This may result in a decrease in systemic side effects and an increase in local activity (see section 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 to keep the bottle tightly closed when not in use.

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

4.3. Contraindications

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 and mianserin) (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).

4.4. Special warnings and precautions for use

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

Ocular effects

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

The possible effect of brinzolamide on corneal endothelial function has not been investigated in patients with 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 when using brinzolamide is recommended, since carbonic anhydrase inhibitors may affect corneal hydration and wearing contact lenses might increase the risk for the cornea (for further instructions on wearing contact lenses, see below under “Benzalkonium chloride”). Careful monitoring of patients with compromised corneas, such as patients with diabetes mellitus or corneal dystrophies, is recommended.

Brimonidine tartrate may cause ocular allergic reactions. If allergic reactions are observed, treatment should be discontinued. Delayed ocular hypersensitivity reactions have been reported with brimonidine 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. While the duration of IOP-lowering effect for SIMBRINZA has not been studied, the IOP-lowering effect of brinzolamide is expected to last for 5-7 days. The IOP-lowering effect of brimonidine may be longer.

Systemic effects

SIMBRINZA contains brinzolamide, a sulphonamide inhibitor of carbonic anhydrase and, although administered topically, is absorbed systemically. The same types of adverse drug reactions that are attributable to sulphonamides may occur with topical administration, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs of serious reactions or hypersensitivity occur, SIMBRINZA should be withdrawn immediately .

Cardiac disorders

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

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

Acid/base disturbances

Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. SIMBRINZA contains brinzolamide, an inhibitor of carbonic anhydrase, and although administered topically, is absorbed systemically. The same types of adverse reactions that are attributable to oral carbonic inhibitors (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 the possible risk of metabolic acidosis. SIMBRINZA is contraindicated in patients with severe renal impairment (see section 4.3).

Hepatic impairment

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

Mental alertness

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

Paediatric population

The safety and efficacy of SIMBRINZA in children and adolescents aged 2 to 17 years have not been established. Symptoms of brimonidine overdose (including loss of consciousness, hypotension, hypotonia, bradycardia, hypothermia, cyanosis and apnoea) have been reported in neonates and infants receiving brimonidine eye drops as part of medical treatment of congenital glaucoma. SIMBRINZA is therefore 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).

Benzalkonium chloride

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

Benzalkonium chloride has been reported to cause eye irritation and symptoms of dry eyes and may affect the tear film and corneal surface. It should be used with caution in dry eye patients and in patients whose 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 specific drug interaction studies have been performed with SIMBRINZA.

SIMBRINZA is contraindicated in patients receiving monoamine oxidase inhibitors and in patients on antidepressants 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 metabolism and 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 some patients. Caution is advised when using medicinal products such as antihypertensives and/or cardiac glycosides 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 with their 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 absorbed systemically. Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. The potential for interactions must be considered in patients receiving SIMBRINZA.

There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and topical brinzolamide. The concomitant administration of SIMBRINZA and oral carbonic anhydrase inhibitors 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 as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin will inhibit the metabolism of brinzolamide 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

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 to reproductive toxicity. In animal studies, brimonidine crossed the placenta and entered into the foetal circulation to a limited extent (see section 5.3). SIMBRINZA is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

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

Fertility

Non-clinical data do not show any effects of brinzolamide or brimonidine on fertility. There are no data on the effect of topical ocular administration of SIMBRINZA on human fertility.

4.7. Effects on ability to drive and use machines

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 or 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 or using machines.

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

4.8. Undesirable effects

Summary of the safety profile

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

Tabulated summary of adverse reactions

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 individual components brinzolamide and brimonidine. They are classified according to the subsequent 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 are presented in order of decreasing seriousness.

System Organ Classification

Adverse reactions

Infections and infestations

Uncommon: nasopharyngitis2, pharyngitis2, sinusitis2

Not known: rhinitis2

Blood and lymphatic system disorders

Uncommon: red blood cells decreased2, blood chloride increased2

Immune system disorders

Uncommon: hypersensitivity3

Psychiatric disorders

Uncommon: apathy2, depression2,3, depressed mood2, insomnia1, libido decreased2, nightmares2, nervousness2

Nervous system disorders

Common: somnolence1, dizziness3, dysgeusia1

Uncommon: headache1, motor dysfunction2, amnesia2, memory impairment2, paraesthesia2

Very rare: syncope3

Not known: tremor2, hypoaesthesia2, ageusia2

Eye disorders

Common: eye allergy1, keratitis1, eye pain1, ocular discomfort1, blurred vision1, abnormal vision3, ocular hyperaemia1, conjunctival blanching3

Uncommon: corneal erosion1, corneal oedema2, blepharitis1, corneal deposits (keratic precipitates)1, conjunctival disorder (papillae)1, photophobia1, photopsia2, eye swelling2, eyelid oedema1, conjunctival oedema1, dry eye1, eye discharge1, visual acuity reduced2, lacrimation increased1, pterygium2, erythema of eyelid1, meibomianitis2, diplopia2, glare2, hypoaesthesia eye2, scleral pigmentation2, subconjunctival cyst2,abnormal sensation in eye1, asthenopia1

Very rare: uveitis3, miosis3

Not known: visual disturbances2, madarosis2

Ear and labyrinth disorders

Uncommon: vertigo1, tinnitus2

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 mediastinal disorders

Uncommon: dyspnoea2, bronchial hyperactivity2, pharyngolaryngeal 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 tissue disorders

Uncommon: dermatitis contact1, urticaria2, rash2, rash maculopapular2, pruritus generalised2, alopecia2, skin tightness2

Not known: Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) (see section 4.4), face oedema3, dermatitis2,3, erythema2,3

Musculoskeletal and connective tissue disorders

Uncommon: back pain2, muscle spasms2, myalgia2

Not known: arthralgia2, pain in extremity2

Renal and urinary disorders

Uncommon: renal pain2

Not known: pollakiuria2

Reproductive system and breast disorders

Uncommon: erectile dysfunction2

General disorders and administration site conditions

Uncommon: pain2, chest discomfort2, feeling abnormal2, feeling jittery2, irritability2, medication residue1

Not known: chest pain2, peripheral oedema2,3

1 adverse reaction observed with SIMBRINZA

2 additional adverse reaction observed with brinzolamide monotherapy

3 additional adverse reaction observed with brimonidine monotherapy

Description of selected adverse reactions

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 nasolacrimal canal and is mainly attributable to the brinzolamide component of SIMBRINZA. Nasolacrimal occlusion 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 with systemic absorption. Gastrointestinal, nervous system, haematological, renal and metabolic effects are generally associated with systemic carbonic anhydrase inhibitors. The same type of adverse reactions attributable to oral carbonic anhydrase inhibitors may occur with topical administration.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system:

United Kingdom

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store

4.9. Overdose

If overdose with SIMBRINZA occurs treatment should be symptomatic and supportive. The patient's airway should be maintained.

Due to the brinzolamide component of SIMBRINZA, electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur. Serum electrolyte levels (particularly potassium) 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 reported that 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.

Paediatric population

Serious adverse reactions following inadvertent ingestion with the brimonidine component of SIMBRINZA by paediatric subjects have been reported. The subjects experienced symptoms of CNS depression, typically temporary coma or low level of consciousness, lethargy, somnolence, hypotonia, bradycardia, hypothermia, pallor, respiratory depression and apnoea, and required admission to intensive care with intubation if indicated. All subjects were reported to have made a full recovery, usually within 6-24 hours.