Simbrinza 10 mg/mL + 2 mg/mL Eye drops, suspension

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

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.

Method of administration

For ocular use. Patients should be instructed to shake the bottle gently 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 medicines to lower intraocular pressure. If more than one topical ophthalmic medicine is being used, the medicines 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 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).

The medicine 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 u201cBenzalkonium chlorideu201d).
• 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 reactions that are attributable to sulphonamides, may occur with topical administration.

Serious hypersensitivity reactions to sulfonamides have been reported including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. Sensitization may recur when a sulfonamide is re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, the use of this medicine should be discontinued immediately, and physician contacted.

Cardiac disorders

Following administration of SIMBRINZA, small decreases in blood pressure were observed in some patients. Caution is advised when using medicine 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. Patients using IOP-lowering medication should be routinely monitored for IOP.

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/coma, hypotension, hypotonia, bradycardia, hypothermia, cyanosis, apnoea, lethargy, pallor, respiratory depression and somnolence) 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. As the possibility of adverse effects on the corneal permeability, and the danger of disruption of the corneal epithelium with prolonged or repeated usage of benzalkonium chloride preserved ophthalmological preparations cannot be excluded, regular ophthalmological examination is required. Caution should be exercised in the use of benzalkonium chloride preserved topical medication over an extended period in patients with extensive ocular surface disease.

• No specific medicine 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 medicines 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 medicines such as beta-blockers (ophthalmic and systemic), antihypertensives and/or cardiac glycosides e.g., digoxin concomitantly with SIMBRINZA.
• Caution is advised when initiating (or changing the dose of) concomitant systemic medicines (irrespective of pharmaceutical form) which may interact with u03b1-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.

Pregnancy

The safety of SIMBRINZA in pregnancy have not been established. Use of SIMBRINZA is not recommended during pregnancy and in women of childbearing potential not using contraception. 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).

Breastfeeding

SIMBRINZA should not be used by women who are breastfeeding their infants. Animal studies have shown that following oral administration, minimal levels of brinzolamide are excreted in breastmilk, and that brimonidine administered orally is excreted in breastmilk.

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.

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).

a. 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 ( u2265 1/10), common ( u2265 1/100 to <1/10), uncommon ( u2265 1/1 000 to <1/100), rare ( u2265 1/10 000 to <1/1000), 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: nasopharyngitis, pharyngitis, sinusitis

Not known: rhinitis

Blood and lymphatic system disorders

Uncommon: red blood cells decreased, blood chloride increased

Immune system disorders

Uncommon: hypersensitivity

Psychiatric disorders

Uncommon: apathy, depression, depressed mood, insomnia, libido decreased, nightmares, nervousness

Nervous system disorders

Common: somnolence, dizziness, dysgeusia

Uncommon: headache, motor dysfunction, amnesia, memory impairment, paraesthesia

Very rare: syncope

Not known: tremor, hypoaesthesia, ageusia

Eye disorders

Common: eye allergy, keratitis, eye pain, ocular discomfort, blurred vision, abnormal vision, ocular hyperaemia, conjunctival blanching

Uncommon: corneal erosion, corneal oedema, blepharitis, corneal deposits (keratic precipitates), conjunctival disorder (papillae), photophobia, photopsia, eye swelling, eyelid oedema, conjunctival oedema, dry eye, eye discharge, visual acuity reduced, lacrimation increased, pterygium, erythema of eyelid, meibomianitis, diplopia, glare, hypoaesthesia eye, scleral pigmentation, subconjunctival cyst, abnormal sensation in eye, asthenopia

Very rare: uveitis, miosis

Not known: visual disturbances, madarosis

Ear and labyrinth disorders

Uncommon: vertigo, tinnitus

Cardiac disorders

Uncommon: cardio-respiratory distress, angina pectoris, arrhythmia, palpitations, heart rate irregular, bradycardia, tachycardia

Vascular disorders

Uncommon: hypotension

Very rare: hypertension

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea, bronchial hyperactivity, pharyngolaryngeal pain, dry throat, cough, epistaxis, upper respiratory tract congestion, nasal congestion, rhinorrhoea, throat irritation, nasal dryness, postnasal drip, sneezing

Not known: asthma

Gastrointestinal disorders

Common: dry mouth

Uncommon: dyspepsia, oesophagitis, abdominal discomfort, diarrhoea, vomiting, nausea, frequent bowel movements, flatulence, hypoaesthesia oral, paraesthesia oral

Hepatobiliary disorders

Not known: liver function test abnormal

Skin and subcutaneous tissue disorders

Uncommon: dermatitis contact, urticaria, rash, rash maculopapular, pruritus generalised, alopecia, skin tightness

Not known: face oedema, dermatitis, erythema

Stevens-Johnson syndrome (SJS), Toxic epidermal necrolysis (TEN)

Musculoskeletal and connective tissue disorders

Uncommon: back pain, muscle spasms, myalgia

Not known: arthralgia, pain in extremity

Renal and urinary disorders

Uncommon: renal pain

Not known: pollakiuria

Reproductive system and breast disorders

Uncommon: erectile dysfunction

General disorders and administration site conditions

Uncommon: pain, chest discomfort, feeling abnormal, feeling jittery, irritability, medication residue

Not known: chest pain, peripheral oedema

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.

If overdose with SIMBRINZA occurs treatment should be symptomatic and supportive. The patientu2019s 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.