4.1. Therapeutic indications

Decrease of 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 dose is one drop of Brinzolamide/Timolol eye drops in the conjunctival sac of the affected eye(s) twice daily.

When using nasolacrimal occlusion or closing the eyelids, the systemic absorption is reduced. This may 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 not exceed one drop in the affected eye (s) twice daily.

When substituting another ophthalmic antiglaucoma medicinal product with Brinzolamide/Timolol eye drops, the other medicinal product should be discontinued and Brinzolamide/Timolol eye drops should be started the following day.

Special populations

Paediatric population

The safety and efficacy of Brinzolamide/Timolol eye drops in children and adolescents aged 0 to 18 years have not yet been established. No data are available.

Hepatic and renal impairment

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

Brinzolamide/Timolol eye drops has not been studied in patients with severe renal impairment (creatinine clearance <30 ml/min) or in patients with hyperchloraemic acidosis (see section 4.3). Since brinzolamide and its main metabolite are excreted predominantly by the kidney, Brinzolamide/Timolol eye drops is therefore contraindicated in patients with severe renal impairment (see section 4.3).

Brinzolamide/Timolol eye drops should be used with caution in patients with severe hepatic impairment (see section 4.4).

Method of administration

For ocular use.

Patients should be instructed to shake the bottle well before use. After cap is removed, if tamper evident 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 the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Instruct patients to keep the bottle tightly closed when not in use.

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

4.3. Contraindications

- 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 severe chronic obstructive pulmonary disease.

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

- Severe allergic rhinitis

- Hyperchloraemic acidosis (see section 4.2).

- Severe renal impairment.

4.4. Special warnings and precautions for use

Systemic effects

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

- Hypersensitivity reactions common to all sulphonamide derivates can occur in patients receiving Brinzolamide/Timolol eye drops as it is absorbed systemically.

Cardiac disorders

In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for 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 to patients with first degree heart block.

Vascular disorders

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

Hyperthyroidism

Beta-blockers may also mask the signs of hyperthyroidism.

Muscle weakness

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

Respiratory disorders

Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers. Brinzolamide/Timolol eye drops should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk.

Hypoglycaemia/diabetes

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

Acid/base disturbances

Brinzolamide/Timolol eye drops contains brinzolamide, a sulphonamide. The same types of adverse reactions that are attributable to sulphonamides may occur with topical administration. Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. This medicinal product should be used with caution in patients with risk of renal impairment because of the possible risk of metabolic acidosis. If signs of serious reactions or hypersensitivity occur, discontinue the use of this medicinal product.

Mental alertness

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination. Brinzolamide/Timolol eye drops is absorbed systemically and therefore this may occur with topical administration.

Anaphylactic reactions

While taking beta-blockers, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge with such allergens and unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.

Serious skin reactions

Brinzolamide is 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, brinzolamide should be withdrawn immediately.

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. of adrenaline. 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 potentiated when timolol is given to the patients already receiving a systemic beta-blocking agent. The response of these patients should be closely observed. The use of two topical beta-adrenergic blocking agents or two 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 inhibition in patients receiving an oral carbonic anhydrase inhibitor and Brinzolamide/Timolol eye drops. The concomitant administration of Brinzolamide/Timolol eye drops and oral carbonic anhydrase inhibitors has not been studied and is not recommended (see section 4.5).

Ocular effects

There is limited experience with Brinzolamide/Timolol eye drops in the treatment of patients with pseudoexfoliative glaucoma or pigmentary glaucoma. Caution should be utilised in treating these patients and close monitoring of IOP is recommended.

Brinzolamide/Timolol eye drops has not been studied in patients with narrow-angle glaucoma and its use is not recommended in these patients.

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

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

Brinzolamide/Timolol eye drops may be used while wearing contact lenses with careful monitoring (see below under 'Benzalkonium chloride').

Benzalkonium chloride

Brinzolamide/Timolol eye drops contains benzalkonium chloride. Benzalkonium chloride has been reported to cause eye irritation, symptoms of dry eyes and may affect the tear film and corneal surface. Should be used with caution in dry eye patients and in patients where the cornea may be compromised. Patients should be monitored in case of prolonged use. It is known to discolour soft contact lenses. Contact with soft contact lenses should be avoided. Patients must be instructed to remove contact lenses prior to the application of Brinzolamide/Timolol eye drops and wait 15 minutes after instillation of the dose before reinsertion.

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

Hepatic impairment

Brinzolamide/Timolol eye drops should be used with caution in patients with severe hepatic impairment.

4.5. Interaction with other medicinal products and other forms of interaction

No specific drug interaction studies have been performed with Brinzolamide/Timolol eye drops.

Brinzolamide/Timolol eye drops contains brinzolamide, 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 Brinzolamide/Timolol eye drops.

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 brinzolamide eye drops. The concomitant administration of eye drops containing brinzolamide 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.

There is a potential for additive effects resulting in hypotension and/or marked bradycardia when an ophthalmic 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. Special caution 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 during combined 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 mask the 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.

4.6. Fertility, pregnancy and lactation

Pregnancy

There are no adequate data regarding the use of ophthalmic brinzolamide and timolol in pregnant women. Studies in animals with brinzolamide have shown reproductive toxicity following systemic administration, see section 5.3. Brinzolamide/Timolol eye drops should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2.

Epidemiological studies have not revealed malformative effects but show a risk for intra uterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms 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 Brinzolamide/Timolol eye drops is administered until delivery, the neonate should be carefully monitored during the first days of life.

Breast-feeding

It is not known whether ophthalmic brinzolamide is excreted in human breast milk. Studies in animals have 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 is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-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 to discontinue breast-feeding or to discontinue/abstain from Brinzolamide/Timolol eye drops therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Studies have not been performed to evaluate the effect of topical ocular administration of Brinzolamide/Timolol eye drops on human fertility.

Non clinical data do not show any effects of either brinzolamide or timolol on male or female fertility following oral dosing. No effects on male or female fertility are anticipated from the use of Brinzolamide/Timolol eye drops.

4.7. Effects on ability to drive and use machines

Brinzolamide/Timolol eye drops 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 or using machines.

Carbonic anhydrase inhibitors may impair the ability 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, the most common adverse reactions were blurred vision, eye irritation and eye pain, occurring in approximately 2% to 7% of patients.

Tabulated summary of adverse reactions

The following adverse reactions have been reported during clinical studies and post-marketing surveillance with Brinzolamide/Timolol eye drops and the individual components brinzolamide and timolol. They are classified 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 <1/1000), 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

MedDRA Preferred Term (v. 18.0)

Infections and infestations

Not known: nasopharyngitis3, pharyngitis3, sinusitis3, rhinitis3

Blood and lymphatic system disorders

Uncommon: white blood cell count decreased1

Not known: decreased red blood cell count3, increased blood chloride3

Immune system disorders

Not known: anaphylaxis2, anaphylactic shock1, systemic allergic reactions including angioedema, 2localised and generalised rash2, hypersensitivity1, urticaria2, pruritus2

Metabolism and nutrition disorders

Not known: hypoglycaemia2

Psychiatric disorders

Rare: insomnia1

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

Nervous system disorders

Common: dysgeusia1

Not known: cerebral ischaemia2, cerebrovascular accident2, syncope2, increases in the signs and symptoms of myasthenia gravis2, somnolence3, motor dysfunction3, amnesia3, memory impairment3, paraesthesia2,3, tremor3, hypoaesthesia3, ageusia3, dizziness1, headache1

Eye disorders

Common: punctate keratitis1, blurred vision1, eye pain1, eye irritation1

Uncommon: keratitis1,2,3, dry eye1, vital dye staining cornea present1, eye discharge1, eye pruritus1, foreign body sensation in eyes1, 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, choroidal detachment following filtration surgery2 (see section 4), keratopathy3, corneal epithelium defect3, corneal epithelium disorder3, increased intraocular pressure3, eye deposit3, corneal staining3, corneal oedema3, decreased corneal sensitivity2, conjunctivitis3, meibomianitis3, diplopia2, 3, glare3, photopsia3, reduced visual acuity3, visual impairment1, pterygium3, ocular discomfort3, keratoconjunctivitis sicca3, hypoaesthesia of the eye3, scleral pigmentation3, subconjunctival cyst3, visual disturbance3, eye swelling3, eye allergy3, 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 heart failure2, atrioventricular block2, cardio-respiratory distress3, angina pectoris3, 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 mediastinal disorders

Uncommon: cough1

Rare: oropharyngeal pain1, rhinorrhoea1

Not known: bronchospasm2 (predominantly in patients with pre-existing bronchospastic disease), dyspnoea1, asthma3, epistaxis1, bronchial hyperactivity3, throat irritation3, nasal congestion3, upper respiratory tract congestion3, postnasal drip3, sneezing3, nasal dryness3

Gastrointestinal disorders

Not known: vomiting2,3, abdominal pain upper1, abdominal pain2, diarrhoea1, dry mouth1, nausea1, oesophagitis3, dyspepsia2,3, abdominal discomfort3, stomach discomfort3, frequent bowel movements3, gastrointestinal disorder3, oral hypoaesthesia3, oral paraesthesia3, flatulence3

Hepatobiliary disorders

Not known: abnormal liver function test3

Skin and subcutaneous tissue disorders

Not known: Stevens-Johnson syndrome (SJS)/toxic epidermal 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 connective tissue disorders

Not known: myalgia1, muscle spasms3, arthralgia3, back pain3, pain in extremity3

Renal and urinary disorders

Uncommon: blood urine present1

Not known: renal pain3, pollakiuria3

Reproductive system and breast disorders

Not known: erectile dysfunction3, sexual dysfunction2, decreased libido2

General disorders and administration site conditions

Uncommon: malaise1,3

Not known: chest pain1, pain3, fatigue1, asthenia2,3, chest discomfort3, feeling jittery3, irritability3, peripheral oedema3, medication residue3

Investigations

Uncommon: blood potassium increase1, blood lactate dehydrogenase increased1

1 adverse reactions observed for Brinzolamide/Timolol eye drops

2 additional adverse reactions observed with timolol monotherapy

3 additional adverse reactions observed with brinzolamide monotherapy

* adverse reactions observed with timolol

Description of selected adverse reactions

Dysgeusia (bitter or unusual taste in the mouth following instillation) was a frequently reported systemic adverse reaction associated with the use of Brinzolamide/Timolol eye drops during clinical trials. It is likely to be caused by passage of the eye drops in the nasopharynx via the nasolacrimal canal and is attributable to brinzolamide. Nasolacrimal occlusion or gently closing the eyelid after instillation may help reduce the occurrence of this effect (see section 4.2).

Brinzolamide/Timolol eye drops 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.

Timolol is absorbed into the systemic circulation. This may cause similar adverse reactions as seen with systemic beta-blocking medicinal products. Listed adverse reactions include reactions seen within the class of ophthalmic beta-blockers. Additional adverse reactions associated with the use of the individual components that may potentially occur with Brinzolamide/Timolol eye drops are included in the table above. The incidence of systemic adverse reactions after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2.

Paediatric population

Brinzolamide/Timolol eye drops is not recommended for use in children and adolescents below 18 years due to a lack of data on safety and efficacy.

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

4.9. Overdose

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

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