4.1. Therapeutic indications

Brinzolamide is indicated to decrease elevated intraocular pressure in:

• ocular hypertension

• open-angle glaucoma

as monotherapy in adult patients unresponsive to beta-blockers or in adult patients in whom beta-blockers are contraindicated, or as adjunctive therapy to beta-blockers or prostaglandin analogues (see also section 5.1).

4.2. Posology and method of administration

Posology

When used as monotherapy or adjunctive therapy, the recommended dose is one drop of Brinzolamide in the conjunctival sac of the affected eye(s) twice daily. Some patients may have a better response with one drop three times a day.

Special populations

Elderly population

No dose adjustment in elderly patients is necessary.

Patients with hepatic and renal impairment

Brinzolamide has not been studied in patients with hepatic impairment and is therefore not recommended in such patients.

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

Paediatric population

The efficacy and safety of brinzolamide in infants, children and adolescents aged 0 to 17 years has not been established. Currently available data are described in sections 4.8 and 5.1. Brinzolamide is not recommended for use in infants, children and adolescents.

Method of administration

For ocular use.

Nasolacrimal occlusion or gently closing the eyelid after instillation is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic side effects.

Instruct the patient to shake the bottle well before use. To prevent contamination of the dropper tip and suspension, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Remove contact lenses prior to application and wait at least 15 minutes before reinsertion. Instruct patients to keep the bottle tightly closed when not in use.

When substituting another ophthalmic antiglaucoma agent with Brinzolamide, discontinue the other agent and start the following day with Brinzolamide.

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

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) three times daily.

4.3. Contraindications

• Hypersensitivity to the active substance or any of the excipients listed in section 6.1

• Known hypersensitivity to sulfonamides (see also section 4.4).

• Severe renal impairment.

• Hyperchloraemic acidosis.

4.4. Special warnings and precautions for use

Systemic effects

Brinzolamide is a sulfonamide inhibitor of carbonic anhydrase and, although administered topically, is absorbed systemically. The same types of adverse drug reactions that are attributable to sulfonamides 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.

Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. Use with caution in patients with risk of renal impairment because the possible risk of metabolic acidosis (see section 4.2).

Brinzolamide has not been studied in pre-term infants (less than 36 weeks gestational age) or those less than 1 week of age. Patients with significant renal tubular immaturity or abnormalities should only receive brinzolamide after careful consideration of the risk benefit balance because of the possible risk of metabolic acidosis.

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

Concomitant therapy

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. The concomitant administration of brinzolamide and oral carbonic anhydrase inhibitors has not been studied and is not recommended (see also section 4.5).

Brinzolamide was primarily evaluated in concomitant administration with timolol during adjunctive glaucoma therapy. Additionally the IOP-reducing effect of brinzolamide as adjunctive therapy to the prostaglandin analogue travoprost has been studied. No long term data are available on the use of brinzolamide as adjunctive therapy to travoprost (see also section 5.1).

There is limited experience with brinzolamide in the treatment of patients with pseudoexfoliative glaucoma or pigmentary glaucoma. Caution should be used in treating these patients and close monitoring of intraocular pressure (IOP) is recommended. Brinzolamide has not been studied in patients with narrow-angle glaucoma and its use is not recommended in these patients.

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 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.

Benzalkonium chloride, which is commonly used as a preservative in ophthalmic products, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since Brinzolamide contains benzalkonium chloride, close monitoring is required with frequent or prolonged use in dry eye patients, or in conditions where the cornea is compromised.

Brinzolamide has not been studied in patients wearing contact lenses. Brinzolamide contains benzalkonium chloride which may cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses is to be avoided. Patients must be instructed to remove contact lenses prior to the application of Brinzolamide and wait at least 15 minutes after instillation of the dose before reinsertion.

Potential rebound effects following cessation of treatment with brinzolamide have not been studied; the IOP-lowering effect is expected to last for 5-7 days.

Paediatric population

The safety and efficacy of brinzolamide in infants, children and adolescents aged 0 to 17 years has not been established and its use is not recommended in infants, children or adolescents.

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

Specific interaction studies with other medicinal products have not been performed with brinzolamide. In clinical studies, brinzolamide was used concomitantly with prostaglandin analogues and timolol ophthalmic preparations without evidence of adverse interactions. Association between brinzolamide and miotics or adrenergic agonists has not been evaluated during adjunctive glaucoma therapy.

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 brinzolamide.

The cytochrome P-450 isozymes responsible for metabolism of brinzolamide include CYP3A4 (main), CYP2A6, 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 ophthalmic brinzolamide in pregnant women. Studies in animals have shown reproductive toxicity following systemic administration (see also section 5.3).

Brinzolamide is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

It is unknown whether brinzolamide/metabolites are excreted in human milk following topical ocular administration. Animal studies have shown the excretion of minimal levels of brinzolamide in breast milk following oral administration.

A risk to the newborns/infants cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from brinzolamide therapy taking in to account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Fertility

Animal studies with brinzolamide demonstrated no effect on fertility. Studies have not been performed to evaluate the effect of topical ocular administration of brinzolamide on human fertility.

4.7. Effects on ability to drive and use machines

Brinzolamide has a 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 (see also section 4.8). 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 to perform tasks requiring mental alertness and/or physical coordination (see also section 4.4 and section 4.8).

4.8. Undesirable effects

Summary of the safety profile

In clinical studies involving 2732 patients treated with brinzolamide as monotherapy or adjunctive therapy to timolol maleate 5 mg/ml, the most frequently reported treatment-related adverse reactions were: dysgeusia (6.0%) (bitter or unusual taste, see description below) and temporary blurred vision (5.4%) upon instillation, lasting from a few seconds to a few minutes (see also section 4.7).

Tabular list of adverse reactions

The following adverse reactions have been reported with brinzolamide 10mg/ml eye drops, suspension and 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 <1/1,000), 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. The adverse reactions were obtained from clinical trials and postmarketing spontaneous reports.

System Organ Classification

MedDRA Preferred Term

Infections and infestations

Uncommon: nasopharyngitis, pharyngitis, sinusitis

Not known: rhinitis

Blood and lymphatic system disorders

Uncommon: red blood cell count decreased, blood chloride increased

Immune system disorders

Not known: hypersensitivity

Metabolism and nutrition disorders

Not known: decreased appetite

Psychiatric disorders

Uncommon: apathy, depression, depressed mood, libido decreased, nightmare, nervousness

Rare: insomnia

Nervous system disorders

Uncommon: motor dysfunction, amnesia, dizziness, paraesthesia, headache

Rare: memory impairment, somnolence

Not known: tremor, hypoaesthesia, ageusia

Eye disorders

Common: blurred vision, eye irritation, eye pain, foreign body sensation in eyes, ocular hyperaemia

Uncommon: corneal erosion, keratitis, punctate keratitis, keratopathy, deposit eye, corneal staining, corneal epithelium defect, corneal epithelium disorder, blepharitis, eye pruritus, conjunctivitis, eye swelling, meibomianitis, glare, photophobia, dry eye, allergic conjunctivitis, pterygium, scleral pigmentation, asthenopia, ocular discomfort, abnormal sensation in eye, keratoconjunctivitis sicca, subconjunctival cyst, conjunctival hyperaemia, eyelids pruritus, eye discharge, eyelid margin crusting, lacrimation increased

Rare: corneal oedema, diplopia, visual acuity reduced, photopsia, hypoaesthesia eye, periorbital oedema, intraocular pressure increased, optic nerve cup/disc ratio increased

Not known: corneal disorder, visual disturbance, eye allergy, madarosis, eyelid disorder, erythema of eyelid

Ear and labyrinth disorders

Rare: tinnitus

Not known: vertigo

Cardiac disorders

Uncommon: cardio-respiratory distress, bradycardia, palpitations

Rare: angina pectoris, heart rate irregular

Not known: arrhythmia, tachycardia, hypertension, blood pressure increased, blood pressure decreased, heart rate increased

Respiratory, thoracic and mediastinal disorders

Uncommon: dyspnoea, epistaxis, oropharyngeal pain, pharyngolaryngeal pain, throat irritation, upper airway cough syndrome, rhinorrhoea, sneezing

Rare: bronchial hyperreactivity, upper respiratory tract congestion, sinus congestion, nasal congestion, cough, nasal dryness

Not known: asthma

Gastrointestinal disorders

Common: dysgeusia

Uncommon: oesophagitis, diarrhoea, nausea, vomiting, dyspepsia, upper abdominal pain, abdominal discomfort, stomach discomfort, flatulence, frequent bowel movements, gastrointestinal disorder, hypoaesthesia oral, paraesthesia oral, dry mouth

Hepatobiliary disorders

Not known: liver function test abnormal

Skin and subcutaneous tissue disorders

Uncommon: rash, rash maculo-papular, skin tightness

Rare: urticaria, alopecia, pruritus generalised

Not known: dermatitis, erythema, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). (see section 4.4)

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, fatigue, feeling abnormal

Rare: chest pain, feeling jittery, asthenia, irritability

Not known: peripheral oedema, malaise

Injury, poisoning and procedural complications

Uncommon: foreign body in eye

Description of selected adverse events

Dysgeusia (bitter or unusual taste in the mouth following instillation) was the most frequently reported systemic adverse reaction associated with the use of brinzolamide during clinical studies. It is likely caused by passage of the eye drops in the nasopharynx via the nasolacrimal canal. Nasolacrimal occlusion or gently closing the eyelid after instillation may help reduce the incidence of this effect (see also section 4.2).

Brinzolamide is a sulfonamide 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 that are attributable to oral carbonic anhydrase inhibitors may occur with topical administration.

No unexpected adverse reactions have been observed with brinzolamide when used as adjunctive therapy to travoprost. The adverse reactions seen with the adjunctive therapy have been observed with each active substance alone.

Paediatric population

In small short-term clinical trials, approximately 12.5% of paediatric patients were observed to experience adverse reactions, the majority of which were local, non-serious ocular reactions such as conjunctival hyperaemia, eye irritation, eye discharge, and lacrimation increased (see also section 5.1).

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.

4.9. Overdose

No case of overdose has been reported.

Treatment should be symptomatic and supportive. 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.