BRINZOLAMIDE EG 10 mg/ml Collyre susp Fl/5ml

Each ml of suspension contains 10 mg of brinzolamide.

One drop contains approximately 309 micrograms of brinzolamide.

Excipients with known effect :

Each ml of suspension contains 0,1 mg of benzalkonium chloride.

BRINZOLAMIDE EG is indicated for the reduction of elevated intraocular pressure in cases of:

• intraocular hypertension;

• open-angle glaucoma.

As monotherapy in adult patients not responding to beta-blockers or in adult patients for whom beta-blockers are contraindicated, or in combination with beta-blockers or prostaglandin analogues (see also section Pharmacodynamics).

Dosage

As monotherapy or in combination, the dosage is one drop of BRINZOLAMIDE EG in the conjunctival sac of the affected eye(s) twice daily. Some patients may have a better response with one drop three times daily.

Special populations

Elderly patients

No dosage adjustment is necessary in elderly subjects.

Hepatic and renal impairment

Brinzolamide has not been studied in patients with hepatic impairment and therefore is not recommended in these 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 metabolites are predominantly excreted by the kidney, BRINZOLAMIDE EG is therefore contraindicated in these patients (see also section Contraindications).

Paediatric population

The safety and efficacy of brinzolamide in infants, children and adolescents aged 0 to 17 years have not been established. The data currently available are described in sections Adverse effects and Pharmacodynamics.

The use of brinzolamide is not recommended in infants, children and adolescents.

Method of administration

Ocular use.

Nasolacrimal occlusion or gentle closure of the eyelids after instillation is recommended. This may reduce systemic absorption of ocularly administered medicinal products and lead to a reduction in systemic side effects.

Patients should be instructed to shake the bottle well before use. After removing the cap, if the safety ring is too loose, remove it before using the product.

To avoid contamination of the dropper tip and the suspension, care should 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.

When replacing another ophthalmic antiglaucoma treatment with BRINZOLAMIDE EG, stop the other medicine and start BRINZOLAMIDE EG the following day.

When several medicinal products administered by the ocular route are used, instillations must be spaced at least 5 minutes apart. Ophthalmic ointments must be administered last.

If an instillation is forgotten, treatment must be continued with the next instillation as planned. The dose must not exceed one drop three times a day in the affected eye(s).

• hypersensitivity to the active substance or to any of the excipients listed in section Composition ;

• known hypersensitivity to sulfonamides (see also section Warnings and precautions) ;

• severe renal impairment;

• hyperchloraemic acidosis.

Systemic effects

Brinzolamide is a sulfonamide carbonic anhydrase inhibitor which, even when administered topically, is absorbed systemically. Adverse effects of sulfonamides may also be observed with topical administration, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). When prescribing, patients must be informed of the signs and symptoms, and skin reactions must be closely monitored. If signs of serious reactions or hypersensitivity appear, brinzolamide must be stopped immediately.

Acid-base disturbances have been reported following oral administration of carbonic anhydrase inhibitors. Use with caution in patients at risk of renal insufficiency due to the potential risk of metabolic acidosis (see section Dosage and administration).

Brinzolamide has not been studied in premature infants (less than 36 weeks gestational age), nor in children less than one week old. Due to the possible risk of metabolic acidosis, patients with immaturity or significant renal tubular abnormalities may be treated with brinzolamide only after a thorough assessment of the benefit-risk ratio.

Oral carbonic anhydrase inhibitors may reduce the ability to perform tasks requiring mental alertness and/or physical coordination. These effects may also occur after topical administration since BRINZOLAMIDE EG has systemic absorption.

Concomitant treatment

In patients receiving an oral carbonic anhydrase inhibitor and brinzolamide, there is a possibility of additive systemic effects inherent to carbonic anhydrase inhibition. The concomitant administration of brinzolamide and oral carbonic anhydrase inhibitors has not been studied and is not recommended (see also section Interactions).

In combination, brinzolamide has been evaluated mainly with timolol in the treatment of glaucoma. In addition, the effect of brinzolamide combined with the prostaglandin analogue travoprost on IOP reduction has been studied. There are no long-term data on the concomitant combination of brinzolamide and travoprost (see also section Pharmacodynamics).

Experience with brinzolamide treatment in patients with pseudoexfoliative glaucoma or pigmentary glaucoma is limited. Particular care should be taken when treating these patients and close monitoring of intraocular pressure (IOP) is recommended. Brinzolamide has not been evaluated 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 studied in patients with compromised corneas (in particular in patients with a low endothelial cell count). In particular, patients wearing contact lenses have not been studied, and careful monitoring is recommended in these patients receiving brinzolamide, since carbonic anhydrase inhibitors may affect corneal hydration and wearing contact lenses may increase the risk to the cornea. Careful monitoring is recommended in patients with compromised corneas, such as patients with diabetes mellitus or corneal dystrophies.

Punctate keratopathy and/or toxic ulcerative keratopathy have been reported with benzalkonium chloride, which is commonly used as a preservative in ophthalmic products. As BRINZOLAMIDE EG contains benzalkonium chloride, close monitoring is necessary during frequent or prolonged use in patients with dry eyes or compromised corneas.

Brinzolamide has not been studied in patients wearing contact lenses. BRINZOLAMIDE EG contains benzalkonium chloride, which may cause eye irritation and is known to discolour/yellow soft contact lenses. Contact with soft contact lenses should be avoided. Patients should be advised to remove their contact lenses before instillation of BRINZOLAMIDE EG and to wait at least 15 minutes after instillation before reinserting contact lenses.

Potential rebound effects on discontinuation of treatment with BRINZOLAMIDE EG have not been studied; the lowering of IOP is expected to last 5 to 7 days.

Paediatric population

The safety and efficacy of BRINZOLAMIDE EG in infants, children and adolescents aged 0 to 17 years have not been established, and its use is not recommended in infants, children and adolescents.

No specific study of interactions with other medicinal products has been performed with. In clinical studies, brinzolamide was used with ophthalmic preparations of prostaglandin analogues and timolol without evidence of drug interactions. The combination of brinzolamide with miotics or adrenergic agonists has not been evaluated during glaucoma treatment.

Brinzolamide is a carbonic anhydrase inhibitor which, although administered topically, has systemic absorption. Acid-base imbalances have been reported with oral carbonic anhydrase inhibitors. The possibility of interactions should be considered in patients treated with brinzolamide.

The cytochrome P-450 iso-enzymes responsible for the metabolism of brinzolamide include CYP3A4 (main), CYP2A6, CYP2C8 and CYP2C9. It is assumed that CYP3A4 inhibitors such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin will inhibit the metabolism of brinzolamide by CYP3A4. Caution is advised when CYP3A4 inhibitors are given concomitantly. However, as renal elimination is the main route, accumulation of brinzolamide is unlikely. Brinzolamide is not an inhibitor of cytochrome P-450 iso-enzymes.

Pregnancy

There are no or limited data on the ophthalmic use of brinzolamide in pregnant women. Animal studies have shown reproductive toxicity following systemic administration (see also section Preclinical safety).

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

Breast-feeding

The excretion of brinzolamide and its metabolites into breast milk after topical ocular administration is not known. Studies in animals have shown a low level of excretion of brinzolamide into breast milk after oral administration.

The existence of a risk for newborns/infants cannot be excluded. The decision to stop breastfeeding or to stop/suspend treatment with BRINZOLAMIDE EG must take into account the benefit of breastfeeding for the child as well as the benefit of the treatment for the woman.

Fertility

Studies in animals have shown no effect on fertility. Studies have not allowed evaluation of the effect of topical ocular administration of brinzolamide on human fertility.

Brinzolamide has a minor influence on the ability to drive and use machines.

Temporary blurred vision or other visual disturbances may reduce the ability to drive vehicles or use machines (see also section Adverse effects). If blurred vision occurs upon instillation, the patient must wait for their vision to return to normal before driving a vehicle or using a machine.

Oral carbonic anhydrase inhibitors may reduce the ability to perform tasks requiring mental alertness and/or physical coordination (see also section Warnings and precautions and section Adverse effects).

Summary of the safety profile

The treatment-related adverse reactions most frequently reported in clinical studies including more than 2732 patients treated with brinzolamide as monotherapy or in combination with timolol maleate 5 mg/ml were: dysgeusia (6.0%) (bitter or unusual taste, see description below) and vision blurred, occurring transiently upon instillation and lasting from a few seconds to a few minutes (5.4%) (see also section Driving and using machines).

Summary table of undesirable effects

The following adverse reactions have been reported with brinzolamide 10 mg/ml eye drops, suspension, and are classified as follows: 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 (frequency cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. These adverse reactions were obtained from clinical studies or spontaneous reports after marketing.

Description of selected adverse reactions

The systemic adverse reaction most frequently reported during clinical trials with brinzolamide was dysgeusia (bitter or unusual taste in the mouth after instillation). It is probably due to passage of the eye drops into the nasopharynx through the nasolacrimal duct. Nasolacrimal occlusion or gentle closure of the eyelids after instillation may help reduce the incidence of this effect (see also section Dosage and administration).

Brinzolamide is a sulfonamide carbonic anhydrase inhibitor absorbed systemically. Gastrointestinal effects, effects affecting the nervous system, haematological, renal and metabolic effects are generally associated with systemic carbonic anhydrase inhibitors. Undesirable effects of oral carbonic anhydrase inhibitors may be observed with the topical route.

No unexpected adverse effects were observed with brinzolamide used in combination with travoprost. The adverse effects observed with concomitant treatment were those reported with each active substance taken separately.

Paediatric population

In clinical studies involving a small number of patients over the short term, approximately 12.5% of paediatric patients experienced adverse effects, the majority of which were local, non-serious ocular effects such as conjunctival hyperaemia, ocular irritation, ocular discharge and increased lacrimation (see also section Pharmacodynamics).

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 reaction via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Centres of Pharmacovigilance - Website: https://signalement.social-sante.gouv.fr.

No cases of overdose have been reported.

Treatment should be symptomatic and general. A fluid and electrolyte imbalance, the development of an acidosis state and possible effects on the nervous system may occur. The electrolyte profile (in particular potassium) and blood pH should be monitored.

Pharmacotherapeutic class: Antiglaucoma agents and miotics, carbonic anhydrase inhibitors, ATC code: S01EC04.

Mechanism of action

Carbonic anhydrase (CA) is an enzyme found in many tissues of the body, including the eye. Carbonic anhydrase catalyses the reversible reaction of hydration of carbon dioxide and dehydration of carbonic acid.

Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases the secretion of aqueous humour, probably by slowing the formation of bicarbonate ions, which leads to a reduction in sodium and water transport. The result is a decrease in intraocular pressure (IOP), which is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. Brinzolamide is an inhibitor of carbonic anhydrase II (CA-II), the predominant isoenzyme in the eye, with an IC50 in vitro of 3,2 nM and a Ki of 0,13 nM against CA-II.

Safety and clinical efficacy

The effect of brinzolamide combined with the prostaglandin analogue travoprost on the reduction of IOP was studied. After a period of 4 weeks of treatment with travoprost, patients who had an IOP ≥ 19 mmHg were randomised to receive additional treatment with brinzolamide or timolol. Additional decreases in mean diurnal IOP, ranging from 3,2 to 3,4 mmHg in the brinzolamide group and from 3,2 to 4,2 mmHg in the timolol group, were observed. The overall incidence of non-serious ocular adverse events, consisting essentially of signs of local irritation, was higher in the brinzolamide/travoprost groups. The effects were moderate and did not change study discontinuation rates (see also section Adverse effects).

A clinical study was conducted with brinzolamide in 32 paediatric patients under 6 years of age, in whom glaucoma or ocular hypertension had been diagnosed. Some patients had never received antiglaucoma medication while others were already taking it. For patients already treated, there was no washout period before initiating brinzolamide monotherapy. In treatment-naive patients (10 patients), the efficacy of brinzolamide was similar to that previously observed in adults, with mean IOP reductions of up to 5 mmHg.

In patients already on antiglaucoma medications (22 patients), mean IOP increased slightly from baseline in the brinzolamide group.

After ocular instillation, brinzolamide is absorbed into the systemic circulation. Due to its high affinity for CA-II, brinzolamide distributes extensively into red blood cells and has a prolonged half-life in whole blood (average of approximately 24 weeks). In humans, the metabolite N-desethylbrinzolamide is formed, which also binds carbonic anhydrase and accumulates in red blood cells. This metabolite binds mainly to CA-I in the presence of brinzolamide. In plasma, concentrations of brinzolamide and N-desethylbrinzolamide are low and generally below the limit of quantification of the assay method (<7,5 ng/ml).

Plasma protein binding is low (approximately 60%). Brinzolamide is mainly eliminated by renal excretion (approximately 60%). Approximately 20% of the dose was recovered in urine as metabolite.

Brinzolamide and N-desethylbrinzolamide are the main components found in urine, with traces (<1%) of N-desmethoxypropyl and O-desmethyl metabolites.

In a pharmacokinetic study with oral administration, healthy volunteers received brinzolamide capsules at 1 mg twice daily for up to 32 weeks, and carbonic anhydrase activity was determined in red blood cells to assess the degree of systemic carbonic anhydrase inhibition.

Saturation of erythrocyte CA-II by brinzolamide was achieved in 4 weeks (intra-erythrocyte concentrations of approximately 20 μM). N-desethylbrinzolamide accumulated in red blood cells to reach a steady state in 20-28 weeks, up to concentrations of 6 to 30 μM. At steady state, inhibition of total erythrocyte CA activity was approximately 70-75%.

Subjects with moderate renal impairment (creatinine clearance of 30 to 60 ml/minute) received 1 mg of brinzolamide orally twice daily for up to 54 weeks. Erythrocyte brinzolamide concentrations were between 20 and 40 μM at the fourth week of treatment. At steady state, erythrocyte concentrations of brinzolamide and its metabolite were between 22,0 and 46,1 μM and between 17,1 and 88,6 μM, respectively.

Erythrocyte concentrations of N-desethylbrinzolamide were increased and total erythrocyte CA activity was decreased as creatinine clearance decreased, but erythrocyte brinzolamide concentrations and CA-II activity remained unchanged. In subjects with the most severe renal impairment, inhibition of total carbonic anhydrase activity was greater, although less than 90% at steady state.

In a study using the ocular route, at steady state, erythrocyte brinzolamide concentrations were similar to those observed in the oral study, but N-desethylbrinzolamide concentrations were lower. Carbonic anhydrase activity was approximately at 40 to 70% of its pre-treatment value.

Non-clinical data from conventional safety pharmacology, repeated-dose toxicity, genotoxicity and carcinogenicity studies revealed no particular risk for humans.

Toxicity studies in rabbits receiving doses of brinzolamide up to 6 mg/kg/day (125 times the recommended human daily therapeutic ophthalmic dose) did not reveal an effect on fetal development despite significant maternal toxicity. Similar studies in rats led to slight reductions in skull ossification and sternal bars in fetuses of dams receiving brinzolamide at doses of 18 mg/kg/day (375 times the recommended human ophthalmic dose); these reductions were not observed at 6 mg/kg/day. These findings appeared at doses causing metabolic acidosis with decreased maternal body weight gain and decreased fetal weights. In offspring of dams receiving oral brinzolamide, dose-dependent decreases in fetal weights were observed, ranging from a slight decrease (approximately 5-6%) at a dose of 2 mg/kg/day to nearly 14% at a dose of 18 mg/kg/day. During lactation, the no-effect dose on litter was 5 mg/kg/day.

3 years.

4 weeks after opening.

This medicine does not require any particular storage precautions.

No special requirements for disposal.

• Indication(s) appearing in the marketing authorisation at the date of publication of this decree