BRINZOLAMIDE SANDOZ 10 mg/ml Col susp Fl/5ml

Each mL of suspension contains 10 mg of brinzolamide (0,33 mg of brinzolamide per drop).

Excipient with known effect :

Each mL of suspension contains 0,10 mg of benzalkonium chloride.

BRINZOLAMIDE SANDOZ is indicated to lower 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 dose is one drop of BRINZOLAMIDE SANDOZ 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 dose adjustment is necessary in elderly patients.

Hepatic and renal impairment

Brinzolamide has not been studied in patients with hepatic impairment and therefore its use 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 hyperchloremic acidosis. Since brinzolamide and its main metabolites are mainly excreted by the kidney, BRINZOLAMIDE SANDOZ is therefore contraindicated in these patients (see section Contraindications).

Paediatric population

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

Method of administration

Ophthalmic use.

Nasolacrimal occlusion or gentle closure of the eyelids after instillation is recommended. This may reduce the systemic absorption of ophthalmically administered medicinal products and lead to a decrease 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 anti-glaucoma treatment with BRINZOLAMIDE SANDOZ, discontinue the other medicine and start BRINZOLAMIDE SANDOZ the following day.

When several ophthalmically administered medicinal products are used, the instillations must be separated by at least 5 minutes. Ophthalmic ointments should 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 SANDOZ is a sulfonamide carbonic anhydrase inhibitor which, even when administered locally, is absorbed systemically. Adverse effects of sulfonamides may also be observed with the topical route, 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 SANDOZ shows systemic absorption.

Concomitant treatment

In patients receiving an oral carbonic anhydrase inhibitor and BRINZOLAMIDE SANDOZ, there is a possibility of additive systemic effects inherent to carbonic anhydrase inhibition. The concomitant administration of BRINZOLAMIDE SANDOZ 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 SANDOZ combined with the prostaglandin analogue travoprost on the reduction of IOP has been studied. There are no long-term data on the concomitant combination of BRINZOLAMIDE SANDOZ and travoprost (see also section Pharmacodynamics).

Experience with brinzolamide treatment in patients with pseudoexfoliative glaucoma or pigmentary glaucoma is limited. Particular caution should be exercised when treating these patients and close monitoring of intraocular pressure (IOP) is recommended. BRINZOLAMIDE SANDOZ 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 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 on brinzolamide, since carbonic anhydrase inhibitors may affect corneal hydration and wearing contact lenses may increase the risk to the cornea. Likewise, careful monitoring is recommended in patients with compromised corneas, such as patients with diabetes mellitus or corneal dystrophies.

This medicine contains 0,10 mg of benzalkonium chloride per mL. Benzalkonium chloride may be absorbed by soft contact lenses and change their colour. Remove contact lenses before application and wait at least 15 minutes before reinserting them.

Benzalkonium chloride is known to cause eye irritation, dry eye syndrome symptoms, and may affect the tear film and corneal surface. Should be used with caution in patients with dry eye and those at risk of corneal damage.

Patients should be monitored in case of prolonged use.

Potential rebound effects upon discontinuation of treatment with BRINZOLAMIDE SANDOZ have not been studied; the lowering of IOP is assumed to last 5 to 7 days.

Paediatric population

The safety and efficacy of BRINZOLAMIDE SANDOZ 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 drug interaction studies have been performed with BRINZOLAMIDE SANDOZ.

In clinical studies, brinzolamide was used with ophthalmic preparations of prostaglandin analogues and timolol without any drug interactions being identified. The combination of brinzolamide with miotics or adrenergic agonists has not been evaluated during glaucoma treatment.

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

The cytochrome P-450 iso-enzymes responsible for the metabolism of brinzolamide include CYP3A4 (principal), 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, since renal elimination is the main route, accumulation of brinzolamide is unlikely. Brinzolamide is not an inhibitor of the 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 SANDOZ 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 discontinue/suspend treatment with BRINZOLAMIDE SANDOZ must take into account the benefit of breastfeeding for the child and the benefit of 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 SANDOZ 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 sections Warnings and precautions and 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 blurred vision, 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 (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), or not known (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 from post-marketing spontaneous reports.

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 SANDOZ is a sulfonamide carbonic anhydrase inhibitor absorbed systemically. Gastrointestinal effects, affecting the nervous system, hematological, renal and metabolic effects are generally associated with systemic carbonic anhydrase inhibitors. The undesirable effects of oral carbonic anhydrase inhibitors may be observed with topical administration.

No unexpected undesirable effects have been observed with brinzolamide used in combination with travoprost. The undesirable effects observed with the combination were those reported with each of the active substances taken separately.

Paediatric population

In small short-term clinical studies, approximately 12.5 % of pediatric patients experienced undesirable effects, the majority of which were local, non-serious ocular effects such as conjunctival hyperemia, eye irritation, eye 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 supportive. Fluid and electrolyte imbalance, development of an acidosis state and possible effects on the nervous system may occur. The electrolytes (in particular potassium) and blood pH should be monitored.

Pharmacotherapeutic class: Antiglaucoma and miotic agents, 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 catalyzes 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 aqueous humor secretion, 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 loss of visual field of glaucomatous origin. Brinzolamide, a carbonic anhydrase II (CA-II) inhibitor, the predominant iso-enzyme in the eye with an IC50 in vitro of 3,2 nM and a Ki of 0,13 nM versus CA-II.

Clinical efficacy and safety

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 pediatric patients aged less than 6 years, 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 monotherapy with brinzolamide. 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 slightly increased 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 (mean 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 by brinzolamide of erythrocyte CA-II 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 ranged between 20 and 40 µM at the fourth week of treatment. At steady state, erythrocyte concentrations of brinzolamide and its metabolite ranged 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 concentrations of brinzolamide and CA-II activity remained unchanged. In subjects with the most severe renal impairment, inhibition of total carbonic anhydrase activity was greater, although below 90% at steady state.

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

Non-clinical data from conventional safety pharmacology, repeated-dose toxicity, genotoxicity and carcinogenesis studies did not reveal any particular risk for humans.

Toxicity studies in rabbits receiving doses of brinzolamide up to 6 mg/kg/day (125 times the recommended human daily ophthalmic therapeutic dose) did not reveal any effect on foetal development despite significant maternal toxicity. Similar studies in rats led to slight reductions in skull and sternebral ossification in foetuses of mothers 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 occurred at doses causing metabolic acidosis with decreased maternal body weight gain and decreased foetal weights. In offspring of mothers receiving oral brinzolamide, dose-dependent decreases in foetal 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 dose with no effect on the litter was 5 mg/kg/day.

2 years.

After first opening: 4 weeks.

This medicine does not require any particular storage precautions.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

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