AZOPT 10 mg/ml Eye drops suspension Bottle/5ml

Eye drops, suspension (white to off-white).
Bottle of 5 mL. Box of 1.

Each mL of suspension contains 10 mg of brinzolamide.

Excipient with known effect:

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

AZOPT is indicated for lowering 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 AZOPT 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

AZOPT has not been studied in patients with hepatic impairment and therefore is not recommended in these patients.

AZOPT has not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients with hyperchloraemic acidosis. As brinzolamide and its main metabolites are predominantly excreted by the kidney, AZOPT is therefore contraindicated in these patients (see section Contraindications).

Paediatric population

The safety and efficacy of AZOPT in infants, children and adolescents aged 0 to 17 years have not been established. Currently available data are described in sections Adverse effects and Pharmacodynamics. The use of AZOPT 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 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 anti-glaucoma medicinal product with AZOPT, discontinue the other medicinal product and start AZOPT the following day.

When several ophthalmic medicinal products are used, the 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 insufficiency.
• Hyperchloraemic acidosis.

Systemic effects

AZOPT is a sulfonamide carbonic anhydrase inhibitor which, even when administered locally, is absorbed systemically. Adverse reactions associated with sulfonamides may also occur 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, AZOPT must be discontinued 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 been studied neither 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 only be treated with brinzolamide 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 AZOPT is absorbed systemically.

Concomitant treatment

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

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

Experience with treatment with AZOPT 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. AZOPT 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.

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

AZOPT has not been studied in patients wearing contact lenses. AZOPT 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 should be advised to remove their contact lenses before instilling AZOPT and to wait at least 15 minutes after instillation before reinserting contact lenses.

Potential rebound effects on discontinuation of treatment with AZOPT have not been studied; the IOP-lowering effect is assumed to last 5 to 7 days.

Paediatric population

The safety and efficacy of AZOPT 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 studies of interactions with other medicinal products have been performed with AZOPT. In clinical studies, AZOPT was used with ophthalmic preparations of prostaglandin analogues and timolol without any drug interactions being identified. The combination of AZOPT with miotics or adrenergic agonists has not been evaluated in the treatment of glaucoma.

AZOPT is a carbonic anhydrase inhibitor which, although administered locally, is absorbed systemically. Acid-base imbalances have been reported with oral carbonic anhydrase inhibitors. The possibility of interactions should be considered in patients treated with AZOPT.

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).

AZOPT 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 AZOPT treatment 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.

AZOPT has a minor influence on the ability to drive vehicles 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 2 732 patients treated with AZOPT as monotherapy or in combination with timolol maleate 5 mg/ml were: dysgeusia (6.0 %) (bitter or unusual taste, see description below) and visual disturbance, occurring transiently upon instillation and lasting 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 frequency 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 spontaneous post-marketing reports.

Description of selected adverse reactions

The most frequently reported systemic adverse reaction during clinical trials with AZOPT was dysgeusia (bitter or unusual taste in the mouth after instillation). It is probably due to the passage of the eye drops into the nasopharynx via 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).

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

No unexpected adverse effects have been observed with AZOPT used in combination with travoprost. The adverse effects observed with concomitant treatment were those reported with each of the active substances taken separately.

Paediatric population

In small short-term clinical studies, 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 reactions via the national reporting system: National Agency for the Safety of Medicines and Health Products (ANSM) and the network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr.

No cases of overdose have been reported.

Treatment should be symptomatic and general. Fluid and electrolyte imbalance, development of an acidosis state and possible effects on the nervous system may occur. The electrolyte balance (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 reduces aqueous humour 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 glaucomatous visual field loss. Brinzolamide is an inhibitor of carbonic anhydrase II (CA-II), the predominant iso-enzyme in the eye, with an IC₅₀ in vitro of 3,2 nM and a K_i of 0,13 nM against CA-II.

Clinical efficacy and safety

The effect of AZOPT combined with the prostaglandin analogue travoprost on the reduction of IOP has been 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 with 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, mainly represented by signs of local irritation, was higher in the brinzolamide/travoprost groups. The effects were moderate and did not change discontinuation rates from studies (see also section Adverse effects).

A clinical study was conducted with AZOPT in 32 paediatric 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 initiation of monotherapy with AZOPT.

In treatment-naive patients (10 patients), the efficacy of AZOPT was similar to that previously observed in adults, with mean IOP reductions of up to 5 mmHg. In patients already on antiglaucoma medicines (22 patients), mean IOP slightly increased relative to baseline in the AZOPT group.

After ocular instillation, brinzolamide is absorbed into the systemic circulation. Due to its high affinity for CA-II, brinzolamide is distributed extensively into red blood cells and has a prolonged half-life in whole blood (mean 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 by oral administration, healthy volunteers received brinzolamide capsules at 1 mg, twice daily, for a duration reaching 32 weeks, and carbonic anhydrase activity was determined in red blood cells in order 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 a duration reaching 54 weeks. Erythrocyte concentrations of brinzolamide 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 17,1 and 88,6 μM.

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 at 40 to 70 % of its pre-treatment value.

Non-clinical data from conventional studies of safety pharmacology, single-dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenesis 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 ophthalmic therapeutic dose) revealed no effect on foetal development despite significant maternal toxicity. Similar studies in rats led to slight reductions in skull and sternebral ossification of 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 appeared 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 litter was 5 mg/kg/day.

2 years.

4 weeks after first opening.

This medicine does not require any particular storage precautions.

No special requirements.