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

Eye drops, suspension.

White to off-white suspension.

Each ml of suspension contains 10 mg of brinzolamide.

Excipient with known effect:

Each mL of suspension contains 0,15 mg of benzalkonium chloride.

Excipients:

BRINZOLAMIDE VIATRIS is indicated for lowering elevated intraocular pressure in cases of:

• Ocular 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 recommended dose is one drop of BRINZOLAMIDE VIATRIS 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 VIATRIS has not been studied in patients with hepatic impairment and therefore is not recommended in these patients.

BRINZOLAMIDE VIATRIS 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 predominantly excreted by the kidney, BRINZOLAMIDE VIATRIS 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 VIATRIS 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.

Ask patients to shake the bottle well before use. To avoid contamination of the dropper tip and the suspension, care must be taken not to touch the eyelids, adjacent surfaces or other surfaces with the dropper tip of the bottle. Remove contact lenses before instillation and wait at least 15 minutes before reinserting them. Instruct patients to keep the bottle tightly closed when not in use.

When replacing another ophthalmic anti-glaucoma treatment with BRINZOLAMIDE VIATRIS, discontinue the other medicinal product and start BRINZOLAMIDE VIATRIS 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 VIATRIS is a sulfonamide carbonic anhydrase inhibitor which, although administered topically, 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). At the time of prescription, 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 VIATRIS 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 only be treated with brinzolamide after a thorough assessment of the benefit-risk ratio.

Oral carbonic anhydrase inhibitors may decrease the ability to perform tasks requiring mental alertness and/or physical coordination. These effects may also occur after topical administration since BRINZOLAMIDE VIATRIS 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 VIATRIS 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 keratopathies and/or toxic ulcerative keratopathies have been reported with benzalkonium chloride, which is commonly used as a preservative in ophthalmic products. As BRINZOLAMIDE VIATRIS contains benzalkonium chloride, close monitoring is required during frequent or prolonged use in patients with dry eyes or a compromised cornea.

BRINZOLAMIDE VIATRIS has not been studied in patients wearing contact lenses. BRINZOLAMIDE VIATRIS 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 BRINZOLAMIDE VIATRIS and to wait at least 15 minutes after instillation before reinserting contact lenses.

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

Paediatric population

The safety and efficacy of brinzolamide 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 brinzolamide. 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 VIATRIS 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 VIATRIS is not recommended during pregnancy and in women of childbearing potential not using contraception.

Breast-feeding

The excretion of brinzolamide and its metabolites into human milk after topical ocular administration is not known. Animal studies 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 must take into account the benefit of breastfeeding for the child as well as the benefit of the treatment for the woman.

Fertility

Animal studies with brinzolamide have shown no effect on fertility. Studies have not allowed evaluation of the effect of topical ocular administration of brinzolamide on human fertility.

BRINZOLAMIDE VIATRIS 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

In clinical studies including more than 2732 patients treated with brinzolamide as monotherapy or in combination with 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 vision disorder (5,4%), occurring transiently upon instillation and lasting from a few seconds to a few minutes (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, < 1/10), uncommon (≥ 1/1 000, < 1/100), rare (≥ 1/10 000, < 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. These adverse reactions were obtained from clinical studies or spontaneous post-marketing reports.

System organ class	MedDRA preferred term
Infections and infestations	Uncommon : rhinopharyngitis, pharyngitis, sinusitis Frequency not known : rhinitis
Blood and lymphatic system disorders lymphatic system	Uncommon : decreased red blood cell count, increased blood chloride level
Immune system disorders	Frequency not known : hypersensitivity
Metabolism and nutrition disorders	Frequency not known : decreased appetite
Psychiatric disorders	Uncommon : apathy, depression, mood disorders, decreased libido, nightmares, nervousness Rare : insomnia
Nervous system disorders	Uncommon : musculoskeletal disorders, amnesia, vertigo, paresthesia, headaches Rare : memory impairment, somnolence Frequency not known : tremor, hypoaesthesia, ageusia
Eye disorders	Common : blurred vision, eye irritation, eye pain, sensation of foreign body in the eyes, ocular hyperaemia Uncommon : corneal erosion, keratitis, punctate keratitis, keratopathy, ocular deposit, corneal staining, involvement of the corneal epithelium, disorders of the corneal epithelium, blepharitis, ocular pruritus, conjunctivitis, eye swelling, meibomitis, glare, photophobia, dry eye, allergic conjunctivitis, pterygium, scleral pigmentation, asthenopia, eye discomfort, abnormal sensation in the eye, keratoconjunctivitis sicca, subconjunctival cyst, conjunctival hyperaemia, eyelid pruritus, eye discharge, crusting on the eyelid margin, increased lacrimation Rare : corneal oedema, diplopia, decreased visual acuity, photopsia, ocular hypoaesthesia, periorbital oedema, increased intraocular pressure, increased optic nerve cup-to-disc ratio Frequency not known : corneal disorder, visual disturbance, ocular allergy, madarosis, eyelid disorder, eyelid erythema
Ear and labyrinth disorders	Rare : tinnitus Frequency not known : vertigo
Cardiac disorders	Uncommon : respiratory distress, bradycardia, palpitations Rare : angina pectoris, irregular heart rhythm Frequency not known : arrhythmia, tachycardia, hypertension, increased blood pressure, decreased blood pressure, accelerated heart rate
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 Frequency not known : asthma
Gastrointestinal disorders	Common : dysgeusia Uncommon : oesophagitis, diarrhoea, nausea, vomiting, dyspepsia, upper abdominal pain, abdominal discomfort, stomach ache, flatulence, frequent stools, gastrointestinal disorders, oral hypoaesthesia, oral paraesthesia, dry mouth
Hepato-biliary disorders	Frequency not known : abnormal liver function tests
Skin and subcutaneous tissue disorders	Uncommon : rash, maculopapular rash, skin tightness Rare : urticaria, alopecia, generalised pruritus Frequency not known : dermatitis, erythema, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) (see section Warnings and precautions)
Musculoskeletal and systemic disorders	Uncommon : back pain, muscle spasms, myalgia Frequency not known : arthralgia, pain in the extremities
Renal and urinary disorders	Uncommon : renal pain Frequency not known : pollakiuria
Disorders of the reproductive system and breast	Uncommon : erectile dysfunction
General disorders and administration site conditions	Uncommon : pain, chest discomfort, fatigue, feeling of malaise Rare : chest pain, feeling of nervousness, asthenia, irritability Frequency not known : peripheral oedema, malaise
Injury, poisoning and procedural complications	Uncommon : foreign body sensation in the eye

Description of selected adverse reactions

A frequently reported systemic adverse effect with the use of brinzolamide during clinical studies 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 through the nasolacrimal duct. Nasolacrimal occlusion or gentle closure of the eyelids after instillation may help reduce the frequency of this effect (see section Dosage and administration).

Brinzolamide is a sulphonamide 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. Adverse effects of oral carbonic anhydrase inhibitors may be observed with topical administration.

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 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 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. 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 group: Antiglaucoma preparations 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 loss of visual field associated with glaucoma. 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 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).

Paediatric population

A clinical study was conducted with brinzolamide in 32 paediatric patients aged less than 6 years, in whom glaucoma or ocular hypertension had been diagnosed. Some patients had never received IOP-lowering treatment, 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 receiving IOP-lowering medications (22 patients), mean IOP slightly increased from baseline in the brinzolamide group.

Absorption, distribution and biotransformation

After topical ocular instillation, brinzolamide is absorbed into the systemic circulation. Due to its high affinity for CA-II, brinzolamide is distributed extensively in 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 to carbonic anhydrase and accumulates in red blood cells.

This metabolite binds mainly to CA-I in the presence of brinzolamide. In plasma, the concentrations of brinzolamide and N-desethylbrinzolamide are low and generally below the quantification limit of the assay method (<7,5 ng/ml). Plasma protein binding is low (approximately 60 %).

Elimination

Brinzolamide is mainly eliminated by renal excretion (approximately 60 %). Approximately 20 % of the dose has been recovered in urine as metabolite. Brinzolamide and N-desethylbrinzolamide are the main components found in urine, with traces (<1 %) of the N-desmethoxypropyl and O-desmethyl metabolites.

Pharmacokinetic/pharmacodynamic relationships

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 a duration of 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 topical ocular administration, 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 40 to 70 % of its pre-treatment value.

Non-clinical data from conventional safety pharmacology, repeated-dose toxicity, genotoxicity and carcinogenicity 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 ophthalmic dose) did not reveal an effect on foetal development despite significant maternal toxicity. Similar studies in rats led to slight reductions in skull ossification and sternal bars of foetuses from 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 results appeared at doses causing metabolic acidosis with decreased maternal body weight gain and decreased foetal weights. In offspring of mothers receiving brinzolamide orally, dose-dependent decreases in foetal weights were observed, ranging from a slight decrease (approximately 5-6 %) at the dose of 2 mg/kg/day to nearly 14 % at the dose of 18 mg/kg/day. During lactation, the dose without effect on litter was 5 mg/kg/day.

Before opening : 30 months.

After first opening : 4 weeks.

Store the bottle in the outer packaging.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400930032886 (Fl/5ml).

Price:

4,07 euros (Fl/5ml).

Social security reimbursement at 65% on the basis of the TFR: 4.07 euros (Fl/5ml) in the indications:

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

Collection.