Azopt eye drops 10 mg/ml dropper bottle drop-tainer 5 ml

Instructions for use: Azopt eye drops 10 mg/ml, dropper bottle, drop-tainer 5 ml

Composition

active ingredient: brinzolamide;

1 ml of suspension contains 10 mg of brinzolamide;

excipients: benzalkonium chloride, mannitol (E 421), carbomer 974P, tyloxapol, disodium edetate, sodium chloride, concentrated hydrochloric acid and/or sodium hydroxide (for pH adjustment), purified water.

Dosage form

Eye drops.

Main physicochemical properties: white or almost white homogeneous suspension.

Pharmacotherapeutic group

Drugs used in ophthalmology. Antiglaucoma drugs and miotics. Carbonic anhydrase inhibitors.

ATX code S01E C04.

Pharmacological properties

Pharmacodynamics

Carbonic anhydrase (CA) is an enzyme found in many tissues of the human 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 body of the eye reduces the secretion of intraocular fluid, mainly by slowing the formation of bicarbonate ions with a subsequent decrease in sodium and fluid transport. The result is a decrease in intraocular pressure (IOP), which is a major risk factor in the pathogenesis of optic nerve damage and visual field loss due to glaucoma. Brinzolamide is an inhibitor of carbonic anhydrase II (CA-II), the dominant isoenzyme of the eye, with an in vitro IC50 of 3.2 nM and a Ki of 0.13 nM relative to CA-II.

The effect of AZOPT® in combination with the prostaglandin analogue travoprost on IOP reduction was studied. After 4 weeks of travoprost, patients with IOP ≥ 19 mmHg were randomly assigned to receive either brinzolamide or timolol. An additional reduction in mean daily IOP of 3.2 to 3.4 mmHg was observed in the brinzolamide group and 3.2 to 4.2 mmHg in the timolol group. The most common ocular adverse reactions observed in the brinzolamide-travoprost groups were mild and mainly related to signs of local irritation. Adverse reactions were mild and generally did not lead to discontinuation of the study (see also section 4.8).

A clinical study of AZOPT® was conducted in 32 children under 6 years of age with glaucoma and ocular hypertension. Some patients were previously untreated for IOP, while others were already taking other IOP-lowering medications. Patients who were taking IOP-lowering medications did not stop taking their medications before starting AZOPT® monotherapy.

When AZOPT® was used in patients who had not previously received IOP-lowering therapy (10 patients), the efficacy was similar to that observed in adults, with a mean IOP reduction of up to 5 mmHg from baseline. The mean IOP tended to increase slightly in patients who had received topical IOP-lowering medications (22 patients) from baseline in the AZOPT® group.

Brinzolamide revealed no special hazard for humans based on conventional non-clinical safety studies, single dose toxicity, repeated dose toxicity, genotoxicity, and carcinogenic potential.

In a toxicity study in rabbits, oral administration of brinzolamide at doses up to 6 mg/kg/day (125 times the recommended therapeutic ophthalmic dose) did not reveal any effects on fetal development, despite significant maternal toxicity. Similar studies in rats showed a slight decrease in ossification of the skull and sternum in fetuses treated with brinzolamide at 18 mg/kg/day (375 times the recommended therapeutic ophthalmic dose), but in fetuses treated with

6 mg/kg/day, this effect was not observed. These results were obtained at doses that caused metabolic acidosis with reduced maternal body weight gain and reduced fetal weights. A dose-dependent decrease in fetal weight was observed in dams receiving oral brinzolamide, ranging from a slight decrease (approximately 5-6%) at 2 mg/kg/day to approximately 14% at 18 mg/kg/day. During lactation, the no-effect dose for the fetus was 5 mg/kg/day.

Pharmacokinetics

Plasma protein binding is not complete (approximately 60%). Brinzolamide is excreted primarily by the kidneys (approximately 60%). Approximately 20% of the dose is recovered in the urine as metabolites. Brinzolamide and N-desethylbrinzolamide are the dominant components excreted in the urine, with trace amounts (< 1%) of the N-desmethoxypropyl and O-desmethyl metabolites.

In a pharmacokinetic study, healthy volunteers received brinzolamide orally as 1 mg capsules twice daily for 32 weeks. Red blood cell (RBC) CA activity was measured to assess the level of systemic CA inhibition.

Brinzolamide reached saturation of erythrocyte CA-II within 4 weeks (concentration was approximately 20 μM). N-desethylbrinzolamide accumulated in erythrocytes to reach steady-state concentrations ranging from 6 to 30 μM within 20 to 28 weeks. Inhibition of total erythrocyte CA-II activity under steady-state conditions was approximately 70 to 75%.

Patients with moderate renal impairment (creatinine clearance 30–60 mL/min) were administered 1 mg brinzolamide orally twice daily for 54 weeks. Brinzolamide concentrations in red blood cells after 4 weeks ranged from 20 to 40 μM. Under steady-state conditions, brinzolamide and its metabolite concentrations in red blood cells ranged from 22 to 46.1 and 17.1 to 88.6 μM, respectively.

As creatinine clearance decreased, erythrocyte N-desethylbrinzolamide concentrations increased and total erythrocyte CA activity decreased, but erythrocyte brinzolamide concentrations and CA-II activity remained unchanged. In patients with severe renal impairment, the inhibition of total CA activity was greater, although it was less than 90% under steady-state conditions.

In studies with topical ocular administration, steady-state brinzolamide concentrations in red blood cells were similar to those observed after oral administration, but N-desethylbrinzolamide concentrations were lower. Carbonic anhydrase activity was approximately 40-70% of its pre-dose level.

Indication

AZOPT® is indicated for the reduction of elevated intraocular pressure in:

ocular hypertension,

open-angle glaucoma,

as monotherapy for adult patients insensitive to beta-blockers or for adult patients in whom beta-blockers are contraindicated, or as add-on therapy to beta-blockers or prostaglandin analogues.

Contraindication

Hypersensitivity to the active substance or to any other component of the drug.

Known hypersensitivity to sulfonamides (see also section "Special warnings and precautions for use").

Severe renal failure.

Hyperchloremic acidosis.

Interaction with other medicinal products and other types of interactions

Specific drug interaction studies with AZOPT® have not been conducted. In clinical trials, AZOPT® was used in combination with prostaglandin analogues and timolol in the form of eye drops, and no evidence of adverse interactions was found. In combination therapy for glaucoma, the interaction between AZOPT® and miotics or adrenergic receptor agonists has not been evaluated.

AZOPT® is a carbonic anhydrase inhibitor and although administered topically, it is absorbed systemically. Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. This interaction should be considered in patients receiving AZOPT®.

The cytochrome P450 isoenzymes responsible for the metabolism of brinzolamide are CYP3A4 (major), CYP2A6, CYP2C8 and CYP2C9. CYP3A4 inhibitors, such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin, are expected to inhibit the metabolism of brinzolamide by the CYP3A4 enzyme. Caution should be exercised when concomitantly administering CYP3A4 inhibitors. Since brinzolamide is primarily excreted by the kidneys, accumulation is unlikely. Brinzolamide is not an inhibitor of cytochrome P450 isoenzymes.

Application features

Systemic effect

AZOPT® is a sulfonamide-type carbonic anhydrase inhibitor and, although used topically, is absorbed systemically. The same adverse reactions as those associated with sulfonamides may occur with topical administration, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Patients should be advised of the signs and symptoms of adverse reactions and should be monitored closely for skin reactions during treatment with AZOPT® eye drops. If signs of serious adverse reactions or hypersensitivity occur, the drug should be discontinued immediately.

Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. As there is a risk of metabolic acidosis, the drug should be used with caution in patients at risk of renal impairment (see section 4.2).

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination. AZOPT® is absorbed systemically, so these effects may also occur with topical application.

Simultaneous use

In patients taking oral carbonic anhydrase inhibitors and AZOPT, there is a potential for an increase in the known systemic side effects of carbonic anhydrase inhibitors. The concomitant use of AZOPT and oral carbonic anhydrase inhibitors has not been studied and is therefore not recommended (see also section 4.5).

AZOPT® has been primarily evaluated in combination with timolol for the treatment of glaucoma. In addition, the intraocular pressure (IOP)-lowering effect of AZOPT® with the prostaglandin analogue travoprost as part of combination therapy has been studied. Long-term data on the use of AZOPT® with travoprost as combination therapy are not available (see section 5.1).

There is limited experience with the use of AZOPT® in patients with pseudoexfoliative glaucoma and pigmentary glaucoma. It is recommended to treat such patients with caution and to closely monitor intraocular pressure. AZOPT® has not been studied in patients with angle-closure glaucoma, and therefore its use in such patients is not recommended.

The potential effect of brinzolamide on corneal endothelial function has not been studied in patients with compromised corneas (particularly those with low endothelial cell counts). No direct studies have been conducted in patients wearing contact lenses, and close monitoring is recommended in such patients, as carbonic anhydrase inhibitors may affect corneal hydration and contact lens wear may increase the risk of corneal damage. Close monitoring is recommended in patients with compromised corneas, such as those with diabetes or corneal dystrophy.

Benzalkonium chloride, commonly used as a preservative in ophthalmic preparations, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. As AZOPT® contains benzalkonium chloride, close monitoring is required with frequent or prolonged treatment of patients with dry eye or corneal lesions.

The use of AZOPT® in patients who wear contact lenses has not been studied.

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 contact lenses before using AZOPT® eye drops and to wait 15 minutes after instillation before reinserting contact lenses.

Withdrawal effects that may potentially occur after discontinuation of AZOPT® treatment have not been studied; the reduction in intraocular pressure is expected to persist for 5–7 days.

Use during pregnancy or breastfeeding

Pregnancy

There are no or limited amount of ophthalmic data from the use of brinzolamide in pregnant women. Animal studies have shown reproductive toxicity when administered systemically (see also section 5.1). AZOPT® should not be administered to pregnant women or women of childbearing potential not using contraception.

Breast-feeding

It is not known whether brinzolamide/its metabolites are excreted in human milk following topical ophthalmic administration. Animal studies have shown that minimal amounts of brinzolamide are excreted in human milk following oral administration.

A risk to the newborn/infant cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from AZOPT therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman.

Reproductive function

No effects of brinzolamide on reproductive function were observed in animal studies. No studies have been conducted on the potential effects of brinzolamide on human reproductive function when used topically in ophthalmology.

Ability to influence reaction speed when driving vehicles or other mechanisms

AZOPT® has minimal effect on the ability to drive or operate machinery.

Temporary blurred vision or other visual disturbances may adversely affect the ability to drive or use machines (see also section "Special precautions for use"). If blurred vision occurs during instillation, the patient should wait until 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 sections “Special warnings and precautions for use” and “Adverse reactions”).

Method of administration and doses

When AZOPT® is used as monotherapy or adjunctive therapy, the dose is 1 drop in the conjunctival sac of the affected eye(s) 2 times daily. Some patients may benefit from 1 drop 3 times daily.

If another ophthalmic antiglaucoma agent is replaced with AZOPT®, the other agent should be discontinued and AZOPT® should be started the next day.

If more than one ophthalmic agent is applied topically, the interval between their applications should be at least 5 minutes. Eye ointments should be applied last.

If a dose is missed, treatment should be continued with the next dose according to the treatment schedule. The dose should not exceed one drop in the affected eye(s) 3 times daily.

Method of application

For ophthalmic use.

It is recommended to apply pressure to the nasolacrimal orifice or gently close the eyelids after instillation. This reduces the systemic absorption of drugs administered into the eye, which reduces the likelihood of systemic side effects.

The patient should be informed about the need to shake the bottle well before using the drug. After the first opening of the bottle, the protective ring intended for first-time opening control should be removed.

To prevent contamination of the dropper tip and the contents of the bottle, care should be taken not to touch the eyelids, surrounding skin or other surfaces with the dropper tip. The patient should be advised to keep the bottle tightly closed during storage.

Special patient groups

Use in elderly patients

No dose adjustment is necessary for elderly patients.

Use in liver and kidney dysfunction.

The use of AZOPT® in patients with hepatic impairment has not been studied and is therefore not recommended for use in such patients.

AZOPT® 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 major metabolite are excreted primarily by the kidneys, AZOPT® is contraindicated in these patients (see also section 4.3).

Children

The safety and efficacy of AZOPT® in children (under 18 years of age) have not been established.

The currently available data on the use of this category of patients are presented in the sections “Features of use” and “Pharmacodynamics”. The use of AZOPT® in children is not recommended.

Overdose

No cases of overdose have been reported.

In case of overdose, treatment should be symptomatic and supportive. Electrolyte imbalance, acidosis, and possible nervous system manifestations may occur. Serum electrolyte levels (especially potassium) and blood pH should be monitored.

Adverse reactions

In clinical trials involving 2732 patients using AZOPT® as monotherapy or in combination therapy with timolol maleate 5 mg/ml, the most frequently reported adverse reactions related to the use of the drug were: dysgeusia 6.0% (bitter or unusual taste, see description below) and temporary blurred vision (5.4%) after instillation, lasting from a few seconds to a few minutes (see also section "Ability to influence the speed of reactions when driving vehicles or using other mechanisms").

The following adverse reactions were assessed as being related to the use of the drug and were classified as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), rare (<1/10,000) or not known (cannot be estimated from the available data). Within each grouping, adverse reactions are presented in order of decreasing seriousness. Information on adverse reactions was obtained from clinical trials and spontaneous reports in the post-marketing period.

In clinical trials with AZOPT® eye drops, a systemic adverse reaction of dysgeusia (a bitter or unusual taste in the mouth after instillation) was commonly reported. This was most likely due to the eye drops entering the nasopharynx via the nasolacrimal duct. Applying pressure to the nasolacrimal orifice or closing the eyelids tightly after instillation may reduce the likelihood of this reaction (see also section “Method of administration and dosage”).

AZOPT® is a systemically absorbed sulfonamide carbonic anhydrase inhibitor. Systemic carbonic anhydrase inhibitors are associated with gastrointestinal, nervous system, hematological, renal, and metabolic adverse reactions. The same types of adverse reactions seen with oral carbonic anhydrase inhibitors may occur with topical administration.

No unexpected adverse reactions were observed during combination therapy with AZOPT® eye drops concomitantly with travoprost. Adverse reactions observed with combination therapy were also observed with each drug administered separately.

Children

During short-term clinical trials, approximately 12.5% of children experienced adverse reactions associated with the use of this medicinal product, the majority of which were non-serious local ophthalmological reactions of mild severity, including conjunctival hyperemia, eye irritation, eye discharge, and lacrimation increased (see section 5.1).

Once a medicinal product has been authorised, it is important to report suspected adverse reactions. This ensures continuous 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.

Expiration date

2 years. Shelf life after first opening the bottle is 4 weeks.

Storage conditions

No special storage conditions are required for the drug. Keep out of the reach of children.

Packaging

5 ml in a dropper bottle; 1 dropper bottle in a cardboard box.

Vacation category

According to the recipe.

Producer

Alcon Couvreur/Alcon Couvreur.

Location of the manufacturer and address of its place of business

Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium.