Azopt^® (Drops) Instructions for Use

Marketing Authorization Holder

Novartis Pharma AG (Switzerland)

Manufactured By

Novartis Manufacturing NV (Belgium)

Contact Information

NOVARTIS PHARMA LLC (Russia)

ATC Code

S01EC04 (Brinzolamide)

Active Substance

Brinzolamide (Rec.INN registered by WHO)

Dosage Form

Azopt®

Eye drops 10 mg/1 ml: dropper bottle 5 ml

Dosage Form, Packaging, and Composition

Eye drops as a homogeneous white or almost white suspension.

Excipients: benzalkonium chloride – 0.1 mg/ml, disodium edetate, sodium chloride, tyloxapol, mannitol, carbomer (974P), sodium hydroxide and/or hydrochloric acid (to adjust pH), purified water.

5 ml – low-density polyethylene dropper bottles (1) – cardboard packs.

The presence of a first-opening control on the cardboard pack is allowed.

Clinical-Pharmacological Group

Antiglaucoma drug – topical carbonic anhydrase inhibitor

Pharmacotherapeutic Group

Drugs used in ophthalmology; antiglaucoma drugs and miotic agents; carbonic anhydrase inhibitors

Pharmacological Action

Mechanism of action

Brinzolamide is a carbonic anhydrase II inhibitor. Inhibition of carbonic anhydrase II slows the formation of bicarbonate ions with a subsequent reduction in sodium and fluid transport, leading to a decrease in the production of intraocular fluid in the ciliary body of the eye. As a result, intraocular pressure (IOP) is reduced.

Clinical efficacy and safety

The IOP-lowering effect of Azopt^® was studied when used as adjunctive therapy to the prostaglandin analogue travoprost. After a 4-week introductory course of treatment with travoprost, patients with IOP ≥19 mm Hg were randomized to receive adjunctive therapy with brinzolamide or timolol. An additional reduction in mean diurnal IOP of 3.2-3.4 mm Hg was observed in the brinzolamide group and 3.2-4.2 mm Hg in the timolol group. Overall, a higher frequency of non-serious ocular adverse reactions, mainly related to signs of local irritation, was observed in the brinzolamide/travoprost group. The events were mild and did not affect the overall number of patients who discontinued treatment in the study.

Azopt^® was studied in a clinical trial of 32 children under 6 years of age diagnosed with glaucoma or ocular hypertension. Some patients had not previously received IOP-lowering therapy, while others were using other IOP-lowering medications. Those who were previously using IOP-lowering medications did not need to discontinue these medications before starting monotherapy with Azopt^®. Among patients not previously treated with IOP-lowering drugs (10 patients), the efficacy of Azopt^® was similar to that previously observed in adults, with a mean IOP reduction from baseline within 5 mm Hg. Among patients previously treated with IOP-lowering drugs (22 patients), the mean IOP increased slightly compared to baseline.

Preclinical safety data

Preclinical data on brinzolamide from standard single-dose toxicity, repeat-dose toxicity, genotoxicity, carcinogenic potential, and local eye irritation studies revealed no special hazard to humans.

Studies on the toxic effects on embryo-fetal development were conducted in pregnant rats administered Brinzolamide at doses of 0, 2, 6, or 18 mg/kg/day via gastric intubation on days 6-17 of pregnancy, corresponding to the period of organogenesis. A reduction in maternal body weight gain was observed at doses of 6 and 18 mg/kg/day. Reduced fetal body weight and decreased skeletal ossification were observed at a dose of 18 mg/kg/day (375 times the MROHD based on BW, and 60 times the MROHD based on Body Surface Area, BSA). The No Observed Effect Level (NOEL) was 2 mg/kg/day (42 times the MROHD based on BW, and 7 times the MROHD based on BSA).

Studies on the toxic effects on embryo-fetal development were conducted in pregnant rabbits administered Brinzolamide at doses of 0, 1, 3, or 6 mg/kg/day via gastric intubation on days 6-18 of pregnancy, corresponding to the period of organogenesis. Maternal body weight loss during pregnancy was observed at a dose of 3 mg/kg/day (63 times the MROHD based on BW, and 20 times the MROHD based on BSA) and higher. At a dose of 6 mg/kg/day, females experienced fatalities, exhaustion, absence of stool, and miscarriages. The NOEL for maternal toxicity was 1 mg/kg/day (21 times the MROHD based on BW, and 7 times the MROHD based on BSA). No treatment-related effects on the fetus were observed up to the maximum tested dose of 6 mg/kg/day (125 times the MROHD based on BW, and 41 times the MROHD based on BSA).

In a peri-/postnatal study in rats, Brinzolamide was administered orally at doses of 1, 5, and 15 mg/kg/day from day 16 of pregnancy until day 20 of lactation. Reduced food intake and average body weight gain were observed in parental females during pregnancy and lactation at a dose of 15 mg/kg/day. Reduced offspring body weight was observed at a dose of 15 mg/kg/day (313 times the MROHD based on BW, and 51 times the MROHD based on BSA). The NOEL for maternal and ontogenetic toxicity was 5 mg/kg/day (104 times the MROHD based on BW, and 17 times the MROHD based on BSA).

After oral administration of ¹⁴C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta, and radioactivity levels in fetal tissues were 3-10 times lower than the levels measured in females.

Pharmacokinetics

Absorption

When applied topically, Brinzolamide penetrates into the systemic circulation. Brinzolamide accumulates in erythrocytes due to selective binding to carbonic anhydrase II. The metabolite N-desethyl brinzolamide is also formed, which also binds to carbonic anhydrase and accumulates in erythrocytes. In the presence of brinzolamide, this metabolite binds primarily to carbonic anhydrase I.

Distribution

In blood plasma, concentrations of brinzolamide and its metabolite are below the quantitation limit (<10 ng/ml). Plasma protein binding is about 60%.

Elimination

T_1/2 is 111 days. Brinzolamide is excreted mainly unchanged in the urine. The main metabolite (N-desethyl Brinzolamide) and low concentrations of other metabolites (N-desmethoxypropyl and O-desmethyl) are also found in the urine.

Indications

Adults for the reduction of elevated intraocular pressure in

• Open-angle glaucoma;
• Ocular hypertension.

ICD codes

Dosage Regimen

The drug is instilled as 1 drop into the conjunctival sac of the affected eye (or eyes) 2 times/day.

The bottle should be shaken before use.

The recommended dose is 1 drop into the conjunctival sac of the affected eye(s) 2 times/day. Some patients may achieve a better therapeutic effect with 1 drop 3 times/day.

If a dose is missed, treatment should be continued with the next scheduled dose. The dose should not exceed 1 drop into the affected eye(s) 3 times/day.

Special patient groups

Elderly patients (65 years and older)

No dose adjustment is required in elderly patients.

Patients with renal impairment

The use of Azopt^® has not been studied in patients with severe renal impairment (CrCl <30 ml/min/1.73 m²) or in patients with hyperchloremic acidosis. Since Brinzolamide and its main metabolite are excreted primarily by the kidneys, Azopt^® is contraindicated in such patients (see also the section “Contraindications”).

Patients with hepatic impairment

The use of Azopt^® has not been studied in patients with hepatic impairment, therefore the use of the drug in such patients is not recommended.

Children

The safety and efficacy of Azopt^® in patients under 18 years of age have not been established. The use of Azopt^® in children is not recommended.

Method of administration

For topical ophthalmic use.

Shake the bottle before use.

After removing the cap, if the tamper-evident ring is loose, it must be removed before using the drug.

Do not touch the tip of the dropper bottle to the eyelids or any surface to avoid contamination of the dropper bottle and its contents.

The bottle must be closed after each use.

After application, nasolacrimal occlusion or gently closing the eye is recommended. This may reduce the systemic absorption of the drug when applied topically and thereby reduce the likelihood of systemic adverse reactions.

When replacing another ophthalmic drug for glaucoma with Azopt^®, the other drug should be discontinued and therapy with Azopt^® should be started the next day. If more than one topical ophthalmic drug is used, an interval of at least 5 minutes should be observed between successive drug applications. Eye ointments should be applied last.

Adverse Reactions

Summary of the safety profile

In clinical studies involving 2732 patients receiving Azopt^® as monotherapy or as adjunctive therapy to timolol maleate 5 mg/ml, the most frequent treatment-related adverse reactions (ARs) were: dysgeusia (6.0%) (bitter or unusual taste, see description below) and temporary blurred vision after instillation (5.4%), lasting from a few seconds to several minutes (see also the subsection “Effects on ability to drive and use machines”).

Tabulated summary of adverse reactions

The following ARs were observed during clinical studies and post-marketing use of the drug and are classified according to the following frequency gradation: very common (≥1/10), common (from ≥1/100 to <1/10), uncommon (from ≥1/1000 to <1/100), rare (from ≥1/10000 to <1/1000), very rare (<1/10000), frequency not known (cannot be estimated from the available data). Within each group, ARs are listed in descending order of their severity.

Post-marketing experience

During post-marketing use of drugs containing Brinzolamide, the following ARs have been identified, the frequency and causal relationship of which with the drug action cannot be established: serious skin and subcutaneous tissue disorders, such as Stevens-Johnson syndrome and toxic epidermal necrolysis.

Reporting of suspected adverse reactions

It is important to report suspected adverse reactions after drug registration to ensure continuous monitoring of the benefit-risk ratio of the drug. Healthcare professionals are encouraged to report any suspected adverse drug reactions through the national adverse reaction reporting system of the member states of the Eurasian Economic Union.

Contraindications

• Hypersensitivity to the active substance or sulfonamides (see section “Special Precautions”), or to any of the excipients of the drug;
• Severe renal impairment;
• Hyperchloremic acidosis.

Use in Pregnancy and Lactation

Pregnancy

No adequate and well-controlled studies on the ophthalmic use of Azopt^® in pregnant women have been conducted.

In studies on the toxic effects on intrauterine development in rats during organogenesis, a toxic effect on fetal development was identified with oral administration of brinzolamide doses 375 times the maximum recommended ophthalmic human dose (MROHD) based on body weight (BW). However, studies in rabbits did not reveal a toxic effect on the fetus after oral administration of brinzolamide doses during organogenesis, 125 times the MROHD based on BW. Azopt^® should not be used during pregnancy except in cases of extreme necessity.

Breast-feeding period

There is insufficient data regarding the use of Azopt^® by women during breast-feeding.

There are no data on the effect of brinzolamide on breastfed infants or on milk production.

It is not known whether Brinzolamide passes into human breast milk after topical ophthalmic application. After oral administration of ¹⁴C-brinzolamide to lactating rats, radioactivity was detected in milk at concentrations lower than in blood or plasma.

The benefits of breastfeeding for development and health should be considered along with the mother’s clinical need for Azopt^® therapy and any potential adverse consequences for the breastfed child.

Fertility

No studies on the effects of Azopt^® use on human fertility have been conducted. In a fertility study in rats, no adverse effects of brinzolamide on fertility or reproductive performance of males or females were observed at doses up to 18 mg/kg/day (375 times the recommended human ophthalmic dose based on BW, and 60 times the MROHD based on BSA).

Azopt^® use is not expected to affect male or female fertility.

Use in Hepatic Impairment

The use of Azopt^® has not been studied in patients with hepatic impairment, therefore the use of the drug in such patients is not recommended.

Use in Renal Impairment

The use of Azopt^® has not been studied in patients with severe renal impairment (CrCl <30 ml/min/1.73 m²) or in patients with hyperchloremic acidosis. Since Brinzolamide and its main metabolite are excreted primarily by the kidneys, Azopt^® is contraindicated in such patients

Pediatric Use

The use of Azopt^® in children is not recommended (safety and efficacy in patients under 18 years of age have not been established).

Geriatric Use

No dose adjustment is required in elderly patients.

Special Precautions

Like other topical ophthalmic drugs, Brinzolamide is systemically absorbed. This can be minimized by nasolacrimal occlusion (see section “Dosage Regimen”).

Brinzolamide is a sulfonamide and, despite topical application as conjunctival instillations, can enter the systemic circulation and cause adverse reactions characteristic of sulfonamides. In rare cases, patients receiving sulfonamides have experienced serious intolerance reactions, including Stevens-Johnson syndrome, toxic epidermal necrolysis, fulminant hepatitis, agranulocytosis, aplastic anemia, and other blood disorders. These reactions may recur upon re-administration of a sulfonamide regardless of the route of administration. If signs of serious reactions or hypersensitivity appear, the use of the drug should be discontinued immediately. When prescribing the drug, the patient should be informed about the relevant signs and symptoms and the need to monitor for skin reactions.

The development of acid-base balance disorders has been described with the use of oral forms of carbonic anhydrase inhibitors. In patients at risk of renal tubular damage, the drug should be used with caution due to the possible risk of metabolic acidosis (see section “Dosage Regimen”).

The use of the drug has not been studied in patients with angle-closure glaucoma, therefore its use is not recommended in this group of patients.

The effect of brinzolamide on corneal endothelial function in patients with corneal disorders (especially patients with low endothelial cell counts) has not been studied. Close monitoring of such patients, including patients with diabetes or corneal dystrophy, is recommended when using brinzolamide.

Excipients

Benzalkonium chloride contained in the drug may cause eye irritation and stain soft contact lenses. Contact of the drug with soft contact lenses should be avoided. Lenses should be removed before using the drug and reinserted no earlier than 15 minutes after instillation of the drug.

Effects on ability to drive and use machines

Azopt^® has a minor influence on the ability to drive and use machines.

If after using the drug the patient experiences temporary blurred vision or other visual disturbances, it is not recommended to drive a vehicle and other machinery, or engage in activities requiring increased attention and reaction, until vision is restored.

In addition, when using the drug, disorders of the nervous system have been described (see the section “Adverse Reactions”), which may affect the ability to drive a vehicle and operate machinery.

Overdose

There is no information on overdose symptoms with topical application.

Symptoms in case of accidental ingestion of the drug may include electrolyte imbalance, development of acidosis, as well as disorders of the nervous system.

Treatment it is necessary to monitor electrolyte levels (especially potassium) and blood pH.

Drug Interactions

Studies of the interaction of the drug Azopt^® with other medicinal products have not been conducted.

The drug Azopt^® is a carbonic anhydrase inhibitor that may be systemically absorbed following topical application. There are reports of acid-base balance disturbances resulting from the use of oral carbonic anhydrase inhibitors. The possibility of such disturbances should be considered in patients using the drug Azopt^®. Concomitant use with oral carbonic anhydrase inhibitors is not recommended, as there is a possibility of increased systemic adverse reactions.

High doses of salicylates increase the risk of systemic side effects.

If necessary, the drug Azopt^® can be used in combination with other topical ophthalmic drugs. In this case, an interval of at least 5 minutes should be observed between successive applications of the drugs. Eye ointments should be applied last.

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 30°C (86°F).

Shelf Life

The shelf life is 2 years.

After opening the bottle, the drug should be used within 28 days.

Dispensing Status

The drug is dispensed by prescription.

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.