Simbrinza^® (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

S01EC54 (Brinzolamide in combination with other drugs)

Active Substances

Brinzolamide (Rec.INN registered by WHO)

Brimonidine (Rec.INN registered by WHO)

Dosage Form

Simbrinza®

Eye drops 2 mg+10 mg/1 ml: 5 ml dropper bottle

Dosage Form, Packaging, and Composition

Eye drops as a homogeneous white or almost white suspension.

Excipients: carbomer 974P, sodium chloride, mannitol, propylene glycol, tyloxapol, boric acid, benzalkonium chloride, sodium hydroxide and/or hydrochloric acid, 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

Pharmacotherapeutic Group

Antiglaucoma drugs and miotics. Carbonic anhydrase inhibitors. Brinzolamide in combination with other drugs

Pharmacological Action

Mechanism of action

Simbrinza^® contains 2 active substances: Brinzolamide and Brimonidine tartrate. These two components reduce intraocular pressure (IOP) in patients with open-angle glaucoma (OAG) and ocular hypertension (OHT) by suppressing the production of aqueous humor in the ciliary body.

Although both Brinzolamide and brimonidine reduce IOP by suppressing aqueous humor production, their mechanisms of action are different.

Brinzolamide acts by inhibiting the enzyme carbonic anhydrase type II (CA-II) in the ciliary epithelium, which reduces the formation of bicarbonate ions with a subsequent reduction in the passage of sodium and fluid through the ciliary epithelium, leading to a decrease in aqueous humor production.

Brimonidine, an α₂-adrenergic receptor agonist, inhibits the enzyme adenylate cyclase and suppresses cAMP-dependent aqueous humor production. In addition, the use of brimonidine leads to an increase in uveoscleral outflow.

Pharmacokinetics

Brinzolamide

Absorption

After topical application, Brinzolamide is absorbed through the cornea. The substance also penetrates into the systemic circulation, where it binds strongly to carbonic anhydrase in erythrocytes. Plasma concentrations of brinzolamide are very low. The T_1/2 from blood in humans is long (>100 days), due to binding to erythrocyte carbonic anhydrase.

A clinical study investigated the pharmacokinetics of Simbrinza^® with topical administration 2 and 3 times/day compared to monotherapy with brinzolamide and brimonidine, administered in the same dosing regimens.

The pharmacokinetics of brinzolamide and N-desethylbrinzolamide in whole blood at steady-state C_ss were similar with the use of the combined drug Simbrinza^® and brinzolamide monotherapy.

Distribution

In rabbit studies, C_max of brinzolamide in eye tissues after topical application is reached in the anterior segment of the eye: in the cornea, conjunctiva, aqueous humor, iris, and ciliary body. The prolonged presence in eye tissues is due to the binding of the drug to carbonic anhydrase. Brinzolamide is moderately bound (about 60%) to human plasma proteins.

Metabolism

Brinzolamide is metabolized by cytochrome P450 isoenzymes in the liver, particularly CYP3A4, CYP2A6, CYP2B6, CYP2C8, and CYP2C9. The main metabolite is N-desethylbrinzolamide, followed by N-desmethoxypropyl and O-desmethyl metabolites, as well as an N-propionic acid analog formed by oxidation of the N-propyl side chain of O-desmethylbrinzolamide. Brinzolamide and N-desethylbrinzolamide do not inhibit cytochrome P450 isoenzymes at concentrations at least 100 times greater than the maximum systemic concentrations.

Excretion

Brinzolamide is primarily excreted unchanged in the urine. In humans, 60% of brinzolamide and 6% of N-desethylbrinzolamide of the administered dose are detected in the urine. In rats, excretion of the drug in bile (about 30% of the administered dose) was also shown, predominantly as metabolites.

Brimonidine

Absorption

Brimonidine is rapidly absorbed into the eye tissues after topical application. In rabbit studies, C_max in eye tissues was reached in most cases in less than 1 hour. Maximum plasma concentrations in humans are <1 ng/ml and are reached within <1 hour. The T_1/2 from plasma is about 2-3 hours. No accumulation is observed with constant use.

The pharmacokinetics of brimonidine at steady-state C_ss in plasma with the use of the fixed combination were similar to those observed with the separate use of brimonidine, except for the group using Simbrinza^® 2 times/day, in which the mean AUC_0-12 was approximately 25% lower than with brimonidine monotherapy 2 times/day.

Distribution

Brimonidine exhibits affinity for pigmented eye tissues, in particular, the iris and ciliary body, due to the known ability of the molecule to bind to melanin. However, clinical and preclinical safety data show that the drug is well tolerated and safe with constant use.

Metabolism

Brimonidine is extensively metabolized by hepatic aldehyde oxidase to form 2-oxobrimonidine, 3-oxobrimonidine, and 2,3-dioxobrimonidine, which are the main metabolites. Oxidative cleavage of the imidazoline ring to 5-bromo-6-guanidinoquinoxaline is also observed.

Excretion

Brimonidine is excreted primarily in the urine as metabolites. In preclinical in vivo experiments, metabolites in urine accounted for 60 to 75% of the administered dose for both oral and intravenous routes of administration.

Linearity/non-linearity

The pharmacokinetics of brinzolamide is inherently non-linear due to saturable binding to carbonic anhydrase in whole blood and various tissues. Steady-state exposure does not increase proportionally with the dose.

In contrast, brimonidine exhibits linear pharmacokinetics in the clinical therapeutic dose range.

Pharmacokinetic-pharmacodynamic relationship

Simbrinza^® is intended for local action within the eye tissues. Assessment of intraocular exposure to effective doses in humans is not possible. The influence of the drug’s pharmacokinetics and pharmacodynamics in humans on IOP reduction has not been established.

Other special patient populations

Studies to determine the influence of age, race, renal or hepatic impairment on the use of Simbrinza^® have not been conducted.

A study of brinzolamide use in Japanese subjects compared to patients of other nationalities showed similar systemic pharmacokinetics in both groups.

A study of brinzolamide in patients with renal impairment showed that the systemic exposure to brinzolamide and N-desethylbrinzolamide in patients with moderate renal impairment was 1.6-2.8 times higher than in patients with normal renal function. This increase in C_ss of the drug and its metabolites did not cause inhibition of erythrocyte carbonic anhydrase to levels associated with systemic side effects. However, the use of the combination drug is contraindicated in patients with severe renal impairment (CrCl <30 ml/min).

C_max, AUC, and T_1/2 of brimonidine are similar in elderly patients (>65 years) and younger adult patients.

The effect of renal and hepatic impairment on the systemic pharmacokinetics of brimonidine has not been evaluated. Given the low systemic exposure to brimonidine after topical ophthalmic application, it is assumed that changes in plasma exposure will not be clinically significant.

Children. The systemic pharmacokinetics of brinzolamide and brimonidine, either as monotherapy or in combination, has not been studied in pediatric patients.

Indications

• Reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension, in whom monotherapy does not provide sufficient IOP reduction.

ICD codes

Dosage Regimen

The drug is intended for topical (ophthalmic) use.

Adults

1 drop into the affected eye(s) up to 2 times/day.

The bottle must be shaken well before use.

After removing the cap, if the tamper-evident ring is not attached to the neck, it must be removed before using the drug.

After applying the drug, to reduce the risk of systemic adverse reactions, it is recommended to close the eyelids and apply light pressure with a finger to the area of the lacrimal sacs at the inner corner of the eye for 2 minutes after instillation of the drug – this reduces systemic absorption of the drug and enhances the local effect (see section “Special Instructions”).

Do not touch the tip of the bottle dropper to the eyelids and other surfaces to avoid contamination of the solution. Also avoid contact of the tip of the dropper bottle with the eyes, as such contact may injure the eye.

The bottle should be tightly closed after use. Store the bottle tightly closed when the drug is not in use.

When switching from another antiglaucoma ophthalmic drug to Simbrinza^®, the other drug should first be discontinued and Simbrinza^® should be started only the next day.

Simbrinza^® can be used concomitantly with other topical ophthalmic drugs to reduce IOP. If more than one topical ophthalmic drug is used, an interval of at least 5 minutes should be observed between the applications of the drugs.

If a dose is missed, treatment should be continued with the next dose according to the schedule. The dose should not exceed 1 drop in the affected eye(s) 2 times/day.

Special patient groups

Elderly patients (over 65 years)

No dose adjustment is required in patients over 65 years of age.

Patients with hepatic and/or renal impairment

The use of Simbrinza^® in patients with hepatic impairment has not been studied, so it is recommended to use the drug with caution in such patients (see subsection “With caution”). The use of Simbrinza^® has not been studied in patients with severe renal impairment (CrCl <30 ml/min) and patients with hyperchloremic acidosis. Since Brinzolamide in Simbrinza^® and its metabolites are primarily excreted by the kidneys, Simbrinza^® is contraindicated in such patients (see section “Contraindications”).

Children

The safety and efficacy of Simbrinza^® in children and adolescents from 2 to 18 years have not been studied, therefore the use of the drug in this category of patients is not recommended (see section “Contraindications”). Simbrinza^® is contraindicated for use in newborns and children under 2 years of age for safety reasons (see section “Contraindications”).

Adverse Reactions

In clinical studies with the use of Simbrinza^® 2 times/day, the most common ADRs were eye hyperemia and allergic-type eye reactions, occurring in approximately 6-7% of patients, and dysgeusia (bitter or unusual taste in the mouth after instillation), observed in approximately 3% of patients.

The following ADRs were reported during clinical studies with the use of Simbrinza^® 2 times/day, as well as during clinical studies and post-marketing surveillance with the use of the individual components, brinzolamide and brimonidine.

ADRs observed in clinical studies are presented by system organ class of the MedDRA dictionary.

ADRs are classified according to the following classification (CIOMS III): very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000); very rare (<1/10000); unknown (cannot be estimated from the available data (post-marketing reports and literature sources)).

Within each frequency group, ADRs are presented in order of decreasing importance.

Infections and infestations uncommon – nasopharyngitis², pharyngitis², sinusitis²; frequency unknown – rhinitis².

Blood and lymphatic system disorders uncommon – decreased red blood cell count², increased blood chloride level².

Immune system disorders uncommon – hypersensitivity³.

Psychiatric disorders uncommon – apathy², depression^2,3, depressed mood², insomnia¹, decreased libido², nightmares², nervousness².

Nervous system disorders common – somnolence¹, dizziness³, dysgeusia¹; uncommon – headache¹, impaired motor function², amnesia², memory impairment², paresthesia²; very rare – syncope³; frequency unknown – tremor², hypoesthesia², ageusia².

Eye disorders common – eye allergic reaction¹, keratitis¹, eye pain¹, eye discomfort¹, visual field defect¹, vision abnormal³, eye hyperemia¹, conjunctival blanching³; uncommon – corneal erosion¹, corneal edema², blepharitis¹, corneal deposits (corneal precipitates)¹, conjunctival disorders (papillae)¹, photophobia¹, photopsia², eye swelling², eyelid edema¹, conjunctival edema¹, dry eye¹, eye discharge¹, visual acuity reduced², hypersecretory lacrimation¹, pterygium², eyelid erythema¹, meibomitis², diplopia², glare², eye hypoesthesia², scleral pigmentation², subconjunctival cyst², eye foreign body sensation¹, asthenopia¹; very rare – uveitis³, miosis³; frequency unknown – visual impairment², madarosis².

Ear and labyrinth disorders uncommon – vertigo¹, tinnitus².

Cardiac disorders uncommon – cardiorespiratory distress², angina pectoris², arrhythmia³, palpitations^2,3, irregular heartbeat², bradycardia^2,3, tachycardia³.

Vascular disorders uncommon – hypotension¹; very rare – hypertension³.

Respiratory, thoracic and mediastinal disorders uncommon – dyspnea², bronchial hyperreactivity², pharyngolaryngeal pain², throat dryness¹, cough², epistaxis², upper airway congestion², nasal congestion¹, rhinorrhea², pharyngeal irritation², nasal dryness¹, postnasal drip¹, sneezing²; frequency unknown – asthma².

Gastrointestinal disorders common – dry mouth¹; uncommon – dyspepsia¹, esophagitis², abdominal discomfort¹, diarrhea², vomiting², nausea², frequent bowel movements², flatulence², oral hypoesthesia², oral paresthesia¹.

Hepatobiliary disorders frequency unknown – abnormal liver function test results².

Skin and subcutaneous tissue disorders uncommon – contact dermatitis¹, urticaria², rash², maculo-papular rash², generalized pruritus², alopecia², skin turgor decreased²; frequency unknown – Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), facial edema³, dermatitis^2,3, erythema^2,3.

Musculoskeletal and connective tissue disorders uncommon – back pain², muscle spasms², myalgia²; frequency unknown – arthralgia², limb pain².

Renal and urinary disorders uncommon – renal pain²; frequency unknown – pollakiuria².

Reproductive system and breast disorders uncommon – erectile dysfunction².

General disorders and administration site conditions uncommon – pain², chest discomfort², malaise², anxiety sensation², irritability², drug residue¹; frequency unknown – chest pain², peripheral edema^2,3.

¹Adverse reactions observed with the use of Simbrinza^®.

²Additional adverse reactions observed with brinzolamide monotherapy.

³Additional adverse reactions observed with brimonidine monotherapy.

Post-marketing experience

During post-marketing use of drugs containing Brinzolamide, the following ADRs 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.

Description of selected adverse reactions

Dysgeusia was the most common systemic adverse reaction associated with the use of Simbrinza^® (3.4%). This is likely due to the eye drops entering the nasopharynx through the nasolacrimal duct and mainly due to the presence of brinzolamide in Simbrinza^®. Occlusion of the nasolacrimal duct or gentle eyelid closure after instillation may reduce the frequency of this effect (see “Dosage Regimen”).

The drug Simbrinza^® contains Brinzolamide, a sulfonamide carbonic anhydrase inhibitor that enters the systemic circulation. Effects on the gastrointestinal tract, nervous system, blood system, kidneys, and metabolism are primarily associated with the systemic action of carbonic anhydrase inhibitors. When carbonic anhydrase inhibitors are applied topically, the same adverse reactions may develop as with oral administration.

Adverse reactions associated with the content of brimonidine in the drug Simbrinza^® include the development of allergic eye reactions, increased fatigue and/or drowsiness, and dry mouth. The use of brimonidine is associated with a minimal decrease in blood pressure. In some patients who received the drug Simbrinza^®, a decrease in blood pressure was observed, similar to that observed with brimonidine monotherapy.

If any of the side effects mentioned in the instructions worsen or any other side effects not listed in the instructions are noticed, a doctor should be informed.

Contraindications

• Hypersensitivity to the active or excipients, or to sulfonamides;
• Therapy with MAO inhibitors;
• Use of antidepressants affecting noradrenergic transmission (e.g., tricyclic antidepressants and mianserin);
• Severe renal impairment;
• Hyperchloremic acidosis;
• Neonates and children under 2 years of age.

With caution

• History of angle-closure glaucoma;
• Hepatic impairment;
• Corneal disorders;
• Severe, unstable and/or uncontrolled cardiovascular diseases;
• Depression;
• Cerebral or coronary insufficiency, Raynaud’s syndrome, orthostatic hypotension, or thromboangiitis obliterans;
• Pregnancy and breastfeeding period (see section “Pregnancy and Lactation”);
• Children aged 2 to 18 years due to insufficient data on efficacy and safety;
• With simultaneous use with substances that depress the central nervous system;
• With concomitant use with drugs that may affect the metabolism and uptake of circulating amines;
• With concomitant use with antihypertensive agents and/or cardiac glycosides;
• With simultaneous treatment (or dose change) with systemic drugs (regardless of dosage form) that may interact with α-adrenergic receptor agonists or interfere with their activity;
• Contact lens wear;
• Patients at risk of renal impairment.

Use in Pregnancy and Lactation

Pregnancy

Data on the use of the drug Simbrinza^® in pregnant women are absent or limited.

Brinzolamide did not show teratogenic effects in rats and rabbits after systemic administration.

In studies of oral administration of brinzolamide in animals, no direct adverse effects on reproductive function were identified.

In reproductive toxicity studies, Brinzolamide, when administered orally to rats during organogenesis, showed toxic effects on the fetus at a dose that, based on body weight (BW), was 375 times the maximum recommended human ophthalmic dose (MRHOD). In rabbits administered Brinzolamide orally during organogenesis at a dose that, based on BW, exceeded the MRHOD by 125 times, no toxic effects on the fetus were observed.

In rats and rabbits administered brimonidine orally during organogenesis at doses that, based on plasma concentration, exceeded the MRHOD by 107 and 27 times, respectively, no signs of teratogenic effects or embryotoxicity were noted.

In animal studies, brimonidine crossed the placenta and entered the fetal bloodstream in limited amounts.

It is not recommended to use the drug Simbrinza^® during pregnancy and in women of reproductive potential not using reliable contraception.

During pregnancy, the drug Simbrinza^® should be used only if the expected benefit to the mother outweighs the potential risk to the fetus.

Breastfeeding period

Data on the effect of brinzolamide or brimonidine tartrate on milk production in breastfeeding women or on the breastfed infant are not available.

It is unknown whether Brinzolamide or brimonidine passes into breast milk in women after topical ophthalmic administration of the drug Simbrinza^®.

In lactating rats that orally received Brinzolamide or brimonidine in two different studies, the latter were detected in breast milk.

The risk to the breastfed infant cannot be ruled out. The decision to discontinue breastfeeding or discontinue/abstain from therapy with the drug should be made taking into account the benefit of breastfeeding for the child and the benefit of therapy for the woman.

Fertility

No studies on the effects of topical ophthalmic use of the drug Simbrinza^® on human fertility have been conducted. In rats, no effect of brinzolamide (at doses up to 375 times the MRHOD based on BW) and brimonidine (at doses up to 60 times the MRHOD based on AUC) on fertility was identified.

No effect on male or female fertility is expected with topical ophthalmic use of the drug Simbrinza^® in humans.

Use in Hepatic Impairment

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

Use in Renal Impairment

The use of the drug Simbrinza^® has not been studied in patients with severe renal impairment (CrCl <30 ml/min) and patients with hyperchloremic acidosis. Since Brinzolamide in the drug Simbrinza^® and its metabolites are primarily excreted by the kidneys, the drug Simbrinza^® is contraindicated in such patients. with caution – in patients at risk of renal impairment.

Pediatric Use

The drug Simbrinza^® is contraindicated for use in neonates and children under 2 years of age for safety reasons (see section “Contraindications”). With caution – in children aged 2 to 18 years due to insufficient data on efficacy and safety.

Geriatric Use

In patients over 65 years of age, dose adjustment is not required.

Special Precautions

The medicinal product should not be administered by injection. Patients should be instructed not to take the drug Simbrinza^® orally.

Effect on the organ of vision

The use of the drug Simbrinza^® has not been studied in patients with angle-closure glaucoma and its use in such patients is not recommended.

The potential effect of brinzolamide on corneal endothelial function in patients with corneal disorders (especially in patients with a low number of endothelial cells) has not been studied. The use of the drug in patients who wear contact lenses has also not been studied, therefore close monitoring of such patients when using brinzolamide is recommended, as carbonic anhydrase inhibitors may affect corneal hydration, and contact lens wear may increase the risk of corneal damage; detailed instructions for contact lens wear are provided below in the subsection “Benzalkonium chloride”. Close monitoring is recommended for patients with corneal disorders, including patients with diabetes or corneal dystrophy.

Brimonidine tartrate may cause allergic eye reactions. If allergic reactions occur, treatment with the drug should be discontinued. There are reports of delayed-type hypersensitivity reactions in the eye with the use of brimonidine tartrate, in some cases accompanied by increased intraocular pressure.

Potential effects after discontinuation of treatment with the drug Simbrinza^® have not been studied. While the duration of the intraocular pressure-lowering effect for the drug Simbrinza^® has not been studied, the intraocular pressure-lowering effect of brinzolamide is expected to last for 5-7 days. The reduction in intraocular pressure with brimonidine use may last longer.

Systemic effects

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. Before prescribing the drug, the patient should be informed about the relevant signs and symptoms and the need to monitor for their occurrence. Systemic absorption can be minimized by nasolacrimal occlusion.

Cardiac disorders

After using the drug Simbrinza^®, a slight decrease in blood pressure was observed in some patients. Caution is recommended with concomitant use of antihypertensive drugs and/or cardiac glycosides, as well as in patients with severe or unstable and uncontrolled cardiovascular diseases (see section “Drug Interactions”). Although in clinical studies the drug Simbrinza^® had a minimal effect on blood pressure, it should be used with caution in patients with severe cardiovascular diseases because it contains Brimonidine tartrate.

Because the drug Simbrinza^® contains Brimonidine tartrate, it should be used with caution in patients with depression, cerebral circulatory insufficiency or coronary insufficiency, Raynaud’s syndrome, orthostatic hypotension, or thromboangiitis obliterans.

Acid-base balance disorders

Acid-base balance disorders have been reported with the use of oral carbonic anhydrase inhibitors. The drug Simbrinza^® contains Brinzolamide, a carbonic anhydrase inhibitor that, despite topical application, enters the systemic circulation. When the drug Simbrinza^® is applied topically, the same adverse reactions may occur as with the use of oral carbonic anhydrase inhibitors (i.e., acid-base balance disorders) (see section “Drug Interactions”).

The drug should be used with caution in patients at risk of renal impairment due to the possible risk of metabolic acidosis. The drug Simbrinza^® is contraindicated in patients with severe renal impairment (see section “Contraindications”).

Hepatic impairment

The use of the drug Simbrinza^® has not been studied in patients with hepatic impairment; caution should be exercised when treating such patients (see section “Dosage Regimen”).

Ability to concentrate

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring concentration and/or physical coordination in elderly patients. The drug Simbrinza^® enters the systemic circulation, so these phenomena may be observed with topical use of the drug (see subsection “Effect on ability to drive and operate machinery”).

Benzalkonium chloride

The drug Simbrinza^® contains benzalkonium chloride, which may cause eye irritation and discolour soft contact lenses. Contact of the drug with soft contact lenses should be avoided. Patients should be instructed to remove contact lenses before instilling the drug Simbrinza^® and wait at least 15 minutes before reinserting them.

Benzalkonium chloride has been reported to cause eye irritation and dry eye symptoms, and may affect the tear film and corneal surface. It should be used with caution in patients with dry eye syndrome and in patients where the cornea may be damaged. Benzalkonium chloride may cause toxic ulcerative/punctate keratopathy with prolonged use of the drug by patients with concomitant corneal diseases. With prolonged use, careful monitoring is required.

Use in children

The safety and efficacy of the drug Simbrinza^® in children and adolescents from 2 to 18 years of age have not been established. In cases where brimonidine eye drops were used as part of the treatment of congenital glaucoma in neonates and infants, symptoms of brimonidine overdose (such as loss of consciousness, decreased blood pressure, hypotension, bradycardia, hypothermia, cyanosis, and apnea) were reported. The drug Simbrinza^® is contraindicated in children under 2 years of age (see section “Contraindications”).

Treatment of children aged 2 years and older (especially those 2-7 years old and/or weighing less than 20 kg) is not recommended due to the possible occurrence of central nervous system side effects (see section “Overdose”).

Effect on ability to drive and operate machinery

The drug Simbrinza^® has a moderate influence on the ability to drive and use machines.

The drug Simbrinza^® may cause dizziness, fatigue and/or drowsiness, which may have a negative effect on the ability to drive or operate machinery.

Temporary blurred vision or other visual disturbances may occur, which may affect the ability to drive and use machinery. If blurred vision occurs during the use of the drug, the patient must wait until vision is restored before driving or operating machinery.

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring concentration and/or physical coordination in elderly patients (see “Special Precautions”).

Overdose

In case of overdose of the drug Simbrinza^®, symptomatic and supportive therapy should be administered. The patient’s airway patency should be monitored.

Due to the presence of brinzolamide in the drug Simbrinza^®, electrolyte imbalance, acidosis, and nervous system disorders may occur. Serum electrolyte levels (particularly potassium) and blood pH should be monitored.

There is very limited information regarding accidental ingestion of brimonidine as part of the drug Simbrinza^® in adult patients. To date, the only reported adverse reaction is decreased blood pressure. It has been reported that an episode of hypotension was accompanied by a rebound increase in blood pressure.

There are reports that overdose with other oral α₂-agonists causes symptoms such as decreased blood pressure, asthenia, vomiting, lethargy, sedation, bradycardia, arrhythmias, miosis, apnea, hypotension, hypothermia, respiratory depression, and convulsions.

Children

There are reports of serious adverse reactions in children after accidental ingestion of brimonidine (as part of the drug Simbrinza^®). Patients experienced symptoms of central nervous system depression: temporary development of coma or reduced level of consciousness, lethargy, drowsiness, hypotension, bradycardia, hypothermia, pallor, respiratory depression, and apnea, which required hospitalization in the intensive care unit and intubation as indicated. According to reports, all phenomena were reversible, usually within 6-24 hours.

Drug Interactions

Specific drug interaction studies with the drug Simbrinza^® have not been conducted.

Based on the drug interactions possible for each component, the following interactions are expected for the drug Simbrinza^®.

The drug Simbrinza^® is contraindicated in patients receiving MAO inhibitors and antidepressants affecting noradrenergic transmission (e.g., tricyclic antidepressants and mianserin) (see section “Contraindications”). Tricyclic antidepressants may reduce the ability of the drug Simbrinza^® to lower intraocular pressure.

Caution is recommended with concomitant use with substances that depress the central nervous system (alcohol, barbiturates, opiates, sedatives, or anesthetics) due to the possibility of an additive or potentiating effect.

Data on the concentration of circulating catecholamines after using the drug Simbrinza^® are not available. However, caution is recommended when treating patients receiving drugs that may affect the metabolism and uptake of circulating amines (e.g., chlorpromazine, methylphenidate, reserpine, serotonin-norepinephrine reuptake inhibitors).

Drugs of the class of α-adrenergic receptor agonists (e.g., Brimonidine tartrate) may reduce heart rate and lower blood pressure. After using the drug Simbrinza^®, a slight decrease in blood pressure was observed in some patients.

Caution is recommended with concomitant use of the drug Simbrinza^® with antihypertensive drugs and/or cardiac glycosides. Caution is recommended when initiating concomitant treatment (or changing the dose) with systemically acting drugs (regardless of dosage form) that may interact with α-adrenergic receptor agonists or interfere with their activity, i.e., agonists or antagonists of adrenergic receptors (e.g., isoprenaline, prazosin).

Brinzolamide is a carbonic anhydrase inhibitor that, despite topical application, enters the systemic circulation. Acid-base balance disorders have been reported with the use of oral carbonic anhydrase inhibitors. Possible interactions should be considered in patients receiving the drug Simbrinza^®.

There is a possibility of enhancement of the known systemic effects of carbonic anhydrase inhibitors in patients receiving an oral carbonic anhydrase inhibitor and topical Brinzolamide. Concomitant use of the drug Simbrinza^® and oral carbonic anhydrase inhibitors is not recommended.

Cytochrome P450 isoenzymes responsible for the metabolism of brinzolamide include CYP3A4 (major), CYP2A6, CYP2B6, CYP2C8, and CYP2C9. CYP3A4 inhibitors such as ketoconazole, itraconazole, clotrimazole, ritonavir, and troleandomycin are expected to inhibit the CYP3A4-mediated metabolism of brinzolamide. Caution is recommended with concomitant use of CYP3A4 inhibitors. However, accumulation of brinzolamide is unlikely, as the primary route of elimination is renal. Brinzolamide is not an inhibitor of cytochrome P450 isoenzymes.

Storage Conditions

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

Shelf Life

Shelf life – 2 years. Do not use after the expiry date stated on the packaging.

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.