Brinzopt plus: detailed information

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRINZOPT PLUS (BRINZOPT PLUS)

Composition:

Active substances: brinzolamide, timolol maleate;

1 ml of eye drops, suspension, contains 10 mg of brinzolamide and 5 mg of timolol (as timolol maleate);

Excipients: tyloxapol, carbomer (974 P), mannitol (E 421), sodium chloride, disodium edetate, benzalkonium chloride, 0.5 M sodium hydroxide solution or 0.5 M hydrochloric acid solution (for pH adjustment), purified water.

Pharmaceutical form. Eye drops, suspension.

Main physicochemical properties: white or almost white suspension, may form a sediment that readily disperses upon shaking.

Pharmacotherapeutic group. Medicinal products used in ophthalmology. Antiglaucoma preparations and miotics. β-blockers. ATC code S01ED51.

Pharmacological Properties

Pharmacodynamics

Mechanism of Action

Brimonopt Plus ophthalmic solution contains two active substances: brinzolamide and timolol maleate. These two components reduce elevated intraocular pressure (IOP) by decreasing the secretion of aqueous humor, but they act via different mechanisms. The combined effect of these two active ingredients results in an additive reduction of IOP compared to the effect achieved with either component used alone.

Brinzolamide is a potent inhibitor of human carbonic anhydrase II (CA-II), the predominant isoenzyme in the eye. Inhibition of carbonic anhydrase in the ciliary processes of the eye reduces aqueous humor secretion, primarily by slowing the formation of bicarbonate ions, which subsequently reduces sodium and fluid transport.

Timolol is a non-selective β-adrenergic receptor blocker that lacks intrinsic sympathomimetic activity and membrane-stabilizing effects, and does not directly depress myocardial contractility. Tonography and fluorophotometric studies in humans have confirmed that its primary action is associated with reduced aqueous humor formation and a slight increase in its outflow.

Pharmacodynamic Effect

Clinical Effects

In a 12-month controlled clinical study in patients with open-angle glaucoma or ocular hypertension, who in the opinion of the investigators could benefit from combination therapy and who had a mean IOP between 25 and 27 mmHg, the mean reduction in IOP with Brimonopt Plus ophthalmic solution administered twice daily was 7 to 9 mmHg. At all time points during all patient visits, the mean reduction in IOP with dorzolamide 20 mg/mL + timolol 5 mg/mL did not exceed the effect observed with Brimonopt Plus.

In a 6-month controlled clinical study in patients with open-angle glaucoma or ocular hypertension and a mean IOP between 25 and 27 mmHg, the mean reduction in IOP with Brimonopt Plus ophthalmic solution administered twice daily was 7 to 9 mmHg, which was 3 mmHg greater than that achieved with brinzolamide 10 mg/mL twice daily and 2 mmHg greater than that achieved with timolol 5 mg/mL twice daily. A statistically significant reduction in mean IOP was observed compared to both brinzolamide and timolol at all visits throughout the study.

In three controlled clinical studies, ocular discomfort after instillation of Brimonopt Plus ophthalmic solution was significantly less than with dorzolamide 20 mg/mL + timolol 5 mg/mL.

Pharmacokinetics

Absorption

Following topical ocular administration, brinzolamide and timolol are absorbed through the cornea into the systemic circulation. In a pharmacokinetic study, healthy volunteers received oral brinzolamide 1 mg twice daily for 2 weeks to shorten the time to reach steady-state concentration before starting Brimonopt Plus ophthalmic solution. After administration of Brimonopt Plus ophthalmic solution twice daily for 13 weeks, the concentration of brinzolamide in red blood cells (RBCs) averaged 18.8 ± 3.29 µM, 18.1 ± 2.68 µM, and 18.4 ± 3.01 µM at weeks 4, 10, and 15, respectively, indicating that a stable concentration of brinzolamide is maintained in RBCs.

At steady-state following administration of Brimonopt Plus ophthalmic solution, the mean maximum plasma concentration (Cmax) and the area under the concentration-time curve (AUC0–12h) of timolol were 27% and 28% lower, respectively (Cmax 0.824 ± 0.453 ng/mL; AUC0–12h 4.71 ± 4.29 ng•h/mL) compared to those observed with timolol 5 mg/mL (Cmax 1.13 ± 0.494 ng/mL; AUC0–12h 6.58 ± 3.18 ng•h/mL). The low systemic exposure to timolol following administration of Brimonopt Plus ophthalmic solution is not clinically significant. After administration of Brimonopt Plus ophthalmic solution, the mean Cmax of timolol in plasma was reached at 0.79 ± 0.45 hours.

Distribution

Plasma protein binding of brinzolamide is moderate (approximately 60%). Due to its high affinity for CA-II and to a lesser extent for CA-I, brinzolamide penetrates into RBCs. Its active metabolite, N-desethylbrinzolamide, also accumulates in RBCs, where it primarily binds to CA-I. The affinity of brinzolamide and its metabolite for RBCs and tissue CA results in low plasma concentrations.

Tissue distribution data from rabbits demonstrated that timolol can be quantitatively detected in aqueous humor for up to 48 hours after administration of Brimonopt Plus ophthalmic solution. At steady-state, timolol can be detected in human plasma for up to 12 hours after administration of Brimonopt Plus ophthalmic solution.

Metabolism

Brinzolamide metabolism involves N-dealkylation, O-dealkylation, and oxidation of its N-propyl side chain. N-desethylbrinzolamide is the main metabolite of brinzolamide in humans. It binds to CA-I in the presence of brinzolamide and accumulates in RBCs. In vitro studies have shown that brinzolamide metabolism is primarily mediated by CYP3A4, as well as at least four other isoenzymes (CYP2A6, CYP2B6, CYP2C8, and CYP2C9).

Timolol is metabolized via two pathways. One involves the formation of an ethanolamine side chain in the thiadiazole ring, and the other involves the formation of an ethanolic side chain on the morpholine nitrogen and a second similar side chain with a carbonyl group adjacent to the nitrogen. Timolol metabolism is primarily mediated by CYP2D6.

Excretion

Brinzolamide is primarily excreted by the kidneys (approximately 60%). Nearly 20% of the dose is found in urine as metabolite. Brinzolamide and N-desethylbrinzolamide are the main components detected in urine, along with trace amounts of N-desmethoxypropyl and O-desmethyl metabolites (<1%).

Timolol and its metabolites are primarily excreted by the kidneys. Approximately 20% of the timolol dose is excreted unchanged in urine, with the remainder excreted as metabolites. The plasma half-life (t1/2) of timolol is 4.8 hours after administration of Brimonopt Plus ophthalmic solution.

Safety Preclinical Data

Brinzolamide

Preclinical data indicate no risk to humans from brinzolamide, as demonstrated by single-dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenic potential, and ocular irritation studies.

In rabbit studies with oral doses of brinzolamide up to 6 mg/kg/day (214 times the recommended daily clinical dose of 28 µg/kg/day), no effects on fetal development were observed despite significant maternal toxicity. Similar studies in rats revealed minor reductions in fetal skull and sternum ossification in dams receiving brinzolamide at 18 mg/kg/day (642 times the recommended daily clinical dose). However, this effect was not observed in dams receiving 6 mg/kg/day. These findings occurred at doses causing metabolic acidosis, reduced maternal body weight gain, and reduced fetal weight. Dose-dependent reductions in fetal weight were observed in dams receiving oral brinzolamide: from minor reductions (approximately 5–6%) at 2 mg/kg/day to approximately 14% at 18 mg/kg/day. No adverse effects on offspring were observed during lactation at a dose of 5 mg/kg/day.

Timolol

Preclinical data indicate no risk to humans from timolol, as demonstrated by single-dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenic potential, and ocular irritation studies.

Toxicity studies on the reproductive effects of timolol showed delayed fetal ossification in rats without postnatal adverse reactions (at a dose of 50 mg/kg/day, 3,500 times the daily clinical dose of 14 µg/kg/day) and increased fetal resorption in rabbits (at a dose of 90 mg/kg/day, 6,400 times the daily clinical dose).

Clinical characteristics.

Indications.

Reduction of intraocular pressure in adult patients with open-angle glaucoma or ocular hypertension in whom monotherapy has not provided sufficient reduction of intraocular pressure.

Contraindications.

Hypersensitivity to the active substances or to any of the excipients of the medicinal product.
Hypersensitivity to other β-blockers.
Hypersensitivity to sulfonamides (see section "Special warnings and precautions for use").
Conditions associated with bronchial hyperreactivity, including bronchial asthma or history of bronchial asthma, severe chronic obstructive pulmonary disease.
Sinus bradycardia, sick sinus syndrome, sinoatrial block, second- or third-degree atrioventricular block not controlled by a pacemaker. Severe cardiac failure, cardiogenic shock.
Severe allergic rhinitis.
Hyperchloremic acidosis (see section "Dosage and administration").
Severe renal impairment.

Interaction with other medicinal products and other forms of interaction.

No studies on ocular Brinzopt Plus regarding its interaction with other medicinal products have been conducted.

Although Brinzopt Plus eye drops containing brinzolamide (a carbonic anhydrase inhibitor) are administered locally, the drug is systemically absorbed. With oral administration of carbonic anhydrase inhibitors, disturbances in acid-base balance have been reported. This potential interaction should be considered in patients using Brinzopt Plus eye drops.

There is a possibility of additive effects on the known systemic effects of carbonic anhydrase inhibitors in patients who are taking oral carbonic anhydrase inhibitors and brinzolamide eye drops. Concomitant use of eye drops containing brinzolamide and oral carbonic anhydrase inhibitors is not recommended.

Cytochrome P450 isoenzymes responsible for brinzolamide metabolism include CYP3A4 (major), CYP2A6, CYP2B6, CYP2C8, and CYP2C9. Inhibitors of CYP3A4 such as ketoconazole, itraconazole, clotrimazole, ritonavir, and troleandomycin are expected to inhibit CYP3A4-mediated metabolism of brinzolamide. Caution should be exercised when co-administering CYP3A4 inhibitors. However, accumulation of brinzolamide is unlikely because it is primarily eliminated by the kidneys. Brinzolamide is not an inhibitor of cytochrome P450 isoenzymes.

There is a possibility of additive effects leading to arterial hypotension and/or marked bradycardia when ophthalmic β-blockers are used concomitantly with oral or intravenous calcium channel blockers (diltiazem), β-blockers, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, and reserpine.

β-blockers may reduce sensitivity to adrenaline during treatment of anaphylactic reactions. Particular caution is required in patients with a history of atopy or anaphylaxis (see section "Special warnings and precautions for use").

Hypertensive response may be enhanced when β-blockers are taken concomitantly with clonidine withdrawal. Caution is recommended when using Brinzopt Plus eye drops together with clonidine.

Enhanced systemic effects of β-blockers (e.g., reduced heart rate, depression) have been reported during combined therapy with CYP2D6 inhibitors (e.g., quinidine, fluoxetine, paroxetine) and timolol. Combination therapy should be used with caution.

β-blockers may enhance the hypoglycemic effect of antidiabetic agents. β-blockers may mask symptoms of hypoglycemia (see section "Special warnings and precautions for use").

Occasionally, mydriasis has been reported with concomitant use of ophthalmic β-blockers and adrenaline (epinephrine).

Special precautions for use.

Systemic effects

Brinzolamide and timolol are systemically absorbed. Due to the presence of the β-adrenergic active component timolol, adverse reactions affecting the cardiovascular system, lungs, and other systemic side effects associated with systemic β-adrenergic receptor blockers may occur during treatment with this medicinal product. The frequency of systemic adverse reactions with topical ophthalmic administration is lower than with systemic administration. For information on minimizing systemic absorption, see section "Dosage and administration".
Since the medicinal product is systemically absorbed, hypersensitivity reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, may occur in patients using Brinzopt Plus eye drops. Patients being treated with Brinzopt Plus eye drops should be informed about the signs and symptoms of hypersensitivity reactions and the need for careful monitoring of skin reactions.

Cardiac disorders

β-blockers should be used with caution in patients with cardiovascular diseases (e.g., ischemic heart disease, Prinzmetal's angina, and heart failure), arterial hypotension, and consideration should be given to alternative treatments. Patients with cardiovascular diseases should be closely monitored to avoid missing signs of worsening conditions or adverse reactions.

Due to their negative effect on impulse conduction time, β-blockers may be administered with caution to patients with first-degree heart block only.

Vascular disorders

Patients with severe peripheral circulatory disorders (e.g., severe forms of Raynaud's disease or Raynaud's syndrome) should be treated with caution.

Hyperthyroidism

β-blockers may mask the symptoms of hyperthyroidism.

Muscle weakness

Exacerbation of muscle weakness associated with myasthenic symptoms (e.g., diplopia, ptosis, and generalized weakness) has been reported during treatment with β-adrenergic receptor blockers.

Respiratory disorders

Respiratory reactions, including fatal outcomes due to bronchospasm in patients with asthma, have been reported following topical ophthalmic use of some β-adrenergic receptor blockers.

Brinzopt Plus eye drops should be used with caution in patients with mild to moderate chronic obstructive pulmonary disease (COPD) and only when the expected benefit outweighs the potential risk.

Hypoglycemia/diabetes mellitus

β-blockers should be used with caution in patients prone to spontaneous hypoglycemia or those with uncontrolled diabetes, as β-blockers may mask the symptoms of acute hypoglycemia.

Acid-base balance disturbances

Brinzopt Plus eye drops contain brinzolamide, which is a sulfonamide. Local administration of the medicinal product may result in the same adverse reactions as those associated with sulfonamides. Disturbances in acid-base balance have been reported with oral administration of carbonic anhydrase inhibitors. Since there is a risk of metabolic acidosis, the medicinal product should be used with caution in patients at risk of renal impairment. If symptoms of serious adverse reactions or hypersensitivity occur, treatment should be discontinued.

Mental alertness

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination. Brinzopt Plus eye drops are systemically absorbed; therefore, these effects may also occur with local administration.

Anaphylactic reactions

Patients with a history of atopy or severe anaphylactic reactions to various allergens may exhibit heightened reactivity to repeated allergen exposure and may not respond to usual doses of adrenaline used to treat anaphylactic reactions while receiving β-adrenergic blockers.

Choroidal detachment

Choroidal detachment has been reported in patients treated with therapies aimed at reducing intraocular fluid secretion (e.g., timolol, acetazolamide) following trabeculotomy.

Surgical anesthesia

Local ocular administration of β-adrenergic receptor blockers may block systemic beta-agonist effects, such as those of adrenaline. If a patient is receiving timolol, the anesthesiologist should be informed.

Concomitant use

The effect on intraocular pressure or the known systemic effects of β-blockers may be enhanced when timolol is administered to patients already receiving systemic β-blockers. Such patients should be closely monitored. Concomitant use of two topical β-blockers or two topical carbonic anhydrase inhibitors is not recommended (see section "Interaction with other medicinal products and other forms of interaction"). There is a potential for additive effects of the known systemic effects of carbonic anhydrase inhibitors in patients receiving oral carbonic anhydrase inhibitors and Brinzopt Plus eye drops. Concomitant use of Brinzopt Plus eye drops and oral carbonic anhydrase inhibitors has not been studied and is therefore not recommended (see section "Interaction with other medicinal products and other forms of interaction").

Ophthalmic effects

Experience with Brinzopt Plus eye drops in the treatment of patients with pseudoexfoliative glaucoma or pigmentary glaucoma is limited. Caution should be exercised when treating such patients, and continuous monitoring of intraocular pressure (IOP) is recommended.

After discontinuation of treatment with the medicinal product, a reduction in IOP may persist for 5–7 days, and a withdrawal effect may potentially occur.

Brinzopt Plus eye drops have not been studied in patients with angle-closure glaucoma and therefore are not recommended for use in this patient population.

Ophthalmic beta-blockers may cause dry eye. Patients with corneal disorders should be treated with caution.

The potential effect of brinzolamide on corneal endothelial function in patients with compromised corneas (particularly those with low endothelial cell counts) has not been studied.

Special attention should be paid to patients who wear contact lenses, as studies in this patient group have not been conducted. Therefore, careful monitoring is recommended when using brinzolamide, as carbonic anhydrase inhibitors may affect corneal hydration. This may lead to corneal edema and decompensation, and contact lens wear may increase the risk of corneal damage. Careful monitoring is also recommended in other corneal disorders, such as in patients with diabetes mellitus or corneal dystrophy.

Brinzopt Plus eye drops may be used during contact lens wear under close supervision (see section "Benzalkonium chloride" below).

Benzalkonium chloride

Brinzopt Plus eye drops contain benzalkonium chloride, which may cause eye irritation and is known to discolor soft contact lenses. Contact with soft contact lenses should be avoided. Patients should be advised to remove contact lenses before instilling Brinzopt Plus eye drops and to wait 15 minutes after instillation before reinserting contact lenses.

Benzalkonium chloride has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Careful monitoring of patients is required during frequent or prolonged use of the drops.

Hepatic impairment

Brinzopt Plus should be used with caution in patients with severe hepatic impairment.

Use during pregnancy or breastfeeding.

Pregnancy

There are no adequate data on the use of brinzolamide and timolol in pregnant women. Animal studies with brinzolamide have demonstrated toxic effects on reproductive function (see "Preclinical safety data"). Brinzopt Plus eye drops should not be used during pregnancy. For information on minimizing systemic absorption, see section "Dosage and administration".

Epidemiological studies have not shown adverse effects on fetal development; however, oral use of β-blockers is associated with a risk of impaired fetal development. In addition, neonates exposed to β-blockers before delivery may exhibit symptoms of β-blockade (e.g., bradycardia, hypotension, respiratory distress, and hypoglycemia). Newborns should be closely monitored during the first days of life if the mother used Brinzopt Plus eye drops before delivery.

Due to the lack of data or limited data on the use of brinzolamide in pregnant women and the confirmed toxic effects on reproductive function in animals, this medicinal product should not be prescribed to pregnant women or women of childbearing potential who are not using contraception.

Breastfeeding

It is unknown whether brinzolamide passes into human breast milk. Animal studies have demonstrated excretion of brinzolamide into breast milk following oral administration (see "Preclinical safety data").

β-blockers pass into human breast milk. However, with topical ocular administration of therapeutic doses of timolol, the concentration in breast milk is unlikely to be sufficient to cause clinical symptoms of β-blockade in infants. For information on minimizing systemic absorption, see section "Dosage and administration". Nevertheless, a risk to the infant during breastfeeding cannot be excluded. The decision to discontinue breastfeeding or to refrain from using Brinzopt Plus eye drops should be made by the physician, taking into account the benefit to the mother and the risk to the infant.

Reproductive function

No studies on the effect of Brinzopt Plus eye drops on human reproductive function following topical ophthalmic administration have been conducted.

Preclinical data did not demonstrate any effects of brinzolamide or timolol on reproductive function in males or females after oral administration.

No effect on reproductive function in males or females is expected with the use of Brinzopt Plus eye drops.

Effects on ability to drive and use machines.

Brinzopt Plus eye drops have minimal influence on the ability to drive or operate machinery.

Transient blurred vision or visual disturbances may affect the ability to drive or operate machinery. If blurred vision occurs after instillation, patients should wait until vision clears before driving or operating machinery.

Carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination (see section "Special precautions for use").

Method of Administration and Dosage

Use in adults, including elderly patients

The dose is 1 drop of Brinzopt Plus eye drops administered into the conjunctival sac of the affected eye(s) twice daily.

Systemic absorption can be reduced by applying pressure to the lacrimal sac area (punctal occlusion) or by closing the eyelids. This reduces systemic adverse reactions and enhances local activity (see section "Special Instructions").

If a dose is missed, treatment should be continued according to the prescribed schedule. The dose should not exceed 1 drop in the affected eye(s) twice daily.

When switching from another ophthalmic anti-glaucoma medication to Brinzopt Plus eye drops, discontinue the previous medication and begin treatment with Brinzopt Plus eye drops the following day.

Patients with hepatic or renal impairment

No studies with Brinzopt Plus or timolol 5 mg/mL eye drops have been conducted in patients with hepatic or renal impairment. Dose adjustment is not required in patients with hepatic impairment or in patients with mild to moderate renal impairment.

Studies on the use of Brinzopt Plus in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients with hyperchloremic acidosis have not been conducted (see section "Contraindications"). Since brinzolamide and its main metabolite are primarily excreted by the kidneys, Brinzopt Plus is contraindicated in these patient groups (see section "Contraindications").

Brinzopt Plus should be used with caution in patients with severe hepatic impairment (see section "Special Instructions").

Method of Administration

For ophthalmic use.

Patients should be advised to shake the bottle well before use.

After first opening the bottle, remove the tamper-evident ring.

To prevent contamination of the dropper tip and the contents of the bottle, care should be taken not to touch the eyelids, surrounding areas, or other surfaces with the tip of the dropper bottle. Patients should be advised to close the bottle tightly after each use.

If more than one ophthalmic preparation is being used, an interval of at least 5 minutes between applications should be maintained. Ophthalmic ointments should be administered last.

Children

The safety and efficacy of Brinzopt Plus eye drops in children under 18 years of age have not been established. Data on use in this patient population are lacking.

Overdose

In case of accidental ingestion of the bottle contents, symptoms of β-blocker overdose may include bradycardia, hypotension, heart failure, and bronchospasm.

In the event of overdose with Brinzopt Plus eye drops, treatment should be symptomatic and supportive. Due to the presence of brinzolamide, electrolyte imbalance and metabolic acidosis may occur, and effects on the central nervous system are possible. Serum electrolyte levels (particularly potassium) and blood pH should be monitored. Studies have shown that timolol is poorly eliminated by dialysis.

Adverse reactions.

Summary of safety data

In clinical studies, the most frequently reported adverse reactions were blurred vision, eye irritation, and eye pain, occurring in approximately 2–7% of patients.

Summary of adverse reactions presented in tabular form

During clinical studies of Brinzopt Plus eye drops and of the components brinzolamide and timolol, as well as in the post-marketing period, the adverse reactions listed below have been reported. These reactions are classified as follows: very common (≥ 1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1000 to < 1/100), rare (≥ 1/10000 to < 1/1000), very rare (< 1/10000), or frequency not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in order of decreasing severity.

System Organ Classes	Adverse Reactions (MedDRA term)
Infections and infestations	Frequency unknown: nasopharyngitis³, pharyngitis³, sinusitis³, rhinitis³
Blood and lymphatic system disorders	Uncommon: leukopenia¹ Frequency unknown: erythrocytopenia³, increased blood chloride levels³
Immune system disorders	Frequency unknown: anaphylaxis², anaphylactic shock¹, systemic allergic reactions including angioedema², localised and generalised rashes², hypersensitivity¹, urticaria², pruritus²
Metabolism and nutrition disorders	Frequency unknown: hypoglycaemia²
Psychiatric disorders	Rare: insomnia¹ Frequency unknown: hallucinations², depression¹, memory loss², apathy³, depressed mood³, decreased libido³, night terrors^2,3, nervousness³
Nervous system disorders	Common: dysgeusia¹ Frequency unknown: cerebral vascular ischaemia², stroke², loss of consciousness², worsening of symptoms of myasthenia gravis², somnolence³, motor dysfunction³, amnesia³, memory impairment³, paraesthesia^2,3, tremor³, hypoesthesia³, loss of taste³, dizziness^1,2, headache¹
Eye disorders	Common: punctate keratitis¹, blurred vision¹, eye pain¹, eye irritation¹ Uncommon: keratitis^1,2,3, dry eyes¹, corneal staining¹, eye discharge¹, eye pruritus^1,3, foreign body sensation in eye¹, ocular hyperaemia¹, conjunctival hyperaemia¹ Rare: corneal erosion¹, anterior chamber flare¹, photophobia¹, increased lacrimation¹, scleral hyperaemia¹, eyelid erythema¹, eyelid crusting¹ Frequency unknown: increased optic disc cupping³, choroidal detachment after trabeculotomy² (see section "Special precautions for use"), keratopathy³, corneal epithelial defect³, corneal epithelial disorder³, increased intraocular pressure³, intraocular precipitates³, corneal pigmentation³, corneal oedema³, decreased corneal sensitivity², conjunctivitis³, meibomitis³, diplopia^2,3, photophobia³, photopsia³, decreased visual acuity^2,3, worsening of vision¹, pterygium³, ocular discomfort³, dry keratoconjunctivitis³, ocular hypoesthesia³, scleral pigmentation³, subconjunctival cyst³, visual disturbance³, eye oedema³, allergic eye reactions³, madarosis³, eyelid disorders³, eyelid oedema¹, ptosis²
Ear and labyrinth disorders	Frequency unknown: vertigo³, tinnitus³
Cardiac disorders	Common: decreased heart rate/pulse reduction¹ Frequency unknown: cardiac arrest², worsening cardiac function², congestive heart failure², atrioventricular block², cardio-respiratory distress³, angina pectoris³, bradycardia^2,3, irregular heartbeat³, arrhythmia^2,3, palpitations^2,3, tachycardia³, increased heart rate³, chest pain², oedema²
Vascular disorders	Uncommon: decreased blood pressure¹ Frequency unknown: arterial hypotension², arterial hypertension³, increased blood pressure¹, Raynaud's phenomenon², cold extremities²
Respiratory, thoracic and mediastinal disorders	Uncommon: cough¹ Rare: throat pain¹, rhinorrhoea¹ Frequency unknown: bronchospasm² (predominantly in patients with pre-existing bronchospastic disease), dyspnoea¹, asthma³, epistaxis¹, bronchial hyperreactivity³, throat irritation³, nasal congestion³, upper respiratory tract congestion³, excessive nasopharyngeal mucus secretion³, sneezing³, dry nose³
Gastrointestinal disorders	Frequency unknown: vomiting^2,3, upper abdominal pain^1,3, abdominal pain², diarrhoea^1,3, dry mouth¹, nausea¹, oesophagitis³, dyspepsia^2,3, abdominal discomfort³, stomach discomfort³, increased intestinal peristalsis³, gastrointestinal disorder³, oral hypoesthesia³, oral paraesthesia³, flatulence³
Hepatobiliary disorders	Frequency unknown: abnormal liver function test results³
Skin and subcutaneous tissue disorders	Frequency unknown: urticaria³, maculopapular rash^2,3, generalised pruritus³, skin induration³, dermatitis³, alopecia¹, psoriasiform rash or exacerbation of psoriasis², rash¹, erythema^1,3, Stevens-Johnson syndrome¹/toxic epidermal necrolysis¹
Musculoskeletal and connective tissue disorders	Frequency unknown: myalgia¹, muscle cramps³, arthralgia³, back pain³, limb pain³
Renal and urinary disorders	Uncommon: haematuria¹ Frequency unknown: renal pain³, polyuria³
Reproductive system and breast disorders	Frequency unknown: erectile dysfunction³, sexual dysfunction², decreased libido²
General disorders and administration site conditions	Uncommon: malaise^1,3 Frequency unknown: chest pain¹, pain³, increased fatigue^1,2, asthenia^2,3, chest discomfort³, anxiety³, irritability³, peripheral oedema³, residual drug³
Investigations	Uncommon: increased blood potassium levels¹, increased blood lactate dehydrogenase levels¹

1 Side effects observed during the use of Brinzopt Plus.

2 Additional side effects observed during the use of timolol as monotherapy.

3 Additional side effects observed during the use of brinzolamide as monotherapy.

Description of some adverse reactions

Dysgeusia (bitter or unusual taste in the mouth after instillation) was a systemic adverse reaction commonly reported in clinical trials and associated with the use of Brinzopt Plus ophthalmic solution. This reaction was likely related to brinzolamide and caused by the entry of eye drops into the nasopharynx via the nasolacrimal duct. Pressure applied to the area of the nasolacrimal duct or careful eyelid closure after instillation may reduce the likelihood of this effect (see section "Dosage and administration").

Brinzopt Plus ophthalmic solution contains brinzolamide, a sulfonamide-class carbonic anhydrase inhibitor that is systemically absorbed. When systemic carbonic anhydrase inhibitors are used, gastrointestinal, neurological, hematological, renal, and metabolic disturbances generally occur. Similar types of adverse reactions characteristic of oral carbonic anhydrase inhibitors may also occur with topical administration.

Timolol is absorbed into the systemic circulation. This may cause the same types of adverse reactions as those associated with systemic β-blockers. The adverse reactions listed above include those typical of the class of ophthalmic β-blockers.

The additional adverse reactions listed above are related to the use of individual components and may potentially occur during the use of Brinzopt Plus ophthalmic solution. The frequency of systemic adverse reactions after topical ophthalmic administration is lower than with systemic administration. For information on minimizing systemic absorption, see section "Dosage and administration".

The following adverse reactions have been reported during systemic therapy with timolol: pulmonary edema, reduced exercise tolerance, increased sweating, exfoliative dermatitis, difficulty concentrating, urinary hesitancy, hyperglycemia, wheezing, and nonspecific thrombocytopenic purpura.

Reporting suspected adverse reactions

Reporting suspected adverse reactions after marketing authorization is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals and pharmacists, as well as patients or their legal representatives, should report all suspected adverse reactions and lack of efficacy through the Automated Pharmacovigilance Information System at: https://aisf.dec.gov.ua.

Shelf life.

2 years.

The shelf life of the product after first opening of the container is 28 days.

Storage conditions.

Store at temperatures not exceeding 25 °C.

Keep out of reach and sight of children.

Packaging.

5 ml in a bottle with dropper cap, in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

K.T. ROMPHARM COMPANY S.R.L.

Manufacturer's address and location of business operations.

Strada Eroilor No. 1A, Otopeni, 075100, Ilfov County, Romania – Building Rompharm 1 and Rompharm 2.