INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRINERA (BRINERA)

Composition:

Active substances: brinzolamide, timolol;

1 ml of suspension contains brinzolamide 10 mg, timolol maleate 6.83 mg equivalent to timolol 5 mg;

Excipients: benzalkonium chloride, mannitol (E 421), carbomer 974P (carbomer homopolymer type B), tyloxapol, edetate disodium, sodium chloride, hydrochloric acid diluted and/or sodium hydroxide (for pH adjustment), water for injections.

Pharmaceutical form. Eye drops, suspension.

Main physicochemical characteristics: suspension from white to almost white in color.

Pharmacotherapeutic group. Agents used in ophthalmology. Antiglaucoma preparations and miotics. β-blockers.

ATC code S01E D51.

Pharmacological properties.

Pharmacodynamics.

Mechanism of action

BRENEUR eye drops contain two active substances: brinzolamide and timolol maleate. These two components reduce elevated intraocular pressure (IOP) by decreasing the secretion of aqueous humor, but they do so through different mechanisms of action. The combined effect of these two active substances results in an additional 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 the formation of aqueous humor, primarily by slowing the formation of bicarbonate ions, followed by a reduction in the transport of sodium and fluid.

Timolol is a non-selective beta-adrenergic receptor blocker that lacks intrinsic sympathomimetic and membrane-stabilizing activity and does not directly depress myocardial contractility. Tonographic and fluorophotometric studies in humans have confirmed that its main effect is associated with reduced formation of aqueous humor and a slight increase in its outflow.

Pharmacodynamic effects

Clinical effects:

In a twelve-month controlled clinical study in patients with open-angle glaucoma or ocular hypertension, who in the opinion of investigators could benefit from combination therapy and who had a mean IOP of 25–27 mm Hg, the mean reduction in IOP with brinzolamide 10 mg/mL + timolol 5 mg/mL eye drops administered twice daily was 7–9 mm Hg. 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 brinzolamide 10 mg/mL + timolol 5 mg/mL.

In a six-month controlled clinical study in patients with open-angle glau游戏副本

Clinical characteristics.

Indications.

Reduction of intraocular pressure in adult patients with open-angle glaucoma or ocular hypertension who have not achieved sufficient reduction of intraocular pressure with monotherapy.

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 precautions for use").
Conditions associated with hyperreactivity of the airways, 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 heart 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 the interaction of BRINER eye drops with other medicinal products have been conducted.

Although BRINER eye drops contain brinzolamide, a carbonic anhydrase inhibitor, and 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 BRINER eye drops.

There is a possibility of additive effects on the known systemic effects of carbonic anhydrase inhibitors in patients receiving both 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 excreted by the kidneys. Brinzolamide is not an inhibitor of cytochrome P450 isoenzymes.

There is a potential for additive effects leading to arterial hypotension and/or marked bradycardia when β-blocker-containing eye drops are used concomitantly with oral or intravenous calcium channel blockers (diltiazem), β-blockers, antiarrhythmics (including amiodarone), cardiac glycosides, parasympathomimetics, guanethidine, and reserpine.

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

Hypertensive response may be enhanced when β-blockers are used during abrupt withdrawal of clonidine. Caution is recommended when BRINER eye drops are used concomitantly 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. Such combinations should be used with caution.

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

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

Special precautions for use.

Systemic effects

Brinzolamide and timolol are systemically absorbed. Due to the presence of the β-adrenergic active component timolol, the same adverse reactions affecting the cardiovascular system, lungs, and other side effects as those observed with systemic administration of β-adrenergic receptor blockers may occur during use of the medicinal product. The frequency of systemic adverse reactions with topical ophthalmic administration is lower than with systemic administration. To reduce systemic absorption, see section "Dosage and administration".
Since the medicinal product is systemically absorbed, hypersensitivity reactions typical of all sulfonamide derivatives, including Stevens-Johnson syndrome and toxic epidermal necrolysis, may occur in patients using BRINERG eye drops. Patients treated with BRINERG eye drops should be informed about signs and symptoms of adverse 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 treatment with alternative medicinal products. Patients with cardiovascular diseases should be closely monitored to avoid missing symptoms of worsening of these conditions or adverse reactions.

Due to the negative effect on impulse conduction time, β-blockers should be prescribed with caution only to patients with first-degree heart block.

Vascular disorders

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

Hyperthyroidism

β-Blockers may mask symptoms of hyperthyroidism.

Muscle weakness

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

Respiratory disorders

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

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

Hypoglycemia/diabetes

β-Adrenergic receptor blockers should be used with caution in patients prone to spontaneous hypoglycemia or in patients with decompensated diabetes, as β-adrenergic receptor blockers may mask symptoms and signs of acute hypoglycemia.

Acid-base balance disturbances

BRINERG eye drops contain brinzolamide, which is a sulfonamide. Undesirable reactions similar to those observed with sulfonamides may occur with topical administration of the medicinal product. 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 reactions or hypersensitivity occur, administration of the medicinal product should be discontinued.

Mental performance

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

Anaphylactic reactions

During treatment with β-adrenergic receptor blockers, patients with a history of atopy or severe anaphylactic reactions to various allergens may have an increased response to repeated exposure to these allergens and may not respond to usual doses of adrenaline used to treat anaphylactic reactions.

Choroidal detachment

Choroidal detachment has been reported during treatment aimed at reducing intraocular fluid secretion (e.g., timolol, acetazolamide) following trabeculectomy.

Surgical anesthesia

When β-adrenergic receptor blockers are administered locally into the eye, they may block systemic β-agonist effects, such as those of adrenaline. If a patient is receiving timolol, the anesthesiologist should be informed.

Concomitant use

The effect on IOP 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 carefully monitored. The 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 to the known systemic effects of carbonic anhydrase inhibitors in patients taking oral carbonic anhydrase inhibitors and BRINERG eye drops. Concomitant use of BRINERG 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 BRINERG eye drops in patients with pseudoexfoliative glaucoma or pigmentary glaucoma is limited. Caution should be exercised when treating such patients, and continuous monitoring of IOP is recommended.

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

BRINERG eye drops have not been studied in patients with angle-closure glaucoma; therefore, their use in this patient population is not recommended.

Ophthalmic β-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 cornea (particularly in patients with low endothelial cell count) has not been studied.

Particular attention should be paid to patients who wear contact lenses, as no studies have been conducted in this patient group. Therefore, careful monitoring is recommended when using brinzolamide, as carbonic anhydrase inhibitors may affect corneal hydration. This may lead to corneal edema and decompensation; thus, contact lens use 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.

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

Benzalkonium chloride

BRINERG 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 instillation of BRINERG 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

The medicinal product 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 section "Preclinical safety data"). BRINERG eye drops should not be used during pregnancy. To reduce systemic absorption, see section "Dosage and administration".

Epidemiological studies have not shown adverse effects on fetal development; however, oral administration of β-blockers has been associated with risks to intrauterine development. In addition, signs and symptoms of β-blockade (e.g., bradycardia, hypotension, respiratory distress, and hypoglycemia) have been observed in newborns whose mothers received β-blockers before delivery. Newborns should be closely monitored during the first days of life if the mother used BRINERG eye drops before delivery.

Given the lack of data or limited number of data on the use of brinzolamide in pregnant women and the demonstration of toxic effects on reproductive function in animal studies, this medicinal product should not be administered during pregnancy or to 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 after oral administration (see section "Dosage and administration").

β-Blockers pass into human breast milk. However, with topical ophthalmic administration of therapeutic doses of timolol, it is unlikely that concentrations in breast milk are sufficient to cause clinical symptoms of β-blockade in infants. To reduce systemic absorption, see section "Preclinical safety data". However, a risk to the breastfed infant cannot be excluded. The decision whether to discontinue breastfeeding or to abstain from using BRINERG eye drops should be made by the physician, taking into account the benefit for the woman and the risk for the infant.

Reproductive function

No studies have been conducted to evaluate the effect of BRINERG eye drops on human reproductive function following topical ophthalmic administration. Preclinical data have not demonstrated any effects of brinzolamide or timolol on reproductive function in men or women.

No effects on reproductive function in men or women are expected with use of the medicinal product.

Ability to affect driving and use of machines.

BRINERG eye drops have minimal effect 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 BRINER eye drops into the conjunctival sac of the affected eye(s) twice daily.

Systemic absorption is reduced by applying pressure to the lacrimal sac area (punctal occlusion) or by closing the eyelids. This reduces systemic side effects and enhances local activity (see section "Special Warnings and Precautions for Use").

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 anti-glaucoma ophthalmic agent to BRINER eye drops, discontinue the other agent and begin BRINER eye drops the following day.

Patients with hepatic or renal impairment

No studies with BRINER or with 5 mg/mL timolol ophthalmic solution 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 with BRINER have not been conducted in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients with hyperchloremic acidosis (see section "Contraindications"). Since brinzolamide and its major metabolite are primarily excreted by the kidneys, BRINER is contraindicated in the treatment of these patient groups (see section "Contraindications").

BRINER should be used with caution in patients with severe hepatic impairment (see section "Special Warnings and Precautions for Use").

Method of Administration

For ophthalmic use only.

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 must be taken not to touch the eyelids, surrounding areas, or any 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 product is being used locally, the interval between applications should be at least 5 minutes. Ophthalmic ointments should be administered last.

Children

The safety and efficacy of BRINER eye drops in children under 18 years of age have not been established. Data on use in this patient group 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 BRINER eye drops overdose, treatment should be symptomatic and supportive. Due to the presence of brinzolamide, electrolyte imbalance and development of acidosis may occur, as well as possible effects on the central nervous system. Serum electrolyte levels (especially potassium) and blood pH should be monitored. Studies have shown that timolol is difficult to remove from the body by dialysis.

Adverse reactions

Summary of safety data

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

Summary of adverse reactions in tabular form

During clinical trials of brinzolamide 10 mg/mL + timolol 5 mg/mL ophthalmic solution, as well as with the individual components brinzolamide and timolol, and in the post-marketing period, the following adverse reactions have been reported, classified according to the following frequency categories: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10,000 to <1/1000), very rare (<1/10,000), and not known (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in decreasing order of severity.

Classes and organ systems	Adverse reactions (MedDRA term (v. 18.0))
Infections and infestations	Frequency unknown: rhinopharyngitis³, pharyngitis³, sinusitis³, rhinitis³
Blood and lymphatic system disorders	Uncommon: decreased white blood cell count¹. Frequency unknown: decreased red blood cell count³, increased blood chloride levels³
Immune system disorders	Frequency unknown: anaphylaxis², anaphylactic shock¹, systemic allergic reactions including angioedema², local and generalized rash², hypersensitivity¹, urticaria², pruritus²
Metabolism and nutrition disorders	Frequency unknown: hypoglycemia²
Psychiatric disorders	Uncommon: insomnia¹. Frequency unknown: depression¹, memory loss², apathy³, depressed mood³, decreased libido³, night terrors^2,3, nervousness³
Nervous system disorders	Common: dysgeusia¹. Frequency unknown: cerebral vascular ischemia², stroke², loss of consciousness², worsening of symptoms of myasthenia gravis², somnolence³, motor disturbances³, amnesia³, memory impairment³, paresthesia^2,3, tremor³, hypesthesia³, 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 pigmentation¹, eye discharge¹, eye pruritus^1,3, foreign body sensation in eyes¹, ocular hyperemia¹, conjunctival hyperemia¹. Rare: corneal erosion¹, anterior chamber flare¹, photophobia¹, increased lacrimation¹, scleral hyperemia¹, eyelid erythema¹, scaling of eyelid margins¹. Frequency unknown: increased optic disc cupping³, choroidal detachment after trabeculotomy² (see section "Special precautions"), keratopathy³, corneal epithelial defect³, corneal epithelial disorder³, increased intraocular pressure³, intraocular precipitates³, corneal pigmentation³, corneal edema³, decreased corneal sensitivity², conjunctivitis³, meibomitis³, diplopia^2,3, photophobia³, photopsia³, decreased visual acuity^2,3, worsening of vision¹, pterygium³, ocular discomfort³, dry keratoconjunctivitis³, ocular hypesthesia³, scleral pigmentation³, subconjunctival cyst³, visual disturbance³, eye swelling³, allergic eye reactions³, madarosis³, eyelid disorders³, eyelid edema¹, ptosis².
Ear and labyrinth disorders	Frequency unknown: vertigo³, tinnitus³
Cardiac disorders	Common: decreased heart rate/pulse reduction¹. Frequency unknown: cardiac arrest², worsening of cardiac function², congestive heart failure², atrioventricular block², cardio-respiratory distress³, angina³, bradycardia^2,3, irregular heart rate³, arrhythmia^2,3, palpitations^2,3, tachycardia³, increased heart rate³, chest pain², edema²
Vascular disorders	Uncommon: decreased blood pressure¹. Frequency unknown: arterial hypotension², hypertension³, increased blood pressure¹, Raynaud's phenomenon², cold extremities²
Respiratory, thoracic and mediastinal disorders	Uncommon: cough¹. Rare: throat pain¹, rhinorrhea¹. Frequency unknown: bronchospasm² (predominantly in patients with pre-existing bronchospastic disease), dyspnea¹, 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, diarrhea^1,3, dry mouth¹, nausea¹, esophagitis³, dyspepsia^2,3, abdominal discomfort³, stomach discomfort³, increased intestinal peristalsis³, gastrointestinal disorders³, oral cavity hypesthesia³, oral cavity paresthesia³, flatulence³
Hepatobiliary disorders	Frequency unknown: abnormal liver function tests³
Skin and subcutaneous tissue disorders	Frequency unknown: urticaria³, maculopapular rash^2,3, generalized pruritus³, skin induration³, dermatitis³, alopecia¹, psoriasiform rash or exacerbation of psoriasis², rash¹, erythema^1,3, Stevens-Johnson syndrome/toxic epidermal necrolysis (see section "Special precautions").
Musculoskeletal and connective tissue disorders	Frequency unknown: myalgia¹, muscle cramps³, arthralgia³, back pain³, limb pain³
Renal and urinary disorders	Uncommon: presence of blood in urine¹. Frequency unknown: kidney 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 edema³, residual drug substance³
Investigations	Uncommon: increased blood potassium levels¹, increased blood lactate dehydrogenase levels¹

1Side effects observed during the use of the medicinal product.

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

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

Description of some side effects

Dysgeusia (bitter or unusual taste in the mouth after instillation) was a systemic side effect frequently reported in clinical trials with ophthalmic solution brinzolamide 10 mg/mL + timolol 5 mg/mL. This effect was likely associated with brinzolamide and caused by the entry of eye drops into the nasopharynx via the nasolacrimal duct. Pressing on the lacrimal sac area or gently closing the eyelids after instillation may reduce the likelihood of this occurrence (see section “Dosage and administration”).

BRINERA eye drops contain brinzolamide, a sulfonamide-class carbonic anhydrase inhibitor that is systemically absorbed. Systemic carbonic anhydrase inhibitors are generally associated with gastrointestinal, neurological, hematological, renal, and metabolic disturbances. Similar types of side effects characteristic of oral carbonic anhydrase inhibitors may also occur with topical administration.

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

The additional side effects listed above are related to the use of individual components and may potentially occur during treatment with BRINERA eye drops. The frequency of systemic side effects after topical ophthalmic administration is lower than with systemic administration. For reduction of systemic absorption, see section “Dosage and administration”.

The following side effects have been reported during systemic therapy with timolol: pulmonary edema, reduced exercise tolerance, increased sweating, exfoliative dermatitis, decreased concentration, difficulty in urination, hyperglycemia, wheezing, and nonspecific thrombocytopenic purpura.

Shelf life.

2 years. Do not use more than 4 weeks after first opening the bottle.

Storage conditions.

No special storage conditions are required for this medicinal product.

Keep out of reach of children.

Packaging.

5 mL in a bottle with dropper; 1 bottle with dropper in a cardboard box.

Prescription status.

Prescription only.

Manufacturer.

Sentiss Pharma Pvt. Ltd., India.

Manufacturer's address and site of manufacturing activity.

Village Khera Nihla, Tehsil Nalagarh, Distt. Solan, Himachal Pradesh, 174 101, India.

Marketing authorization holder.

Sentiss Pharma Private Limited, India / Sentiss Pharma Private Limited, India.

Address of the marketing authorization holder.

212, Ashirwad Commercial Complex, D-1, Green Park, New Delhi - 110016, India /

212, Ashirwad Commercial Complex, D-1, Green Park, New Delhi - 110016, India.

Brinera

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT BRINERA (BRINERA)

Composition:

Pharmacological properties.

Clinical characteristics.

Special precautions for use.

Method of Administration and Dosage

Adverse reactions

Adverse reactions