Brinarga, eye drops 1%+0.5% 5 ml

Pharmacodynamics

Mechanism of action

Brinarga contains two active ingredients: brinzolamide and timolol maleate, which reduce elevated intraocular pressure (IOP) primarily by reducing intraocular fluid secretion, but in different ways. The combined effect of brinzolamide and timolol exceeds the effect of each agent alone to reduce IOP.

Brinzolamide is a carboanhydrase ΙΙ inhibitor. Inhibition of carboanhydrase in the ciliary body of the eyeball reduces intraocular fluid production, presumably by slowing the formation of bicarbonate ions with a consequent reduction in sodium and fluid transport.

Timolol is a non-selective blocker of β-adrenoreceptors without sympathomimetic activity, has no direct depressant effect on the myocardium and has no membrane stabilizing activity. A number of studies have shown that when used topically, timolol decreases intraocular fluid formation and slightly increases its outflow.

Pharmacokinetics

Absorption

When used topically, brinzolamide and timolol penetrate the systemic bloodstream.

The maximum concentration (C_max) in erythrocytes is about 18.4 µM.

In equilibrium, after administration of brinzolamide and timolol, the mean C_max of timolol in plasma and the area under the concentration-time curve over 12 hours (AUC_0-12h) of timolol was 0.824 ± 0.453 ng/mL and 4.71 ± 4.29ng_*h/mL, respectively, and the mean C_mah of timolol was achieved at 0.79 ± 0.45 h.

Distribution

Brinzolamide binds moderately to plasma proteins (about 60%) and accumulates in erythrocytes as a result of selective binding to carboanhydrase II and, to a lesser extent, to carboanhydrase I. Its active metabolite N-dezethylbrinzolamide also accumulates in erythrocytes, where it binds predominantly to carboanhydrase I. Due to the affinity of brinzolamide and its metabolite to erythrocytes and tissue carboanhydrase, their concentration in plasma is low.

Metabolism

The metabolism of brinzolamide occurs by N-dealkylation, O-dealkylation and oxidation of the N-propyl side chain. The main metabolite, N-dezethylbrinzolamide, in the presence of brinzolamide, binds to carboanhydrase I and also accumulates in erythrocytes. In vitro studies have shown that the CYP3A4 isoenzyme, but also the CYP2A6, CYP2B6, CYP2C8 and CYP2C9 isoenzymes are primarily responsible for the metabolism of brinzolamide.

The metabolism of timolol occurs in two ways: with the formation of an ethanol side chain on the thiadiazole ring and with the formation of an ethanol side chain at the morpholine nitrogen and a similar side chain with a carbonyl group coupled to the nitrogen. Thymolol metabolism is carried out mainly by CYP2D6.

Evolution

Brinzolamide is excreted mainly with urine and feces in comparative amounts of 32% and 29%, respectively. About 20% is excreted as metabolites in the urine. Brinzolamide and N-dezethylbrinzolamide as well as residual amounts (<1 %) of other metabolites (N-desmethoxypropyl and O-desmethyl) are found mainly in urine.

Timolol and its metabolites are excreted mainly by the kidneys. About 20% of timolol is excreted unchanged in the urine, the rest as metabolites. T_1/2 timolol is 4.8 h after topical combined use of brinzolamide and timolol.

Indications

Reduction of elevated intraocular pressure in open-angle glaucoma and intraocular hypertension in patients in whom monotherapy has been insufficient to reduce intraocular pressure.

Active ingredient

Brinzolamide, Timolol

Composition

Active ingredients

Brinzolamide 10 mg,

Timolol maleate 6.83 mg, equivalent to timolol 5 mg.

Auxiliary substances:

Benzalkonium chloride 0.1 mg; disodium edetate 0.1 mg; sodium chloride 1.0 mg; tyloxapol 0.25 mg; mannitol 33 mg; carbomer 974P 4.2 mg; sodium hydroxide and/or hydrochloric acid to pH 7.3; water for injection to 1.0 ml.

How to take, the dosage

Topically. Shake the bottle before use.

1 drop in the conjunctival sac of the eye 2 times a day.

After use to decrease the risk of systemic adverse reactions, gentle finger pressure on the projection area of the lacrimal sac at the inner corner of the eye for 1-2 minutes after instillation of the drug is recommended to reduce systemic absorption of the drug.

If a dose is missed, treatment should be continued with the next scheduled dose. The dose should not exceed 1 drop in the conjunctival sac of the eye 2 times a day.

If any antiglaucoma medication is replaced with Brinarga, use of Brinarga should be started the day after withdrawal of the previous medication.

Do not touch the tip of the drip tip with any surface to avoid contaminating the vial and its contents.

The bottle should be closed after each use.

Interaction

Brinarga contains brinzolamide, a carboanhydrase inhibitor, which may be absorbed systemically when used topically. There have been described cases of acid-base equilibrium disturbances due to the use of oral carboanhydrase inhibitors. The possibility of such disorders should be taken into account in patients using Brinarga.

The concomitant use with oral carboanhydrase inhibitors is not recommended because of the possibility of increased systemic adverse reactions. Cytochrome P-450 isoenzymes are responsible for metabolism of brinzolamide: CYP3A4 (mainly), CYP2A6, CYP2B6, CYP2C8 and CYP2C9. Caution should be exercised when prescribing drugs that inhibit CYP3A4 isoenzyme, such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin due to possible inhibition of brinzolamide metabolism by CYP3A4 isoenzyme. Caution should be exercised when coadministering CYP3A4 isoenzyme inhibitors. However, accumulation of brinzolamide is unlikely because it is excreted by the kidneys. Brinzolamide is not an inhibitor of cytochrome P-450 isoenzymes.

The systemic effects of β-adrenoblockers (decreased heart rate, depression) may be enhanced with concomitant use of CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine) and timolol.

There is a possibility of increased hypotensive effect and/or development of marked bradycardia when using topical β-adrenoblockers with oral calcium channel blockers, guanethidine, β-adrenoblockers, antiarrhythmic drugs (including amiodarone), foxglove glycosides and parasympathomimetics simultaneously.

The β-adrenoblockers may decrease the response to adrenaline in the treatment of anaphylactic reactions. Caution should be exercised when prescribing the drug in patients with atopy or with a history of anaphylaxis (see section “Special Precautions”).

In some cases, the concomitant use of local β-adrenoblockers and adrenaline (epinephrine) may lead to mydriasis.

The effects on intraocular pressure or the known effects of systemic β-adrenoblockers may be enhanced if timolol is administered to a patient already receiving a systemic β-adrenoblocker. Such patients should be closely monitored.

The use of two topical beta-adrenoblockers is not recommended.

If used with other topical ophthalmic medications, the interval between applications should be at least 5 minutes.

Special Instructions

Systemic effects

Brinezolamide and timolol may undergo systemic absorption. Timolol when used topically may cause the same cardiovascular and respiratory adverse reactions and other adverse reactions as systemic β-adrenoblockers.

Hypersensitivity reactions, typical of all sulfonamide derivatives, may develop when using Brinarga due to systemic absorption. In case of serious adverse reactions or hypersensitivity reactions, the drug should be discontinued.

Cardiac disorders

. In patients with cardiovascular disease (e.g., coronary heart disease, Prinzmetal angina, heart failure) and hypotension, therapy with β-blockers should be critically evaluated and treatment with other active agents should be considered. The appearance of signs of exacerbation and adverse reactions in patients with cardiovascular disease should be closely monitored.

Vascular disorders

Patients with severe peripheral circulatory disorders/disorders (Raynaud’s disease or severe Raynaud’s syndrome) should be treated with caution.

Hyperthyroidism

Β-adrenoblockers may mask symptoms of hyperthyroidism.

Muscular weakness

It has been reported that β-adrenoblockers increase the muscle weakness seen in some myasthenia gravis symptoms (e.g., diplopia, ptosis, and general weakness).

Respiratory system disorders

Respiratory system reactions, including death from bronchospasm, have been reported in patients with AD following administration of β-adrenoblockers for topical use.

Hypoglycemia/diabetes

β-adrenoblockers should be prescribed with caution in patients with a tendency to spontaneous hypoglycemia or patients with a labile course of diabetes, as these drugs may mask symptoms of acute hypoglycemia.

Disruption of acid-base balance

Disruption of acid-base balance has been described when using oral forms of carboanhydrase inhibitors. In patients at risk of renal failure, the drug should be used with caution due to the possible risk of metabolic acidosis.

Concentration

Orally administered carboangiidrase inhibitors may affect the ability to engage in activities requiring increased attention and/or physical coordination in elderly patients. These phenomena may be observed because brinzolamide penetrates into the systemic bloodstream when administered topically.

Anaphylactic reactions

. Patients with a history of atopy or severe anaphylactic reactions to various allergens who receive β-adrenoblockers may react more strongly to exposure to these allergens and may also be resistant to conventional doses of adrenaline in the treatment of anaphylactic reactions.

Ocular choroidal detachment

Cases of ocular choroidal detachment have been described with the use of drugs that prevent intraocular fluid formation (e.g., timolol, acetazolamide) after filter surgery.

Surgical anesthesia

The action of β-adrenoblockers in ophthalmic drugs may block the systemic action of β-agonists such as adrenaline. The anesthesiologist should be informed that the patient is taking timolol.

Companion therapy

When using Brinarga in patients who are taking systemic β-adrenoblockers, the possible mutual reinforcement of the pharmacological effects of the drugs with respect to both the known systemic effects of β-adrenoblockers and the decrease in intraocular pressure should be considered.

The close monitoring of such patients is necessary.

The combined use of two local β-adrenoblockers is not recommended. There is a possibility of increased systemic effects due to carboenhydrase inhibition in patients taking oral carboenhydrase inhibitors and Brinarga. Simultaneous administration of Brinarga and oral carboangiidrase inhibitors is not recommended.

Effects on the visual organ

The effect of Brinzolamide on corneal endothelial function in patients with corneal disorders (especially patients with low endothelial cell counts) has not been studied. In patients who wear contact lenses, their corneal condition should be closely monitored when using brinzolamide because carboenhydrase inhibitors may affect corneal hydration. Close monitoring of patients with corneal disorders, such as patients with diabetes mellitus or corneal dystrophy, is recommended.

Benzalkonium chloride

Benzalkonium chloride in Brinarga may cause eye irritation and may also change the color of soft contact lenses. Contact with soft contact lenses should be avoided.

Contact lenses should be removed and put back in no earlier than 15 minutes after application of the drug.

Brinarga contains benzalkonium chloride which may cause pitting keratopathy and/or toxic ulcerative keratopathy. Patients should be closely monitored during long-term use of the drug.

Hepatic dysfunction

Brinarga should be used with caution in patients with severe hepatic impairment.

Influence on driving and operating ability

Brinarga has a slight effect on the ability to drive and operate machinery.

If the patient has a temporary blurring of vision after using the drug, it is not recommended to drive or engage in activities that require increased attention and reaction until it is restored.

Carboanhydrase inhibitors may impair the ability to perform tasks requiring concentration and/or coordination of movements.

Synopsis

The suspension is white or almost white in color.

Contraindications

Individual hypersensitivity to the components of the drug, sulfonamides or other β-adrenoblockers.

Reactive respiratory diseases, including bronchial asthma (BA), BA in the anamnesis, chronic obstructive pulmonary diseases of severe course. Sinus bradycardia, sinus node weakness syndrome, sinoatrial block, grade II-III atrioventricular (AV) block, severe heart failure or cardiogenic shock.

Allergic rhinitis with a severe course.

Hyperchloremic acidosis. Severe renal failure.

Pregnancy, lactation, children under 18 years of age.

Side effects

Safety Profile Overview

The most commonly reported adverse reactions in clinical trials were blurred vision, eye irritation, and eye pain, which occurred in approximately 2-7% of patients.

The following are the adverse reactions noted during clinical trials of Brinarg and its individual components brinzolamide and timolol.

The undesirable reactions are listed using the following frequency designations: Very common (>1/10), common (>1/100 to <1/10), infrequent (>1/1000 to <1/100), rare (>1/10000 to <1/1000), very rare (<1/10000) and frequency unknown (cannot be estimated from available data). Within each frequency category, adverse reactions are listed in decreasing order of severity.

Infectious and parasitic diseases Frequency unknown: nasopharyngitis3, pharyngitis3, sinusitis3, rhinitis3

Blood and lymphatic system disorders Frequency unknown: decreased red blood cell count3, increased blood chloride3

Immune system disorders Frequency unknown: anaphylaxis2, systemic lupus erythematosus2, systemic allergic reactions including angioedema2, local and generalized rash2, hypersensitivity1, urticaria2, itching2.
Metabolic and nutritional disorders Frequent unknown: hypoglycemia2, decreased appetite3

Mental disorders Infrequent: insomnia1
Frequent unknown: depression1, memory loss2, apathy3, depressed mood3, decreased libido3, nightmares2,3,nervousness3.

Nervous system disorders Frequent: dysgeusia1
Frequency unknown: cerebral ischemia2,cerebrovascular disorder2,syncope2,increased signs and symptoms of myasthenia gravis2,somnolence3,motor dysfunction3,amnesia3,memory impairment3,paresthesia2,3,tremor3,hypoesthesia3,aguesia3,dizziness1,2,headache1

Visual disorders Frequently: blurred vision1, eye pain1, eye irritation1
Infrequent: Corneal erosion1, pitting keratitis1, effusion into the anterior chamber of the eye1, photophobia1, dry eye syndrome1, ocular discharge1, itching in the eye1,3, foreign body sensation in the eye1, eye hyperemia1, sclera hyperemia1, increased tear production1, conjunctival hyperemia1, erythema eyelid1
Frequent unknown: increased optic disc escavation3, vascular detachment after filtering surgery2, keratitis2,3, keratopathy3, corneal epithelium defect3, corneal epithelium disruption3, increased IOP3, ocular deposits3, corneal staining3, corneal edema3, decreased corneal sensitivity2, conjunctivitis3, meibomian gland inflammation3, diplopia2,3, decreased visual contrast3 photopsia3, decreased visual acuity2,3, visual disturbance1, pterygium3, feeling of discomfort in the eye3, “dry” keratoconjunctivitis3, hypoesthesia of the eye3, sclera pigmentation3, subconjunctival cyst3 visual disturbances3, ocular puffiness3, ocular allergic reactions3, madarosis3, eyelid disorders3, eyelid edema1, ptosis2, blepharitis3, asthenopia3, crusts on eyelid margins3 , excessive lacrimation3/p>

Hearing and labyrinth disorders Frequency unknown: Vertigo3 , tinnitus3

Heart disorders Frequency unknown: cardiac arrest2, heart failure2, chronic heart failure2, AV block2, cardio-respiratory distress syndrome3, angina3, bradycardia2,3, irregular heart rate3, arrhythmia2,3, palpitations2,3, tachycardia3, increased heart rate3, chest pain2, edema2

/p>

Vascular disorders Infrequent: decreased blood pressure1
Frequency unknown: hypotension2, hypertension3, increased blood pressure1, Raynaud’s phenomenon2, cold hands and feet2

Respiratory, thoracic and mediastinal disorders Infrequent: cough1
Frequency unknown: bronchospasm2 (mostly in patients with a history of bronchospastic disease), shortness of breath1, asthma3, nasal bleeding1, bronchial hyperresponsiveness3, laryngeal irritation3, nasal congestion3, upper airway congestion3, postnasal congestion syndrome3, sneezing3, feeling dry nose3, pharyngolaryngeal pain3, rhinorrhea3

Gastrointestinal (GI) disorders Frequency unknown: vomiting2,3, upper abdominal pain1,3, abdominal pain2, diarrhea1,3, dry mouth1, nausea1,3, esophagitis3, dyspepsia2,3, feeling of abdominal discomfort3, feeling of stomach discomfort3, increased peristalsis3, gastrointestinal distress3, oral hypoesthesia and paresthesia3, flatulence3

/p>

Liver and biliary tract disorders Frequency unknown: impaired liver function3

Skin and subcutaneous tissue disorders Frequency unknown: urticaria3, maculopapular rash2,3, generalized itching3, skin thickening3, dermatitis3, alopecia1, psoriasiform rash or exacerbation of psoriasis2, rash1, erythema1,3

Musculoskeletal and connective tissue disorders Frequency unknown: Myalgia1, muscle cramps3, arthralgia3, back pain3, pain in extremities3

Renal and urinary tract disorders Frequency unknown: renal pain3, pollakiuria3

Genital and mammary tract disorders Frequency unknown: erectile dysfunction3, sexual dysfunction2, decreased libido2
General disorders and disorders at the site of administration Frequency unknown: chest pain1, pain3, fatigue1,2, asthenia2,3, malaise3, feeling of discomfort in chest3, abnormal sensation3, feeling of anxiety3, irritability3, peripheral edema3, drug residues3

Laboratory and instrumental
findings Frequency unknown: increased blood potassium1, increased blood lactate dehydrogenase1

¹ Adverse reactions observed with the combination of brinzolamide + timolol.

² Some adverse reactions observed with timolol monotherapy.

³ Adverse reactions seen with brinzolamide monotherapy.

Description of Individual Adverse Reactions

Dysgeusia (bitter or unusual taste in the mouth after instillation) is a frequently reported systemic adverse reaction associated with the use of Brinarg during clinical trials. It is probably related to brinzolamide and is caused by penetration of the eye drops into the nasopharynx through the lacrimal canal. Occluding the lacrimal ducts or carefully closing the eyelids after instillation may help reduce this effect (see “Dosage and administration” section).

Brinarga contains brinzolamide, which is a carboenhydrase inhibitor and is systemically absorbed. The effects occurring in the gastrointestinal tract, nervous system, blood and lymphatic system, kidneys and urinary tract, metabolism and nutrition are mainly related to the systemic action of carboanhydrase inhibitors. Similar adverse reactions typical of oral forms of carboangiidrase inhibitors may also be observed when they are used topically.

When used topically, timolol penetrates into the systemic bloodstream, which may cause adverse reactions similar to those that occur with systemic administration of β-adrenoblockers. The listed adverse reactions include those encountered when using other β-adrenoblockers in the form of eye drops. Additional adverse reactions associated with the use of individual active ingredients that may potentially occur with the use of Brinarga are described above. The incidence of systemic adverse reactions is lower with topical administration than with systemic administration. For information on decreased systemic absorption, see “Dosage and administration”.

Overdose

Symptoms

Symptoms of β-adrenoblocker overdose may occur if the drug is accidentally ingested: bradycardia, hypotension, heart failure and bronchospasm.

Brinzolamide may cause electrolyte imbalance, development of acidosis, and central nervous system disorders.

Treatment

Symptomatic and supportive therapy. Serum electrolyte levels (particularly potassium) and blood pH should be monitored. Studies have shown that timolol hemodialysis is ineffective.

Pregnancy use

The drug Brinarga is contraindicated in pregnancy and during breastfeeding.

Similarities

Azarraga