Brinarga eye drops, 5ml

Decrease in increased intra-diffuse pressure in open-angle glaucoma and intraocular hypertension in patients in whom monotherapy was insufficient to reduce intraocular pressure.

Locally. Shake the bottle before use.

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

After using the drug, to reduce the risk of developing systemic adverse reactions, it is recommended to lightly press with a finger on the projection area of ??the lacrimal sacs at the inner corner of the eye for 1-2 minutes after instillation of the drug - this reduces the systemic absorption of the drug.

If a dose has been missed, then 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.

In case of replacing any antiglaucoma drug with Brinarga, you should start using Brinarga the next day after the previous drug is canceled.

Do not touch the tip of the dropper stopper to any surface to avoid contamination of the bottle and its contents. The bottle must be closed after each use.

The active ingredients are
Brinzolamide 10 mg,
Timolol maleate 6.83 mg, equivalent to timolol 5 mg.
Excipients:
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 up to 1.0 ml.

• Individual hypersensitivity to drug components, sulfonamides or other ?-blockers.

• Reactive diseases of the respiratory tract, incl. bronchial asthma (BA), history of asthma, chronic obstructive pulmonary disease of severe course. Sinus bradycardia, sick sinus syndrome, sinoatrial block, II-III degree atrioventricular (AV) block, severe heart failure or cardiogenic shock.

• Severe allergic rhinitis.

• Hyperchloremic acidosis.

• Severe renal failure.

• Pregnancy, lactation period,

• children under 18 years of age.

Pharmacological properties

Pharmacodynamics

Mechanism of action

Brinarga's drug contains two active substances: brinzolamide and timolol maleate, which reduce increased intraocular pressure (IOP), primarily by reducing the secretion of intraocular fluid, but in different ways. The combined effect of brinzolamide and timolol exceeds the effect of each substance separately for lowering IOP.

Brinzolamide is a carbonic anhydrase II inhibitor. Inhibition of carbonic anhydrase in the ciliary body of the eyeball reduces the production of intraocular fluid, presumably due to a slowdown in the formation of bicarbonate ions with a subsequent decrease in sodium and fluid transport.

Timolol is a non-selective blocker of ?-adrenergic receptors without sympathomimetic activity, does not have a direct depressive effect on the myocardium, and does not have membrane stabilizing activity. A number of studies have shown that when applied topically, timolol reduces the formation of intraocular fluid and slightly increases its outflow.

Pharmacokinetics

Absorption

When applied topically, brinzolamide and timolol enter the systemic circulation.

The maximum concentration (Cmax) in erythrocytes is about 18.4 pM.

In the equilibrium state, after the use of brinzolamide and timolol, the average Cmax of timolol in plasma and the area under the concentration-time curve for 12 hours (AUC0-12h) of timolol was 0.824 ± 0.453 ng / ml and 4.71 ± 4.29ng * h / ml, respectively, and the average Cmax 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 carbonic anhydrase II and, to a lesser extent, to carbonic anhydrase I. Its active metabolite N-desethylbrinzolamide also accumulates in erythrocytes, where it binds mainly to carbonic anhydrase I. Due to the affinity of brinzolamide and its metabolite for erythrocytes and tissue carbonic anhydrase, their plasma concentration is low.

Metabolism

Brinzolamide is metabolized by N-dealkylation, O-dealkylation and oxidation of the N-propyl side chain. The main metabolite, N-desethylbrinzolamide, in the presence of brinzolamide, binds to carbonic anhydrase I and also accumulates in erythrocytes. In vitro studies have shown that the metabolism of brinzolamide is mainly responsible for the CYP3A4 isoenzyme, as well as the CYP2A6, CYP2B6, CYP2C8 and CYP2C9 isoenzymes.

Timolol metabolism occurs in two ways: with the formation of an ethanolamine 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 attached to nitrogen. Timolol metabolism is carried out mainly by CYP2D6.

Withdrawal

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

Timolol and its metabolites are excreted mainly by the kidneys. About 20% of timolol is excreted in the urine unchanged, the rest in the form of metabolites. T1 / 2 of timolol is 4.8 hours after topical combined use of brinzolamide and timolol.

Overdose

Symptoms

Symptoms of an overdose of? -Adrenergic blockers may occur in case of accidental ingestion of the drug: bradycardia, hypotension, heart failure and bronchospasm.

As a result of the action of brinzolamide, electrolyte imbalance, the development of an acidosis state, and disturbances in the central nervous system can occur.

Treatment

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

Interaction with other medicinal products

Brinarga contains brinzolamide, a carbonic anhydrase inhibitor, which, when applied topically, can be absorbed systemically. Cases of violation of acid-base balance as a result of the use of oral carbonic anhydrase inhibitors have been described. Consideration should be given to the possibility of such disorders in patients using Brinarga.

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

An increase in the systemic action of ?-blockers (decreased heart rate, depression) can develop with the simultaneous use of CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine) and timolol.

There is a possibility of an increase in the hypotensive effect and / or the development of severe bradycardia with the simultaneous use of ?-blockers for topical use with calcium channel blockers for oral administration, guanethidine, ?-blockers, antiarrhythmic drugs (including amiodarone), digitalis glycosides and parasympathomimetics.

?-blockers can reduce the response to epinephrine in the treatment of anaphylactic reactions. Care should be taken to prescribe the drug to patients with atopy or with a history of anaphylaxis (see section 'Special instructions').

In some cases, as a result of the simultaneous use of? -Adrenergic blockers for topical use and adrenaline (epinephrine), mydriasis may develop.

The effect on intraocular pressure, or the known effects of systemic ?-blockers, may be enhanced if timolol is prescribed to a patient already receiving a systemic ?-blocker. These patients must be closely monitored.

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

In the case of use with other local ophthalmic drugs, the interval between their use should be at least 5 minutes.

special instructions

Systemic Effects

Brinzolamide and timolol may undergo systemic absorption. When applied topically, Timolol can cause the same adverse reactions from the cardiovascular and respiratory systems, as well as other undesirable reactions, as systemic ?-blockers.

Hypersensitivity reactions characteristic of all sulfonamide derivatives can develop with the use of Brinarga due to systemic absorption. In case of serious adverse reactions or hypersensitivity reactions, the drug should be discontinued.

Heart disorders

In patients with cardiovascular disease (eg, ischemic heart disease, Prinzmetal's angina, heart failure) and hypotension, ?-blocker therapy should be critically evaluated and the possibility of treatment with other active substances should be considered. You should closely monitor the appearance of signs of exacerbation of the disease and adverse reactions in patients with cardiovascular diseases.

Vascular disorders

Caution should be given to patients with severe impairment / disorder of peripheral circulation (Raynaud's disease or severe Raynaud's syndrome).

Hyperthyroidism

B-blockers can mask the symptoms of hyperthyroidism.

Muscle weakness

It has been reported that ?-blockers increase muscle weakness, which is observed with some symptoms of myasthenia gravis (for example, diplopia, ptosis, and general weakness).

Respiratory system disorders

Respiratory reactions, including death from bronchospasm, have been reported in patients with asthma after taking topical ?-blockers.

Hypoglycemia / Diabetes

?-blockers should be used with caution in patients with a tendency to spontaneous hypoglycemia or in patients with labile diabetes, since these drugs can mask the symptoms of acute hypoglycemia.

Violation of acid-base balance

The development of acid-base imbalance with the use of oral forms of carbonic anhydrase inhibitors is described. In patients at risk of renal failure, the drug should be used with caution, due to the possible risk of metabolic acidosis.

Concentration of attention

Oral carbonic anhydrase inhibitors may interfere with the ability to engage in activities requiring increased attention and / or physical coordination in older patients. These phenomena can be observed, because brinzolamide enters the systemic circulation when applied topically.

Anaphylactic reactions

Patients with atopy or with severe anaphylactic reactions to various allergens in history, receiving ?-blockers, may react more strongly to the effects of these allergens, and may also be resistant to usual doses of epinephrine in the treatment of anaphylactic reactions.

Detachment of the choroid

Cases of detachment of the choroid are described when using drugs that prevent the formation of intraocular fluid (for example, timolol, acetazolamide) after filtering operations.

Surgical anesthesia

The action of ?-blockers in ophthalmic drugs can block the systemic action of ?-agonists, for example, adrenaline. The anesthesiologist should be informed about the patient's intake of timolol.

Concomitant therapy

When using the drug Brinarga in patients who take systemic ?-blockers, it is necessary to take into account the possible mutual enhancement of the pharmacological action of the drugs both in relation to the known systemic effects of ?-adrenergic blockers, and in relation to a decrease in intraocular pressure.

Careful monitoring of such patients is necessary.

The combined use of two topical ?-blockers is not recommended. There is a possibility of increased systemic effects resulting from inhibition of carbonic anhydrase in patients taking oral carbonic anhydrase inhibitors and Brinarga. Simultaneous administration of Brinarga and oral carbonic anhydrase inhibitors is not recommended.

Effects on the part of the organ of vision

The effect of brinzolamide on corneal endothelial function in patients with corneal disorders (especially patients with a low endothelial cell count) has not been studied. In patients wearing contact lenses, it is necessary to carefully monitor their state of the cornea when using brinzolamide, since carbonic anhydrase inhibitors can affect corneal hydration. Close monitoring of patients with corneal abnormalities, such as those with diabetes mellitus or corneal dystrophy, is recommended.

Benzalkonium chloride

Benzalkonium chloride, which is part of Brinarga, can cause eye irritation and discoloration of soft contact lenses. Contact with soft contact lenses should be avoided.

Before using the drug, contact lenses should be removed and reinstalled no earlier than 15 minutes after using the drug.

Brinarga contains benzalkonium chloride, which can cause punctate keratopathy and / or toxic ulcerative keratopathy. With prolonged use of the drug, you should carefully monitor the condition of patients.

Liver dysfunction

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

Influence on the ability to drive vehicles, mechanisms

Brinarga's drug has little effect on the ability to drive and use machinery.

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

Carbonic anhydrase inhibitors can impair the ability to perform tasks that require concentration and / or coordination of movements.