Azarga - instructions for use, doses, side effects, contraindications

Active substanceBrinzolamide + TimololBrinzolamide + Timolol

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Azarga®

drops d / eye

ALKON PHARMACEUTICS, LLC Russia

Dosage form: & nbspeye drops

Composition:

Active substances:

Brinzolamide 10 mg

Timolol 5 mg in view timolol maleate 6.8 mg.

Excipients:

Benzalkonium chloride (as a 50% solution) 0.1 mg; disodium edetate 0.1 mg; Sodium Chloride 1.0 mg; tyloxapol 0.25 mg; mannitol 33 mg; Carbomer (974P) 4 mg; sodium hydroxide and / or hydrochloric acid concentrated to adjust the pH; water purified to 1.0 ml.

Description:

Homogeneous suspension of white or almost white color.

Pharmacotherapeutic group:Antiglaucoma combined (carbonic anhydrase inhibitor + beta-adrenoblocker)

ATX: & nbsp

S.01.E.D. Beta-blockers

S.01.E.C.54 Brinzolamide in combination with other drugs

Pharmacodynamics:

Mechanism of action

The drug AZARGA contains two active substances: brenzolamide and timolol maleate, which reduce the increased intraocular pressure, primarily by reducing the secretion of intraocular fluid, however in various ways. The combined action of Brinzolamide and Timolol exceeds the action of each substance separately to reduce intraocular pressure.

Brinzolamide is an inhibitor of carbonic anhydrase II.Inhibition of carbonic anhydrase in the ciliary body of the eyeball reduces the production of intraocular fluid, presumably due to the slowing of the formation of bicarbonate ions, followed by a decrease in the transport of sodium and liquid.

Timolol - a non-selective beta-adrenergic blocker without sympathomimetic activity, does not have a direct depressive effect on the myocardium, does not have membrane-stabilizing activity. A number of studies have shown that with topical application timolol reduces the formation of intraocular fluid and slightly increases its outflow.

Pharmacokinetics:

Absorption

With topical application brenzolamide and timolol penetrate into the systemic circulation. The maximum concentration of Stax brinzolamide in erythrocytes is about 18.4 pM.

In the equilibrium state, after application of the Azarga preparation, the average maximum concentration of C max of timolol in plasma and AUC0-124 timolol was 0.824 ± 0.453 ng / ml and 4.71 ± 4.29 g * h / ml, respectively, and the mean Timolol Stach was reached at 0.79 ± 0.45 h.

Distribution

Brinzolamide moderately binds 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-dezetilbrinzolamid also accumulates in erythrocytes, which binds preferentially to carbonic anhydrase I. Due affinity brinzolamide and its metabolite to erythrocytes tissue carbonic anhydrase and their concentration in the plasma is low.

Metabolism

The metabolism of Brinzolamide occurs by N-dealkylation, O-dealkylation and oxidation Npropyl side chain. The main metabolite - N-dezetilbrinzolamid, in the presence of brinzolamide binds to carbonic anhydrase I and also accumulates in erythrocytes. Research in vitro showed that for the metabolism of Brinzolamide is responsible, mainly, isoenzyme CYP3A4, as well as isozymes CYP2A6, CYP2B6, CYP2C8 and CYP2C9.

Metabolism of timolol occurs in two ways: to form ethanolamine side chain on the thiadiazole ring, and ethanol to form the side chain nitrogen of morpholine and similar side chain with a carbonyl group connected to the nitrogen. Metabolism of timolol is carried out mainly CYP2D6.

Excretion

Brinzolamide is excreted mainly in urine and feces in comparative quantities, 32% and 29%, respectively. About 20% is excreted in the form of metabolites with urine. In urine are found, basically, brenzolamide and N-de-ethylbenzenamide, as well as residual quantities (<1%) of other metabolites (N-de-methoxypropyl 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 timolol is 4.8 hours after topical application of Azarga.

Indications:

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

Contraindications:

Individual hypersensitivity to the components of the drug, sulfonamides or other beta-blockers.

Respiratory diseases of the respiratory tract, incl. bronchial asthma, history of bronchial asthma, chronic obstructive pulmonary disease of the severe course. Sinus bradycardia, syndrome of sinus node weakness, sinoatrial block, atrioventricular block II-III degree, severe heart failure or cardiogenic shock.

Allergic rhinitis of severe course.

Hyperchloremic acidosis.

Severe kidney failure.

Pregnancy, lactation, children under 18 years.

Dosing and Administration:

Locally. Vial before use shake.

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

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

If the dose was missed, the treatment should be continued from the next dose on schedule. The dose should not exceed 1 drop in the conjunctival sac of the eye 2 times a day.

If you replace an antiglaucoma drug with AZARGA, you should start using AZARGA the day after the previous drug was discontinued.

Do not touch the tip of the dropper bottle to any surface to avoid contamination of the dropper and its contents.

The bottle must be closed after each use.

Side effects:

Security Profile Overview

The most frequently reported adverse reactions in clinical studies were blurred vision, eye irritation, eye pain, which occurred in about 2-7% of patients.

Below are the undesirable reactions noted during clinical studies of AZARGA and its individual components - Brinzolamide and Timolol.

Undesirable reactions are listed using the following frequency designations: very often (> 1/10), often (> 1/100 to <1/10), infrequently (> 1/1000 to <1/100), rarely (> 1/10000 to <1/1000), very rarely (<1/10000) and the frequency is unknown (it is impossible to estimate based on available data). Within each frequency category, adverse reactions are given in order of severity.

Infectious and parasitic diseases	Frequency unknown: nasopharyngitis³, pharyngitis^3,sinusitis³, rhinitis³
Violations of the blood and lymphatic system	Frequency unknown: Reduction of the number of red blood cells³, an increase in the chloride content in the blood³
Immune system disorders	Frequency unknown: anaphylaxis³, systemic lupus erythematosus², systemic allergic reactions, including angioedema², local and generalized rash², hypersensitivity¹, urticaria², itching².
Disorders from the metabolism and nutrition	Frequency unknown: hypoglycemia², decreased appetite³
Disorders of the psyche	Infrequently: insomnia¹ Frequency unknown: Depression¹, memory loss², apathy³, depressed mood³, decreased libido³, nightmares^2,3, nervousness³.
Disturbances from the nervous system	Often: dysgeusia¹ Frequency unknown: cerebral ischemia², cerebrovascular disorder², faint², increased signs and symptoms of myasthenia gravis gravis², drowsiness³, motor dysfunction³, amnesia³, memory impairment³, paresthesia^2,3, tremor³, hypoesthesia³, agavezia³, dizziness^1,2, headache¹
Disturbances on the part of the organ of sight	Often: blurring of vision¹, pain in the eye¹, eye irritation¹ Infrequently: corneal erosion¹, point keratitis¹, effusion into the anterior chamber of the eye¹, photophobia¹, dry eye syndrome¹, discharge from the eye¹, itching in the eye^1,3, the sensation of a foreign body in the eyes¹, hyperemia of the eye¹, sclera hyperemia¹, increased lacrimation¹, conjunctival hyperemia¹, erythema century¹ Frequency unknown: Increased esotation of the optic nerve³, detachment of the choroid after filtration operation², keratitis^2,3, keratopathy³, defect of the epithelium of the cornea³, violation of the epithelium of the cornea³, increased intraocular pressure³, deposits in the eye³, staining of the cornea³, corneal edema³, decreased sensitivity of the cornea², conjunctivitis³, inflammation of the meibomian glands³, diplopia^2,3, decreased contrast of vision³, photopsy³, decreased visual acuity^2,3, impaired vision¹, pterygium³, a feeling of discomfort in the eye³, "dry" keratoconjunctivitis³, eye hypoesthesia³, scleral pigmentation³, subconjunctival cyst³, a vision disorder³, swelling of the eyes³, allergic reactions of the eye³, madarose³, eyelid disorders³, edema of the eyelids¹, ptosis2, blepharitis³, astenopia³, the formation of crusts on the edges of the eyelids³ , increased lacrimation³.
Hearing disorders and labyrinthine disorders	Frequency unknown: vertigo³, ringing in the ears³
Heart Disease	Frequency unknown: cardiac arrest², heart failure², chronic heart failure², AB-block², cardio-respiratory distress syndrome³, angina pectoris³, bradycardia^2,3, irregular heart rate³, arrhythmia^2,3, a feeling of heartbeat^2,3, tachycardia³, an increase in heart rate³, chest pain², edema²
Violations from sides of blood vessels	Infrequently: lowering of blood pressure¹ Frequency unknown: hypotension², hypertension³, increased blood pressure¹, the Raynaud phenomenon², cold hands and feet²
Violations from respiratory system, bodies chest and the mediastinum	Infrequently: cough¹ Frequency unknown: bronchospasm² (predominantly patients with bronchospastic disease in history), dyspnea¹, asthma¹, nose bleed¹, bronchial hyperreactivity³, irritation of the larynx³, nasal congestion³, congestion of the upper respiratory tract³, postnasal edema syndrome³, sneezing³, a feeling of dryness of the nose³, pharyngolaringitis pain³, rhinorrhea³
Violations from side of the gastro- intestinal tract	Frequency unknown: vomiting ^2,3, pain in the upper abdomen^1,3, abdominal pain², diarrhea^1,3, dry mouth¹, nausea^1,3, esophagitis³, dyspepsia^2,3, a feeling of discomfort in the abdominal cavity³, a feeling of discomfort in the stomach³, strengthening of peristalsis³, gastrointestinal upset³, hypesthesia and paresthesia of the oral cavity³, flatulence³
Violations from side of the liver and bile excretory ways	Frequency unknown: impaired liver function³
Violations from the skin and subcutaneous tissue	Frequency unknown: urticaria³, maculopapular rash^2,3, generalized itching³, skin firming³, dermatitis³, alopecia¹, psoriasis rash or exacerbation of psoriasis², rash¹, erythema^1,3
Violations from side of the skeletal- muscular and connective tissue	Frequency unknown: myalgia¹, muscle spasms³, arthralgia³, backache³, pain in the extremities³
Disorders from the kidneys and urinary tract	Frequency unknown: pain in the kidney³, pollakiuria³
Violations of the genitals and mammary gland	Frequency unknown: erectile disfunction³, sexual dysfunction², decreased libido²
General disorders and disorders at the site of administration	Frequency unknown: chest pain¹, pain³, fatigue^1,², asthenia^2,3, malaise³, a feeling of discomfort in the chest³, abnormal sensations³, a feeling of anxiety³, irritability³, peripheral edema³, drug residues³
Laboratory and instrumental data	Frequency unknown: an increase in the potassium content in the blood, 1 an increase in lactate dehydrogenase in the blood¹

¹ Adverse reactions observed with the administration of AZARGA

²Adverse reactions observed with monotherapy with timolol

³ Adverse reactions observed with monotherapy with brenzolamide

Description of individual adverse reactions

Dysgeusia (a bitter or unusual taste in the mouth after instillation) is a frequently reported systemic undesired reaction associated with the use of AZARGA during clinical trials. This is probably due to brinzolamide and is caused by the penetration of eye drops into the nasopharynx through the tear duct. Occlusion of lacrimal ducts or careful closing of the eyelids after instillation can help to reduce this effect (see section "Dosing and Administration").

The preparation of AZARG contains brenzolamide, which is an inhibitor of carbonic anhydrase and has systemic absorption. Effects arising from the gastrointestinal tract, nervous system, blood and lymphatic system, kidney and urinary tract, metabolism and nutrition, are mainly related to the systemic action of carbonic anhydrase inhibitors.Similar undesirable reactions, characteristic of oral forms of inhibitors of carbonic anhydrase, can also be observed when applied locally.

With topical application timolol penetrates into the systemic bloodstream, which can cause unwanted reactions, similar to those that occur during the systemic administration of beta-blockers. These unwanted reactions include reactions that occur with the use of other beta-blockers in the form of eye drops. Additional undesirable reactions associated with the use of individual active components that may potentially occur with the use of the AZAPA are described above. The frequency of systemic adverse reactions with topical application is lower than with systemic administration. For information on reducing systemic absorption, see "Method of administration and dose".

Overdose:

Symptoms of an overdose of beta-blockers in case of accidental ingestion of the drug may be observed: bradycardia, hypotension, heart failure and bronchospasm.

As a result of the action of brinzolamide, electrolyte imbalance, the development of an acidosis state, and disorders of the central nervous system may occur.It is necessary to monitor the level of electrolytes in the blood serum (in particular, the content of potassium) and the pH of the blood. Hemodialysis is not effective.

Interaction:

The preparation of AZARG contains brenzolamide, an inhibitor of carbonic anhydrase, which, when applied topically, can be absorbed systemically. Cases of acid-base balance disturbance as a result of application of oral inhibitors of carbonic anhydrase are described. The possibility of such disorders should also be considered in patients using AZARGA.

It is not recommended simultaneous use with oral inhibitors of carbonic anhydrase, since there is a possibility of increasing systemic adverse reactions. For the metabolism of Brinzolamide, isoenzymes of cytochrome P-450: CYP3A4 (basically), CYP2A6, CYP2B6, CYP2C8 and CYP2C9. Caution is necessary to prescribe drugs that inhibit the isoenzyme CYP3A4, such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin, due to the possible inhibition of the metabolism of brenzolamide by isoenzyme CYP3A4. Caution should be exercised when co-prescribing isoenzyme inhibitors CYP3A4. However, the accumulation of brinzolamide is unlikely, since it is excreted by the kidneys. Brinzolamide is not an inhibitor of cytochrome P-450 isoenzymes.

Increased systemic action of beta-blockers (reduction in heart rate, depression) can develop with the simultaneous use of inhibitors CYP2D6 (quinidine, fluoxetine, paroxetine) and timolol.

There is a possibility of increasing the hypotensive effect and / or development of severe bradycardia with simultaneous use of beta-blockers for topical use with calcium channel blockers for oral administration, guanethidine, beta-blockers, antiarrhythmics (including amiodarone), glycogenides of digitalis and parasympatomimetics.

beta-adrenoceptors can reduce the response to adrenaline in the treatment of anaphylactic reactions. Caution is advised to prescribe the drug to patients with atopy or anaphylaxis in the anamnesis (see section "Special instructions"),

In some cases, as a result of simultaneous application betaadrenoblokatorov for topical application and adrenaline (epinephrine), may develop mydriasis.

The effect on intraocular pressure, or known effects of systemic beta-blockers, can be enhanced if timolol is assigned to a patient already receiving a systemic beta-adrenergic blocker. Such patients should be carefully observed.

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

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

Special instructions:

System Effects

Brinzolamide and timolol can be systemically absorbed.

Timolol with topical application can cause the same adverse reactions from the cardiovascular and respiratory systems, as well as other unwanted reactions, as well as systemic beta-blockers.

Hypersensitivity reactions, characteristic of all derivatives of sulfonamides, can develop with the use of AZARGA due to systemic absorption. In case of serious adverse reactions or hypersensitivity reactions, stop taking the drug.

Heart Disease

In patients with cardiovascular diseases (eg, coronary heart disease, Prinzmetal angina, heart failure) and hypotension, beta-blocker therapy should be critically evaluated and the possibility of treatment with other active substances should be considered.It should be closely monitored for signs of exacerbation of the disease and adverse reactions in patients suffering from cardiovascular diseases.

Vascular disorders

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

Hyperthyroidism

Beta-blockers can mask symptoms of hyperthyroidism.

Muscle weakness

It has been reported that beta-blockers increase muscle weakness, which is observed with certain symptoms of myasthenia gravis (eg, diplopia, ptosis and general weakness).

Disturbances from the respiratory system

There have been reports of reactions from the respiratory system, including death from bronchospasm in patients with bronchial asthma after taking beta-adrenoconvertors for topical application.

Hypoglycemia / Diabetes

beta-adrenoconjugators should be administered with caution to patients with a tendency to spontaneous hypoglycemia or patients suffering from a labile course of diabetes, as these drugs can mask the symptoms of acute hypoglycemia.

Violation of acid-base equilibrium

The development of a violation of acid-base balance with the use of oral forms of inhibitors of carbonic anhydrase is described. In patients with risk of renal failure, the drug should be used with caution, in connection with the possible risk of metabolic acidosis.

Concentration of attention

Carbonic anhydrase inhibitors used orally may affect the ability to engage in activities requiring increased attention and / or physical coordination in elderly patients. These phenomena can be observed, because brenzolamide penetrates into the systemic blood stream with topical application.

Anaphylactic reactions

Patients with atopy or with severe anaphylactic reactions to various allergens in a history who receive beta-blockers can respond more strongly to the effects of these allergens, and may also be resistant to conventional adrenaline doses in the treatment of anaphylactic reactions.

Detachment of the choroid

We describe cases of detachment of the choroid of the eye with the use of drugs that prevent the formation of intraocular fluid (eg, timolol, acetazolamide) after filtering operations.

Surgical anesthesia

The action of beta-blockers in ophthalmic preparations can block the systemic action of beta-agonists, for example, adrenaline. An anesthesiologist must be informed of the timolol patient's admission.

Concomitant therapy

When using AZAPTA with patients who take systemic beta-blockers, it is necessary to take into account the possible mutual enhancement of the pharmacological action of the drugs both with respect to the known systemic effects of beta-blockers and with respect to reducing intraocular pressure. Careful observation of such patients is necessary.

The combined use of two topical beta-blockers is not recommended. There is a possible increase in systemic effects resulting from the inhibition of carbonic anhydrase in patients taking oral carbonic anhydrase inhibitors and AZARGA. Simultaneous administration of AZARGA and oral carbonic anhydrase inhibitors is not recommended.

Effects of the organ of vision

The effect of Brinzolamide on the function of the corneal endothelium in patients with corneal disorders (especially patients with a low number of endothelial cells) has not been studied.In patients wearing contact lenses, it is necessary to carefully monitor their corneal state with brinzolamide, since carbonic anhydrase inhibitors can influence the hydration of the cornea. It is recommended to closely monitor patients with corneal disorders, for example, patients with diabetes mellitus or corneal dystrophy.

Benzalkonium chloride

Benzalkonium chloride, which is part of AZAPA, can cause eye irritation, as well as change the color of soft contact lenses. Avoid contact with soft contact lenses.

Before using the drug, contact lenses should be removed and placed back no earlier than 15 minutes after the drug is used.

The preparation of AZARG contains benzalkonium chloride, which can cause point keratopathy and / or toxic ulcer keratopathy. With prolonged use of the drug should carefully monitor the condition of patients.

Impaired liver function

Caution should be used in patients with severe hepatic insufficiency.

Effect on the ability to drive transp. cf. and fur:

The drug AZARTA has a slight effect on the ability to drive and control mechanisms.

If the patient has a temporary blurred vision after using the drug, it is not recommended to drive the car and engage in activities requiring increased attention and reaction before recovery.

Carboanhydrase inhibitors can weaken the ability to perform tasks that require concentration of attention and / or coordination of movements.

Form release / dosage:

Eye drops.

Packaging:5 ml each in a plastic dropper bottle "Droptainer ™". For 1 bottle with instructions for use in a pack of cardboard.

Storage conditions:

At a temperature of 2 to 30 ° C, out of the reach of children.

Shelf life:

2 years.

Do not use after the expiry date printed on the package.

Use within 4 weeks after opening the vial.

Terms of leave from pharmacies:On prescription

Registration number:LSR-003647/10

Date of registration:30.04.2010

Expiration Date:Unlimited

The owner of the registration certificate:ALKON PHARMACEUTICS, LLC ALKON PHARMACEUTICS, LLC Russia

Manufacturer: & nbsp

ALCON-COUVREUR, n.v. s.a. Belgium

Information update date: & nbsp04.02.2017

Illustrated instructions

Instructions

Azarga® (Azarga®)