Azarga

Azarga is an ophthalmologic drug. It belongs to the category of β-blockers. It is used as a miotic and antiglaucoma drug.

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Indications Azarga

It is indicated for lowering the level of intraocular pressure in patients with open-angle glaucoma or ocular hypertension, for whom the use of monotherapy has not allowed lowering the intraocular pressure to the required level.

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Release form

It is produced in the form of eye drops in dropper bottles (so-called “drop containers”) with a volume of 5 ml.

Pharmacodynamics

Azarga eye drops contain 2 active ingredients - brinzolamide and timolol maleate. They help reduce high intraocular pressure. This effect develops by reducing the secretion of intraocular fluid - this process is carried out using several different mechanisms of action. When combining the properties of these substances, a more effective reduction in IOP occurs (in comparison with the effect achieved when using these elements separately).

Brinzolamide is a potent inhibitor of CA-II, which is considered the dominant ocular enzyme. By inhibiting carbonic anhydrase within the ciliary segments of the eye, fluid secretion is reduced. This occurs primarily by inhibiting the formation of bicarbonate ions and further slowing the movement of sodium with fluid.

Timolol is a non-selective β-adrenoreceptor blocker. It does not have intrinsic sympathomimetic or membrane-stabilizing activity, and in addition, it does not have a direct suppressive effect on the myocardium. Fluorophotometric tests and tonography procedures have confirmed that the effect of this element is mainly associated with slowing down the production of intraocular fluid, and in addition with a slight acceleration of its outflow processes.

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Pharmacokinetics

After local use, the active components are absorbed into the systemic bloodstream through the cornea.

In the course of the drug pharmacokinetic study, healthy volunteers took brinzolamide orally at a dose of 1 mg 2 times a day for 2 weeks - this was necessary to reduce the period of achieving stable concentration values before starting to use the drug. After using eye drops 2 times a day for 13 weeks, the average brinzolamide value inside red blood cells was 18.8 ± 3.29 μM, and in addition 18.1 ± 2.68 μM, as well as 18.4 ± 3.01 μM after 4, 10, and 15 weeks, respectively. This indicates that the level of this component inside the RBC remains stable.

At a stable level of concentration of active substances after using the drops, the average C max of timolol in the blood plasma, as well as the AUC-time (0-12 hours) indicators are lower (by 27 and 28%), and are, respectively: C max 0.824 ± 0.453 ng / ml; AUC 0-12 hours 4.71 ± 4.29 ng h / ml compared to the use of timolol in a volume of 5 mg / ml (C max is 1.13 ± 0.494 ng / ml, and the AUC 0-12 hours indicator: 6.58 ± 3.18 ng h / ml).

The weak systemic effect of timolol after use of the drug is not clinically important. The average Cmax value in the blood plasma after instillation of drops of timolol is reached after approximately 0.79±0.45 hours.

Brinzolamide is synthesized with plasma protein in moderate quantities (about 60%). High affinity with the element CA-II, and also less strong with the element CA-I, helps brinzolamide to pass into the CCT. The active product of the breakdown of this substance is N-desethylbrinzolamide, which also accumulates inside the CCT, binding there mainly with CA-I. Due to the affinity of brinzolamide and its metabolite with the CCT and CA tissues, a low plasma concentration is formed.

Information on the distribution within the eye tissues of rabbits shows that timolol can be quantitatively determined in the intraocular fluid for 48 hours after the use of drops. After reaching a stable concentration, the component is determined in human blood plasma for 12 hours after the use of the drug.

The metabolic pathways of brinzolamide include N- and O-dealkylation, as well as oxidation of its N-propyl side chain. In vitro testing has shown that the metabolism of brinzolamide is primarily mediated by CYP3A4, and at least 4 other isoenzymes (CYP2A6 and CYP2B6, as well as CYP2C8 and CYP2C9).

The metabolism of the substance timolol occurs in 2 stages. During the first, an ethanolamine side chain is formed in the thiodiazole ring, and during the second, an ethanol side chain is formed within the morpholine nitrogen, as well as another similar chain that is connected to the carbonyl group, which is adjacent to the nitrogen. The metabolic processes of this active component are mainly associated with the CYP2D6 element.

Brinzolamide is excreted mainly via the kidneys (approximately 60%). About 20% of the dose can be detected in the urine (as a breakdown product). Brinzolamide with N-desethylbrinzolamide are the main elements found in the urine. There are also traces of the breakdown products N-desmethoxypropyl, and in addition O-desmethyl (less than 1%).

Timolol, together with its breakdown products, is excreted mainly through the kidneys. About 20% of the timolol dosage is excreted unchanged in the urine. The remainder of the component is also excreted in the urine as breakdown products.

The half-life of timolol in blood plasma occurs 4.8 hours after use of the drug.

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Dosing and administration

Dosage for adult patients (including the elderly): 1 drop in the conjunctival sac of the eye twice a day.

Systemic absorption can be reduced by pressing on the nasolacrimal opening or by closing the eyelids for 2 minutes. This method helps reduce the risk of developing systemic side effects and also enhances the local activity of the drug.

If a dose is missed, treatment should be continued according to the application schedule. The daily dosage may not exceed 2 drops in one eye sac.

If Azarga is substituted for another antiglaucoma ophthalmologic drug, the use of the latter must be discontinued. It is necessary to start using Azarga from the following day.

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Use Azarga during pregnancy

There is no relevant information on the use of the components timolol and brinzolamide during pregnancy. When testing brinzolamide on animals, toxic effects on the reproductive system were found. Therefore, pregnant women are not recommended to use the drug Azarga.

Contraindications

Among the contraindications:

• presence of bronchial asthma (also in the anamnesis);
• severe obstructive pulmonary pathologies in chronic form;
• cardiogenic shock;
• sinus bradycardia;
• bronchial hyperresponse;
• 2-3 degree AV block;
• severe form of heart failure;
• allergic rhinitis in a severe form;
• severe renal failure (creatinine clearance rate is less than 30 ml/min);
• closed-angle glaucoma;
• combination with orally administered carbonic anhydrase inhibitors;
• lactation period;
• age under 18 years;
• intolerance to elements from the category of β-blockers, and in addition, hyperchloremic acidosis;
• hypersensitivity to sulfanilamide drugs, and also to the active substances of the drug.

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Side effects Azarga

The use of this drug may cause the development of the following side effects:

• local: in 1-10% of all cases, blurred vision occurs, irritation or pain in the eye area occurs, and in addition, a feeling of a foreign object in it. In about 0.1-1% of all situations, the following disorders develop: corneal erosion, Thygeson keratitis, dry keratoconjunctivitis, and in addition, itching or discharge from the eyeballs; in addition, blepharitis (including allergic) or an allergic form of conjunctivitis, redness of the ocular mucosa, effusion into the anterior chamber of the eye may develop; crusts may also form on the edges of the eyelids, discomfort in the eye area may be felt, erythema of the eyelids or visual fatigue may develop;
• systemic: dysgeusia develops in approximately 1-10% of all cases. About 0.1-1% of all cases – development of insomnia, chronic obstructive pulmonary pathologies, drop in blood pressure, pain in the oropharynx and cough, as well as disruption of the hair growth process, rhinorrhea, and lichen planus.

Local reactions to brinzolamide include: development of keratopathy or keratitis, diplopia, photophobia, meibomitis, photopsia, keratoconjunctivitis sicca, as well as mydriasis, pterygium, and conjunctivitis. IOP may also increase, optic disc excavation may increase, ocular hypoesthesia may occur, as well as subconjunctival cyst and scleral pigmentation. Possible effects include visual impairment, ocular allergy or edema (eye or eyelid), increased lacrimation, and visual impairment. Corneal reactions include defects on the cornea and in its epithelium, edema, and deposits on the cornea.

Systemic reactions: depression or apathy, feeling of drowsiness or nervousness, nightmares, and motor dysfunctions. Memory may also deteriorate and amnesia or CNS disorder may develop, and libido may also decrease.

As a treatment: it is necessary to immediately wash the eyes with water. Then supportive treatment and therapy aimed at eliminating symptoms are required. It is necessary to monitor the pH of the blood, as well as electrolytes. The hemodialysis procedure does not give the desired result.

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Overdose

Accidental oral ingestion of the contents of the vial may result in manifestations of β-blocker overdose, including heart failure, hypotension, bronchospasm, and bradycardia.

To eliminate these symptoms, supportive and symptomatic therapy is prescribed. Since the drug contains brinzolamide, electrolyte imbalance, development of acidosis, and negative impact on the central nervous system are possible. It is necessary to carefully monitor the electrolyte level in the blood serum (especially potassium), as well as the blood pH. According to research, it is quite difficult to remove timolol from the body using dialysis.

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Interactions with other drugs

No studies have been conducted on the interaction of the drug with other drugs. It is prohibited to combine it with internally administered inhibitors of the element carbonic anhydrase, because there is a risk of increasing the manifestations of systemic adverse reactions.

The processes of metabolism of brinzolamide are carried out with the help of isoenzymes of hemoprotein P450: these are CYP3A4 (most often), and also CYP2A6 and CYP2B6, and together with them CYP2C8 with CYP2C9. It is necessary to carefully prescribe in combination with Azarga drugs that slow down the isoenzyme CYP3A4 (these are itraconazole, ketoconazole, ritonavir, as well as clotrimazole with troleandomycin), since they can inhibit the process of metabolism of brinzolamide. Caution is also necessary when combining the drug with inhibitors of the isoenzyme CYP3A4. The probability of accumulation of brinzolamide in the body is quite low, because it is excreted through the kidneys. This component is not an inhibitor of isoenzymes of hemoprotein P450.

There is a risk of increasing the hypotensive effect, and in addition, the development of bradycardia (pronounced form) in the case of a combination of timolol and orally taken Ca channel blockers, and in addition to this, guanethidine, β-blockers, antiarrhythmic drugs, parasympathomimetics, and cardiac glycosides.

In case of abrupt discontinuation of clonidine while using β-blockers, hypertension may develop.

Increased systemic exposure to β-blockers (slowing of heart rate) may result from the combination of timolol with inhibitors of the CYP2D6 element (such as cimetidine or quinidine).

Beta-blockers can increase the hypoglycemic properties of antidiabetic drugs. In addition, these elements have the ability to mask the manifestations of hypoglycemia.

When combined with other local ophthalmic drugs, the interval between the use of these drugs should be at least 15 minutes.

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Storage conditions

No special conditions are required for storing the medicine. It must be kept in a place inaccessible to small children. Temperature indicators are within 2-30°C.

Shelf life

Azarga can be used for 2 years from the date of manufacture of the drug. However, after opening the bottle, the medicine can be used for a maximum of 1 month.

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