Azarga
Ukraine
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INSTRUCTION for medical use of the medicinal product AZARGA® (AZ ARGA Ò) Composition: Active substances: brinzolamide, timolol maleate; 1 ml of suspension contains 10 mg of brinzolamide, 5 mg of timolol (as timolol maleate); Excipients: benzalkonium chloride, mannite (E 421), carbomer 974P, tyloxapol, disodium edetate, sodium chloride, hydrochloric acid and/or sodium hydroxide (for pH adjustment), purified water. Pharmaceutical form. Eye drops. Main physicochemical properties: white or almost white homogeneous suspension. Pharmacotherapeutic group. Medicinal products used in ophthalmology. Antiglaucoma agents and miotics. β-blockers. ATC code S01ED51. Pharmacological properties. Pharmacodynamics. Mechanism of action AZARGA® eye drops contain two active substances: brinzolamide and timolol maleate. These two components reduce elevated intraocular pressure (IOP) by decreasing aqueous humor secretion, but do so via different mechanisms of action. The combined effect of these two active substances results in additional reduction of IOP compared to the effect achieved with either component 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 aqueous humor secretion, primarily by slowing bicarbonate ion formation, thereby decreasing sodium and fluid transport. Timolol is a non-selective β-adrenergic receptor blocker that lacks intrinsic sympathomimetic and membrane-stabilizing activity and does not directly depress myocardial contractility. Tonography and fluorophotometric studies in humans have confirmed that its primary action is associated with reduced aqueous humor formation and a slight increase in its outflow. Pharmacodynamic effect Clinical effects In a 12-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 mean IOP values between 25 and 27 mm Hg, mean IOP reduction with AZARGA® eye drops administered twice daily was 7 to 9 mm Hg. At all time points during all patient visits, mean IOP reduction with dorzolamide 20 mg/ml + timolol 5 mg/ml did not exceed the effect achieved with AZARGA®. In a 6-month controlled clinical study in patients with open-angle glaucoma or ocular hypertension with mean IOP values between 25 and 27 mm Hg, mean IOP reduction with AZARGA® eye drops administered twice daily was 8 to 9 mm Hg, which exceeded the effect of brinzolamide 10 mg/ml twice daily by 3 mm Hg and that of timolol 5 mg/ml twice daily by 2 mm Hg. Statistically significant reduction in mean IOP was observed compared to brinzolamide and timolol at all visits throughout the study. In three controlled clinical studies, ocular discomfort after instillation of AZARGA® eye drops was significantly less than with dorzolamide 20 mg/ml + timolol 5 mg/ml. Pharmacokinetics. Absorption After topical ocular application, brinzolamide and timolol are absorbed through the cornea into systemic circulation. In a pharmacokinetic study, healthy volunteers received oral brinzolamide 1 mg twice daily for 2 weeks to shorten the time to reach steady-state concentration before starting AZARGA® eye drops. After administration of AZARGA® eye drops twice daily for 13 weeks, brinzolamide concentration in red blood cells (RBCs) averaged 18.8 ± 3.29 µM, 18.1 ± 2.68 µM, and 18.4 ± 3.01 µM at weeks 4, 10, and 15, respectively, indicating stable RBC concentrations of brinzolamide. At steady-state after administration of AZARGA® eye drops, mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC0-12h) of timolol were 27% and 28% lower, respectively (Cmax 0.824 ± 0.453 ng/ml; AUC0-12h 4.71 ± 4.29 ng·h/ml) compared to timolol 5 mg/ml (Cmax 1.13 ± 0.494 ng/ml; AUC0-12h 6.58 ± 3.18 ng·h/ml). The low systemic impact of timolol after AZARGA® eye drops is not clinically significant. After administration of AZARGA® eye drops, mean maximum plasma concentration (Cmax) of timolol was reached at 0.79 ± 0.45 hours. Distribution Brinzolamide plasma protein binding is moderate (approximately 60%). Due to its high affinity for CA-II and to a lesser extent for CA-I, brinzolamide penetrates into RBCs. Its active metabolite, N-desethylbrinzolamide, also accumulates in RBCs, where it primarily binds to CA-I. The affinity of brinzolamide and its metabolite for red blood cells and tissue CA leads to low plasma concentrations. Tissue distribution data in rabbits demonstrated that timolol can be quantitatively detected in aqueous humor for up to 48 hours after administration of AZARGA® eye drops. At steady-state, timolol can be detected in human plasma for up to 12 hours after administration of AZARGA® eye drops. Metabolism Brinzolamide metabolism pathways include N-dealkylation, O-dealkylation, and oxidation of its N-propyl side chain. N-desethylbrinzolamide is the main metabolite of brinzolamide in humans. It binds to CA-I in the presence of brinzolamide and accumulates in RBCs. In vitro studies demonstrated that brinzolamide metabolism is primarily associated with CYP3A4, as well as at least four other isoenzymes (CYP2A6, CYP2B6, CYP2C8, and CYP2C9). Timolol is metabolized via two pathways. One involves formation of an ethanolic side chain in the thiadiazole ring, and the other involves formation of an ethanolic side chain at the morpholine nitrogen and a second similar side chain adjacent to a carbonyl group. Timolol metabolism is primarily associated with CYP2D6. Excretion Brinzolamide is primarily excreted by the kidneys (approximately 60%). Nearly 20% of the dose is found in urine as metabolite. Brinzolamide and N-desethylbrinzolamide are the main components detected in urine, along with traces of N-desmethoxypropyl and O-desmethyl metabolites (<1%). Timolol and its metabolites are primarily excreted by the kidneys. Approximately 20% of the timolol dose is excreted unchanged in urine, with the remainder excreted in urine as metabolites. The plasma elimination half-life (t1/2) of timolol is 4.8 hours after administration of AZARGA® eye drops. Preclinical safety data Brinzolamide Preclinical data indicate no risk to humans from brinzolamide use, as shown by single-dose toxicity studies, repeated-dose toxicity studies, genotoxicity, carcinogenic potential, and local ocular irritation studies. In rabbit toxicity studies with oral brinzolamide doses up to 6 mg/kg/day (214 times the recommended daily clinical dose of 28 µg/kg/day), no effect on fetal development was observed despite significant maternal toxicity. Similar studies in rats revealed slight reduction in fetal skull and sternum ossification in females receiving 18 mg/kg/day (642 times the recommended daily clinical dose). However, this effect was not observed in females receiving 6 mg/kg/day. These results were obtained at doses causing metabolic acidosis, reduced maternal body weight gain, and reduced fetal weight. Dose-dependent reduction in fetal weight was observed in females receiving oral brinzolamide: from slight reduction (approximately 5–6%) at 2 mg/kg/day to about 14% at 18 mg/kg/day. No adverse effects on offspring were observed during lactation at 5 mg/kg/day. Timolol Preclinical data indicate no risk to humans from timolol use, as shown by single-dose toxicity studies, repeated-dose toxicity studies, genotoxicity, carcinogenic potential, and local ocular irritation studies. Studies on timolol's toxic effects on reproductive function showed delayed fetal ossification in rats without postnatal adverse effects (at 50 mg/kg/day, 3500 times the daily clinical dose of 14 µg/kg/day) and increased fetal resorption in rabbits (at 90 mg/kg/day, 6400 times the daily clinical dose). Clinical characteristics. Indications. Reduction of intraocular pressure in adult patients with open-angle glaucoma or ocular hypertension who have not achieved sufficient IOP reduction with monotherapy. Contraindications.
Interaction with other medicinal products and other forms of interaction. No studies have been conducted on interactions of AZARGA® eye drops with other medicinal products. Although AZARGA® eye drops containing brinzolamide (a carbonic anhydrase inhibitor) are administered topically, 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 AZARGA® eye drops. There is a possibility of additive effects on known systemic effects of carbonic anhydrase inhibitors in patients taking 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 (primary), CYP2A6, CYP2B6, CYP2C8, and CYP2C9. Inhibitors of CYP3A4 such as ketoconazole, itraconazole, clotrimazole, ritonavir, and troleandomycin are expected to inhibit CYP3A4-mediated brinzolamide metabolism. Caution is advised when co-administering CYP3A4 inhibitors. However, accumulation of brinzolamide is unlikely since it is primarily excreted by the kidneys. Brinzolamide is not an inhibitor of cytochrome P450 isoenzymes. There is a possibility of additive effects leading to arterial hypotension and/or marked bradycardia when eye drops containing β-blockers are used concomitantly with oral or intravenous calcium channel blockers (diltiazem), β-blockers, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine, and reserpine. β-blockers may reduce sensitivity to adrenaline in the treatment of anaphylactic reactions. Particular caution is required in patients with atopy or history of anaphylaxis (see section "Special precautions"). With β-blocker use, hypertensive response may be intensified upon sudden discontinuation of clonidine. Caution is recommended when using AZARGA® eye drops 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 symptoms of hypoglycemia (see section "Special precautions"). Occasionally, mydriasis has been reported with concomitant use of ophthalmic β-blockers and adrenaline (epinephrine). Special precautions. Systemic effects
Cardiac disorders. β-blockers should be used with caution in patients with cardiovascular disorders (e.g., ischemic heart disease, Prinzmetal's angina, heart failure), hypotension, and consideration should be given to alternative treatments. Patients with cardiovascular disorders should be closely monitored to avoid missing symptoms of worsening conditions or adverse reactions. Due to the negative effect on impulse conduction time, β-blockers may be cautiously prescribed to patients with first-degree heart block. Vascular disorders Patients with severe peripheral circulation disorders (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 Worsening of muscle weakness associated with myasthenic symptoms (e.g., diplopia, ptosis, and general weakness) has been reported with β-adrenergic receptor blockers. Respiratory disorders Respiratory reactions, including fatal bronchospasm, have been reported in asthmatic patients after topical ophthalmic use of some β-adrenergic receptor blockers. AZARGA® eye drops should be used with caution in patients with mild to moderate chronic obstructive pulmonary disease (COPD) and only when expected benefit outweighs potential risk. Hypoglycemia/diabetes β-adrenergic receptor blockers should be used with caution in patients prone to spontaneous hypoglycemia or with decompensated diabetes, as β-adrenergic blockers may mask symptoms of acute hypoglycemia. Acid-base balance disorders AZARGA® eye drops contain brinzolamide, a sulfonamide. Similar adverse reactions as with systemic sulfonamides may occur with topical use. Acid-base balance disturbances have been reported with oral carbonic anhydrase inhibitors. Since there is a risk of metabolic acidosis, the drug should be used with caution in patients at risk of kidney impairment. If symptoms of serious reactions or hypersensitivity occur, drug use should be discontinued. Mental performance Oral carbonic anhydrase inhibitors may impair ability to perform tasks requiring mental alertness and/or physical coordination. AZARGA® eye drops are systemically absorbed; therefore, these effects may also occur with topical use. Anaphylactic reactions Patients with a history of atopy or severe anaphylactic reactions to various allergens may have more pronounced reactions to re-exposure to these allergens and may not respond to usual doses of adrenaline used to treat anaphylactic reactions when taking β-adrenergic blockers. Choroidal detachment Choroidal detachment has been reported during treatment aimed at reducing aqueous humor secretion (e.g., timolol, acetazolamide) following trabeculotomy. Surgical anesthesia Topical ocular β-adrenergic receptor blockers may block systemic beta-agonist effects, such as those of adrenaline. If a patient is receiving timolol, the anesthesiologist should be informed. Concomitant use The effect on intraocular pressure or known systemic effects of β-blockers may be enhanced in patients already receiving systemic β-blockers when timolol is administered. Such patients should be closely monitored. 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 possibility of additive effects on known systemic effects of carbonic anhydrase inhibitors in patients taking oral carbonic anhydrase inhibitors and AZARGA® eye drops. Concomitant use of AZARGA® 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 AZARGA® eye drops for treating patients with pseudoexfoliative glaucoma or pigmentary glaucoma is limited. Caution is advised in treating such patients, and continuous IOP monitoring is recommended. After discontinuation of treatment, reduction in intraocular pressure is expected to persist for 5–7 days, and a withdrawal effect may potentially occur. AZARGA® eye drops have not been studied in patients with closed-angle glaucoma; therefore, their use in this patient group is not recommended. Ophthalmic beta-blockers may cause dry eye. Patients with corneal disorders should be treated with caution. Potential effects of brinzolamide on corneal endothelial function in patients with compromised cornea (particularly those with low endothelial cell count) have not been studied. Special attention should be paid to patients wearing 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, and contact lens use may increase the risk of corneal damage. Careful monitoring is also recommended in other corneal injuries, such as in patients with diabetes or corneal dystrophy. AZARGA® eye drops can be used during contact lens wear under careful monitoring (see section "Benzalkonium chloride" below). Benzalkonium chloride AZARGA® 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 instilling AZARGA® eye drops and 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 with frequent or prolonged use of the drops. Hepatic function disorders AZARGA® 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 demonstrated toxic effects on reproductive function (see section "Preclinical safety data"). AZARGA® eye drops should not be used during pregnancy. For ways to reduce systemic absorption, see section "Dosage and administration". Epidemiological studies have not shown negative effects on fetal development, but with oral β-blockers there is a risk of intrauterine growth disturbances. Additionally, newborns exposed to β-blockers before delivery may exhibit symptoms of β-blockade (e.g., bradycardia, hypotension, respiratory distress, hypoglycemia). Newborns should be closely monitored during the first days of life if the mother used AZARGA® eye drops before delivery. Due to the lack of data or limited data on brinzolamide use in pregnant women and confirmed toxic effects on reproductive function in animals, this drug should not be prescribed to pregnant women or women of reproductive age not using contraception. Breastfeeding period It is unknown whether brinzolamide passes into human breast milk. Animal studies demonstrated excretion of brinzolamide into milk after oral administration (see section "Dosage and administration"). β-blockers pass into human breast milk. However, with therapeutic ocular doses of timolol, it is unlikely that its presence in breast milk is sufficient to cause clinical symptoms of β-blockade in infants. For ways to reduce systemic absorption, see section "Preclinical safety data". However, risk to the infant during breastfeeding cannot be excluded. The decision to discontinue breastfeeding or to refrain from using AZARGA® eye drops should be made by the physician, considering benefit to the woman and risk to the infant. Reproductive function No studies have been conducted on the effect of topical ophthalmic use of AZARGA® eye drops on human reproductive function. Preclinical data did not demonstrate any effects of brinzolamide or timolol on reproductive function in males or females after oral administration. No effect on reproductive function in males or females is expected with use of AZARGA® eye drops. Ability to affect reaction speed when driving or operating machinery. AZARGA® 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 ability to perform tasks requiring mental alertness and/or physical coordination (see section "Special precautions"). Dosage and administration. Use in adults, including elderly patients The dose is 1 drop of AZARGA® eye drops into the conjunctival sac of the affected eye(s) twice daily. Systemic absorption is reduced by applying pressure to the nasolacrimal duct or closing the eyelids. This reduces systemic adverse reactions and increases local activity (see section "Special precautions"). If a dose is missed, treatment should continue with the next dose according to the schedule. The dose should not exceed 1 drop in the affected eye(s) twice daily. When replacing another ophthalmic antiglaucoma agent with AZARGA® eye drops, the other agent should be discontinued and AZARGA® eye drops started the next day. Patients with hepatic or renal impairment No studies have been conducted with AZARGA® or timolol 5 mg/ml eye drops in patients with hepatic or renal impairment. No dose adjustment is necessary in patients with hepatic impairment or mild to moderate renal impairment. No studies have been conducted on use of AZARGA® in patients with severe renal impairment (creatinine clearance < 30 ml/min) or hyperchloremic acidosis (see section "Contraindications"). Since brinzolamide and its main metabolite are primarily excreted by the kidneys, AZARGA® is contraindicated in this patient group (see section "Contraindications"). AZARGA® should be used with caution in patients with severe hepatic impairment (see section "Special precautions"). Method of administration For ophthalmic use. Patients should be advised to shake the bottle well before use. After first opening, remove the protective ring designed for first opening control. To prevent contamination of the dropper tip and bottle contents, care should be taken not to touch eyelids, adjacent areas, or other surfaces with the dropper tip. Patients should be advised to close the bottle tightly after use. If more than one ophthalmic agent is used locally, the interval between applications should be at least 5 minutes. Ophthalmic ointments should be applied last. Children. Safety and efficacy of AZARGA® 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 case of AZARGA® eye drops overdose, treatment is symptomatic and supportive. Due to brinzolamide content, electrolyte imbalance and acidosis may develop, and possible effects on the central nervous system may occur. Serum electrolyte levels (especially potassium) and blood pH should be monitored. Studies have shown that timolol is poorly removed by dialysis. Adverse reactions. Brief overview of safety data In clinical studies, the most common adverse reactions were blurred vision, eye irritation, and eye pain, occurring in approximately 2% to 7% of patients. Brief overview of adverse reactions presented in table form During clinical studies of AZARGA® eye drops and components brinzolamide and timolol, as well as in the post-marketing period, the following adverse reactions were reported, classified as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1000 to <1/100), rare (≥1/10000 to <1/1000), or very rare (<1/10000), or frequency not known (cannot be estimated from available data). Within each group, adverse reactions are listed in order of decreasing severity.
1Adverse reactions observed during the use of AZARGA®. 2Additional adverse reactions observed with timolol when used as monotherapy. 3Additional adverse reactions observed with brinzolamide when used as monotherapy. Description of some adverse reactions Dysgeusia (bitter or unusual taste in the mouth after instillation) was a systemic adverse reaction commonly reported in clinical studies with AZARGA® eye drops. This reaction was likely associated with brinzolamide and caused by the entry of eye drops into the nasopharynx via the nasolacrimal duct. Applying pressure to the nasolacrimal duct area or gently closing the eyelids after instillation may reduce the likelihood of this effect (see section "Dosage and administration"). AZARGA® eye drops contain brinzolamide, a sulfonamide-class carbonic anhydrase inhibitor that is systemically absorbed. Systemic carbonic anhydrase inhibitors generally cause gastrointestinal, neurological, hematological, renal, and metabolic disturbances. Similar types of adverse reactions associated with oral carbonic anhydrase inhibitors may also occur with topical administration. Timolol is absorbed into the systemic circulation. This may result in adverse reactions similar to those of systemic β-blockers. The listed adverse reactions include those typical of the class of ophthalmic β-blockers. The additional adverse reactions listed above are related to the individual components and may potentially occur with the use of AZARGA® eye drops. The frequency of systemic adverse reactions following topical ophthalmic administration is lower than with systemic administration. For information on minimizing systemic absorption, see section "Dosage and administration". The following adverse reactions 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. Reporting suspected adverse reactions It is important to report suspected adverse reactions after marketing authorization of the medicinal product. This ensures ongoing monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are encouraged to report any suspected adverse reactions. Shelf life. 2 years. Do not use more than 4 weeks after first opening the bottle. Storage conditions. No special storage conditions are required. Keep out of reach and sight of children. Packaging. 5 ml in dropper bottles. One dropper bottle per cardboard box. Prescription status. Prescription only. Manufacturer. Novartis Manufacturing NV / Novartis Manufacturing NV. Manufacturer's address . Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium / Rijksweg 14, Puurs-Sint-Amands, 2870, Belgium. |