Instructions for use Azarga eye drops, dropper bottle, drop-tainer, 5 ml
Composition
active ingredients: brinzolamide, timolol maleate;
1 ml of suspension contains 10 mg of brinzolamide, 5 mg of timolol (as timolol maleate);
excipients: benzalkonium chloride, mannitol (E 421), carbomer 974P, tyloxapol, disodium edetate, sodium chloride, hydrochloric acid and/or sodium hydroxide (for pH adjustment), purified water.
Dosage form
Eye drops.
Main physicochemical properties: white or almost white homogeneous suspension.
Pharmacotherapeutic group
Drugs used in ophthalmology. Antiglaucoma drugs and miotics. β-blockers. ATX code S01E D51.
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 reducing the secretion of aqueous humor, but they do so through different mechanisms of action. The combined effect of these two active substances results in an additional reduction in 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 segments of the eye reduces aqueous humor secretion, primarily by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport.
Timolol is a non-selective β-adrenergic receptor blocker that does not exhibit intrinsic sympathomimetic or membrane-stabilizing activity, nor does it have a direct myocardial depressant effect. Tonography and fluorophotometric studies in humans have confirmed that its main action is associated with a decrease in the formation of intraocular fluid and a slight increase in its outflow.
Pharmacodynamic action
Clinical effects
In a 12-month controlled clinical trial in patients with open-angle glaucoma or ocular hypertension who were considered by the investigators to benefit from combination therapy and who had a mean IOP of 25 to 27 mmHg, the mean IOP reduction with AZARGA® eye drops twice daily was 7 to 9 mmHg. At all time points and all patient visits, it was demonstrated that the mean IOP reduction with dorzolamide 20 mg/ml + timolol 5 mg/ml was not greater than that with AZARGA® alone.
In a six-month controlled clinical trial in patients with open-angle glaucoma or ocular hypertension with a mean IOP of 25 to 27 mmHg, the mean IOP reduction with AZARGA® eye drops twice daily was 8 to 9 mmHg, which was 3 mmHg greater than that with brinzolamide 10 mg/ml twice daily and 2 mmHg greater than that with timolol 5 mg/ml twice daily. Statistically significant mean IOP reductions were observed compared with brinzolamide and timolol at all visits during the study.
In three controlled clinical trials, ocular discomfort following instillation of AZARGA® eye drops was significantly less than with dorzolamide 20 mg/ml + timolol 5 mg/ml.
Pharmacokinetics.
Absorption
After topical ocular administration, brinzolamide and timolol are absorbed through the cornea into the systemic circulation. In a pharmacokinetic study, healthy volunteers received oral brinzolamide 1 mg twice daily for 2 weeks to reduce the time to reach steady-state concentrations before initiating AZARGA® eye drops. After 13 weeks of twice daily administration of AZARGA® eye drops, mean brinzolamide red blood cell (RBC) concentrations were 18.8 ± 3.29 μM, 18.1 ± 2.68 μM, and 18.4 ± 3.01 μM at 4, 10, and 15 weeks, respectively, indicating that steady-state brinzolamide concentrations are maintained in the RBC.
At steady state, the mean maximum plasma concentration (Cmax) of timolol and the concentration-time curve (AUC0-12h) were 27% and 28% lower, respectively, after administration of AZARGA® eye drops (Cmax 0.824 ± 0.453 ng/ml; AUC0-12h 4.71 ± 4.29 ng g/ml) compared to timolol 5 mg/ml (Cmax 1.13 ± 0.494 ng/ml; AUC0-12h 6.58 ± 3.18 ng g/ml). The low systemic exposure to timolol after administration of AZARGA® eye drops is not clinically relevant. The mean maximum plasma concentration (Cmax) of timolol was reached after 0.79 ± 0.45 hours after administration of AZARGA® eye drops.
Distribution
Ocular tissue distribution data in rabbits have demonstrated that timolol can be quantified in the intraocular fluid for 48 hours after administration of AZARGA® eye drops. When steady-state concentrations are achieved, timolol can be detected in human plasma for 12 hours after administration of AZARGA® eye drops.
Metabolism
The metabolic pathways of brinzolamide include N-dealkylation, O-dealkylation, and oxidation of its N-propyl side chain. N-desethylbrinzolamide is the major metabolite of brinzolamide in humans. It binds to CA-I in the presence of brinzolamide and accumulates in the gastrointestinal tract. In vitro studies have demonstrated that the metabolism of brinzolamide is primarily mediated by CYP3A4, with at least four other isoenzymes (CYP2A6, CYP2B6, CYP2C8, and CYP2C9).
Timolol is metabolized by two pathways. The first pathway involves the formation of an ethanolamine side chain on the thiodiazole ring, and the other involves the formation of an ethanol side chain on the morpholino nitrogen and a second similar side chain with a carbonyl group adjacent to the nitrogen. The metabolism of timolol is primarily mediated by CYP2D6.
Excretion
Brinzolamide is excreted primarily by the kidneys (approximately 60%). Approximately 20% of the dose is recovered in the urine as metabolites. Brinzolamide and N-desethylbrinzolamide are the major components recovered in the urine, along with traces of the 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 in the urine as unchanged drug, and the remainder is also excreted in the urine as metabolites. The plasma half-life (t1/2) of timolol is 4.8 hours after administration of AZARGA® eye drops.
Preclinical safety data
Brinzolamide
Preclinical data indicate that there is no risk to humans from the use of brinzolamide, as evidenced by studies of single-dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenic potential and local eye irritation.
In a toxicity study in rabbits, oral doses of brinzolamide up to 6 mg/kg/day (214 times the recommended daily clinical dose of 28 mcg/kg/day) did not show any effects on foetal development, despite significant maternal toxicity. Similar studies in rats showed a slight reduction in ossification of the skull and sternum in foetuses in dams given brinzolamide at 18 mg/kg/day (642 times the recommended daily clinical dose). However, this effect was not observed in dams given 6 mg/kg/day. These results were obtained at doses that caused metabolic acidosis with reduced maternal body weight gain and reduced foetal weights. A dose-dependent decrease in fetal weight was observed in dams receiving oral brinzolamide, ranging from a slight decrease (approximately 5-6%) at 2 mg/kg/day to approximately 14% at 18 mg/kg/day. No adverse effects on the fetus were observed during lactation at 5 mg/kg/day.
Timolol
Preclinical data indicate that there is no risk to humans from the use of timolol, as evidenced by studies of single-dose toxicity, repeated-dose toxicity, genotoxicity, carcinogenic potential and local eye irritation studies.
Studies of the toxic effects of timolol on reproductive function showed delayed fetal ossification in rats in the absence of adverse effects in the postnatal period (at a dose of 50 mg/kg/day, which is 3500 times higher than the daily clinical dose of 14 mcg/kg/day) and increased fetal resorption in rabbits (at a dose of 90 mg/kg/day, which is 6400 times higher than the daily clinical dose).
Indication
Reduction of intraocular pressure in adult patients with open-angle glaucoma or ocular hypertension in whom monotherapy has not resulted in sufficient reduction of intraocular pressure.
Contraindication
Hypersensitivity to the active substances or to any of the excipients of the drug.
Hypersensitivity to other β-blockers.
Hypersensitivity to sulfonamides (see section "Special warnings and precautions for use").
Conditions accompanied by airway hyperresponsiveness, including bronchial asthma or a history of bronchial asthma, severe chronic obstructive pulmonary disease.
Sinus bradycardia, sick sinus syndrome, sinoatrial block, second or third degree atrioventricular block not controlled by a pacemaker. Severe heart failure, cardiogenic shock.
Severe allergic rhinitis.
Hyperchloremic acidosis (see section "Method of administration and dosage").
Severe renal failure.
Interaction with other medicinal products and other types of interactions
No studies have been conducted on AZARGA® eye drops regarding their interactions with other drugs.
There is a potential for an additive effect to the already known systemic effects of carbonic anhydrase inhibitors in patients taking oral carbonic anhydrase inhibitors and brinzolamide eye drops. Concomitant use of brinzolamide-containing eye drops and oral carbonic anhydrase inhibitors is not recommended.
Cytochrome P450 isoenzymes responsible for the metabolism of brinzolamide include CYP3A4 (major), CYP2A6, CYP2B6, CYP2C8 and CYP2C9. CYP3A4 inhibitors such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin are expected to inhibit the metabolism of brinzolamide mediated by the CYP3A4 isoenzyme. Caution should be exercised when concomitantly administering CYP3A4 inhibitors. However, accumulation of brinzolamide is unlikely as 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 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.
Beta-blockers may reduce the sensitivity to adrenaline in the treatment of anaphylactic reactions. Particular caution should be exercised in patients with atopy or a history of anaphylaxis (see section 4.4).
When taking β-blockers, the hypertensive reaction may be exacerbated if clonidine is abruptly discontinued. Caution is recommended when AZARGA® eye drops are used concomitantly with clonidine.
Increased systemic effects of β-blockers (e.g. decreased heart rate, depression) have been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol. Caution is recommended when the combinations are used.
Beta-blockers may enhance the hypoglycaemic effect of antidiabetic agents. Beta-blockers may mask the symptoms of hypoglycaemia (see section 4.4).
Mydriasis has occasionally been reported with concomitant use of ophthalmic β-blockers and adrenaline (epinephrine).
Application features
Systemic effects
Brinzolamide and timolol are absorbed systemically. Due to the presence of the β-adrenergic active component timolol, the same cardiovascular, pulmonary and other adverse reactions as with systemic use of β-adrenergic receptor blockers may occur with the use of the drug. The incidence of systemic adverse reactions with topical ophthalmic use is lower than with systemic use. Regarding the possibility of reduced systemic absorption, see section "Method of administration and dosage".
Since the drug is absorbed systemically, patients using AZARGA® eye drops may experience hypersensitivity reactions common to all sulfonamide derivatives, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). During treatment with AZARGA® eye drops, patients should be informed of the signs and symptoms of hypersensitivity reactions and of the need to closely monitor for skin reactions.
Heart disorders.
β-Blockers should be used with caution in patients with cardiovascular disease (e.g., coronary artery disease, Prinzmetal's angina, and heart failure) and hypotension, and other treatment options should be considered if necessary. Patients with cardiovascular disease should be closely monitored for signs of worsening of these conditions and adverse reactions.
Due to the negative effect on impulse conduction time, β-blockers should be administered with caution to patients with only first-degree heart block.
Vascular disorders
Patients with severe peripheral circulatory disorders/diseases (e.g. severe Raynaud's disease or Raynaud's syndrome) should be treated with caution.
Hyperthyroidism
β-blockers may mask the symptoms of hyperthyroidism.
Muscle weakness
There have been reports of increased muscle weakness associated with myasthenic symptoms (e.g. diplopia, ptosis and general weakness) occurring with the use of β-adrenergic receptor blockers.
Respiratory dysfunction
Respiratory reactions, including fatal ones, due to bronchospasm have been reported in patients with asthma following the use of some topical ophthalmic β-adrenergic receptor blockers.
AZARGA® eye drops should be used with caution in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the expected benefit outweighs the potential risk.
Hypoglycemia/diabetes
Beta-blockers should be used with caution in patients prone to spontaneous hypoglycemia or in patients with decompensated diabetes, as beta-blockers may mask the symptoms of acute hypoglycemia.
AZARGA® eye drops contain brinzolamide, which is a sulfonamide. The same adverse reactions as with sulfonamides may occur with topical use of the drug. Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. Because of the risk of metabolic acidosis, the drug should be used with caution in patients at risk of renal impairment. If symptoms of serious reactions or hypersensitivity occur, the drug should be discontinued.
Mental activity
Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination. AZARGA® eye drops are absorbed systemically, therefore, these effects may also occur with topical application of the drug.
Anaphylactic reactions
When using β-adrenergic blockers, patients with a history of atopy or a history of severe anaphylactic reactions to various allergens may react more actively to repeated exposure to these allergens and may not respond to the usual doses of adrenaline used to treat anaphylactic reactions.
Detachment of the choroid of the eye
Choroid detachment has been reported with treatment aimed at reducing aqueous humor secretion (e.g. timolol, acetazolamide) following trabeculotomy.
Surgical anesthesia
When applied topically to the eye, β-adrenergic receptor blockers may block the systemic beta-agonist effects of, for example, adrenaline. If the patient is prescribed timolol, the anaesthetist should be informed of this.
Simultaneous use
The effect on intraocular pressure or the known systemic effects of β-blockers may be potentiated by the use of timolol in patients already receiving systemic β-blockers. Such patients should be closely monitored. The use of two topical β-blockers or two topical carbonic anhydrase inhibitors is not recommended (see section 4.5). There is a potential for an additive effect to the already known systemic effects of carbonic anhydrase inhibitors in patients receiving oral carbonic anhydrase inhibitors and AZARGA® eye drops. The concomitant use of AZARGA® eye drops and oral carbonic anhydrase inhibitors has not been studied and is therefore not recommended (see section 4.5).
Ophthalmological effects
There is limited experience with the use of AZARGA® eye drops in patients with pseudoexfoliative glaucoma or pigmentary glaucoma. Caution should be exercised when treating such patients and continuous monitoring of IOP is recommended.
After discontinuation of treatment with the drug, the reduction in intraocular pressure is expected to continue for 5–7 days and a withdrawal effect may potentially occur.
AZARGA® eye drops have not been studied in patients with angle-closure glaucoma, therefore their use in this category of patients is not recommended.
Ophthalmic beta-blockers may cause dry eye. Patients with corneal diseases should be treated with caution.
The potential effect of brinzolamide on corneal endothelial function in patients with damaged corneas (particularly in patients with low endothelial cell counts) has not been studied.
Particular attention should be paid to patients who wear contact lenses, as studies have not been conducted in this patient population. Therefore, close monitoring of such patients is recommended when using brinzolamide, as carbonic anhydrase inhibitors may affect corneal hydration. This may lead to corneal edema and decompensation, and contact lens wear may increase the risk of corneal damage. Close monitoring is also recommended in patients with other corneal disorders, such as those with diabetes mellitus or corneal dystrophy.
AZARGA® eye drops can be used while wearing contact lenses under close supervision (see section “Benzalkonium chloride” below).
Benzalkonium chloride
AZARGA® eye drops contain benzalkonium chloride, which may cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses should be avoided. Patients should be advised to remove contact lenses before using AZARGA® eye drops and to 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 necessary with frequent or prolonged use of the drops.
Liver dysfunction
AZARGA® should be used with caution in patients with severe hepatic impairment.
Use during pregnancy or breastfeeding
Pregnancy
Epidemiological studies have not shown any adverse effects on fetal development, but there is a risk of intrauterine growth retardation with oral β-blockers. In addition, symptoms of β-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in neonates when β-blockers were administered antepartum. Neonates should be closely monitored during the first days of life if the mother has used AZARGA® eye drops before delivery.
Given the lack of or limited data on the use of brinzolamide in pregnant women and the confirmed presence of reproductive toxicity in animals, this drug should not be prescribed to pregnant women and women of childbearing potential not using contraceptives.
Breastfeeding period
It is not known whether brinzolamide is excreted in human milk. Animal studies have shown excretion of brinzolamide in breast milk following oral administration (see section 4.2).
β-Blockers are excreted in human milk. However, when therapeutic doses of timolol are used in the eye, it is unlikely that its presence in breast milk is sufficient to cause clinical symptoms of β-blockade in infants. Regarding the possibility of reduced systemic absorption, see section 5.3. However, a risk to the child during breast-feeding cannot be excluded. A decision on whether to discontinue breast-feeding or to abstain from the use of AZARGA® eye drops should be made by the physician, taking into account the benefit to the woman and the risk to the child.
Reproductive function
No studies have been conducted on the effects on human reproductive function with topical ophthalmic use of AZARGA® eye drops.
Preclinical data have not demonstrated any effects of brinzolamide or timolol on male or female reproductive function following oral administration.
The use of AZARGA® eye drops is not expected to have any effect on male or female reproductive function.
Ability to influence reaction speed when driving vehicles or other mechanisms
AZARGA® eye drops have minimal effect on the ability to drive or use machines.
Temporary blurred vision or visual disturbances may affect the ability to drive or use machines. If blurred vision occurs during instillation, the patient should wait until the vision clears before driving or using other machines.
Carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination (see section "Special warnings and precautions for use").
Method of administration and doses
Use in adults, including elderly patients
The dose is 1 drop of AZARGA® eye drops in the conjunctival sac of the affected eye(s) 2 times daily.
Systemic absorption is reduced by applying pressure to the nasolacrimal canal or closing the eyelids. This reduces systemic side effects and increases local activity (see section "Special instructions").
If a dose is missed, treatment should be continued with the next dose according to the schedule. The dose should not exceed 1 drop in the affected eye(s) 2 times a day.
When replacing another ophthalmic antiglaucoma agent with AZARGA® eye drops, the other agent should be discontinued and AZARGA® eye drops should be started the next day.
Patients with impaired liver and kidney function
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 in patients with mild to moderate renal impairment.
AZARGA® has not been studied in patients with severe renal impairment (creatinine clearance < 30 mL/min) or in patients with hyperchloraemic acidosis (see section 4.3). Since brinzolamide and its major metabolite are primarily excreted by the kidneys, AZARGA® is contraindicated in these patients (see section 4.3).
AZARGA® should be used with caution in patients with severe hepatic impairment (see section 4.4).
Method of application
For ophthalmic use.
The patient should be advised to shake the bottle well before use.
After the first opening of the bottle, the protective ring intended to control the first opening should be removed.
To prevent contamination of the dropper tip and contents of the bottle, care should be taken not to touch the eyelids, surrounding areas, or other surfaces with the dropper tip. The patient should be advised to close the bottle tightly after use.
If more than one ophthalmic agent is applied topically, the interval between their applications should be at least 5 minutes. Eye ointments should be applied last.
The safety and efficacy of AZARGA® eye drops in children under the age of 18 have not been established. There are no data on the use in this category of patients.
Overdose
If the contents of the vial are accidentally swallowed, symptoms of β-blocker overdose may include bradycardia, hypotension, heart failure, and bronchospasm.
In case of overdose with AZARGA® eye drops, treatment is symptomatic and supportive. Due to the content of brinzolamide, electrolyte imbalance, acidosis 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 difficult to remove from the body by dialysis.
Side effects
Safety data summary
In clinical studies, the most common adverse reactions were blurred vision, eye irritation, and eye pain, occurring in approximately 2% to 7% of patients.
Summary of adverse reactions in tabular form
The following adverse reactions have been reported during clinical trials with AZARGA® eye drops and the components brinzolamide and timolol, as well as during post-marketing experience, and are classified as follows: very common (≥1/10), common (≥1/100 to <1/10), uncommon (≥1/1,000 to <1/100), rare (≥1/10,000 to <1/1,000) or rare (<1/10,000) or not known (cannot be estimated from the available data). Within each grouping, adverse reactions are presented in order of decreasing seriousness.
| Types of organs and systems | Adverse reactions (corresponding MedDRA term (v. 18.0)) |
| Infectious and parasitic diseases | Frequency not known: rhinopharyngitis3, pharyngitis3, sinusitis3, rhinitis3 |
| Blood and lymphatic system diseases | Uncommon: decreased white blood cell count1 Frequency not known: decreased red blood cell count3, increased blood chloride3 |
| On the part of the immune system | Frequency unknown: anaphylaxis2, anaphylactic shock1, systemic allergic reactions including angioedema2, local and generalised rashes2, hypersensitivity1, urticaria2, pruritus2 |
| Metabolic | Frequency not known: hypoglycemia2 |
| Mental disorders | Uncommon: insomnia1 Frequency unknown: hallucinations2, depression1, memory loss2, apathy3, depressed mood3, decreased libido3, nightmares2,3, nervousness3 |
| From the nervous system | Common: dysgeusia1 Frequency unknown: Cerebral ischemia2, stroke2, loss of consciousness2, increased symptoms of myasthenia gravis2, drowsiness3, motor disorders3, amnesia3, memory impairment3, paraesthesia2,3, tremor3, hypoaesthesia3, loss of taste3, dizziness1,2, headache1 |
| Ophthalmological disorders | Common: punctate keratitis1, vision blurred1, eye pain1, eye irritation1 Uncommon: keratitis1,2,3, dry eye1, corneal discoloration1, eye discharge1, eye pruritus1,3, foreign body sensation in eyes1, ocular hyperaemia1, conjunctival hyperaemia1 Uncommon: corneal erosion1, anterior chamber opalescence1, photophobia1, lacrimation increased1, scleral hyperaemia1, eyelid erythema1, eyelid margin scaling1 Frequency not known: increased optic disc excavation3, choroid detachment after trabeculotomy2 (see section “Special instructions”), keratopathy3, corneal epithelial defect3, corneal epithelial disorder3, increased intraocular pressure3, ocular precipitate3, corneal staining3, corneal edema3, decreased corneal sensitivity2, conjunctivitis3, meibomianitis3, diplopia2,3, increased sensitivity to bright light3, photopsia3, decreased visual acuity2,3, visual impairment1, pterygium3, ocular discomfort3, keratoconjunctivitis sicca3, ocular hypoaesthesia3, scleral pigmentation3, subconjunctival cyst3, visual impairment3, eye edema3, ocular allergic manifestations3, madarosis3, eyelid disorder3, eyelid edema1, ptosis2 |
| Hearing and balance disorders | Frequency unknown: vertigo3, tinnitus3 |
| From the side of the cardiovascular system | Common: decreased heart rate/pulse rate1 Frequency unknown: cardiac arrest2, cardiac function deterioration2, congestive heart failure2, atrioventricular block2, cardiorespiratory distress3, angina3, bradycardia2,3, heart rate irregular3, arrhythmia2,3, palpitations2,3, tachycardia3, heart rate increased3, chest pain2, edema2 |
| Vascular disorders | Uncommon: decreased blood pressure1 Frequency not known: hypotension2, hypertension3, blood pressure increased1, Raynaud's phenomenon2, cold extremities2 |
| Respiratory, thoracic and mediastinal disorders | Uncommon: cough1 Rare: sore throat1, rhinorrhea1 Frequency not known: bronchospasm2 (predominantly in patients with pre-existing bronchospastic disease), dyspnoea1, asthma3, epistaxis1, bronchial hyperactivity3, throat irritation3, nasal congestion3, upper respiratory tract congestion3, nasopharyngeal mucus hypersecretion3, sneezing3, nasal dryness3 |
| Frequency not known: vomiting2,3, abdominal pain upper1,3, abdominal pain2, diarrhoea1,3, dry mouth1, nausea1, oesophagitis3, dyspepsia2,3, abdominal discomfort3, stomach discomfort3, increased intestinal peristalsis3, gastrointestinal disorder3, oral hypoaesthesia3, oral paraesthesia3, flatulence3 |
| Liver and biliary tract | Frequency not known: liver function tests abnormal3 |
| Skin and subcutaneous tissue disorders | Frequency not known: urticaria3, maculopapular rash2,3, generalised pruritus3, skin induration3, dermatitis3, alopecia1, psoriatic rash or exacerbation of psoriasis2, rash1, erythema1,3, Stevens-Johnson syndrome1/toxic epidermal necrolysis1 |
| Musculoskeletal and connective tissue disorders | Frequency unknown: myalgia1, muscle spasms3, arthralgia3, back pain3, pain in extremity3 |
| Renal and urinary disorders | Uncommon: blood in the urine1 Frequency not known: renal pain3, pollakiuria3 |
| Reproductive and breast function disorders | Frequency unknown: erectile dysfunction3, sexual dysfunction2, decreased libido2 |
| General disorders and administration site conditions | Uncommon: malaise1,3 Frequency not known: chest pain1, pain3, fatigue1,2, asthenia2,3, chest discomfort3, anxiety3, irritability3, peripheral oedema3, drug residue3 |
| Laboratory indicators | Uncommon: blood potassium increased1, blood lactate dehydrogenase increased1 |
1Adverse reactions observed with the use of AZARGA®.
2 Additional adverse reactions observed with timolol as monotherapy.
3Additional adverse reactions observed with brinzolamide as monotherapy.
Description of some adverse reactions
Dysgeusia (a bitter or unusual taste in the mouth after instillation) was a systemic adverse reaction associated with the use of AZARGA® eye drops, which was commonly reported in clinical trials. It was probably related to brinzolamide and was caused by the eye drops entering the nasopharynx via the nasolacrimal duct. Applying pressure to the nasolacrimal duct or gently closing the eyelids after instillation may reduce the likelihood of this occurrence (see section 4.2).
AZARGA® eye drops contain brinzolamide, which is a systemically absorbed sulfonamide carbonic anhydrase inhibitor. Gastrointestinal, nervous, hematological, renal and metabolic disorders are common with systemic carbonic anhydrase inhibitors. The same types of adverse reactions that are common with oral carbonic anhydrase inhibitors may occur with topical administration.
Timolol is absorbed into the systemic circulation. This may cause the same adverse reactions as those seen with systemic β-blockers. The adverse reactions listed include those seen with ophthalmic β-blockers as a class.
The above are additional adverse reactions associated with the use of individual components that may potentially occur with the use of AZARGA® eye drops. The incidence of systemic adverse reactions after topical ophthalmic administration is lower than with systemic administration. For the possibility of reduced systemic absorption, see section "Method of administration and dosage".
The following adverse reactions have been reported during therapy with systemic timolol:
