Azarga · 4.3 Contraindications · 1

HOS-095184 · has-adverse-reaction-information · PDF-Seite 7

Summary of the safety profile In clinical trials, the most common adverse reactions were blurred vision, eye irritation and eye pain, occurring in approximately 2% to 7% of patients. Tabulated summary of adverse reactions The following adverse reactions have been reported during clinical studies and post-marketing surveillance with AZARGA and the individual components brinzolamide and timolol. They are classified according to the following convention: 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), very rare (<1/10 000), or not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. 7 System Organ MedDRA Preferred Term (v. 18.0) Classification Infections and infestations Not known: nasopharyngitis3, pharyngitis3, sinusitis3, rhinitis3 Blood and lymphatic Uncommon: white blood cell count decreased1 system disorders Not known: decreased red blood cell count3, increased blood chloride3 Immune system disorders Not known: anaphylaxis2, anaphylactic shock1, systemic allergic reactions including angioedema, 2 localised and generalised rash2, hypersensitivity1, urticaria2, pruritus2 Metabolism and nutrition Not known: hypoglycaemia2 disorders Psychiatric disorders Rare: insomnia1 Not known: hallucinations2, depression1, memory loss2, apathy3, depressed mood3, decreased libido3, nightmare2,3, nervousness3 Nervous system disorders Common: dysgeusia1 Not known: cerebral ischaemia2, cerebrovascular accident2, syncope2, increases in the signs and symptoms of myasthenia gravis2, somnolence3, motor dysfunction3, amnesia3, memory impairment3, paraesthesia2,3, tremor3, hypoaesthesia3, ageusia3, dizziness1, headache1 Eye disorders Common: punctate keratitis1, blurred vision1, eye pain1, eye irritation1 Uncommon: keratitis1,2,3, dry eye1, vital dye staining cornea present1, eye discharge1, eye pruri

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HOS-095180 · has-contraindication-information · PDF-Seite 3

• Hypersensitivity to the active substances or to any of the excipients listed in section 6.1. • Hypersensitivity to other beta-blockers. • Hypersensitivity to sulphonamides (see section 4.4). • Reactive airway disease including bronchial asthma or a history of bronchial asthma, or severe chronic obstructive pulmonary disease. • Sinus bradycardia, sick sinus syndrome, sino-atrial block, second or third degree atrioventricular block not controlled with pace-maker. Overt cardiac failure, cardiogenic shock. • Severe allergic rhinitis • Hyperchloraemic acidosis (see section 4.2). • Severe renal impairment.

HOS-095179 · has-indication-information · PDF-Seite 2

Decrease of intraocular pressure (IOP) in adult patients with open-angle glaucoma or ocular hypertension for whom monotherapy provides insufficient IOP reduction (see section 5.1).

HOS-095182 · has-interaction-information · PDF-Seite 6

No specific drug interaction studies have been performed with AZARGA. AZARGA contains brinzolamide, a carbonic anhydrase inhibitor and, although administered topically, is absorbed systemically. Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. The potential for interactions must be considered in patients receiving AZARGA. There is a potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide eye drops. The concomitant administration of eye drops containing brinzolamide and oral carbonic anhydrase inhibitors is not recommended. The cytochrome P-450 isozymes responsible for metabolism of brinzolamide include CYP3A4 (main), CYP2A6, CYP2B6, CYP2C8 and CYP2C9. It is expected that inhibitors of CYP3A4 such as ketoconazole, itraconazole, clotrimazole, ritonavir and troleandomycin will inhibit the metabolism of brinzolamide by CYP3A4. Caution is advised if CYP3A4 inhibitors are given concomitantly. However, accumulation of brinzolamide is unlikely as renal elimination is the major route. Brinzolamide is not an inhibitor of cytochrome P-450 isozymes. There is a potential for additive effects resulting in hypotension and/or marked bradycardia when an ophthalmic beta-blocker solution is administered concomitantly with oral calcium channel blockers, beta-adrenergic blocking agents, antiarrhythmics (including amiodarone), digitalis glycosides, parasympathomimetics, guanethidine. Beta blockers can decrease the response to adrenaline used to treat anaphylactic reactions. Special caution should be exercised in patients with a history of atopy or anaphylaxis (see section 4.4). The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta- blockers. Caution is recommended in the concomitant use of this medicinal product with clonidine. Potentiated systemic beta-blockade (e.g. decreased heart rate, depression) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, fluoxetine, paroxetine) and timolol. Caution is recommended. Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see section 4.4). Mydriasis resulting from concomitant use of ophthalmic beta-blockers and adrenaline (epinephrine) has been reported occasionally.

HOS-095183 · has-pregnancy-information · PDF-Seite 6

Pregnancy There are no adequate data regarding the use of ophthalmic brinzolamide and timolol in pregnant women. Studies in animals with brinzolamide have shown reproductive toxicity following systemic administration, see section 5.3. AZARGA should not be used during pregnancy unless clearly necessary. To reduce the systemic absorption, see section 4.2. Epidemiological studies have not revealed malformative effects but show a risk for intra uterine growth retardation when beta-blockers are administered by the oral route. In addition, signs and symptoms of beta-blockade (e.g. bradycardia, hypotension, respiratory distress and hypoglycaemia) have been observed in the neonate when beta-blockers have been administered until delivery. If AZARGA is administered until delivery, the neonate should be carefully monitored during the first days of life. 6 Breast-feeding It is not known whether ophthalmic brinzolamide is excreted in human breast milk. Studies in animals have shown that following oral administration brinzolamide is excreted in breast milk, see section 5.3. Beta-blockers are excreted in breast milk. However, at therapeutic doses of timolol in eye drops it is not likely that sufficient amounts would be present in breast milk to produce clinical symptoms of beta-blockade in the infant. To reduce the systemic absorption, see section 4.2. However, a risk to the suckling child cannot be excluded. A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from AZARGA therapy taking into account the benefit of breast-feeding for the child and the benefit of therapy for the woman. Fertility Studies have not been performed to evaluate the effect of topical ocular administration of Azarga on human fertility. Non-clinical data do not show any effects of either brinzolamide or timolol on male or female fertility following oral dosing. No effects on male or female fertility are anticipated from the use of AZARGA.

HOS-095181 · has-warning-information · PDF-Seite 3

Systemic effects • Brinzolamide and timolol are absorbed systemically. Due to the beta-adrenergic blocking component, timolol, the same types of cardiovascular, pulmonary and other adverse reactions seen with systemic beta-adrenergic blocking agents may occur. The incidence of systemic adverse reactions after topical ophthalmic administration is lower than for systemic administration. To reduce the systemic absorption, see section 4.2. • Hypersensitivity reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) reported with sulphonamide derivates can occur in patients receiving AZARGA as it is absorbed systemically. At the time of prescription, patients should be advised of the signs and symptoms and monitored closely for skin reactions. If signs of serious reactions or hypersensitivity occur, AZARGA should be withdrawn immediately. Cardiac disorders In patients with cardiovascular diseases (e.g. coronary heart disease, Prinzmetal's angina and cardiac failure) and hypotension, therapy with beta-blockers should be critically assessed and the therapy with other active substances should be considered. Patients with cardiovascular diseases should be watched for signs of deterioration of these diseases and of adverse reactions. 3 Due to its negative effect on conduction time, beta-blockers should only be given with caution to patients with first degree heart block. Vascular disorders Patients with severe peripheral circulatory disturbance/disorders (i.e. severe forms of Raynaud’s disease or Raynaud’s syndrome) should be treated with caution. Hyperthyroidism Beta-blockers may also mask the signs of hyperthyroidism. Muscle weakness Beta-adrenergic blocking medicinal products have been reported to potentiate muscle weakness consistent with certain myasthenic symptoms (e.g. diplopia, ptosis and generalised weakness). Respiratory disorders Respiratory reactions, including death due to bronchospasm in patients with asthma have been reported following administration of some ophthalmic beta-blockers. AZARGA should be used with caution, in patients with mild/moderate chronic obstructive pulmonary disease (COPD) and only if the potential benefit outweighs the potential risk. Hypoglycaemia/diabetes Beta-blockers should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with la

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