Alcon Laboratories (U.K) Limited

AZARGA 10 mg/ml + 5 mg/ml eye drops, suspension

One ml of suspension contains 10 mg brinzolamide and 5 mg timolol (as timolol maleate).

Excipients:

One ml of suspension contains 0.10 mg benzalkonium chloride.

For a full list of excipients, see section 6.1.

Eye drops, suspension (eye drops)

White to off-white uniform suspension, pH 7.2 (approximately).

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).

Use in adults, including the elderly

The dose is one drop of AZARGA in the conjunctival sac of the affected eye(s) twice daily. Nasolacrimal occlusion or gently closing the eyelid after instillation is recommended. This may reduce the systemic absorption of medicinal products administered via the ocular route and result in a decrease in systemic adverse reactions.

If more than one topical ophthalmic medicinal product is being used, the medicines must be administered at least 5 minutes apart.

If a dose is missed, treatment should be continued with the next dose as planned. The dose should not exceed one drop in the affected eye (s) twice daily.

When substituting another ophthalmic antiglaucoma agent with AZARGA, the other agent should be discontinued and AZARGA should be started the following day.

Paediatric patients

AZARGA is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

Use in hepatic and renal impairment

No studies have been conducted with AZARGA or with timolol 5 mg/ml eye drops in patients with hepatic or renal impairment. No dosage 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. Since brinzolamide and its main metabolite are excreted predominantly by the kidney, AZARGA is therefore contraindicated in patients with severe renal impairment (see section 4.3).

Method of administration

For ocular use

Instruct patients to shake the bottle well before use.

To prevent contamination of the dropper tip and solution, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Instruct patients to keep the bottle tightly closed when not in use.

• Hypersensitivity to the active substances, or to any of the excipients.

• Bronchial asthma, a history of bronchial asthma, or severe chronic obstructive pulmonary disease.

• Sinus bradycardia, second or third degree atrioventricular block, overt cardiac failure, or cardiogenic shock.

• Severe allergic rhinitis and bronchial hyperreactivity; hypersensitivity to other beta-blockers.

• Hyperchloraemic acidosis (see section 4.2).

• Severe renal impairment.

• Hypersensitivity to sulphonamides (see section 4.4).

Systemic effects

Like other topically applied ophthalmic agents, brinzolamide and timolol are absorbed systemically. Due to the beta-adrenergic component, timolol, the same types of cardiovascular and pulmonary adverse reactions as seen with systemic beta-adrenergic blocking agents may occur. Cardiac failure should be adequately controlled before beginning therapy with timolol. Patients with a history of severe cardiac disease should be watched for signs of cardiac failure and have their pulse rates checked. Respiratory reactions and cardiac reactions, including death due to bronchospasm in patients with asthma and, rarely, death in association with cardiac failure, have been reported following administration of timolol maleate. Beta-adrenergic blocking agents should be administered with caution in patients subject to spontaneous hypoglycaemia or to patients with labile insulin-dependent diabetes as beta-adrenergic blocking agents may mask the signs and symptoms of acute hypoglycaemia. They may also mask the signs of hyperthyroidism and cause worsening of Prinzmetal angina, severe peripheral and central circulatory disorders and hypotension.

AZARGA contains brinzolamide, a sulphonamide. The same types of undesirable effects that are attributable to sulphonamides may occur with topical administration. Acid-base disturbances have been reported with oral carbonic anhydrase inhibitors. If signs of serious reactions or hypersensitivity occur, discontinue the use of this medicinal product.

There is potential for an additive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and AZARGA. The concomitant administration of AZARGA and oral carbonic anhydrase inhibitors has not been studied and is not recommended (see section 4.5).

Anaphylactic reactions

While taking beta-adrenergic blocking agents, patients with a history of atopy or a history of severe anaphylactic reaction to a variety of allergens may be unresponsive to the usual doses of adrenaline used to treat anaphylactic reactions.

Concomitant therapy

Timolol may interact with other medicinal products (see section 4.5).

The effect on intraocular pressure or the known effects of systemic beta blockade may be potentiated when AZARGA is given to patients already receiving an oral beta-adrenergic blocking agent. The use of two local beta-adrenergic blocking agents or two local carbonic anhydrase inhibitors is not recommended.

Ocular effects

There is limited experience with AZARGA in the treatment of patients with pseudoexfoliative glaucoma or pigmentary glaucoma. Caution should be utilised in treating these patients and close monitoring of IOP is recommended.

AZARGA has not been studied in patients with narrow-angle glaucoma and its use is not recommended in these patients.

Oral carbonic anhydrase inhibitors may impair the ability to perform tasks requiring mental alertness and/or physical coordination in elderly patients. AZARGA is absorbed systemically and therefore this may occur with topical administration.

The possible role of brinzolamide on corneal endothelial function has not been investigated in patients with compromised corneas (particularly in patients with low endothelial cell count). Specifically, patients wearing contact lenses have not been studied and careful monitoring of these patients when using brinzolamide is recommended, since carbonic anhydrase inhibitors may affect corneal hydration and wearing contact lenses might increase the risk for the cornea. Careful monitoring of patients with compromised corneas, such as patients with diabetes mellitus or corneal dystrophies, is recommended.

Benzalkonium chloride, which is commonly used as a preservative in ophthalmic products, has been reported to cause punctate keratopathy and/or toxic ulcerative keratopathy. Since AZARGA contains benzalkonium chloride, close monitoring is required with frequent or prolonged use

AZARGA contains benzalkonium chloride which may cause eye irritation and is known to discolour soft contact lenses. Contact with soft contact lenses is to be avoided. Patients must be instructed to remove contact lenses prior to the application of AZARGA and wait 15 minutes after instillation of the dose before reinsertion.

No 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.

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 eye drops with timolol are administered concomitantly with oral calcium channel blockers, guanethidine or beta-blocking agents, antiarrhythmics, digitalis glycosides or parasympathomimetics.

The hypertensive reaction to sudden withdrawal of clonidine can be potentiated when taking beta-blockers.

Potentiated systemic beta-blockade (e.g. decreased heart rate) has been reported during combined treatment with CYP2D6 inhibitors (e.g. quinidine, cimetidine) and timolol.

Beta-blockers may increase the hypoglycaemic effect of antidiabetic agents. Beta-blockers can mask the signs and symptoms of hypoglycaemia (see section 4.4).

Pregnancy

There are no adequate data from the use of brinzolamide in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.

Well-controlled epidemiological studies with systemic use of beta-blockers did not indicate malformative effects, but some pharmacological effects such as bradycardia have been observed in foetuses or neonates. Data on a limited number of exposed pregnancies indicate no adverse effects of timolol in eye drops on pregnancy or on the health of the foetus/newborn child but bradycardia and arrhythmia have been reported in one case in the foetus of a woman treated with timolol eye drops. To date, no other relevant epidemiological data are available.

AZARGA should not be used during pregnancy unless clearly necessary.

Lactation

It is not known whether brinzolamide is excreted in human breast milk. Animal studies have shown excretion of brinzolamide in breast milk. Timolol does appear in human breast milk. However, at therapeutic doses of AZARGA, no effects on the breastfed newborns/infants are anticipated. AZARGA can be used during breast-feeding.

As with any eye drops, temporary blurred vision or other visual disturbances may affect the ability to drive or use machines. If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machines.

Oral carbonic anhydrase inhibitors may impair the ability of elderly patients to perform tasks requiring mental alertness and/or physical coordination (see section 4.4).

Summary of the safety profile

In two clinical trials of 6 and 12 months duration involving 394 patients treated with AZARGA, the most frequently reported adverse reaction was transient blurred vision upon instillation (3.6%), lasting from a few seconds to a few minutes.

Tabulated summary of adverse reactions

The following adverse reactions are classified according to the following convention: very common (1/10), common1/100 to <1/10), uncommon (1/1,000 to <1/100), rare (1/10,000 to <1/1000), or very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in order of decreasing seriousness.

Description of selected adverse reactions

Dysgeusia (bitter or unusual taste in the mouth following instillation) was a frequently reported systemic adverse reaction associated with the use of AZARGA during clinical trials. It is likely to be caused by passage of the eye drops in the nasopharynx via the nasolacrimal canal and is attributable to brinzolamide. Nasolacrimal occlusion or gently closing the eyelid after instillation may help reduce the occurrence of this effect (see section 4.2).

AZARGA contains brinzolamide which is a sulphonamide inhibitor of carbonic anhydrase with systemic absorption. Gastrointestinal, nervous system, haematological, renal and metabolic effects are generally associated with systemic carbonic anhydrase inhibitors. The same type of adverse reactions attributable to oral carbonic anhydrase inhibitors may occur with topical administration.

AZARGA contains brinzolamide and timolol (as timolol maleate). Additional adverse reactions associated with the use of the individual components observed in clinical trials and postmarketing experience that may potentially occur with AZARGA include:

Paediatric population

AZARGA is not recommended for use in children below 18 years due to a lack of data on safety and efficacy.

No case of overdose has been reported.

If overdose with AZARGA eye drops occurs, treatment should be symptomatic and supportive. Electrolyte imbalance, development of an acidotic state, and possibly central nervous system effects may occur. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Studies have shown that timolol does not dialyse readily.

Pharmacotherapeutic group: Antiglaucoma preparation and miotics

ATC code: S01ED51

Mechanism of action

AZARGA contains two active substances: brinzolamide and timolol maleate. These two components decrease elevated IOP primarily by reducing aqueous humour secretion, but do so by different mechanisms of action. The combined effect of these two active substances results in additional IOP reduction compared to either compound alone.

Brinzolamide is a potent inhibitor of human carbonic anhydrase II (CA-II), the predominant iso-enzyme in the eye. Inhibition of carbonic anhydrase in the ciliary processes of the eye decreases aqueous humour secretion, presumably by slowing the formation of bicarbonate ions with subsequent reduction in sodium and fluid transport.

Timolol is a non-selective adrenergic-blocking agent that has no intrinsic sympathomimetic, direct myocardial depressant or membrane-stabilising activity. Tonography and fluorophotometry studies in man suggest that its predominant action is related to reduced aqueous humour formation and a slight increase in outflow facility.

Pharmacodynamic effects

Clinical effects:

In a twelve-month, controlled clinical trial in patients with open-angle glaucoma or ocular hypertension who, in the investigator's opinion could benefit from a combination therapy, and who had baseline mean IOP of 25 to 27 mmHg, the mean IOP-lowering effect of AZARGA dosed twice daily was 7 to 9 mmHg. The non-inferiority of AZARGA as compared to dorzolamide 20 mg/ml + timolol 5 mg/ml in the mean IOP reduction was demonstrated across all time-points at all visits.

In a six-month, controlled clinical study in patients with open-angle glaucoma or ocular hypertension and baseline mean IOP of 25 to 27 mmHg, the mean IOP-lowering effect of AZARGA dosed twice daily was 7 to 9 mmHg, and was up to 3 mmHg greater than that of brinzolamide 10 mg/ml dosed twice daily and up to 2 mmHg greater than that of timolol 5 mg/ml dosed twice daily. A statistically superior reduction in mean IOP was observed compared to both brinzolamide and timolol at all time-points and visits throughout the study.

In three controlled clinical trials, the ocular discomfort upon instillation of AZARGA was significantly lower than that of dorzolamide 20 mg/ml + timolol 5 mg/ml.

Absorption

Following topical ocular administration, brinzolamide and timolol are absorbed through the cornea and into the systemic circulation. In a pharmacokinetic study, healthy subjects received oral brinzolamide (1 mg) twice daily for 2 weeks to shorten the time to reach steady-state prior to starting AZARGA administration. Following twice daily dosing of AZARGA for 13 weeks, red blood cell (RBC) concentrations of brinzolamide 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 that steady-state RBC concentrations of brinzolamide were maintained

At steady state, following administration of AZARGA, the mean plasma C_max and AUC_0-12h of timolol were 27% and 28% lower (C_max: 0.824 ± 0.453 ng/ml; AUC_0-12h: 4.71 ± 4.29 ng·h/ml), respectively, in comparison to the administration of timolol 5 mg/ml (C_max: 1.13 ± 0.494 ng/ml; AUC_0-12h: 6.58 ± 3.18 ng·h/ml). The lower systemic exposure to timolol following AZARGA administration is not clinically relevant. Following administration of AZARGA, mean C_max of timolol was reached at 0.79 ± 0.45 hours.

Distribution

Plasma protein binding of brinzolamide is moderate (about 60%). Brinzolamide is sequestered in RBCs due to its high affinity binding to CA-II and to a lesser extent to CA-I. Its active N-desethyl metabolite also accumulates in RBCs where it binds primarily to CA-I. The affinity of brinzolamide and metabolite to RBC and tissue CA results in low plasma concentrations.

Ocular tissue distribution data in rabbits showed that timolol can be measured in aqueous humour up to 48 hours after administration of AZARGA. At steady-state, timolol is detected in human plasma for up to 12 hours after administration of AZARGA.

Metabolism

The metabolic pathways for the metabolism of brinzolamide involve N-dealkylation, O-dealkylation and oxidation of its N-propyl side chain. N-desethyl brinzolamide is a major metabolite of brinzolamide formed in humans, which also binds to CA-I in the presence of brinzolamide and accumulates in RBCs. In vitro studies show that the metabolism of brinzolamide mainly involves CYP3A4 as well as at least four other isozymes (CYP2A6, CYP2B6, CYP2C8 and CYP2C9).

Timolol is metabolised by two pathways. One route yields an ethanolamine side chain on the thiadiazole ring and the other giving an ethanolic side chain on the morpholine nitrogen and a second similar side chain with a carbonyl group adjacent to the nitrogen. Timolol metabolism is mediated primarily by CYP2D6.

Excretion

Brinzolamide is eliminated primarily by renal excretion (approximately 60%). About 20% of the dose has been accounted for in urine as metabolite. Brinzolamide and N-desethyl-brinzolamide are the predominant components found in the urine along with trace levels (<1%) of the N-desmethoxypropyl and O-desmethyl metabolites.

Timolol and its metabolites are primarily excreted by the kidneys. Approximately 20% of a timolol dose is excreted in the urine unchanged and the remainder excreted in urine as metabolites. The plasma t_1/2 of timolol is 4.8 hours after administration of AZARGA.

Brinzolamide

Non-clinical data reveal no special hazard for humans with brinzolamide based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential.

Developmental toxicity studies in rabbits with oral doses of brinzolamide of up to 6 mg/kg/day (214 times the recommended daily clinical dose of 28 µg/kg/day) revealed no effect on foetal development despite significant maternal toxicity. Similar studies in rats resulted in slightly reduced ossification of skull and sternebrae of foetuses of dams receiving brinzolamide at doses of 18 mg/kg/day (642 times the recommended daily clinical dose), but not 6 mg/kg/day. These findings occurred at doses that caused metabolic acidosis with decreased body weight gain in dams and decreased foetal weights. Dose-related decreases in foetal weights were observed in pups of dams receiving brinzolamide orally ranging from a slight decrease (about 5-6%) at 2 mg/kg/day to nearly 14% at 18 mg/kg/day. During lactation, the no adverse effect level in the offspring was 5 mg/kg/day.

Timolol

Non-clinical data reveal no special hazard for humans with timolol based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, and carcinogenic potential. Reproduction toxicity studies with timolol showed delayed foetal ossification in rats with no adverse effects on postnatal development (at 50 mg/kg/day or 3500 times the daily clinical dose of 14 μg/kg/day) and increased foetal resorptions in rabbits (at 90 mg/kg/day or 6400 times the daily clinical dose).

Benzalkonium chloride

Mannitol (E421)

Carbopol 974P

Tyloxapol

Disodium edetate

Sodium chloride

Hydrochloric acid and/or sodium hydroxide (for pH adjustment)

Purified water

Not applicable.

2 years

4 weeks after first opening

This medicinal product does not require any special storage conditions.

5 ml round opaque low density polyethylene bottles with a dispensing plug and white polypropylene screw cap (DROP-TAINER) containing 5 ml suspension.

Cartons containing 1 or 3 bottles. Not all pack sizes may be marketed.

No special requirements.

Alcon Laboratories (UK) Ltd.

Pentagon Park

Boundary Way

Hemel Hempstead

Herts HP2 7UD

United Kingdom

EU/1/08/482/001-002

Date of first Authorisation: 25^th November 2008

28.11.08