AZOPT 10 mg/ml eye drops, suspension

1 ml of suspension contains 10 mg brinzolamide.

Excipients: benzalkonium chloride 0.15 mg, (see section 4.4).

For a full list of excipients, (see section 6.1).

Eye drops, suspension .

Azopt is a white to offwhite suspension.

AZOPT is indicated to decrease elevated intraocular pressure in:

• ocular hypertension

• open-angle glaucoma

as monotherapy in patients unresponsive to betablockers or in patients in whom betablockers are contraindicated, or as adjunctive therapy to betablockers or prostaglandin analogues (see section 5.1).

When used as monotherapy or adjunctive therapy, the dose is one drop of AZOPT in the conjunctival sac of the affected eye(s) twice daily. Some patients may have a better response with one drop three times a day.

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 side effects.

When substituting another ophthalmic antiglaucoma agent with AZOPT, discontinue the other agent and start the following day with AZOPT.

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

Shake well before use. To prevent contamination of the dropper tip and suspension, care must be taken not to touch the eyelids, surrounding areas or other surfaces with the dropper tip of the bottle. Keep the bottle tightly closed when not in use.

Use in elderly

No dosage alteration in elderly patients is necessary.

Use in children

The efficacy and safety of AZOPT in patients below the age of 18 have not been established and its use is not recommended in these patients. However, there is limited experience in children.

The safety and efficacy of AZOPT have been studied in a small number of paediatric patients less than 6 years of age (see also 4.4, 4.8 and 5.1).

Use in hepatic and renal impairment

AZOPT has not been studied in patients with hepatic impairment and is therefore not recommended in such patients.

AZOPT 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, AZOPT is therefore contraindicated in such patients (see also 4.3).

• Hypersensitivity to brinzolamide or any of the excipients.

• Known hypersensitivity to sulphonamides (see also 4.4).

• Severe renal impairment.

• Hyperchloraemic acidosis (see also 4.2).

AZOPT is a sulphonamide inhibitor of carbonic anhydrase and, although administered topically, is absorbed systemically. Acidbase disturbances have been reported with oral carbonic anhydrase inhibitors. Brinzolamide has not been studied in preterm infants (less than 36 weeks gestational age) or those less than 1 week of age. Patients with significant renal tubular immaturity or abnormalities should only receive brinzolamide after careful consideration of the risk benefit balance because of the possible risk of metabolic acidosis. The same types of undesirable effects that are attributable to sulphonamides may occur with topical administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation.

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 AZOPT. The concomitant administration of AZOPT and oral carbonic anhydrase inhibitors has not been studied and is not recommended.

There is limited experience with AZOPT in the treatment of patients with pseudoexfoliative glaucoma or pigmentary glaucoma.

AZOPT was primarily evaluated in concomitant administration with timolol during adjunctive glaucoma therapy. Additionally the IOPreducing effect of Azopt as adjunctive therapy to the prostaglandin analogue travoprost has been studied. No long term data are available on the use of AZOPT as adjunctive therapy to travoprost.(see section 5.1)

AZOPT has not been studied in patients with narrowangle glaucoma.

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. Likewise, in other cases of compromised corneas such as patients with diabetes mellitus, careful monitoring 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 AZOPT contains benzalkonium chloride, close monitoring is required with frequent or prolonged use in dry eye patients, or in conditions where the cornea is compromised.

AZOPT has not been studied in patients wearing contact lenses. AZOPT contains the preservative benzalkonium chloride which may cause eye irritation. Benzalkonium chloride may be absorbed by soft contact lenses and is known to discolour soft contact lenses. Therefore, patients must be instructed to wait 15 minutes after instillation of AZOPT before inserting contact lenses. AZOPT must not be administered while wearing contact lenses.

Potential rebound effects following cessation of treatment with AZOPT have not been studied; the IOPlowering effect is expected to last for 57 days.

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

Specific interaction studies with other medicinal products have not been performed with AZOPT. In clinical studies, AZOPT was used concomitantly with prostaglandin analogues and timolol ophthalmic preparations without evidence of adverse interactions. Association between AZOPT and miotics or adrenergic agonists has not been evaluated during adjunctive glaucoma therapy.

AZOPT is 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 AZOPT.

The cytochrome P450 isozymes responsible for metabolism of brinzolamide include CYP3A4 (main), CYP2A6, 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 P450 isozymes.

Pregnancy

There are no adequate data from the use of brinzolamide in pregnant women. Studies in animals have shown reproductive toxicity (see 5.3). The potential risk for humans is unknown. AZOPT should not be used during pregnancy unless clearly necessary.

Nursing mothers

It is not known whether brinzolamide is excreted in human milk, however, this substance is excreted in rat milk. It is strongly recommended to avoid the use of AZOPT when breastfeeding.

Temporary blurred vision or other visual disturbances, may affect the ability to drive or use machines (see also 4.8 Undesirable effects). If blurred vision occurs at instillation, the patient must wait until the vision clears before driving or using machinery.

In clinical studies involving over 1800 patients treated with AZOPT as monotherapy or adjunctive therapy to timolol maleate 5 mg/ml, the most frequently reported treatment-related adverse events were: dysgeusia (5.8%) (bitter or unusual taste, see description below) and temporary blurred vision (5.8%) upon instillation, lasting from a few seconds to a few minutes (see also 4.7 Effects on ability to drive and use machines).

The following undesirable effects were assessed to be treatment-related and 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 <1/1000), or very rare (<1/10,000). Within each frequency grouping, undesirable effects are presented in decreasing order of seriousness.

Cardiac disorders:

Uncommon: cardiorespiratory distress, angina pectoris, bradycardia, heart rate irregular

Blood and lymphatic system disorders:

Uncommon: red blood cell count decreased, blood chloride increased

Nervous system disorders:

Common: dysgeusia, headache

Uncommon: somnolence, motor dysfunction, amnesia, memory impairment, dizziness, paraesthesia

Eye disorders:

Common: blepharitis, blurred vision, eye irritation, eye pain, dry eye, eye discharge, eye pruritus, foreign body sensation in eyes, ocular hyperaemia

Uncommon: corneal erosion, keratitis, punctate keratitis, keratopathy, deposit eye, corneal staining, corneal epithelium defect, intraocular pressure increased, optic nerve cup/disc ratio increased, corneal oedema, conjunctivitis, meibomianitis, diplopia, glare, photophobia, photopsia, visual acuity reduced, allergic conjunctivitis, pterygium, scleral pigmentation, asthenopia, ocular discomfort, abnormal sensation in eye, keratoconjunctivitis sicca, hypoaesthesia eye, subconjunctival cyst, conjunctival hyperaemia, eyelids pruritus, eyelid margin crusting, lacrimation increased

Ear and labyrinth disorders:

Uncommon: tinnitus

Respiratory, thoracic and mediastinal disorders:

Uncommon: dyspnoea, bronchial hyperactivity, cough, epistaxis, pharyngolaryngeal pain, throat irritation, nasal congestion, upper respiratory tract congestion, postnasal drip, rhinorrhoea, sneezing, nasal dryness

Gastrointestinal disorders:

Common: dry mouth

Uncommon: oesophagitis, diarrhoea, nausea, dyspepsia, upper abdominal pain, abdominal discomfort, stomach discomfort, flatulence, frequent bowel movements, gastrointestinal disorder, hypoaesthesia oral, paraesthesia oral

Renal and urinary disorders:

Uncommon: renal pain

Skin and subcutaneous tissue disorders:

Uncommon: urticaria, rash, rash maculopapular, pruritus generalized, alopecia, skin tightness

Musculoskeletal and connective tissue disorders:

Uncommon: back pain, muscle spasms, myalgia

Infections and infestations:

Uncommon: nasopharyngitis, pharyngitis, sinusitis

Injury, poisoning and procedural complications:

Uncommon: foreign body in eye

General disorders and administrative site conditions:

Uncommon: pain, chest discomfort, asthenia, fatigue, feeling abnormal, feeling jittery, irritability

Reproductive system and breast disorders:

Uncommon: erectile dysfunction

Psychiatric disorders:

Uncommon: apathy, depression, depressed mood, libido decreased, nightmare, insomnia, nervousness

Adverse reactions identified from post-marketing experience that have not been reported previously in clinical trials with AZOPT are listed below. They are derived from spontaneous reports for which the frequency cannot be estimated. Thus, the frequency grouping is categorised as not known.

Cardiac disorders: arrhythmia, palpitations, tachycardia, hypertension, blood pressure increased, heart rate increased

Nervous system disorders: tremor, hypoaesthesia, ageusia

Eye disorders: corneal epithelium disorder, corneal disorder, visual disturbance, eye swelling, eye allergy, madarosis, eyelid disorder, eyelid oedema, erythema of eyelid

Ear and labyrinth disorders: vertigo

Respiratory, thoracic and mediastinal disorders: asthma

Gastrointestinal disorders: vomiting

Renal and urinary disorders: pollakiuria

Skin and subcutaneous tissue disorders: dermatitis, erythema

Musculoskeletal and connective tissue disorders: arthralgia, pain in extremity

Infections and infestations: rhinitis

General disorders and administration site conditions: chest pain, peripheral edema, malaise, medication residue

Immune system disorders: hypersensitivity

Hepatobiliary disorders: liver function test abnormal

In small shortterm clinical trials, approximately 12.5% of paediatric patients were observed to experience drug related adverse effects, the majority of which were local, nonserious ocular effects such as conjunctival hyperaemia, eye irritation, eye discharge, and lacrimation increased (see section 5.1).

Dysgeusia (bitter or unusual taste in the mouth following instillation) was the most frequently reported systemic undesirable effect associated with the use of AZOPT during clinical studies. It is likely caused by passage of the eye drops in the nasopharynx via the nasolacrimal canal. Nasolacrimal occlusion or gently closing the eyelid after instillation may help reduce the incidence of this effect (see also 4.2 Posology and method of administration).

AZOPT 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 undesirable effects that are attributable to oral carbonic anhydrase inhibitors may occur with topical administration.

No unexpected adverse events have been observed with AZOPT when used as adjunctive therapy to travoprost. The adverse events seen with the adjunctive therapy have been observed with each active substance alone.

No case of overdose has been reported.

Treatment should be symptomatic and supportive. Electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur. Serum electrolyte levels (particularly potassium) and blood pH levels must be monitored.

Pharmacotherapeutic Group: Antiglaucoma preparations and miotics, carbonic anhydrase inhibitors.

ATC code: S01EC

Carbonic anhydrase (CA) is an enzyme found in many tissues of the body, including the eye. Carbonic anhydrase catalyses the reversible reaction involving the hydration of carbon dioxide and the dehydration of carbonic acid.

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. The result is a reduction in intraocular pressure (IOP) which is a major risk factor in the pathogenesis of optic nerve damage and glaucomatous visual field loss. Brinzolamide, an inhibitor of carbonic anhydrase II (CAII), the predominant isoenzyme in the eye, with an in vitro IC₅₀ of 3.2 nM and a K_i of 0.13 nM against CAII.

The IOPreducing effect of AZOPT as adjunctive therapy to the prostaglandin analogue travoprost was studied. Following a 4 week runin with travoprost, patients with an IOP 19 mmHg were randomized to receive added treatment with brinzolamide or timolol. An additional decrease in mean diurnal IOP of 3.2 to 3.4 mmHg for the brinzolamide group and 3.2 to 4.2 mmHg for the timolol group were observed. There was an overall higher incidence of nonserious ocular adverse events, mainly related to signs of local irritation, in the brinzolamide/travoprost groups. The events were mild and did not affect the overall discontinuation rates in the studies (see section 4.8).

A clinical trial was conducted with AZOPT in 32 paediatric patients less than 6 years of age, diagnosed with glaucoma or ocular hypertension. Some patients were naive to IOP therapy whilst others were on other IOPlowering medicinal product(s). Those who had been on previous IOP medicinal products were not required to discontinue their IOP medicinal product(s) until initiation of monotherapy with AZOPT. Among patients who were naive to IOP therapy (10 patients), the efficacy of AZOPT was similar to that seen previously in adults, with mean IOP reductions from baseline ranging up to 5 mmHg. Among patients who were on topical IOPlowering medicinal products (22 patients), mean IOP increased slightly from baseline in the AZOPT group.

Following topical ocular administration, brinzolamide is absorbed into the systemic circulation. Due to its high affinity for CAII, brinzolamide distributes extensively into the RBCs and exhibits a long halflife in whole blood (mean of approximately 24 weeks). In humans, the metabolite Ndesethylbrinzolamide is formed, which also binds to CA and accumulates in RBCs. This metabolite binds mainly to CAI in the presence of brinzolamide. In plasma, both brinzolamide and Ndesethylbrinzolamide concentrations are low and generally below assay quantitation limits (<7.5 ng/ml).

Binding to plasma proteins is not extensive (about 60%). Brinzolamide is eliminated primarily by renal excretion (approximately 60%). About 20% of the dose has been accounted for in urine as metabolite. Brinzolamide and Ndesethylbrinzolamide are the predominant components in the urine along with trace levels of the Ndesmethoxypropyl and Odesmethyl metabolites.

In an oral pharmacokinetic study, healthy volunteers received 1 mg capsules of brinzolamide twice daily for up to 32 weeks and RBC CA activity was measured to assess the degree of systemic CA inhibition.

Brinzolamide saturation of RBC CAII was achieved within 4 weeks (RBC concentrations of approximately 20 µM). NDesethylbrinzolamide accumulated in RBCs to steady state within 2028 weeks reaching concentrations ranging from 630 µM. The inhibition of total RBC CA activity at steady state was approximately 7075%.

Subjects with moderate renal impairment (creatinine clearance of 3060 ml/minute) were administered 1 mg of brinzolamide twice daily orally for up to 54 weeks. Brinzolamide RBC concentration ranged from about 20 to 40 µM by week 4 of treatment. At steadystate, brinzolamide and its metabolite RBC concentrations ranged from 22.0 to 46.1 and 17.1 to 88.6 µM, respectively.

Ndesethylbrinzolamide RBC concentrations increased and total RBC CA activity decreased with decreasing creatinine clearance but brinzolamide RBC concentrations and CAII activity remained unchanged. In subjects with the highest degree of renal impairment inhibition of total CA activity was greater although it was inferior to 90% at steadystate.

In a topical ocular study, at steadystate, brinzolamide RBC concentrations were similar to those found in the oral study, but levels of Ndesethyl-brinzolamide were lower. Carbonic anhydrase activity was approximately 4070% of predose levels.

Topical ocular administration of brinzolamide to rabbits for one to six months resulted in slight, statistically significant increases in corneal thickness when given at concentrations of 1%, 2% and 4%, four times a day; these changes were not observed in other species. Chronic administration of brinzolamide to rats at a dose level of 8 mg/kg/day (up to 250 times the recommended human ophthalmic dose) resulted in changes associated with the pharmacology of carbonic anhydrase inhibition (i.e., urine volume and electrolyte changes, slight differences in serum electrolytes).

A statistically significant increase in urinary bladder tumours was observed in female mice given brinzolamide 10 mg/kg/day (250 times the recommended human ophthalmic dose), orally, for 24 months. Doserelated proliferative changes in the urinary bladder were observed among female mice at 1, 3 and 10 mg/kg/day, and among males at 3 and 10 mg/kg/day. The elevated bladder tumour incidence, which was statistically significant, was primarily due to the increased incidence of a tumour considered unique to mice.

Developmental toxicity studies in rabbits with oral doses of brinzolamide of up to 6 mg/kg/day (125 times the recommended human ophthalmic dose) 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 (375 times the recommended human ophthalmic 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. Doserelated decreases in foetal weights were observed in pups of dams receiving brinzolamide orally ranging from a slight decrease (about 56%) at 2 mg/kg/day to nearly 14% at 18 mg/kg/day.

Benzalkonium chloride,

mannitol,

carbomer 974P,

tyloxapol,

edetate disodium,

sodium chloride,

hydrochloric acid/sodium hydroxide (to adjust pH)

purified water.

Not applicable.

2 years

4 weeks after first opening.

This medicinal product does not require any special storage conditions.

5 and 10 ml opaque low density polyethylene bottles with polypropylene screw caps (droptainer).

The following pack sizes are available: outer cartons containing 1 x 5 ml, 3 x 5 ml and 1 x 10 ml 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/1/00/129/0013

Date of first authorisation: 9 March 2000

Date of last renewal: 9 March 2005

20 June 2008