Carbonic anhydrase inhibitors.

Brinzolamide

Eye drops, suspension.

Eye drops, brinzolamide 10mg/ml.

To decrease elevated intraocular pressure in ocular hypertension and open-angle glaucoma. As monotherapy in patients unresponsive to beta-blockers or patients in whom beta-blockers are contraindicated, or as adjunctive therapy to beta-blockers.

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 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.

Under 18 years, not recommended.

No dosage alteration in elderly patients is necessary.

Hypersensitivity to brinzolamide or any of the excipients.

• Known hypersensitivity to sulphonamides
• Severe renal impairment.
• Hyperchloraemic acidosis

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.

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.

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.

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.

Alcon

(POM)

26 June 2009