Azopt

1 INDICATIONS AND USAGE AZOPT is a carbonic anhydrase inhibitor indicated in the treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma. AZOPT is a carbonic anhydrase inhibitor indicated for the treatment of elevated intraocular pressure (IOP) in patients with ocular hypertension or open-angle glaucoma. ( 1 )

2 DOSAGE AND ADMINISTRATION The recommended dose is one drop of AZOPT in the affected eye(s) 3 times daily. Shake well before use. AZOPT may be used concomitantly with other topical ophthalmic drug products to lower IOP. If more than one topical ophthalmic drug is being used, the drugs should be administered at least 10 minutes apart. • Instill one drop in the affected eye(s) 3 times daily. ( 2 ) • If more than one topical ophthalmic drug is being used, the drugs should be administered at least 10 minutes apart. ( 2 )

4 CONTRAINDICATIONS AZOPT is contraindicated in patients who are hypersensitive to any component of this product. Hypersensitivity to any component of this product. ( 4 )

5 WARNINGS AND PRECAUTIONS • Sulfonamide hypersensitivity reactions. ( 5.1 ) • Corneal edema may occur in patients with low endothelial cell counts. ( 5.2 ) 5.1 Sulfonamide Hypersensitivity Reactions AZOPT is a sulfonamide and although administered topically, it is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of AZOPT. Fatalities have occurred, although rarely, due to severe reactions to sulfonamides, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), fulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide is readministered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of this preparation immediately. 5.2 Corneal Endothelium Carbonic anhydrase activity has been observed in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for developing corneal edema in patients with low endothelial cell counts. Caution should be used when prescribing AZOPT to this group of patients. 5.3 Severe Renal Impairment AZOPT has not been studied in patients with severe renal impairment [creatinine clearance (CrCl) less than 30 mL/min]. Because AZOPT and its metabolite are excreted predominantly by the kidney, AZOPT is not recommended in such patients. 5.4 Acute Angle-Closure Glaucoma The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. AZOPT has not been studied in patients with acute angle-closure glaucoma. 5.5 Risk of Contamination Avoid allowing the tip of the dispensing container to contact the eye or surrounding structures or other surfaces, since the product can become contaminated by common bacteria known to cause ocular infections. Serious damage to the eye and subsequent loss of vision may result from using contaminated solutions. 5.6 Contact Lens Wear The preservative in AZOPT, benzalkonium chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of AZOPT, but may be reinserted 15 minutes after instillation.

7 DRUG INTERACTIONS • There is a potential additive effect of the known systemic effects of carbonic anhydrase inhibition in patients receiving both oral and topical carbonic anhydrase inhibitors. ( 7.1 ) • Rare instances of acid-base alterations have occurred with high-dose salicylate therapy. ( 7.2 ) 7.1 Oral Carbonic Anhydrase Inhibitors 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 is not recommended. 7.2 High-Dose Salicylate Therapy Carbonic anhydrase inhibitors may produce acid-base and electrolyte alterations. These alterations were not reported in the clinical trials with brinzolamide. However, in patients treated with oral carbonic anhydrase inhibitors, rare instances of acid-base alterations have occurred with high-dose salicylate therapy. Therefore, the potential for such drug interactions should be considered in patients receiving AZOPT.

6 ADVERSE REACTIONS Most common adverse reactions (incidence 5% to 10%) are blurred vision and bitter, sour, or unusual taste. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Sandoz Inc. at 1-800-525-8747 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical studies of AZOPT, the most frequently reported adverse reactions reported in 5% to 10% of patients were blurred vision and bitter, sour, or unusual taste. Adverse reactions occurring in 1% to 5% of patients were blepharitis, dermatitis, dry eye, foreign body sensation, headache, hyperemia, ocular discharge, ocular discomfort, ocular keratitis, ocular pain, ocular pruritus, and rhinitis. The following adverse reactions were reported at an incidence below 1%: allergic reactions, alopecia, chest pain, conjunctivitis, diarrhea, diplopia, dizziness, dry mouth, dyspnea, dyspepsia, eye fatigue, hypertonia, keratoconjunctivitis, keratopathy, kidney pain, lid margin crusting or sticky sensation, nausea, pharyngitis, tearing, and urticaria. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of brinzolamide containing products. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious skin and subcutaneous tissue reactions, such as Stevens-Johnson syndrome (SJS) and Toxic epidermal necrolysis (TEN) may occur with the use of brinzolamide due to its sulfonamide component [see Warnings and Precautions (5.1)] .

8.1 Pregnancy Risk Summary There are no adequate and well-controlled studies in pregnant women to inform drug-associated risk. In reproductive toxicity studies, brinzolamide administered orally to rats induced fetal toxicity at 375 times the recommended human ophthalmic dose (RHOD) based on mg/kg. In rabbits, no fetal toxicity was observed following oral administration (see Data) . The background risk of major birth defects and miscarriage for the indicated population is unknown; however, in the U.S. general population, the estimated background risk of major birth defects is 2% to 4%, and of miscarriage is 15% to 20%, of clinically recognized pregnancies. Data Animal Data Embryo-fetal studies were conducted in pregnant rats administered 0, 2, 6, or 18 mg/kg/day brinzolamide by oral gavage on gestation days 6 to 17, to target the period of organogenesis. Decreased fetal body weight with reduced skeletal ossification were observed at 18 mg/kg/day (375 times the RHOD based on mg/kg). The no-observed-adverse-effect-level (NOAEL) for fetal toxicity was 6 mg/kg/day (125 times the RHOD). Decreased maternal weight gain was observed at 18 mg/kg/day. The NOAEL for maternal toxicity was 6 mg/kg/day (125 times the RHOD). Embryo-fetal studies were conducted in pregnant rabbits administered 0, 1, 3, or 6 mg/kg/day of brinzolamide by oral gavage on gestation days 6 to 18, to target the period of organogenesis. No treatment-related fetal effects were observed at any dose. The NOAEL for fetal toxicity was 6 mg/kg/day (125 times the RHOD based on mg/kg). Maternal weight loss during pregnancy was observed at 3 mg/kg/day (63 times the RHOD) and above. The NOAEL for maternal toxicity was 1 mg/kg/day (21 times the RHOD). A peri-/postnatal study was conducted in rats administered brinzolamide by oral gavage from gestation day 16 through lactation day 20. Decreased pup body weight was observed at 15 mg/kg/day (313 times the RHOD based on mg/kg). The NOAEL for developmental toxicity was 5 mg/kg/day (104 times the RHOD). Following oral administration of 14 C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood.