MAR 2014

EyeWorld is the official news magazine of the American Society of Cataract & Refractive Surgery.

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Page 44 of 210

E W NEWS & OPINION 42 only included them if they had trace or no posterior subcapsular c ataract," he said. Dr. Koenig described trefoil's role here as an image-quality metric that may relate to cortical cataracts in combination with the Y-sutures. "Although it was a small contribu- tor, it didn't surprise us too much because it may relate to cortical cataract changes, the focus of the s tudy," he explained. For his part, Dr. Applegate was encouraged by the fact that these o ptical markers could be identified. "Prior studies using slit lamp images of cataract have been notoriously bad at predicting who's going to need surgery first," he said. "The reason you or a camera sees the cataract when using a slit lamp is the cataract back scatters light out of the eye, not toward the retina." He explained that as you increase parti- cle size more light is forward scat- t ered toward the retina. "The veiling effects of the scattered light from the cataract can be large but appear small in the doctor's view," Dr. Applegate said. "What we found was that changes in optical image quality (not scatter as measured by Shack-Hartmann wavefront sensing) was the major early driver of correla- tion, not changes in nuclear opales- cence as seen in the slit lamp." This is not surprising since early changes in scatter have very little if any im- pact on acuity. He went on to add, " Where slit lamp appearance of the cataract was important was if there was any indication of a posterior subcapsular cataract." Foretelling the future Dr. Koenig hopes that now that a correlation between the metrics identified by the study and acuity change has been found the work can be continued in an attempt to predict who will have the greatest v ision change. "We would like to think that we can use the same equation of metrics to then go back and predict acuity change either in the next iteration as these patients continue to come back or on a dif- ferent population of patients with similar changes," Dr. Koenig said. If the predictive value of these metrics is substantiated, Dr. Koenig thinks it will have merit on several levels. "What the metrics allow us to do is to monitor smaller changes in vision quality due to cataracts," he said. "That might be helpful to the researcher who is using some form of therapy to try to forestall cataract development"—thus providing a metric for determining who has responded to the treatment and who has not. For his part, Dr. Applegate takes the following long view: If a predic- tive test could be developed to identify those on the fast track for cataract development, it would make a world of difference. Relying on changes in visual acuity as we currently do is too slow a measure, he stressed. With a more sensitive marker, it would be possible to test drugs to potentially alter the natural history of the disease. "If you alter the natural history of the disease just five years, you save billions of dollars," Dr. Applegate said. "People die of other causes—it's a late-in-life- event." EW Editors' note: The University of Houston has patent interests in ophthalmic image quality metrics on which Dr. Applegate is a listed inventor. Dr. Koenig has no financial interests related to this article. This work was supported by NIH/NEI R01 grant EY08520 to RAA. March 2014 BRIEF SUMMARY OF PRESCRIBING INFORMATION I NDICATIONS AND USAGE SIMBRINZA™ (brinzolamide/brimonidine tartrate ophthalmic s uspension) 1%/0.2% is a fixed combination of a carbonic anhydrase inhibitor and an alpha 2 adrenergic receptor agonist indicated for the reduction of elevated intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension. DOSAGE AND ADMINISTRATION The recommended dose is one drop of SIMBRINZA™ Suspension in the affected eye(s) three times daily. Shake well before use. SIM- BRINZA™ Suspension may be used concomitantly with other topical ophthalmic drug products to lower intraocular pressure. If more than one topical ophthalmic drug is being used, the drugs should be administered at least five (5) minutes apart. DOSAGE FORMS AND STRENGTHS Suspension containing 10 mg/mL brinzolamide and 2 mg/mL brimonidine tartrate. CONTRAINDICATIONS H ypersensitivity - SIMBRINZA™ Suspension is contraindicated in patients who are hypersensitive to any component of this product. Neonates and Infants (under the age of 2 years) - SIMBRINZA™ Suspension is contraindicated in neonates and infants (under the age of 2 years) see Use in Specific Populations WARNINGS AND PRECAUTIONS Sulfonamide Hypersensitivity Reactions - SIMBRINZA™ Suspension contains brinzolamide, a sulfonamide, and although administered topically is absorbed systemically. Therefore, the same types of adverse reactions that are attributable to sulfonamides may occur with topical administration of SIMBRINZA™ Suspension. Fatalities have occurred due to severe reactions to sulfonamides including Stevens-Johnson syndrome, toxic epidermal necrolysis, f ulminant hepatic necrosis, agranulocytosis, aplastic anemia, and other blood dyscrasias. Sensitization may recur when a sulfonamide i s re-administered irrespective of the route of administration. If signs of serious reactions or hypersensitivity occur, discontinue the use of t his preparation [see Patient Counseling Information] Corneal Endothelium - Carbonic anhydrase activity has been o bserved in both the cytoplasm and around the plasma membranes of the corneal endothelium. There is an increased potential for de- veloping corneal edema in patients with low endothelial cell counts. Caution should be used when prescribing SIMBRINZA™ Suspension to this group of patients. Severe Renal Impairment - SIMBRINZA™ Suspension has not been specifically studied in patients with severe renal impairment (CrCl < 30 mL/min). Since brinzolamide and its metabolite are excreted predominantly by the kidney, SIMBRINZA™ Suspension is not recom- mended in such patients. A cute Angle-Closure Glaucoma - The management of patients with acute angle-closure glaucoma requires therapeutic interventions in addition to ocular hypotensive agents. SIMBRINZA™ Suspension has not been studied in patients with acute angle-closure glaucoma. Contact Lens Wear - The preservative in SIMBRINZA™, benzalkoni- um chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA™ Suspension but may be reinserted 15 minutes after instillation [see Patient Counseling Information]. Severe Cardiovascular Disease - Brimonidine tartrate, a component of SIMBRINZA TM Suspension, has a less than 5% mean decrease in blood pressure 2 hours after dosing in clinical studies; caution should be exercised in treating patients with severe cardiovascular disease. Severe Hepatic Impairment - Because brimonidine tartrate, a component of SIMBRINZA™ Suspension, has not been studied in patients with hepatic impairment, caution should be exercised in such patients. Potentiation of Vascular Insufficiency - Brimonidine tartrate, a component of SIMBRINZA T M Suspension, may potentiate syndromes associated with vascular insufficiency. SIMBRINZA™ Suspension should be used with caution in patients with depression, cerebral or coronary insufficiency, Raynaud's phenomenon, orthostatic hypoten- sion, or thromboangitis obliterans. Contamination of Topical Ophthalmic Products After Use - There have been reports of bacterial keratitis associated with the use of multiple-dose containers of topical ophthalmic products. These containers have been inadvertently contaminated by patients who, in most cases, had a concurrent corneal disease or a disruption of the ocular epithelial surface [see Patient Counseling Information]. ADVERSE REACTIONS Clinical Studies Experience - Because clinical studies are conduct- ed under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to the rates in the clinical studies of another drug and may not reflect the rates observed in practice. SIMBRINZA™ Suspension - In two clinical trials of 3 months duration 435 patients were treated with SIMBRINZA™ Suspension, and 915 were treated with the two individual components. The most frequently reported adverse reactions in patients treated with SIM- BRINZA™ Suspension occurring in approximately 3 to 5% of patients in descending order of incidence were blurred vision, eye irritation, dysgeusia (bad taste), dry mouth, and eye allergy. Rates of adverse reactions reported with the individual components were comparable. Treatment discontinuation, mainly due to adverse reactions, was reported in 11% of SIMBRINZA™ Suspension patients. Other adverse reactions that have been reported with the individual components during clinical trials are listed below. Brinzolamide 1% - In clinical studies of brinzolamide ophthalmic s uspension 1%, the most frequently reported adverse reactions r eported 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, l id margin crusting or sticky sensation, nausea, pharyngitis, tearing and urticaria. Brimonidine Tartrate 0.2% - In clinical studies of brimonidine tartrate 0.2%, adverse reactions occurring in approximately 10 to 30% of the subjects, in descending order of incidence, included oral d ryness, ocular hyperemia, burning and stinging, headache, blurring, foreign body sensation, fatigue/drowsiness, conjunctival follicles, ocular allergic reactions, and ocular pruritus. Reactions occurring in approximately 3 to 9% of the subjects, in d escending order included corneal staining/erosion, photophobia, eyelid erythema, ocular ache/pain, ocular dryness, tearing, upper respiratory symptoms, eyelid edema, conjunctival edema, dizziness, blepharitis, ocular irritation, gastrointestinal symptoms, asthenia, conjunctival blanching, abnormal vision and muscular pain. The following adverse reactions were reported in less than 3% of the patients: lid crusting, conjunctival hemorrhage, abnormal taste, insomnia, conjunctival discharge, depression, hypertension, anxiety, palpitations/arrhythmias, nasal dryness and syncope. Postmarketing Experience - The following reactions have been identified during postmarketing use of brimonidine tartrate ophthalmic solutions in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency c annot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to brimonidine tartrate ophthalmic solutions, or a combination of these factors, include: bradycardia, hypersensitivity, iritis, keratoconjunctivitis sicca, miosis, nausea, skin reactions (including erythema, eyelid pruritus, rash, and vasodilation), and tachycardia. Apnea, bradycardia, coma, hypotension, hypothermia, hypotonia, lethargy, pallor, respiratory depression, and somnolence have been reported in infants receiving brimonidine tartrate ophthalmic solutions [see Contraindications]. DRUG INTERACTIONS O ral Carbonic Anhydrase Inhibitors - There is a potential for an a dditive effect on the known systemic effects of carbonic anhydrase inhibition in patients receiving an oral carbonic anhydrase inhibitor and brinzolamide ophthalmic suspension 1%, a component of S IMBRINZA™ Suspension. The concomitant administration of SIMBRINZA™ Suspension and oral carbonic anhydrase inhibitors is not recommended. 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 ophthalmic suspension 1%. 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 SIMBRINZA™ Suspension. CNS Depressants - Although specific drug interaction studies have not been conducted with SIMBRINZA ™ , the possibility of an additive or potentiating effect with CNS depressants (alcohol, opiates, barbitu- rates, sedatives, or anesthetics) should be considered. Antihypertensives/Cardiac Glycosides - Because brimonidine tar- trate, a component of SIMBRINZA™ Suspension, may reduce blood pressure, caution in using drugs such as antihypertensives and/or cardiac glycosides with SIMBRINZA™ Suspension is advised. Tricyclic Antidepressants - Tricyclic antidepressants have been reported to blunt the hypotensive effect of systemic clonidine. It is not known whether the concurrent use of these agents with SIMBRINZA ™ Suspension in humans can lead to resulting interference with the IOP lowering effect. Caution is advised in patients taking tricyclic antidepressants which can affect the metabolism and uptake of circulating amines. Monoamine Oxidase Inhibitors - Monoamine oxidase (MAO) inhib- itors may theoretically interfere with the metabolism of brimonidine tartrate and potentially result in an increased systemic side-effect such as hypotension. Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines. USE IN SPECIFIC POPULATIONS Pregnancy - Pregnancy Category C: Developmental toxicity studies with brinzolamide in rabbits at oral doses of 1, 3, and 6 mg/ kg/day (20, 60, and 120 times the recommended human ophthalmic dose) produced maternal toxicity at 6 mg/kg/day and a significant increase in the number of fetal variations, such as accessory skull bones, which was only slightly higher than the historic value at 1 and 6 mg/kg. In rats, statistically decreased body weights of fetuses from dams receiving oral doses of 18 mg/kg/day (180 times the recom- mended human ophthalmic dose) during gestation were proportional to the reduced maternal weight gain, with no statistically significant effects on organ or tissue development. Increases in unossified sternebrae, reduced ossification of the skull, and unossified hyoid that occurred at 6 and 18 mg/kg were not statistically significant. No treatment-related malformations were seen. Following oral adminis- tration of 14 C-brinzolamide to pregnant rats, radioactivity was found to cross the placenta and was present in the fetal tissues and blood. Developmental toxicity studies performed in rats with oral doses of 0.66 mg brimonidine base/kg revealed no evidence of harm to the fetus. Dosing at this level resulted in a plasma drug concentration approximately 100 times higher than that seen in humans at the recommended human ophthalmic dose. In animal studies, brimoni- dine crossed the placenta and entered into the fetal circulation to a limited extent. T here are no adequate and well-controlled studies in pregnant wom- en. SIMBRINZA™ Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers - In a study of brinzolamide in lactating rats, decreases in body weight gain in offspring at an oral dose of 15 mg/ k g/day (150 times the recommended human ophthalmic dose) were o bserved during lactation. No other effects were observed. However, following oral administration of 14 C-brinzolamide to lactating rats, radioactivity was found in milk at concentrations below those in the blood and plasma. In animal studies, brimonidine was excreted in breast milk. It is not known whether brinzolamide and brimonidine tartrate are e xcreted in human milk following topical ocular administration. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SIM- B RINZA™ (brinzolamide/brimonidine tartrate ophthalmic suspension) 1 %/0.2%, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the d rug to the mother. Pediatric Use - The individual component, brinzolamide, has been studied in pediatric glaucoma patients 4 weeks to 5 years of age. The i ndividual component, brimonidine tartrate, has been studied in pedi- atric patients 2 to 7 years old. Somnolence (50-83%) and decreased alertness was seen in patients 2 to 6 years old. SIMBRINZA™ Suspension is contraindicated in children under the age of 2 years [see Contraindications]. Geriatric Use - No overall differences in safety or effectiveness have b een observed between elderly and adult patients. OVERDOSAGE Although no human data are available, electrolyte imbalance, development of an acidotic state, and possible nervous system effects may occur following an oral overdose of brinzolamide. Serum electrolyte levels (particularly potassium) and blood pH levels should be monitored. Very limited information exists on accidental ingestion of brimonidine in adults; the only adverse event reported to date has been hypo- tension. Symptoms of brimonidine overdose have been reported in neonates, infants, and children receiving brimonidine as part of med- ical treatment of congenital glaucoma or by accidental oral ingestion. Treatment of an oral overdose includes supportive and symptomatic therapy; a patent airway should be maintained. PATIENT COUNSELING INFORMATION Sulfonamide Reactions - Advise patients that if serious or unusual ocular or systemic reactions or signs of hypersensitivity occur, they should discontinue the use of the product and consult their physician. Temporary Blurred Vision - Vision may be temporarily blurred following dosing with SIMBRINZA™ Suspension. Care should be exercised in operating machinery or driving a motor vehicle. Effect on Ability to Drive and Use Machinery - As with other drugs in this class, SIMBRINZA™ Suspension may cause fatigue and/or drowsiness in some patients. Caution patients who engage in haz- ardous activities of the potential for a decrease in mental alertness. Avoiding Contamination of the Product - Instruct patients that ocular solutions, if handled improperly or if the tip of the dispensing container contacts the eye or surrounding structures, 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 [see Warnings and Precau- tions ]. Always replace the cap after using. If solution changes color or becomes cloudy, do not use. Do not use the product after the expiration date marked on the bottle. Intercurrent Ocular Conditions - Advise patients that if they have ocular surgery or develop an intercurrent ocular condition (e.g., trauma or infection), they should immediately seek their physician's advice concerning the continued use of the present multidose container. Concomitant Topical Ocular Therapy - If more than one topical ophthalmic drug is being used, the drugs should be administered at least five minutes apart. Contact Lens Wear - The preservative in SIMBRINZA™, benzalkoni- um chloride, may be absorbed by soft contact lenses. Contact lenses should be removed during instillation of SIMBRINZA™ Suspension, but may be reinserted 15 minutes after instillation. ©2013 Novartis U.S. Patent No: 6,316,441 ALCON LABORATORIES, INC. Fort Worth, Texas 76134 USA 1-800-757-9195 alcon.medinfo@alcon.com © 2013 Novartis 8/13 SMB13064JAD 84880 SMB13064JAD_PI EW.indd 1 2/3/14 11:09 AM Ophthalmic continued from page 41 continued on page 43 18-47 News_EW March 2014-DL2 copy_Layout 1 3/7/14 9:30 AM Page 42

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