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EW CATARACT 86 April 2016 RESTASIS ® (Cyclosporine Ophthalmic Emulsion) 0.05% BRIEF SUMMARY—PLEASE SEE THE RESTASIS ® PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION. INDICATION AND USAGE RESTASIS ® ophthalmic emulsion is indicated to increase tear production in patients whose tear production is presumed to be suppressed due to ocular inflammation associated with keratoconjunctivitis sicca. Increased tear production was not seen in patients currently taking topical anti-inflammatory drugs or using punctal plugs. CONTRAINDICATIONS RESTASIS ® is contraindicated in patients with known or suspected hypersensitivity to any of the ingredients in the formulation. WARNINGS AND PRECAUTIONS Potential for Eye Injury and Contamination To avoid the potential for eye injury and contamination, be careful not to touch the vial tip to your eye or other surfaces. Use with Contact Lenses RESTASIS ® should not be administered while wearing contact lenses. Patients with decreased tear production typically should not wear contact lenses. If contact lenses are worn, they should be removed prior to the administration of the emulsion. Lenses may be reinserted 15 minutes following administration of RESTASIS ® ophthalmic emulsion. ADVERSE REACTIONS 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 rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, the most common adverse reaction following the use of RESTASIS ® was ocular burning (17%). Other reactions reported in 1% to 5% of patients included conjunctival hyperemia, discharge, epiphora, eye pain, foreign body sensation, pruritus, stinging, and visual disturbance (most often blurring). Post-marketing Experience The following adverse reactions have been identified during post approval use of RESTASIS ® . 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. Reported reactions have included: hypersensitivity (including eye swelling, urticaria, rare cases of severe angioedema, face swelling, tongue swelling, pharyngeal edema, and dyspnea); and superficial injury of the eye (from the vial tip touching the eye during administration). USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Pregnancy Category C Adverse effects were seen in reproduction studies in rats and rabbits only at dose levels toxic to dams. At toxic doses (rats at 30 mg/kg/day and rabbits at 100 mg/kg/day), cyclosporine oral solution, USP, was embryo- and fetotoxic as indicated by increased pre- and postnatal mortality and reduced fetal weight together with related skeletal retardations. These doses are 5,000 and 32,000 times greater (normalized to body surface area), respectively, than the daily human dose of one drop (approximately 28 mcL) of 0.05% RESTASIS ® twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is absorbed. No evidence of embryofetal toxicity was observed in rats or rabbits receiving cyclosporine at oral doses up to 17 mg/kg/day or 30 mg/kg/day, respectively, during organogenesis. These doses in rats and rabbits are approximately 3,000 and 10,000 times greater (normalized to body surface area), respectively, than the daily human dose. Offspring of rats receiving a 45 mg/kg/day oral dose of cyclosporine from Day 15 of pregnancy until Day 21 postpartum, a maternally toxic level, exhibited an increase in postnatal mortality; this dose is 7,000 times greater than the daily human topical dose (0.001 mg/kg/day) normalized to body surface area assuming that the entire dose is absorbed. No adverse events were observed at oral doses up to 15 mg/kg/day (2,000 times greater than the daily human dose). There are no adequate and well-controlled studies of RESTASIS ® in pregnant women. RESTASIS ® should be administered to a pregnant woman only if clearly needed. Nursing Mothers Cyclosporine is known to be excreted in human milk following systemic administration, but excretion in human milk after topical treatment has not been investigated. Although blood concentrations are undetectable after topical administration of RESTASIS ® ophthalmic emulsion, caution should be exercised when RESTASIS ® is administered to a nursing woman. Pediatric Use The safety and efficacy of RESTASIS ® ophthalmic emulsion have not been established in pediatric patients below the age of 16. Geriatric Use No overall difference in safety or effectiveness has been observed between elderly and younger patients. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenesis: Systemic carcinogenicity studies were carried out in male and female mice and rats. In the 78-week oral (diet) mouse study, at doses of 1, 4, and 16 mg/kg/day, evidence of a statistically significant trend was found for lymphocytic lymphomas in females, and the incidence of hepatocellular carcinomas in mid-dose males significantly exceeded the control value. In the 24-month oral (diet) rat study, conducted at 0.5, 2, and 8 mg/kg/day, pancreatic islet cell adenomas significantly exceeded the control rate in the low-dose level. The hepatocellular carcinomas and pancreatic islet cell adenomas were not dose related. The low doses in mice and rats are approximately 80 times greater (normalized to body surface area) than the daily human dose of one drop (approximately 28 mcL) of 0.05% RESTASIS ® twice daily into each eye of a 60 kg person (0.001 mg/kg/day), assuming that the entire dose is absorbed. Mutagenesis: Cyclosporine has not been found to be mutagenic/genotoxic in the Ames Test, the V79-HGPRT Test, the micronucleus test in mice and Chinese hamsters, the chromosome-aberration tests in Chinese hamster bone-marrow, the mouse dominant lethal assay, and the DNA- repair test in sperm from treated mice. A study analyzing sister chromatid exchange (SCE) induction by cyclosporine using human lymphocytes in vitro gave indication of a positive effect (i.e., induction of SCE). Impairment of Fertility: No impairment in fertility was demonstrated in studies in male and female rats receiving oral doses of cyclosporine up to 15 mg/kg/day (approximately 2,000 times the human daily dose of 0.001 mg/kg/day normalized to body surface area) for 9 weeks (male) and 2 weeks (female) prior to mating. PATIENT COUNSELING INFORMATION Handling the Container Advise patients to not allow the tip of the vial to touch the eye or any surface, as this may contaminate the emulsion. To avoid the potential for injury to the eye, advise patients to not touch the vial tip to their eye. Use with Contact Lenses RESTASIS ® should not be administered while wearing contact lenses. Patients with decreased tear production typically should not wear contact lenses. Advise patients that if contact lenses are worn, they should be removed prior to the administration of the emulsion. Lenses may be reinserted 15 minutes following administration of RESTASIS ® ophthalmic emulsion. Administration Advise patients that the emulsion from one individual single-use vial is to be used immediately after opening for administration to one or both eyes, and the remaining contents should be discarded immediately after administration. Rx Only Based on package insert 71876US18 © 2014 Allergan, Inc. Irvine, CA 92612, U.S.A. ® marks owned by Allergan, Inc. APC21XT14 Patented. See www.allergan.com/products/patent_notices Made in the U.S.A. by Rich Daly EyeWorld Contributing Writer given the small magnitude of PME (1.17%)." One of the largest studies of PME in routine real world clinical practice, the study was the first to isolate each risk factor sequentially to quantify the relative risk from each, according to the authors from the United Kingdom Pseudophakic Macular Edema Study Group. Risk factors The large patient population was able to identify findings that differed from previous research, such as the finding that intraoperative capsule rupture was associated with a higher risk of PME, which was not identi- fied as significant in other smaller studies. The relative risk was in- creased in eyes with capsule rupture with or without vitreous loss. Eyes in which PME developed within 90 days of surgery were more likely male, older, and demonstrated risk factors. The increased incidence attributed to male gender was not found in previous studies. "It is unclear why men are at higher risk, but it is unlikely to be a confounding factor resulting from age because they were on average younger than the female patients included in the study," the authors wrote. In addition to capsule rupture, relative risk was increased by a pre- vious diagnosis of epiretinal mem- brane, uveitis, retinal vein occlusion, or retinal detachment repair. The overall incidence of PME increased P seudophakic macular edema (PME) can occur after phacoemulsification cataract surgery even in the absence of complica- tions and risk factors, according to new research. A large retrospective study using structured electronic medical record (EMR) data quantified the relative risks of PME and the risk present with Early Treatment Diabetic Retinopathy Study (ETDRS) grading severity of diabetic retinopathy. The baseline incidence of PME in 81,984 eyes undergoing cataract surgery without operative com- plications, diabetes, or risk factors was 1.17%, according to the study published in the February issue of the journal Ophthalmology. PME was first recorded a mean of 39.5 days postop. The study was adequately struc- tured for its primary conclusion, and it reflected the clinical experience of Rohit Varma, MD, professor and chair, Department of Ophthalmol- ogy, Keck School of Medicine, Uni- versity of Southern California (USC), Los Angeles, and director, USC Eye Institute. The PME incidence also fell within previously reported rates of PME, which were between 0.2% and 2.35%. "This shows the value of having a large database, which gives one the power to assess risk relationships," Dr. Varma said. "Smaller studies may not be able to provide accurate data Data from electronic medical records was used to define and quantify the key risk factors for pseudophakic macular edema after cataract surgery PME risk in cataract surgery quantified

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