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EW GLAUCOMA 80 February 2015 BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Ocular Surgery DUREZOL ® a topical corticosteroid, is indicated for the treatment surgery. Endogenous Anterior Uveitis DUREZOL ® Emulsion is also indicated for the treatment of endogenous anterior uveitis. DOSAGE AND ADMINISTRATION Ocular Surgery eye 4 times daily beginning 24 hours after surgery postoperative period, followed by 2 times daily for a week and then a taper based on the response. Endogenous Anterior Uveitis eye 4 times daily for 14 days followed by tapering as clinically indicated. DOSAGE FORMS AND STRENGTHS DUREZOL ® a sterile preserved emulsion for topical ophthalmic administration. CONTRAINDICATIONS The use of DUREZOL ® Emulsion, as with other ophthalmic corticosteroids, is contraindicated in most active viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal disease of ocular structures. WARNINGS AND PRECAUTIONS IOP Increase Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects be used with caution in the presence of glaucoma. If this product is used for 10 days or longer, intraocular pressure should be monitored. Cataracts Use of corticosteroids may result in posterior subcapsular cataract formation. Delayed Healing The use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. The initial prescription and renewal of the medication order beyond 28 days should be made by a physician only after examination slit lamp biomicroscopy and, where appropriate, Bacterial Infections Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. If signs and symptoms fail to improve after 2 days, the patient should be re- evaluated. Viral Infections Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Fungal Infections Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. Fungal culture should be taken when appropriate. Topical Ophthalmic Use Only DUREZOL ® Emulsion is not indicated for intraocular administration. Contact Lens Wear DUREZOL ® Emulsion should not be instilled while wearing contact lenses. Remove contact lenses prior to instillation of DUREZOL ® Emulsion. The preservative in DUREZOL ® Emulsion may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of DUREZOL ® Emulsion. ADVERSE REACTIONS Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. Ocular Surgery Ocular adverse reactions occurring in 5-15% of subjects in clinical studies with DUREZOL ® Emulsion included corneal edema, ciliary and conjunctival hyperemia, eye pain, photophobia, posterior capsule ocular adverse reactions occurring in 1-5% of subjects included reduced visual acuity, punctate keratitis, occurring in < 1% of subjects included application site discomfort or irritation, corneal pigmentation and striae, episcleritis, eye pruritus, eyelid irritation and crusting, foreign body sensation, increased lacrimation, macular edema, sclera hyperemia, and uveitis. Most of these reactions may have been the consequence of the surgical procedure. Endogenous Anterior Uveitis A total of 200 subjects participated in the clinical trials for endogenous anterior uveitis, of which 106 were exposed to DUREZOL ® Emulsion. The most common adverse reactions of those exposed to DUREZOL ® Emulsion occurring in 5-10% of subjects included blurred vision, eye irritation, eye pain, headache, increased IOP, iritis, limbal and conjunctival hyperemia, punctate keratitis, and uveitis. Adverse reactions occurring in 2-5% of subjects included anterior photophobia, and reduced visual acuity. USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic E shown to be embryotoxic (decrease in embryonic and teratogenic (cleft palate and skeletal) anomalies when administered subcutaneously to rabbits during organogenesis at a dose of 1–10 mcg/kg/day. The to be a teratogenic dose that was concurrently found in the toxic dose range for fetuses and pregnant females. Treatment of rats with 10 mcg/kg/day subcutaneously during organogenesis did not result in any reproductive toxicity, nor was it maternally toxic. At 100 mcg/kg/day after subcutaneous administration in rats, there was a decrease in fetal weights and human doses of DUREZOL ® Emulsion, since DUREZOL ® Emulsion is administered topically with minimal were not measured in the reproductive animal studies. pregnancy has not been evaluated and cannot rule out the possibility of harm, DUREZOL ® Emulsion should Nursing Mothers It is not known whether topical ophthalmic administration of corticosteroids could result in quantities in breast milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward ® Emulsion is administered to a nursing woman. Pediatric Use Geriatric Use been observed between elderly and younger patients. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, and Impairment of Fertility in vitro in the Ames test, and in cultured mammalian cells CHL/IU (a female Chinese hamsters). An in vivo micronucleus Treatment of male and female rats with subcutaneous mating did not impair fertility in either gender. Long term studies have not been conducted to evaluate the Animal Toxicology and/or Pharmacology In multiple studies performed in rodents and non-rodents, subchronic and chronic toxicity tests as suppression of body weight gain; a decrease in lymphocyte count; atrophy of the lymphatic thinning of the skin; all of which were due to the pharmacologic action of the molecule and are well The NOEL for the subchronic and chronic toxicity tests were consistent between species and ranged from 1–1.25 mcg/kg/day. PATIENT COUNSELING INFORMATION Risk of Contamination This product is sterile when packaged. Patients should be advised not to allow the dropper tip to touch any surface, as this may contaminate the emulsion. Use of the same bottle for both eyes is not recommended with topical eye drops that are used in association with surgery. Risk of Secondary Infection becomes aggravated, the patient should be advised to consult a physician. Contact Lens Wear DUREZOL ® Emulsion should not be instilled while wearing contact lenses. Patients should be advised to remove contact lenses prior to instillation of DUREZOL ® Emulsion. The preservative in DUREZOL ® Emulsion may be absorbed by soft contact lenses. Lenses may be reinserted after 10 minutes following administration of DUREZOL ® Emulsion. Revised: May 2013 U.S. Patent 6,114,319 DUREZOL ® Emulsion was evaluated in a 3-month, multicenter, double-masked, trial in 79 pediatric patients (39 DUREZOL ® Emulsion; 40 prednisolone acetate) 0 to 3 years of age for the treatment of inammation following cataract surgery. A similar safety prole was observed in pediatric patients comparing DUREZOL ® Emulsion to prednisolone acetate ophthalmic suspension, 1%. © 2014 Novartis 3/14 DUR14031JAD Manufactured For: Alcon Laboratories, Inc. 6201 South Freeway Fort Worth, Texas 76134 USA 1-800-7579195 Manufactured By: Alcon Laboratories, Inc. 6201 South Freeway Fort Worth, Texas 76134 USA or Catalent Pharma Solutions Woodstock, IL 60098 Postoperative continued from page 78 The ability to fully control wound healing may ultimately provide clinicians the ability to set the intraocular pressure in the low teens for all patients undergoing glaucoma surgery. Not all blebs are the same Many trabeculectomies do work, but not all blebs look the same, according to Prof. Wong. Ophthal- mologists know too well that the same operation can be done on a single patient with different results in each eye. Several factors influence the early wound healing response of the fibroblast. "One of them is aqueous humor, by providing TGF-beta that transforms fibroblast into myofibroblast," Dr. Grehn said. "There are external factors com- ing from inflammation, and this is mainly mediated by TGF-beta 1. Another one is that the velocity of aqueous flow induces transition of fibroblast into myofibroblast, which means the faster the flow of the new outflow system, the more scar formation you may have." Understanding the mechanism behind fibrosis is necessary in order to modulate the wound healing process. "The problem is that there is a lot about the pathophysiology, the fundamental course of a bleb leaking, that is still under research," Prof. Wong said. "However, we do know their contribution to the aqueous humor and vascularization and mechanical factors have been reported. The biomechanics of the bleb can cause an increase in the rate of scar tissue formation." Dr. Grehn outlined the intro- duction of a classification scheme in the practice of glaucoma surgery, based on 4 points: vascularity, pres- ence or absence of cork screw vessels according to the size of the bleb, encapsulation (which is best seen with a slit lamp in 3D observation), and the presence of microcyst in the bleb. "The first 3 points are the bad guys of early bleb formation," Dr. Grehn said. "For example, if the IOP is a little bit high and there is a lot of microcyst, then you are much more relaxed compared to when the IOP is a little bit high and there are a lot of cork screw vessels." Summarizing this classification scheme in numbers, according to Dr. Grehn, forces clinicians to look at the bleb in these 4 categories. "So if the number is between 12 and 10, you can relax, the bleb will develop well," he said. "If it's between 9 and 7, be critical and start increased steroid medication or 5-FU injections. Numbers less than 7 are not a good prospect for the bleb." As the scarring process is better understood, the most effective and safe therapies can be chosen to reach the resolution of the wound for the perfect bleb. This, according to Prof. Wong, is probably going to be based on cellular regulation of scarring and a way to adapt or to change the mechanical environment. "Future antifibrotics will have a multi-targeted approach, from wound formation to scar formation; the timing and mode of delivery is crucial," she said. "New therapeutics need extensive long-term clinical and safety evaluation." Indeed, there are exciting new areas of progress in the use of antimetabolites to improve safety, including growth factor neutraliza- tion and future molecular therapies to control wound healing. EW Editors' note: Dr. Grehn and Prof. Wong have no financial interests related to their comments. Contact information Grehn: f.grehn@augenklinik.uni-wuerzburg.de Wong: tina.wong.t.l@snec.com.sg

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