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EW NEWS & OPINION 14 Prior to treatment, clinical severity was equivalent among all groups. Forty-eight hours after treat- ment, the moxifloxacin/cholesterol group had a significantly lower mean slit lamp examination score (4.41 +/–0.71) than any other groups (PBS: 8.55+/–0.67, cholesterol-only: 7.45 +/–0.95, and moxifloxacin- only: 7.24 +/–0.44). Significantly lower myeloperoxi- dase activity occurred in eyes treated with moxifloxacin/cholesterol com- pared to the moxifloxacin-only and cholesterol-only groups. "Eyes treated with moxifloxacin/ cholesterol had fewer immune cells and less corneal destruction than eyes from all other treatment groups," Dr. Marquart noted. Further, the minimum in- hibitory concentration (MIC) for combined moxifloxacin and choles- terol was 0.0625 microns/mL, which is lower than that of moxifloxacin alone, at 0.125 microns/mL. Moxifloxacin-only and moxi- floxacin/cholesterol groups had sim- ilar effects on colony-forming units, lowering them significantly com- pared to the PBS or cholesterol-only groups. "The current findings indicate that combination therapy with mox- ifloxacin and soluble cholesterol would be an effective means of not only killing S. pneumoniae in the cornea, but also reducing the clinical severity of pneumococcal keratitis," Dr. Marquart reported. In fact, previous research found that cholesterol alone could lower the severity of pneumococcal kerati- tis infection and the bacterial load. Cholesterol alone did not have the same beneficial effect in this study— perhaps because of the difference in bacterial strains used. "The ocular strain used in the current study could be more resist- ant to treatment with cholesterol, which highlights the importance of using combination therapy with an effective antibiotic," Dr. Marquart concluded. "Even though choles- terol alone did not inhibit growth of bacteria, cholesterol appeared to have a synergistic effect when mixed with moxifloxacin as demonstrated by the lower MIC when compared to moxifloxacin alone." As to why cholesterol is benefi- cial, Dr. Marquart explained that the activity of the toxin pneumolysin— which is produced by S. pneumo- niae—is inhibited by exogenous cholesterol. The lack of pneumolysin activ- ity does make a difference. It was found, for example, that a pneu- molysin-deficient mutant of S. pneu- moniae caused keratitis infection that was less severe than the parent strain, Dr. Marquart reported. Bjorn Johansson, M.D., Linkoping University Hospital, Swe- den, confirmed that moxifloxacin is a very potent and broad antibiotic that covers a lot of bacteria and kills them off effectively. However, Dr. Johansson said that he hasn't come across the combination of moxi- floxacin and cholesterol being espe- cially useful. "If it has something to do with the way the antibiotic enters through the wound of the bacteria or if cholesterol helps in any way to cause penetration of antibiotic through the wall, I didn't come across [that] use," Dr. Johansson said. March 2011 Durezol QID (n = 107) Vehicle (n = 220) Day 8 15 8 15 Anterior Chamber cell clearing (% subjects) 24 (22%)* 44 (41%)* 17 (7%) 25 (11%) Pain free (% subjects) 62 (58%)* 67 (63%)* 59 (27%) 76 (35%) HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all of the information needed to use Durezol ® safely and effectively. See full prescribing information for Durezol. DUREZOL ® (diuprednate ophthalmic emulsion) 0.05% Initial U.S. approval: 2008 ---------------------------INDICATIONS AND USAGE------------------------ Durezol is a topical corticosteroid that is indicated for the treatment of inammation and pain associated with ocular surgery. (1) ------------------------DOSAGE AND ADMINISTRATION-------------------- Instill one drop into the conjunctival sac of the affected eye(s) 4 times daily beginning 24 hours after surgery and continuing throughout the árst 2 weeks of the postoperative period, followed by 2 times daily for a week and then a taper based on the response. (2) --------------------DOSAGE FORMS AND STRENGTHS---------------------- Durezol contains 0.05% diuprednate, as a sterile preserved ophthalmic emulsion for topical ophthalmic use only. (3) ----------------------------CONTRAINDICATIONS--------------------------- Durezol, as with other ophthalmic corticosteroids, is contraindicated in most 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 diseases of ocular structures. (4) ------------------------WARNINGS AND PRECAUTIONS------------------------ • Intraocular pressure (IOP) increase - Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and áelds of vision. If this product is used for 10 days or longer, IOP should be monitored. (5.1) • Cataracts - Use of corticosteroids may result in posterior subcapsular cataract formation. (5.2) • 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 of the patient with the aid of magniácation such as slit lamp biomicroscopy and, where appropriate, uorescein staining. (5.3) • 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. (5.4) • 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). (5.5) • 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. (5.6) To report SUSPECTED ADVERSE REACTIONS, contact Alcon Laboratories, Inc. at 1-800-757-9195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION. Revised date: March 2010 FULL PRESCRIBING INFORMATION: CONTENTS* 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 IOP Increase 5.2 Cataracts 5.3 Delayed Healing 5.4 Bacterial Infections 5.5 Viral Infections 5.6 Fungal Infections 5.7 Topical Ophthalmic Use Only 6 ADVERSE REACTIONS 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.3 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 13.2 Animal Toxicology and/or Pharmacology 14 CLINICAL STUDIES 14.1 Postoperative Ocular Inammation and Pain 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE Durezol (diuprednate ophthalmic emulsion) 0.05%, a topical corticosteroid, is indicated for the treatment of inammation and pain associated with ocular surgery. 2 DOSAGE AND ADMINISTRATION Instill one drop into the conjunctival sac of the affected eye(s) 4 times daily beginning 24 hours after surgery and continuing throughout the árst 2 weeks of the postoperative period, followed by 2 times daily for a week and then a taper based on the response. 3 DOSAGE STRENGTHS Durezol contains 0.05% diuprednate as a sterile preserved emulsion for topical ophthalmic administration. 4 CONTRAINDICATIONS The use of Durezol, 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. 5 WARNINGS AND PRECAUTIONS 5.1 IOP Increase Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and áelds of vision. Steroids should be used with caution in the presence of glaucoma. If this product is used for 10 days or longer, intraocular pressure should be monitored. 5.2 Cataracts Use of corticosteroids may result in posterior subcapsular cataract formation. 5.3 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 of the patient with the aid of magniácation such as slit lamp biomicroscopy and, where appropriate, uorescein staining. 5.4 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. 5.5 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). 5.6 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. 5.7 Topical ophthalmic use only Durezol is not indicated for intraocular administration. 6 ADVERSE REACTIONS Adverse reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and áeld defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. Ocular adverse reactions occurring in 5–15% of subjects in clinical studies with Durezol included corneal edema, ciliary and conjunctival hyperemia, eye pain, photophobia, posterior capsule opaciácation, anterior chamber cells, anterior chamber are, conjunctival edema, and blepharitis. Other ocular adverse reactions occurring in 1–5% of subjects included reduced visual acuity, punctate keratitis, eye inammation, and iritis. Ocular adverse events occurring in < 1% of subjects included application site discomfort or irritation, corneal pigmentation and striae, episcleritis, eye pruritis, eyelid irritation and crusting, foreign body sensation, increased lacrimation, macular edema, scleral hyperemia, and uveitis. Most of these events may have been the consequence of the surgical procedure. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects Pregnancy Category C. Diuprednate has been shown to be embryotoxic (decrease in embryonic body weight and a delay in embryonic ossiácation) and teratogenic (cleft palate and skeletal) anomalies when administered subcutaneously to rabbits during organogenesis at a dose of 1–10 μg/kg/day. The no-observed-effect-level (NOEL) for these effects was 1 μg/kg/day, and 10 μg/kg/day was considered to be a teratogenic dose that was concurrently found in the toxic dose range for fetuses and pregnant females. Treatment of rats with 10 μg/kg/day subcutaneously during organogenesis did not result in any reproductive toxicity, nor was it maternally toxic. At 100 μg/kg/day after subcutaneous administration in rats, there was a decrease in fetal weights and delay in ossiácation, and effects on weight gain in the pregnant females. It is difácult to extrapolate these doses of diuprednate to maximum daily human doses of Durezol, since Durezol is administered topically with minimal systemic absorption, and diuprednate blood levels were not measured in the reproductive animal studies. However, since use of diuprednate during human pregnancy has not been evaluated and cannot rule out the possibility of harm, Durezol should be used during pregnancy only if the potential beneát justiáes the potential risk to the embryo or fetus. 8.3 Nursing Mothers It is not known whether topical ophthalmic administration of corticosteroids could result in sufácient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when Durezol is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in pediatric patients has not been established. 8.5 Geriatric Use No overall differences in safety or effectiveness have been observed between elderly and younger patients. 11 DESCRIPTION Durezol (diuprednate ophthalmic emulsion) 0.05% is a sterile, topical anti-inammatory corticosteroid for ophthalmic use. The chemical name is 6α,9diuoro-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione 21-acetate 17-butyrate (CAS number 23674-86-4). Diuprednate is represented by the following structural formula: Diuprednate has a molecular weight of 508.56, and the empirical formula is C27H34F2O7. Each mL contains: ACTIVE: diuprednate 0.5 mg (0.05%); INACTIVE: boric acid, castor oil, glycerin, polysorbate 80, puriáed water, sodium acetate, sodium EDTA, sodium hydroxide (to adjust the pH to 5.2 to 5.8). The emulsion is essentially isotonic with a tonicity of 304 to 411 mOsm/kg. PRESERVATIVE: sorbic acid 0.1%. 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Corticosteroids inhibit the inammatory response to a variety of inciting agents that may delay or slow healing. They inhibit edema, ábrin deposition, capillary dilation, leukocyte migration, capillary proliferation, ábroblast proliferation, deposition of collagen, and scar formation associated with inammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inammation such as prostaglandins and leukotreines by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A 2 . Diuprednate is structurally similar to other corticosteroids. 12.3 Pharmacokinetics Diuprednate undergoes deacetylation in vivo to 6α,9-diuoroprednisolone 17-butyrate (DFB), an active metabolite of diuprednate. Clinical pharmacokinetic studies of diuprednate after repeat ocular instillation of 2 drops of diuprednate (0.01% or 0.05%) QID for 7 days showed that DFB levels in blood were below the quantiácation limit (50 ng/mL) at all time points for all subjects, indicating the systemic absorption of diuprednate after ocular instillation of Durezol is limited. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility Diuprednate was not genotoxic in vitro in the Ames test, and in cultured mammalian cells CHL/IU (a ábroblastic cell line derived from the lungs of newborn female Chinese hamsters). An in vivo micronucleus test of diuprednate in mice was also negative. Treatment of male and female rats with subcutaneous diuprednate up to 10 μg/kg/day prior to and during mating did not impair fertility in either gender. Long term studies have not been conducted to evaluate the carcinogenic potential of diuprednate. 13.2 Animal Toxicology and/or Pharmacology In multiple studies performed in rodents and non-rodents, subchronic and chronic toxicity tests of diuprednate showed systemic effects such as suppression of body weight gain; a decrease in lymphocyte count; atrophy of the lymphatic glands and adrenal gland; and for local effects, thinning of the skin; all of which were due to the pharmacologic action of the molecule and are well known glucocorticosteroid effects. Most, if not all of these effects were reversible after drug withdrawal. The NOEL for the subchronic and chronic toxicity tests were consistent between species and ranged from 1–1.25 μg/kg per day. 14 CLINICAL STUDIES 14.1 Postoperative Ocular In°ammation and Pain Clinical efácacy was evaluated in 2 randomized, double-masked, placebo- controlled trials in which subjects with an anterior chamber cell grade ≥ "2" (a cell count of 11 or higher) after cataract surgery were assigned to Durezol or placebo (vehicle) following surgery. One drop of Durezol or vehicle was self instilled either 2 (BID) or 4 (QID) times per day for 14 days, beginning the day after surgery. The presence of complete clearing (a cell count of 0) was assessed 8 and 15 days post-surgery using a slit lamp binocular microscope. In the intent-to-treat analyses of both studies, a signiácant beneát was seen in the QID Durezol-treated group in ocular inammation and reduction of pain when compared with placebo. The consolidated clinical trial results are provided below. *Statistically signiácantly better than vehicle, p<0.01 16 HOW SUPPLIED/STORAGE AND HANDLING Durezol (diuprednate ophthalmic emulsion) 0.05% is a sterile, aqueous topical ophthalmic emulsion supplied in an opaque plastic bottle with a controlled drop tip and a pink cap in the following size: 5 mL in a 5 mL bottle (NDC 42826-601-05). Storage Store at 15-25°C (59-77°F). Do not freeze. Protect from light. When not in use keep the bottles in the protective carton. 17 PATIENT COUNSELING INFORMATION 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. If pain develops or if redness, itching, or inammation becomes aggravated, the patient should be advised to consult a physician. As with all ophthalmic preparations containing a preservative, patients should be advised not to wear contact lenses when using Durezol. Revised: March 2010 References: 1. Bikowski J, Pillai R, Shroot B. The position not the presence of the halogen in corticosteroids inuences potency and side effects. J Drugs Dermatol. 2006;5(2):125-130. 2. Tajika T, Isowaki A, Sakaki H. Ocular distribution of diuprednate ophthalmic emulsion 0.05% in rabbits [published online ahead of print December 1, 2010]. J Ocul Pharmacol Ther. doi:10.1089/jop.2010.0093. 3. Ponec M, Kempenaar J, Shroot B, Caron JC. Glucocorticoids: binding afánity and lipophilicity. J Pharm Sci. 1986;75(10):973-975. 4. Korenfeld MS, Silverstein SM, Cooke DL, Vogel R, Crockett RS; Diuprednate Ophthalmic Emulsion 0.05% (Durezol) Study Group. Diuprednate ophthalmic emulsion 0.05% for postoperative inammation and pain. J Cataract Refract Surg. 2009;35(1):26-34. 5. Fingertip Formulary. November 2010. ©2010 Alcon, Inc. 12/10 DUR11500JAD U.S. Patent No. 6,114,319 Manufactured For Alcon Laboratories, Inc. 6201 South Freeway Fort Worth, Texas 76134 USA 1-800-757-9195 MedInfo@AlconLabs.com Manufactured By: Catalent Pharma Solutions Woodstock, IL 60098 Study continued from page 13 continued on page 20

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