THE IMPACT OF OCULAR SURFACE DISEASE ON CATARACT AND ... · 5/7/2016 · the outcomes of...

$: THE IMPACT OF OCULAR SURFACE DISEASE ON CATARACT AND ... · 5/7/2016 · the outcomes of refractive and cataract surgery can be profound.3,4 Accurate intraocular lens (IOL) power$
participants

Marguerite B. McDonalD, MD, Facs

Douglas Katsev, MD

terrence p. o’Brien, MD

John shepparD, MD, MMsc

THE IMPACT OF OCULAR SURFACE DISEASE ON CATARACT AND

REFRACTIVE SURGERY A ROUNDTABLE DISCUSSION

May 7, 2016 | New Orleans, LA

sponsored by

THE IMPACT OF OCULAR SURFACE DISEASE ON CATARACT AND REFRACTIVE SURGERY: A ROUNDTABLE DISCUSSION

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The term ocular surface disease (OSD) refers to a group of disorders of the eyelids, conjunctiva, cornea, and associated glands that are often divided into dry eye disease and non-dry eye disease forms, with the latter divided into eyelid-related (eg, blepharitis and meibomian gland dysfunction) and non-eyelid-related disorders (eg, conjunctivitis and keratitis).1

These conditions frequently overlap—blepharitis, for example, is a major cause of evaporative dry eye—and they are highly prevalent. A telephone survey of 5019 adults conducted in 2008 indicated that up to 32% of respondents reported having at least one symptom of lid-related disorders at least half the time in the previous 12 months.2

Although the signs and symptoms of a progressive OSD such as blepharitis may be subtle, the effect on the outcomes of refractive and cataract surgery can be profound.3,4 Accurate intraocular lens (IOL) power calculations, which are essential for good uncorrected vision after cataract surgery, depend on reliable and repeatable keratometry to measure anterior corneal curvature.5-7 An OSD such as blepharitis contributes to an unstable tear film, reducing the quality of corneal reflections and compromising keratometric (K) readings, and increases the risk of infection.5,7 If not addressed, tear film problems can retard healing and vision recovery. Because OSD is more prevalent with increased age, tear film instability is a common concern in the cataract surgery population.5

For many surgeons, myself included, ZYLET® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) is our go-to treatment for a variety of conditions that can be characterized as ocular inflammation with a risk of bacterial infection.8 ZYLET includes a broad-spectrum antibiotic, tobramycin; the efficacy of topical antibiotics in eradicating bacteria from the lid margins has been well documented.9 The active antiinflammatory agent in ZYLET, loteprednol etabonate 0.5%, has an established safety profile, with low risk of intraocular pressure (IOP) increases but with the efficacy to control inflammatory OSD.10 In the following pages, four anterior segment specialists discuss how we use ZYLET to treat the inflammation and risk of infection associated with OSD, including blepharitis and contact lens-induced acute red eye (CLARE), for patients who are about to undergo refractive and cataract surgery.

— Marguerite B. McDonald, MD, FACS

ROUNDTABLEPARTICIPANTS

Marguerite B. McDonald, MD, FACS, practices at Ophthalmic Consultants of Long Island, Lynbrook, NY, and is a clinical professor of ophthalmology at both NYU Langone School of Medicine, New York, NY, and Tulane University Health Sciences Center, New Orleans, LA.

Douglas Katsev, MD, is chair of ophthalmology at Cottage Hospital and co-chair of ophthalmology at the Sansum Clinic, Santa Barbara, CA.

Terrence P. O’Brien, MD, is a professor of ophthalmology and the Charlotte Breyer Rogers Distinguished Chair at the University of Miami Miller School of Medicine, and director of the Refractive Surgery Service, Bascom Palmer Eye Institute at Palm Beach Gardens, FL.

John Sheppard, MD, MMSc, is a specialist in corneal and cataract surgery; president and managing partner of Virginia Eye Consultants in Norfolk; and professor of ophthalmology, microbiology, and molecular biology at Eastern Virginia Medical School, also in Norfolk.

PANELISTS


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Please see Important Safety Information on pages 6 and 8, and Prescribing Information for ZYLET on pages 11, 12 and 13.

Terrence O’Brien As technology has advanced, so have expec-tations. Many cataract patients that I currently see anticipate perfect outcomes and spectacle independence.

Douglas Katsev For premium IOLs, patient expectations have also risen because they are paying out of pocket. With the ad-ditional cost of premium lens, which has benefited our profes-sion, we have an added responsibility.

McDonald Don’t forget the role that social media has played. The patient who is 20/15 the day after surgery without correc-tion may share that on social media, including Facebook and Twitter.

THE OCULAR SURFACE & SURGICAL OUTCOMESMcDonald Inaccuracies in biometry and IOL power prediction can have a profound impact on surgical outcomes, which are particularly important given heightened patient expectations, especially for premium-channel IOLs. In a study by Epitropoulos and coworkers, patients from three practices were segregated into two groups using tear osmolarity. All participants had two preoperative measurements. The hyperosmolar group (n = 50) had a significantly higher variability in the average K reading (P = .05) than the normal group (n = 25) and a significantly higher percentage of eyes with a 1.0 diopter (D) or greater dif-ference in the measured corneal astigmatism (P = .02). A sig-nificantly higher percentage of eyes in the hyperosmolar group had an IOL power difference of more than 0.5 D (P = .02).11

Katsev Blepharitis and meibomian gland dysfunction (MGD) can also impact pre-op testing and surgical outcomes.

O’Brien In the Prospective Health Assessment of Cataract Pa-tients’ Ocular Surface (PHACO) study, Trattler and colleagues showed that the prevalence of OSD is much higher than pre-viously expected in cataract patients. 136 patients (272 eyes) presenting for routine cataract surgery were examined for signs and symptoms of dry eye disease. The average tear film break-up time (TBUT) was 4.95 seconds; 171 eyes (63%) had a TBUT of ≤5 seconds. Most eyes (77%) had corneal staining, and one-fifth of the patients had abnormally low Schirmer test scores (<5 mm).12

Sheppard Significantly, many of the PHACO patients were asymptomatic. When patients don’t have symptoms, it can be more challenging to motivate them to undergo treatment despite impending cataract surgery.

O’Brien Some patients with chronic OSD have decreased cor-neal sensation, therefore they don’t experience the symptoms of irritation.

RISING PATIENT EXPECTATIONSMarguerite McDonald In the past few years, a great deal of attention has been paid to the impact of the ocular surface on surgical outcomes. How have patient expectations influenced this shift?

John Sheppard 20 years ago, we started seeing heightened expectations for corneal-based refractive surgery. Now, we’re seeing the expectations of the cataract patient—both premium and routine—converge with those of the refractive patient.

INDICATIONS AND USAGE ZYLET (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) is a topical anti-infective and corticosteroid combination for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists.

Ocular steroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe such as allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, and where the inherent risk of steroid use in certain infective conjunctivitides is accepted to obtain a diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or penetration of foreign bodies.

The use of a combination drug with an anti-infective component is indicated where the risk of superficial ocular infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye.

The particular anti-infective drug in this product (tobramycin) is active against the following common bacterial eye pathogens: Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains. Streptococci, including some of the Group A-beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, most Proteus vulgaris strains, Haemophilus influenzae, and H. aegyptius, Moraxella lacunata, Acinetobacter calcoaceticus and some Neisseria species.

See Important Safety Information on pages 6 and 8.


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McDonald Most medical specialties struggle with treating peo-ple for serious conditions without symptoms—hypertension, for example, is a major risk factor for stroke. Objective evidence from topography and meibography can show asymptomatic pa-tients that they have signs of OSD (Figure 1, Table I).

FIGURE 1 A. Normal eyelid (Meibomian). B. Gland (oil) dropout (Images captured using LipiView II with DMI by TearScience, Inc.)

Katsev If OSD throws off our IOL calculations and interferes with patients’ vision after surgery, the surgeon will be seen as the cause, not the patients’ blepharitis and/or MGD for example.

BLEPHARITISMcDonald What proportion of patients that we prepare for re-fractive or cataract surgery have blepharitis?

Katsev Up to 30% of my cataract patients, maybe even high-er in some categories. The proportion is not quite as high for refractive patients because they are younger, but it’s still sub-stantial in my practice.

O’Brien Depending on definitions, the prevalence in my prac-tice of dry eye disease may be anywhere from 5% up to 50%; for blepharitis in the cataract patient, the prevalence in my practice can be from 30% all the way up to 100%.

Sheppard If you extrapolate from the PHACO study, in which approximately 75% of cataract patients had dry eye as revealed by positive fluorescein corneal staining, and the Lemp survey, in which 86% of dry eye disease patients had blepharitis,2 then about 64% of cataract patients may have blepharitis. Luchs and coworkers enrolled 100 patients presenting for biometry prior to cataract surgery; 59% of the patients had a diagnosis of blepharitis, and 61% percent had a TBUT of ≤7 seconds.14 The majority of patients in this study had mild to moderate symptoms.14 In my practice, these types of patients don’t vol-untarily bring their symptoms to my attention.

McDonald What signs and symptoms are present in patients with anterior versus posterior blepharitis?

O’Brien There is tremendous overlap in symptoms. In terms of signs, there is no artificial, anatomic delineation that clearly separates anterior from posterior. Classically, anterior bleph-aritis is excessive colonization of the the anterior lid margin involving the cilia. Often, we see collarettes that may be cul-ture-positive, especially for gram-positive organisms. The posterior disease is harder to define; sometimes the posterior glands may look normal yet the patients’ symptoms are out of proportion to the signs. With chronicity, however, posterior blepharitis can cause congestion of the meibomian glands along with lid margin telangiectasias and inflammation.

STAGE SYMPTOMS CORNEAL STAININGMGD GRADE

TABLE I — MGD STAGING13

+ (minimally altered expressibility and secretion quality)

++ (mildly altered expressibility and secretion quality)

+++ (moderately altered expressibility and secretion quality)

++++ (severely altered expressibility and secretion quality)

Co-existing or accompanying disorders of the ocular surface and/or eyelids

None

Minimal to mild

Moderate

Marked

None

None to limited

Mild to moderate; mainly peripheral

Marked; central in addition

1

2

3

4

"Plus" disease


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month prior to his pre-op workup and to perform hot lid soaks and scrubs twice daily. In addition, he was prescribed ZYLET along with omega-3 nutritional supplements. Upon return one month later, his meibomian gland inspissation was trace, con-junctival erythema was trace OU, and papillary changes were trace OU. A complete pre-op workup then proceeded unevent-fully; the patient underwent LASIK and had a one day post-op UCVA of 20/20 OD and 20/25 + 2 OS.

O’Brien We begin with a validated questionnaire that takes a few seconds for the patient to fill out, and I empower my technicians to look for blepharitis. If we have a positive MMP9 and hyperosmolar state, we stop the evaluation and initiate a multifactorial treatment to bring the inflammation and risk of infection under control before having the patient come back.

Figure 2 Slit lamp biomicroscopy showing trace-1+ scurf along the anterior lid margins and 2-3+ MGD with 1+ lid margin telangiectasias. (Image courtesy Dr. O’Brien.)

As an example, a 71-year-old attorney presented to us recently complaining of a painless, progressive deterioration in vision over the past 2 years. His law partner had cataract surgery 1 year prior and bragged about his spectacle independence thanks to a multifocal IOL. Slit lamp biomicroscopy disclosed trace-1+ scurf along the anterior lid margins and 2 to 3+ MGD with 1+ lid margin telangiectasias (Figure 2). There were trace-1+ punctate epithelial erosions of the cornea along the inferior cornea adjacent to the lid margin (Figure 3) and a rapid TBUT of <3 seconds (Figure 4). Tear film osmolarity measured 309 OD and 319 OS; and MMP9 screening test was positive in both eyes. The right eye had 1+ nuclear opalescence and trace-1+ brunescence with trace posterior subcapsular cata-ract. The left eye had 2+ nuclear opalescence and 1-2+ bru-nescence with 1+ axial posterior subcapsular cataract. The corneal topography was difficult to interpret and irregular, with areas of dropout (Figure 5). The mean K values obtained on biometry were inconsistent (Figure 6).

Sheppard Both anterior and posterior blepharitis can affect cilia positioning: follicle destruction in the inflamed anterior lamella, and cicatricial entropion from the damaged posterior tarsal plate. We need to treat both locales of blepharitis to nor-malize that aspect of the patient’s anatomy, as pre-op lid and lash abnormalities can have a deleterious effect upon surgical outcomes.

O’Brien We should consider blepharitis like glaucoma: a pro-gressive disease that can negatively impact vision.

Sheppard There is no more powerful tool than dynamic meibog-raphy for demonstrating the anatomy of the inferior meibomian glands. Patients can see truncation, atrophic changes, and dropout with complete loss of normal gland architecture. This type of readily discernable pictorial depiction of pathology often motivates patients to treat their disease more aggressively.

O’Brien It helps patients to know what we’re treating. At our practice, we have a large digital screen to show patients their lid margins. Seeing firsthand the conditions of eyelids at higher magnification can be highly motivating.

McDonald We also have a digital screen in addition to a lami-nated card in each exam lane. Patients can look at their lids on screen and then compare with what their lids should look like.

Katsev I empower my staff to discuss test results with me that they aren’t comfortable with. Sometimes they pick up signs that I missed.

MANAGING BLEPHARITISMcDonald How do you decide whether a patient requires pre-surgical treatment for blepharitis?

Katsev If I’m implanting a premium IOL, I treat anyone that has noticeable blepharitis before doing the IOL calculations. I will cut short the visit that day and start them on ZYLET.

McDonald I tell the technicians to let me see patients before dilation so that I can perform osmolarity and other OSD testing. If I find signs pointing to blepharitis, I prescribe ZYLET and then finish up the tests once the ocular surface has normalized.

As an example, a 39-year-old male presented to us with a his-tory of a recent decrease in his contact lens tolerance, for which he was seeking laser refractive surgery. Because of burning and fluctuating vision, he was only able to wear his contact lenses for 4 to 6 hours a day. The relevant features of his exam were: uncorrected visual acuity (UCVA) of 20/400 OD; counting fingers at 5 feet OS; manifest refraction of -2.25 sphere OD, -3.50 - 0.25 x 180 degrees OS; 2+ to 3+ meibomian gland in-spissation OU without scurf; 2+ conjunctival erythema OU; and 2+ to 3+ papillary changes, some giant.

I told him to discontinue contact lenses completely for one


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FIGURE 3 Trace-1+ punctate epithelial erosions of the cornea along the inferior cornea adjacent to the lid margin. (Image courtesy Dr. O’Brien.)

The patient was eager to proceed with surgery and initially up-set when I told him that he had significant ocular surface dis-ease and thus cataract surgery could not take place immedi-ately. He was more understanding, however, after being shown

the digital slit-lamp biomicroscopic images and a review of the corneal topography and biometry demonstrating the mixed anterior and posterior blepharitis with associated OSD. He was willing to postpone cataract surgery and eager to comply ful-ly with an aggressive treatment plan: 4 weeks of ZYLET, oral doxycycline, omega-3 supplements, warm compresses, and lid scrubs.

He returned in 5 weeks with a marked subjective improvement in overall symptoms and much less redness. There was no scurf present, decreased MGD with trace lid margin telangiectasias, and no corneal staining with fluorescein sodium. The TBUT measured 9 mm OU and tear film osmolarity measured 287 OD and 296 OS. The corneal topography analysis was regular and the mean K values after treatment were consistent.

We proceeded with femtosecond laser-assisted arcuate keratot-omy and cataract extraction with multifocal lens implantation (+2.75 Add) to the left eye. The surgery went smoothly. Postop-eratively he noted some initial dryness but his unaided vision at distance, intermediate, and near was good. At 5 weeks, his post-op UCVA was 20/15 OS and J1+ @ 14”.

FIGURE 4 Rapid TBUT of <3 seconds. (Image courtesy Dr. O’Brien.)

McDonald To my knowledge, I have never lost a patient by starting treatment first. As another example from my practice, this time of a cataract patient: Ms. KL, a 64-year-old female patient, came to us because she was unable to drive at night due to glare. My examination revealed best-corrected visual acuity (BCVA) of 20/30-2 OD and 20/40-1 OS; a decreased tear lake OU; 3+ to 4+ meibomian gland inspissation with trace to 1+ scurf OU; 2+ papillary changes in the conjunctivae OU; 2+ conjunctival erythema OU; and 3+ nuclear sclerotic changes OU. On testing, Ms. KL had tear osmolarity scores of 316 and 307; a TBUT of 3.0 and 4.0 seconds; and 2+ to 3+ dropout of her glands on meibography OU. Due to her blepharitis/OSD, the cataract evaluation was cut short that day. She was instructed to perform hot soaks and scrubs of the lids BID OU and to use artificial tears QID OU. In addition, she was placed on omega-3 nutritional supplementation and ZYLET for 2 weeks. After one

IMPORTANT SAFETY INFORMATION• ZYLET 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 infections of the eye and fungal diseases of ocular structures.

• Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, and defects in visual acuity and fields 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.

• Use of corticosteroids may result in posterior subcapsular cataract formation.

• 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 should be made by a physician only after examination of the patient with the aid of magnification such as a slit lamp biomicroscopy and, where appropriate, fluorescein staining.

Important Safety Information continued on page 8.


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month, she had marked improvement of her ocular surface: 1+ to 2+ meibomian gland inspissation without scurf; trace to 1+ papillary changes; and trace erythema of the conjunctivae. Ms. KL underwent uneventful cataract surgery, aiming for a target of plano OU. Within 1 week of her second surgery, Ms. KL had a UCVA of 20/25 + 2 OD and 20/25+1 OS.

Katsev I have had similar experiences treating blepharitis pa-tients with ZYLET before cataract surgery. An elderly patient with poor vision presented to us recently with blepharitis. Her BCVA was 20/100 OU and her cataracts were about 20/50 dense. I pretreated her with lid hygiene and ZYLET. After 2 weeks her BCVA improved to 20/70, and we were able to obtain good topography and K readings before implanting a premium IOL (Figure 7). Her vision is now 20/20 at distance and J3 read-ing at intermediate.

McDonald How important is the tobramycin component of ZYLET? How well does it cover the organisms that are most likely to be involved in blepharitis?

O’Brien Many clinicians think of tobramycin as a gram-neg-ative acting agent. In fact, tobramycin has gram-positive ac-tivity (eg, against staphylococci and streptococci, including resistant strains). Tobramycin has an excellent spectrum of coverage against common bacterial eye pathogens (Table II).

FIGURE 5 Irregular corneal topography with areas of dropout. (Image courtesy Dr. O’Brien.)

FIGURE 6 Inconsistent mean K values obtained on biometry. (Image courtesy Dr. O’Brien.)

TABLE II — TOBRAMYCIN: A BROAD-SPECTRUM ANTIBIOTIC13

Staphylococci

Streptococci

Most Proteus vulgaris

Escherichia coli

Pseudomonas aeruginosa

Klebsiella pneumoniae

Enterobacter aerogenes

Proteus mirabilis

Morganella morganii

Haemophilus influenzae

Haemophilus aegyptius

Moraxella lacunata

Acinetobacter calcoaceticus

Some Neisseria species


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Sheppard Tobramycin was formally introduced into our armamentarium long before the fluoroquinolones. Now the ami-noglycosides are established medicines against methicillin-re-sistant Staphylococcus epidermidis (MRSE) and methicillin-re-sistant Staphylococcus aureus (MRSA). The mild irritant effect can be counterbalanced by a concomitant steroid, and a pulsed 7-to-10-day therapy with a dual agent can reduce significant bacterial counts that have their own intrinsic inflammatory ef-fect. As an example, a 65-year-old male patient presented to me recently with variable blurred vision, glare, chronic pain, and discharge. His lid culture was MRSE-positive (Figure 8). After 2 weeks of treatment with ZYLET, the symptoms, except-ing glare, resolved prior to biometry and premium toric cataract surgery.

McDonald How about inflammatory versus infectious mecha-nisms and blepharitis?

FIGURE 7 Intraocular implant. (Image courtesy Dr. Katsev.)

FIGURE 8 65-year-old male patient with variable blurred vision, glare, chronic pain, and discharge; his lid culture was MRSE positive. (Image courtesy Dr. Sheppard.)

O’Brien Microbial colonization plays a role in posterior lid mar-gin disease. Lipases that are produced by the bacteria break down meibum into free fatty acid and soap, which trigger in-flammation on the ocular surface. By controlling excessive col-onization with an effective antibacterial agent like tobramycin and combining an anti-inflammatory, we really cover both sides of known pathophysiological mechanisms in blepharitis.

CLAREMcDonald Let’s move on to contact lens-induced acute red eye (CLARE), which is a term used almost exclusively in optometry. Linked to extended contact lens wear, CLARE is an acute inflam-matory reaction of the cornea and conjunctiva with patients being either awakened by their symptoms or noticing them soon after waking.15-16 Symptoms include moderate to severe redness, irritation/moderate pain, tearing, and photophobia. Bacterial cultures often reveal the presence of gram-negative bacteria (Figure 9).17

IMPORTANT SAFETY INFORMATION (CONTINUED)• 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 infections. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated.

• Employment of 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 exacerbate the severity of many viral infections of the eye (including herpes simplex).

• 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.

• Most common adverse reactions reported in patients were injection and superficial punctate keratitis, increased intraocular pressure, and burning and stinging upon instillation.


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O’Brien Optometrists are seeing these patients earlier in the course of what may be a spectrum up to frank microbial kera-titis. Ophthalmologists are more familiar with contact lens-as-sociated ulcerative keratitis. But the optometrists are seeing them earlier.

Katsev We sometimes call it contact lens overwear or tight lens syndrome.

O’Brien CLARE is probably due to microbial toxins that are released and then trapped underneath the contact lens. The gram-negative endotoxin lipopolysaccharide may be an import-ant trigger.

FIGURE 9 CLARE. (Image courtesey Bausch & Lomb)

McDonald Most cases of CLARE are caused by gram-negative bacteria—eg, Pseudomonas and Haemophilus are bad ac-tors—and occur in people who are in extended-wear lenses or abuse their daily or two-week disposables, such as by sleeping in them.17 The pain will often wake patients up in the middle of the night, but they rarely have a corneal epithelial defect. Instead, they typically have subepithelial infiltrates that are denser toward the limbus and usually less dense toward the center of the cornea. These patients tend to respond to a com-bination agent like ZYLET.

McDonald How often do surgical candidates have contact lens-related ocular surface disease? I would say this used to be a problem only with laser vision correction. But unlike the WWII generation, the baby boomers wear contacts.

Sheppard And the older our baby boomers survive, the more contact lens-intolerant they become. Particularly the hyper-opes, who are optically dependent upon their contacts: they are ideal candidates for refractive lens exchange, or in an old-er-aged group, cataract surgery.

McDonald CLARE is another reason we might have to stop the pre-op workup. I typically have patients refrain from wearing contacts and treat them for 3 weeks for soft lenses, and 4 weeks for soft-toric or gas permeable.

ZYLET: EFFICACY AND SAFETYMcDonald What are the key attributes of ZYLET?

O’Brien ZYLET has established efficacy. In a parallel-group, in-vestigator-masked, prospective study of 276 adults diagnosed with blepharokeratoconjunctivitis (BKC) and randomized either to ZYLET (n = 138) or TobraDex (n = 138) administered 4 times daily for 14 days, there was no significant difference between the ZYLET- and TobraDex-treated groups at any time point as measured by mean change from baseline in BKC signs and symptoms (Figure 10).18

FIGURE 10 Comparable efficacy: ZYLET vs. TobraDex.18

Katsev ZYLET also has an established safety profile with low incidence of IOP elevation. In a randomized, double-masked, multicenter, parallel-group trial of 306 healthy volunteers who received either ZYLET (n = 156) or TobraDex (n = 150) at 4-hour intervals 4 times a day in both eyes for 28 days, 1.95% of the ZYLET-treated group vs 7.48% of the TobraDex-treated group (P = 0.028) had an IOP increase ≥10 mm Hg over baseline in either eye at any study visit (Figure 11). If ZYLET is used for 10 days or longer, IOP should be monitored.19


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FIGURE 11 IOP changes: ZYLET vs. TobraDex.19

O’Brien Similar to what we see in clinical trials, I have encoun-tered patients who have been using a dexamethasone-contain-ing agent such as TobraDex and have substantially elevated IOP. Ketone steroids may remain in the anterior chamber for longer periods than ester corticosteroids such as loteprednol etabonate.19

Sheppard Often the disease being treated, and sometimes the antibiotic, can be inflammatory. The synergistic effect of having the steroid on board counteracts the effects of the in-flammation.

McDonald When the infection is under control, my focus becomes the inflammation. There is a continued need for the anti-inflammatory component of ZYLET, which I prescribe until the infection and inflammation are under control.

O’Brien In the Steroids for Corneal Ulcers Trial, the addition of a corticosteroid did not negatively impact the treatment course.13

Sheppard ZYLET is my agent of choice for multifactorial man-agement of multifactorial infectious and inflammatory condi-tions on the ocular surface.

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11. Epitropoulos AT, Matossian C, Berdy GJ, Malhotra RP, Potvin R. Effect of tear osmolarity on repeatability of keratometry for cataract surgery planning. J Cataract Refract Surg. 2015;41:1672-7.

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13. Srinivasan M, Mascarenhas J, Rajaraman R, et al; Steroids for Corneal Ulcers Trial Group. Corticosteroids for bacterial keratitis: the Steroids for Corneal Ulcers Trial (SCUT). Arch Ophthalmol. 2012 Feb;130(2):143-50.

14. Luchs J, Buznego C, Trattler W. Incidence of blepharitis in patients scheduled for phacoemulsification. Poster presented at the American Society of Cataract and Refractive Surgery Symposium and Congress; April 9-14, 2010; Boston, MA.

15. Contact Lens-Induced Acute Red Eye (CLARE). Living Library. Association of Optometric Contact Lens Educators. http://www.aocle.org/livingL/clare.html.

16. Sweeney DF, Jalbert I, Covey M, et al. Clinical characterization of corneal infiltrative events observed with soft cataract lens wear. Cornea. 2003;22(5):435-442.

17. Willcox M, Sharma S, Naduvilath TJ, Sankaridurg PR, Gopinathan U, Holden BA. External ocular surface and lens microbiota in contact lens wearers with corneal infiltrates during extended wear of hydrogel lenses. Eye Contact Lens. 2011;37(2):90-95.

18. White EM, Macy JI, Bateman KM, Comstock TL. Comparison of the safety and efficacy of loteprednol 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of blepharokeratoconjunctivitis. Curr Med Res Opin. 2008;24(1):287-96.

19. Holland EJ, Bartlett JD, Paterno MR, Usner DW, Comstock TL. Effects of loteprednol/tobra-mycin versus dexamethasone/tobramycin on intraocular pressure in healthy volunteers. Cornea. 2008;27(1):50-5.

ZYLET is a trademark of Bausch & Lomb Incorporated or its affiliates. ©2018 Bausch & Lomb Incorporated. ZYL.0063.USA.18

11

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing2.2 Prescription Guideline

3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS

4.1 Nonbacterial Etiology

5 WARNINGS AND PRECAUTIONS5.1 Intraocular Pressure (IOP) Increase5.2 Cataracts5.3 Delayed Healing5.4 Bacterial Infections5.5 Viral Infections5.6 Fungal Infections5.7 Aminoglycoside Hypersensitivity

6 ADVERSE REACTIONS8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use

11 DESCRIPTION12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION* Sections or subsections omitted from the full prescribing information are not listed.

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use ZYLET® (loteprednol etabonate and tobramycin ophthalmic suspension) safely and effectively. See full prescribing information for ZYLET (loteprednol etabonate and tobramycin ophthalmic suspension, 0.5%/0.3%).

Zylet (loteprednol etabonate and tobramycin ophthalmic suspension) 0.5%/0.3% Initial U.S. Approval: 2004

---------------------------- INDICATIONS AND USAGE --------------------------Zylet is a topical anti-infective and steroid combination for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists. (1)

-------------------------DOSAGE AND ADMINISTRATION -----------------------Apply one or two drops of Zylet into the conjunctival sac of the affected eye every four to six hours. (2.1)

----------------------- DOSAGE FORMS AND STRENGTHS ----------------------Zylet contains 5 mg/mL loteprednol etabonate and 3 mg/mL tobramycin. (3)

------------------------------ CONTRAINDICATIONS -----------------------------Zylet, as with other steroid anti-infective ophthalmic combination drugs, 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. (4.1)

------------------------- WARNINGS AND PRECAUTIONS ------------------------• Intraocular pressure (IOP)-Prolonged use of corticosteroids may result in

glaucoma with damage to the optic nerve, defects in visual acuity and fields 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 should be made by a physician only after examination of the patient with the aid of a magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. (5.3)

• Bacterial infections–Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infection. 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)

------------------------------ADVERSE REACTIONS ----------------------------Most common adverse reactions reported in patients were injection and superficial punctate keratitis, increased intraocular pressure, burning and stinging upon instillation. (6)

To report SUSPECTED ADVERSE REACTIONS, contact Bausch + Lomb, a division of Valeant Pharmaceuticals North America LLC, at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. See 17 for PATIENT COUNSELING INFORMATION.

Revised: 08/2016

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGEZylet® is a topical anti-infective and corticosteroid combination for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists.Ocular steroids are indicated in inflammatory conditions of the palpebral and bulbar conjunctiva, cornea and anterior segment of the globe such as allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster keratitis, iritis, cyclitis, and where the inherent risk of steroid use in certain infective conjunctivitides is accepted to obtain a diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or penetration of foreign bodies.The use of a combination drug with an anti-infective component is indicated where the risk of superficial ocular infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye.

The particular anti-infective drug in this product (tobramycin) is active against the following common bacterial eye pathogens:Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains. Streptococci, including some of the Group A-beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, most Proteus vulgaris strains, Haemophilus influenzae, and H. aegyptius, Moraxella lacunata, Acinetobacter calcoaceticus and some Neisseria species.

2 DOSAGE AND ADMINISTRATION2.1 Recommended DosingApply one or two drops of Zylet into the conjunctival sac of the affected eye every four to six hours. During the initial 24 to 48 hours, the dosing may be increased, to every one to two hours. Frequency should be decreased gradually as warranted by improvement in clinical signs. Care should be taken not to discontinue therapy prematurely.

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2.2 Prescription GuidelineNot more than 20 mL should be prescribed initially and the prescription should not be refilled without further evaluation [see Warnings and Precautions (5.3)].

3 DOSAGE FORMS AND STRENGTHSZylet (loteprednol etabonate and tobramycin ophthalmic suspension) 0.5%/0.3% contains 5 mg/mL loteprednol etabonate and 3 mg/mL tobramycin.

4 CONTRAINDICATIONS4.1 Nonbacterial EtiologyZylet, as with other steroid anti-infective ophthalmic combination drugs, 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.

5 WARNINGS AND PRECAUTIONS 5.1 Intraocular Pressure (IOP) IncreaseProlonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields 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 CataractsUse of corticosteroids may result in posterior subcapsular cataract formation.5.3 Delayed HealingThe 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 should be made by a physician only after examination of the patient with the aid of magnification such as a slit lamp biomicroscopy and, where appropriate, fluorescein staining.5.4 Bacterial InfectionsProlonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions of the eye, 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 InfectionsEmployment 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 InfectionsFungal 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 cultures should be taken when appropriate.5.7 Aminoglycoside HypersensitivitySensitivity to topically applied aminoglycosides may occur in some patients. If hypersensitivity develops with this product, discontinue use and institute appropriate therapy.

6 ADVERSE REACTIONS Adverse reactions have occurred with steroid/anti-infective combination drugs which can be attributed to the steroid component, the anti-infective component, or the combination.Zylet:In a 42-day safety study comparing Zylet to placebo, ocular adverse reactions included injection (approximately 20%) and superficial punctate keratitis (approximately 15%). Increased intraocular pressure was reported in 10% (Zylet) and 4% (placebo) of subjects. Nine percent (9%) of Zylet subjects reported burning and stinging upon instillation.Ocular reactions reported with an incidence less than 4% include vision disorders, discharge, itching, lacrimation disorder, photophobia, corneal deposits, ocular discomfort, eyelid disorder, and other unspecified eye disorders.The incidence of non-ocular reactions reported in approximately 14% of subjects was headache; all other non-ocular reactions had an incidence of less than 5%.Loteprednol etabonate ophthalmic suspension 0.2% - 0.5%:Reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with infrequent optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, delayed wound healing and secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.

In a summation of controlled, randomized studies of individuals treated for 28 days or longer with loteprednol etabonate, the incidence of significant elevation of intraocular pressure (≥10 mm Hg) was 2% (15/901) among patients receiving loteprednol etabonate, 7% (11/164) among patients receiving 1% prednisolone acetate and 0.5% (3/583) among patients receiving placebo.Tobramycin ophthalmic solution 0.3%:The most frequent adverse reactions to topical tobramycin are hypersensitivity and localized ocular toxicity, including lid itching and swelling and conjunctival erythema. These reactions occur in less than 4% of patients. Similar reactions may occur with the topical use of other aminoglycoside antibiotics. Secondary Infection:The development of secondary infection has occurred after use of combinations containing steroids and antimicrobials. Fungal infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroids.The possibility of fungal invasion must be considered in any persistent corneal ulceration where steroid treatment has been used.Secondary bacterial ocular infection following suppression of host responses also occurs.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic effects: Loteprednol etabonate has been shown to be embryotoxic (delayed ossification) and teratogenic (increased incidence of meningocele, abnormal left common carotid artery, and limb fixtures) when administered orally to rabbits during organogenesis at a dose of 3 mg/kg/day (35 times the maximum daily clinical dose), a dose which caused no maternal toxicity. The no-observed-effect-level (NOEL) for these effects was 0.5 mg/kg/day (6 times the maximum daily clinical dose). Oral treatment of rats during organogenesis resulted in teratogenicity (absent innominate artery at ≥5 mg/kg/day doses, and cleft palate and umbilical hernia at ≥50 mg/kg/day) and embryotoxicity (increased post-implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with ≥50 mg/kg/day). Treatment of rats at 0.5 mg/kg/day (6 times the maximum daily clinical dose) during organogenesis did not result in any reproductive toxicity. Loteprednol etabonate was maternally toxic (significantly reduced body weight gain during treatment) when administered to pregnant rats during organogenesis at doses of ≥5 mg/kg/day.Oral exposure of female rats to 50 mg/kg/day of loteprednol etabonate from the start of the fetal period through the end of lactation, a maternally toxic treatment regimen (significantly decreased body weight gain), gave rise to decreased growth and survival and retarded development in the offspring during lactation; the NOEL for these effects was 5 mg/kg/day. Loteprednol etabonate had no effect on the duration of gestation or parturition when administered orally to pregnant rats at doses up to 50 mg/kg/day during the fetal period.Reproductive studies have been performed in rats and rabbits with tobramycin at doses up to 100 mg/kg/day parenterally and have revealed no evidence of impaired fertility or harm to the fetus. There are no adequate and well-controlled studies in pregnant women. Zylet should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.8.3 Nursing MothersIt is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemic steroids that appear in human milk could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when Zylet is administered to a nursing woman.8.4 Pediatric UseTwo trials were conducted to evaluate the safety and efficacy of Zylet® (loteprednol etabonate and tobramycin ophthalmic suspension) in pediatric subjects age zero to six years; one was in subjects with lid inflammation and the other was in subjects with blepharoconjunctivitis. In the lid inflammation trial, Zylet with warm compresses did not demonstrate efficacy compared to vehicle with warm compresses. Patients received warm compress lid treatment plus Zylet or vehicle for 14 days. The majority of patients in both treatment groups showed reduced lid inflammation. In the blepharoconjunctivitis trial, Zylet did not demonstrate efficacy compared to vehicle, loteprednol etabonate ophthalmic suspension, or tobramycin ophthalmic solution. There was no difference between treatment groups in mean change from baseline blepharoconjunctivitis score at Day 15.There were no differences in safety assessments between the treatment groups in either trial.

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8.5 Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger patients.

11 DESCRIPTIONZylet (loteprednol etabonate and tobramycin ophthalmic suspension) is a sterile, multiple dose topical anti-inflammatory corticosteroid and anti-infective combination for ophthalmic use. Both loteprednol etabonate and tobramycin are white to off-white powders. The chemical structures of loteprednol etabonate and tobramycin are shown below.

Loteprednol etabonate:

C24H31ClO7 Mol. Wt. 466.96

Chemical name: chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate

Tobramycin:

C18H37N5O9 Mol. Wt. 467.52

Chemical Name:O-3-Amino-3-deoxy-α-D-glucopyranosyl-(1→4)-O-[2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl-(1→6)]-2-deoxystreptamine

Each mL contains: Actives: Loteprednol Etabonate 5 mg (0.5%) and Tobramycin 3 mg (0.3%). Inactives: Edetate Disodium, Glycerin, Povidone, Purified Water, Tyloxapol, and Benzalkonium Chloride 0.01% (preservative). Sulfuric Acid and/or Sodium Hydroxide may be added to adjust the pH to 5.7-5.9. The suspension is essentially isotonic with a tonicity of 260 to 320 mOsm/kg.

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of ActionCorticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. 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 inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid.Arachidonic acid is released from membrane phospholipids by phospholipase A2. Corticosteroids are capable of producing a rise in intraocular pressure.Loteprednol etabonate is structurally similar to other corticosteroids. However, the number 20 position ketone group is absent.The anti-infective component in the combination (tobramycin) is included to provide action against susceptible organisms. In vitro studies have demonstrated that tobramycin is active against susceptible strains of the following microorganisms:Staphylococci, including S. aureus and S. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains.Streptococci, including some of the Group A-beta-hemolytic species, some nonhemolytic species, and some Streptococcus pneumoniae. Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Enterobacter aerogenes, Proteus mirabilis, Morganella morganii, most Proteus vulgaris strains, Haemophilus influenzae and H. aegyptius, Moraxella lacunata, Acinetobacter calcoaceticus and some Neisseria species.12.3 Pharmacokinetics In a controlled clinical study of ocular penetration, the levels of loteprednol etabonate in the aqueous humor were found to be comparable between Lotemax and Zylet treatment groups.

Results from a bioavailability study in normal volunteers established that plasma levels of loteprednol etabonate and Δ1 cortienic acid etabonate (PJ 91), its primary, inactive metabolite, were below the limit of quantitation (1 ng/mL) at all sampling times.The results were obtained following the ocular administration of one drop in each eye of 0.5% loteprednol etabonate ophthalmic suspension 8 times daily for 2 days or 4 times daily for 42 days. This study suggests that limited (<1 ng/mL) systemic absorption occurs with 0.5% loteprednol etabonate.

13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of loteprednol etabonate or tobramycin.Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma TK assay, a chromosome aberration test in human lymphocytes, or in an in vivo mouse micronucleus assay.Oral treatment of male and female rats at 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, (500 and 250 times the maximum clinical dose, respectively) prior to and during mating did not impair fertility in either gender. No impairment of fertility was noted in studies of subcutaneous tobramycin in rats at 100 mg/kg/day (1700 times the maximum daily clinical dose).

16 HOW SUPPLIED/STORAGE AND HANDLINGZylet (loteprednol etabonate and tobramycin ophthalmic suspension) is supplied in a white low density polyethylene plastic bottle with a white controlled drop tip and a white polypropylene cap in the following sizes:5 mL (NDC 24208-358-05) in a 7.5 mL bottle10 mL (NDC 24208-358-10) in a 10 mL bottleUSE ONLY IF IMPRINTED NECKBAND IS INTACT.Storage: Store upright at 15º-25ºC (59º-77ºF). PROTECT FROM FREEZING. SHAKE VIGOROUSLY BEFORE USING.

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 suspension. If pain develops, redness, itching or inflammation becomes aggravated, the patient should be advised to consult a physician. As with all ophthalmic preparations containing benzalkonium chloride, patients should be advised not to wear soft contact lenses when using Zylet.

Bausch + Lomb, a division of Valeant Pharmaceuticals North America LLCBridgewater, NJ 08807 USA© Bausch & Lomb IncorporatedZylet is a trademark of Bausch & Lomb Incorporated or its affiliates.

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