Loteprednol Loteprednol Etabonate Etabonate Technical Technical paper paper | Part | Part III: III: Seasonal Seasonal Allergic

Allergic Conjunctivitis Conjunctivitis | August | August 2010 2010 1

Considerations in the Treatment of Ocular Inflammation: III. Seasonal Allergic Conjunctivitis

Christopher E. Starr, MD, FACS
ABSTRACT Seasonal allergic conjunctivitis is a common cause of ocular discomfort. A type-1 hypersensitivity reaction, it is optimally treated with dual-action antihistamine/mast cell stabilizers, topical corticosteroids, or various non-pharmacologic palliative measures. Treating this self-limited, non-vision-threatening condition with a topical steroid requires weighing steroid efficacy against the potential hazards of steroid use. In this setting, the demonstrated efficacy of ALREX (loteprednol etabonate ophthalmic suspension 0.2%) for the treatment of seasonal allergic conjunctivitis and its safety profile make it an excellent optionand my first choicefor treating seasonal ocular allergy.
Even though I practice in New York City, the treatment of seasonal allergic conjunctivitis is an important part of what I do. Not only can pollen and other allergen counts be surprisingly high in the city, but people who are genetically susceptible to allergy who move to the city (and away from the allergens that gave them trouble in the past) often develop allergies to a different set of antigens in their new location. So even in an urban practice, seasonal allergic conjunctivitis is a very common complaint. Although loss of vision is almost never a consequence of seasonal allergies, allergic conjunctivitis can cause significant ocular and patient discomfort. The symptoms of allergic conjunctivitis (itching, redness) are unpleasant and unsightly and can affect how patients go about their activities of daily living. Seasonal allergy can create a preoccupation with ones eyes, and in some cases can cause emotional distress.1 For patients in contact lenses, allergy season can mean a choice between extreme discomfort or glassesand a surprising number of patients choose discomfort. In severe cases of allergy that cause patients to continually rub their eyes, there is evidence that rubbing may be a factor in the pathogenesis of keratoconus.2

Diagnosis
Seasonal allergic conjunctivitis is typically a clinical diagnosis based on the patients history, symptoms, and clinical findings on slit lamp examination. Of course the clinical hallmark of allergic conjunctivitis is ocular itchingif the patient doesnt report itch-

LOTEPREDNOL ETABONATE FOR THE TREATMENT OF Seasonal ALLERGIC CONJUNCTIVITIS

Two pivotal phase III trials of loteprednol etabonate ophthalmic suspension 0.2% enrolled 133 and 135 patients, respectively.1,2 Designed to evaluate the efficacy and safety of loteprednol etabonate 0.2% in reducing the signs and symptoms of seasonal allergic conjunctivitis, both investigations were randomized, double-masked, placebo-controlled, parallel group, multicenter studies in which patients were given loteprednol etabonate or placebo four times a day in both eyes for 42 days. RESULTSThere were no statistically significant differences between treatment groups with regard to age, sex, race, iris color, or baseline pollen counts in either trial. With regard to safety, loteprednol etabonate and placebo were well tolerated in both trials. In one of the phase III trials, mean intraocular pressure (IOP) at study entry was 14.6 and 14.4 mm Hg for the loteprednol etabonate and placebo treatment groups, respectively. No patient in either treatment group had an IOP increase of 10 mm Hg or greater during the 6 weeks of treatment.1 In the other trial, mean IOP at study entry was 14.9 and

15.7 mm Hg for the loteprednol etabonate and placebo treatment groups, respectively. One patient (of 67) in the loteprednol etabonate group and 1 of 68 in the placebo group had an IOP elevation of 10 mm Hg or greater during the 6 weeks of treatment. Cessation of investigational therapy was sufficient to allow the IOP to decrease.2 CONCLUSION In these two phase III trials, loteprednol etabonate ophthalmic suspension 0.2% had a safety profile similar to that of placebo. SOURCES 1. Dell SJ, Lowry GM, Northcutt JA, et al. A randomized, double-masked, placebo-controlled parallel study of loteprednol etabonate 0.2% in patients with seasonal allergic conjunctivitis. J Allergy Clin Immunol 1998;102:251-5. 2. Shulman DG, Lothringer LL, Rubin JM, et al. A randomized, double-masked, placebo-controlled parallel study of loteprednol etabonate 0.2% in patients with seasonal allergic conjunctivitis. Ophthalmology 1999;Feb;106(2):362-9.

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Loteprednol Etabonate Technical paper | Part III: Seasonal Allergic Conjunctivitis | August 2010

ing, an allergic etiology has to be questioned. Classic symptoms of seasonal allergic conjunctivitis include itching, redness, burning, puffy swollen lids, and discharge. It is sometimes difficult to distinguish between dry eyes, infectious conjunctivitis (particularly viral conjunctivitis), and allergic conjunctivitis, due to overlapping symptoms and findings. While dry eye tends to worsen in winter, its seasonal variability is very different from that of allergy. With respect to viral conjunctivitis, a careful history will often distinguish between it and allergic conjunctivitis. In viral conjunctivitis patients often say that their symptoms started in one eye and then began in the fellow eye a day or two later; they also frequently report having recently had an upper respiratory illness or contact with someone with bacterial conjunctivitis. In allergic conjunctivitis the symptoms typically affect both eyes equally and simultaneously. Sometimes, however, patients with viral conjunctivitis report more or less simultaneous onset and cant remember either an illness or contact with an affected individual. Although the slit lamp examination can often distinguish an allergic from a viral etiology, that isnt always the case. Diffuse conjunctival injection and chemosis, papillae or mixed papillofollicular reactions, whitish mucus-like discharge, epiphora, and photophobia, can be found in either condition. It is rare, however, to encounter a palpable preauricular node or corneal findings such as subepithelial infiltrates, conjunctival membranes, or pseudomembranes in allergic conjunctivitisthese findings are more common in viral conjunctivitis. If I am uncertain, I often use an in-office adenovirus detection device (Adeno Detector; RPS Products) to confirm or rule out a viral etiology.

ing and redness characteristic of seasonal ocular allergy. Their mast cell stabilizing effects may reduce the volume of mediators released at the next antigen exposure. Mast cell stabilization is essentially prophylaxis, and pure mast cell stabilizers do nothing to treat current symptoms. As a class, the dual-action agents are believed to be quite safe, so one can be comfortable using them for their prophylactic effect in advance of allergy season.3,4

Allergy and Inflammation: The Role of Steroids

As we have learned more about the pathogenesis of common eye conditions, we have come to realize the degree to which inflammation is involved in symptom formation. Allergic conjunctivitis, for example, is a type I hypersensitivity reaction. That is, it is a reaction in which antigen-specific immunoglobulin E (IgE) generates an immune response. In allergic conjunctivitis, IgE binds to mast cells in the conjunctiva, triggering their degranulation which, in turn, releases intracellularly stored mediators including histamine, tryptase, chymase, heparin, chondroitin sulfate, prostaglandins, thromboxanes, and leukotrienes.5 Release of these inflammatory mediators together with multiple chemotactic factors results in increased vascular permeability and the attraction and migration of eosinophils and neutrophils. Thus, in seasonal allergic conjunctivitis, as in many other common ocular surface conditions, inflammation plays a very significant role in pathogenesis and symptom formation; and antiinflammatory drugs can play a role in managing the condition. Corticosteroids, the gold standard for inflammation control, work by preventing the formation of arachidonic acid, effectively blocking both the cyclooxygenase and lipoxygenase pathways.6 In addition, corticosteroids suppress inflammatory cell migration and fibroblast function, reduce capillary permeability, and stabilize lysosomes.7 Nonsteroidal antiinflammatory drugs (NSAIDs) can inhibit part of the inflammatory cascade, but they act only on the cyclooxygenase pathway.7 For this reason, NSAIDS are limited in the treatment of allergic conjunctivitis.

Treating Seasonal Allergic Conjunctivitis

I prescribe a topical steroid or a topical dual-action antihistamine/mast cell stabilizer for virtually every seasonal allergy patient I see. These agents provide rapid blockade of histamine receptors to stop the histamine-mediated reaction that produces the itch-

Double-masked, Placebo-controlled STUDY OF Loteprednol Etabonate for Seasonal Allergic Conjunctivitis

This randomized, double-masked, placebo-controlled, parallel-group study compared loteprednol etabonate 0.2% with placebo (vehicle) to determine the drugs safety and efficacy for reducing the signs and symptoms of seasonal allergic conjunctivitis. One hundred thirty-five patients with signs and symptoms of seasonal allergic conjunctivitis participated in the study for a total of 6 weeks. Patients received loteprednol etabonate 0.2% or vehicle four times a day in both eyes for 42 days. The primary outcome measures were bulbar conjunctival injection and itching over the first 2 weeks of treatment. ResultsThe data showed no statistically significant differences between treatment groups with regard to age, sex, race, iris color, or baseline pollen counts. Both treatment groups showed improvement in bulbar conjunctival injection. On a three-point scale used to evaluate severity (with 0 = none and 3 = severe), the mean score for both groups at enrollment was 2.2. At the 2-week evaluation, the loteprednol etabonate-treated group showed a reduction in severity of 1.5 units versus 1.0 units for the placebotreated group.

Both groups also showed improvement in itching. A fourpoint scale was used to evaluate severity (with 0 = none and 4 = severe); all patients had a +4 score at enrollment. At the 2-week evaluation, the loteprednol etabonate-treated group showed a reduction in itching of 3.4 units versus 3.0 units for the placebo-treated group. In addition, the loteprednol etabonate-treated group showed statistically significant improvement when compared to placebo with regard to palpebral conjunctival injection, discomfort, erythema, and epiphora at the 2-week evaluation. No serious or unexpected adverse events were reported in either treatment group. conclusion Loteprednol etabonate 0.2% was found to provide clinically and statistically significant improvement in signs and symptoms of seasonal allergic conjunctivitis. Its safety profile was comparable to that of placebo. source Shulman DG, Lothringer LL, Rubin JM, et al. Randomized, double-masked, placebo-controlled parallel study of loteprednol etabonate 0.2% in patients with seasonal allergic conjunctivitis. Ophthalmology 1999;Feb;106(2):362-9.

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Loteprednol Etabonate Technical paper | Part III: Seasonal Allergic Conjunctivitis | August 2010

Steroid Selection and Usage

When a steroid is to be used, the quesPalliative Measures tion becomes: which steroid is most approPatients with itching eyes feel an urgent need to rub their eyes to alleviate priate? For seasonal allergic conjunctivitis the itch. Rubbing, however, is counterproductive, as it can cause mast cell deand other forms of allergic conjunctivitis granulation, which releases histamine and stimulates further itching. If patients that may require treatment, I use lotepredneed something to provide immediate relief, they can try cool compresses or chilled artificial tears. nol etabonate ophthalmic suspension 0.5% Isolation from offending antigens also can be very helpful in reducing sympor 0.2% exclusively. In repeated studies, toms. With seasonal allergies triggered by environmental antigens, it is often and in my clinical experience, loteprednol fairly easy to identify the offending substance. Unfortunately, its much more etabonate has demonstrated both the podifficult to avoid ubiquitous outdoor antigens like pollen. Sometimes, however, tency to quell inflammation and a safety simple measures, like wearing a hat outdoors to keep the pollen out of ones profile that enables me to recommend its hair or sleeping in an air conditioned room may help. Referral to an allergist use in conditions, such as seasonal allermay provide the patient with additional solutions. gic conjunctivitis, that are not inherently vision-threatening.8,9 My steroid of choice for treating seasonal allergic conjunctiSafety Issues vitis is ALREX (loteprednol etabonate ophthalmic suspension The dangers in topical steroid use are well known: intraocular 0.2%; Bausch + Lomb). For more severe cases, I may use the more pressure (IOP) rise, cataract formation, infection, and unwanted concentrated loteprednol etabonate formulation, LOTEMAX wound healing effects. In treating seasonal ocular allergy, the primary (loteprednol etabonate ophthalmic suspension 0.5%). safety concerns involve IOP spikes and cataract formation. These dangers exist with all steroids, and I discuss them with my patients. Important Risk Information for ALREX However, the safety of topical loteprednol etabonate ophthalmic ALREX is contraindicated in most viral diseases of the corsuspension (in both 0.2% and 0.5% concentrations) has been repeatnea and conjunctiva including epithelial herpes simplex keratitis edly studied, and even when the higher concentration was used in (dendritic keratitis), vaccinia, and varicella, and also in mycoknown steroid responders, the data show significantly less IOP elevabacterial infection of the eye and fungal diseases of the ocular tion with loteprednol etabonate than with prednisolone acetate.10,11 structures. ALREX is also contraindicated in individuals with In fact, a retrospective study of 30 post-corneal transplant patients known or suspected hypersensitivity to any of the ingredients of found that switching known steroid responders from prednisolone this preparation and to other corticosteroids. acetate 1.0% to loteprednol etabonate 0.5% was successful in reducProlonged use of ALREX is associated with several warnings ing IOP. Even when used in non-steroid responders, the incidence and precautions, including glaucoma with optic nerve damage, of significant elevation of IOP was 2% (15/901) among patients redefects in visual acuity, cataract formation, secondary ocular inceiving loteprednol etabonate, 7% (11/164) among patients receiving fections, exacerbation or prolongation of viral ocular infections prednisolone acetate 1.0%, and .5% (3/583) among patients receiving (including herpes simplex), delay in wound healing and increase placebo (from a summation of controlled, randomized studies of inin bleb formation. dividuals treated for 28 days or longer with loteprednol etabonate). If this product is used for 10 days or longer, intraocular presWith respect to ALREX (loteprednol etabonate ophthalmic sure should be monitored. The initial prescription and renewal suspension 0.2%), the safety data is impressive. For example, in of the medication order beyond 14 days should be made by a two multicenter clinical trials that were submitted to the FDA, physician only after examination of the patient with the aid of there was no difference regarding number of patients with IOP magnification. Fungal infections of the cornea may develop with rise of 10 mm Hg or greater between ALREX and placebo when prolonged use of corticosteroids. used QID for 42 days.8,9 Despite its safety profile, I still counsel Ocular adverse reactions occurring in 515% of patients treated patients about the risks and regularly monitor any patient who with loteprednol etabonate ophthalmic suspension (0.2%0.5%) is on a loteprednol etabonate drop for more than a few weeks. in clinical studies included abnormal vision/blurring, burning on instillation, chemosis, discharge, dry eyes, epiphora, foreign body Conclusion sensation, itching, injection, and photophobia. In both clinical studies and in my practice ALREX has been an effective antiinflammatory for the treatment of seasonal allergic A Regimen for the Treatment of Seasonal Allergic conjunctivitis. Its safety profile has been demonstrated in multiple Conjunctivitis studies, and I personally have never had a loteprednol etabonateWhen patients present with active symptoms of seasonal related adverse reaction in any of my patients. I feel very comfortallergic conjunctivitis, I will typically prescribe a dual-action able using it with the proper patient education and surveillance. And antihistamine/mast cell stabilizer and a steroid, typically ALREX. my patients appreciate the reduction in symptoms that it brings. I may suggest an oral antihistamine as well, if the patient has significant nasal symptoms. Finally, I talk about palliative measures Christopher E. Starr, MD FACS, is director of the residency prothe patient can take. gram in ophthalmology, director of refractive surgery, director of I have the patient continue on the topical antihistamine/mast cell the fellowship program in cornea, cataract, and refractive surgery, stabilizer for as long as it takes for symptoms to resolve and allergy and assistant professor of ophthalmology, Weill Cornell Medical season to pass. I use the steroid in pulse fashion to treat flare-ups Center, New York-Presbyterian Hospital, New York, NY. typically I prescribe it for 7 to 10 days or until the symptoms subside.

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highly lipid soluble which enhances its penetration into cells. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism to inactive carboxylic acid metabolites. Results from a bioavailability study in normal volunteers established that plasma levels of loteprednol etabonate and 1 cortienic acid

Loteprednol Etabonate Technical paper |

etabonate (PJ 91), its primary, inactive/metabolite, below the limit of quantitation (1 ng/mL) at all sampling times. The results were AW #: 9005502-9007902 SPEC: L-3002 L-3102 were COLORS: Black APPROVALS / DATE: obtained following the ocular administration of one drop in each eye of 0.5% loteprednol etabonate 8 times daily for 2 days or 4 times daily 42 days. This study suggests that limited (<1 ng/mL) systemic absorption occurs with ALREX. DESCRIPTION: USfor Alrex Part III: Seasonal Allergic Conjunctivitis | GPE: August 2010 ___________________________________ SPECIAL INSTRUCTIONS: Clinical Studies: DIELINES DOES NOT PRINT PRINT PER SPECIFICATION ALREX provided reduction in bulbar conjunctival injection and itching, beginning approximately 2 hours after instillation of the first dose

RA: ____________________________________ SCANNER BAR LOCATION: NA In two double-masked, placebo-controlled six-week environmental studies of 268 patients with seasonal allergic conjunctivitis, ALREX, dosed MUST four times per VERIFIED day was superior to placebo in AND the treatment of the signs and symptoms of seasonal allergic conjunctivitis. MKT/SALES: _____________________________ PRINTED BARwhen CODES BE READABLE ACCURATE

ALREX 9. Dell SJ, Lowry GM, Northcutt JA, et al. A randomized, double-masked, plaOphthalmic Suspension is indicated for the temporary relief of the signs and symptoms of seasonal allergic conjunctivitis. 1. Postolache TT, Lapidus M, Sander ER, et al. Changes in allergy symptoms and AW #: 9005502-9007902 SPEC: L-3002 / L-3102 COLORS: Black APPROVALS / DATE: cebo-controlled parallel study of loteprednol etabonate 0.2% in patients with depression scores are positively correlated in patients with recurrent mood CONTRAINDICATIONS: DESCRIPTION: US Alrex disorders exposed to seasonal peaks in aeroallergens. seasonal allergic conjunctivitis. Allergy Clin 1998;102:251-5. c World Journal ALREX, as with other ophthalmic corticosteroids, isJ contraindicated in Immunol most viral diseases of the cornea and conjunctiva including GPE:Scienti ________________________________________ epithelial 10. Holland EJ, Djalilian AR, Sanderson JP. Attenuation of ocular hypertension SPECIAL INSTRUCTIONS: DIELINES DOES NOT PRINT PRINT PER SPECIFICATION herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial infection of the eye and fungal 2007 Dec 17;7:1968-77. RA: _________________________________________ diseases of ocular structures. ALREX is also contraindicated in individuals with known or suspected hypersensitivity to any with the use of topical loteprednol etabonate 0.5% in steroid responders aft er of the ingredients SCANNER BAR LOCATION: NA2. McMonnies CW. Abnormal rubbing and keratectasia. Eye Contact Lens 2007 of thiscorneal transplantation. preparation and to other corticosteroids. Cornea 2009 Dec;28(10):1139-43. MKT/SALES: __________________________________ PRINTED BAR CODES MUST BE VERIFIED READABLE AND ACCURATE Nov;33(6 Pt 1):265-71. 11. Bartlett JD, Horwitz B, Laibovitz, et al. Intraocular pressure response to lotepreWARNINGS: 3. Abelson MB. A review of olopatadine for the treatment of ocular allergy. Expert G.LEGAL: _____________________________________ BY VENDOR TO THE HUMAN READABLE INDICATED ON ARTWORK. Prolonged use of corticosteroids may result in glaucoma with damage to optic nerve, defects 1993;9:157-65. in visual acuity and fields of vision, and dnol etabonate in known steroid responders. J the Ocul Pharmacol Opin Pharmacother . 2004 Sep;5(9):1979-94. BAUSCH & LOMB, 8500 HIDDEN RIVER PARKWAY, TAMPA, FL 33637 posterior subcapsular cataract formation. Steroids should be used with caution in the presence of glaucoma. in 12. Ilyas H, Slonim C, Braswell GR, et al. Long-term safety of loteprednol etabonate AW #: 9005502-9007902 SPEC: L-3002 / L-3102 COLORS: Black 4. Pradhan S, Abhishek K, Mah F. Epinastine: topical ophthalmic second generaAPPROVALS / DATE: 813-866-2485 FAX: 813-866-2525 Eyeocular infections. DESCRIPTION: US0.2% in the treatment of seasonal and perennial allergic conjunctivitis. Alrex Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary tion antihistamine without signifi cant systemic side eff ects. Expert Opin Drug GPE: ____________________________________ Contact Lens 2004;30:10-13. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. In acute Metab Toxicol 2009 Sep;5(9):1135-40. SPECIAL INSTRUCTIONS: DIELINES DOES NOT PRINT PRINT PER SPECIFICATION purulent conditions of the eye, steroids may mask infection or enhance existing infection. RA: ____________________________________ 5. Abelson MB, Smith L, Chapin M. Ocular Allergic Disease: Mechanisms, Disease SCANNER BAR LOCATION: NA Sub-types, Treatment. Ocul Surf. 2003;1(3):127-49. MKT/SALES: _____________________________ Use of ocular MUST steroids may the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). PRINTED BAR CODES BEprolong VERIFIED READABLE AND ACCURATE Please see the brief summary below regarding contraindications, warnEmployment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. 6. van der Velden VH. Glucocorticoids: mechanisms of action and anti-infl amG.LEGAL: ________________________________ BY VENDOR TO THE HUMAN READABLE INDICATED ON ARTWORK. ings, precautions, and adverse reactions. Carcinogenesis, mutagenesis, impairment of fertility: Long-term animal studies have not been conducted to evaluate the carcinogenic matory potential in asthma. Mediators In amm 1998;7(4):229-37. PRECAUTIONS: BAUSCH & LOMB, 8500 HIDDEN RIVERLoteprednol PARKWAY, TAMPA, FLwas 33637 potential of loteprednol etabonate. etabonate not genotoxic in vitro in the Ames test, the mouse lymphoma tk assay, 7. Sendrowski DP, Jaanus SD. Anti-infl ammatory Drugs, in Bartlett JD, Jaanus General: For ophthalmic use The initial prescription and renewal of the medication order beyond 14 days should be made by a 813-866-2485 only. FAX: or in a chromosome aberration test813-866-2525 in human lymphocytes, or in vivo in the single dose mouse micronucleus assay. Treatment of male physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, SD, eds: Clinical Ocular Pharmacology 2008[5th edition], pp 221-45. and female rats with up to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, (1500 and 750 times the maximum ALREX is a registered trademark of Bausch + Lomb Incorporated. fluorescein staining. 8. Shulman DG, Lothringer LL, Rubin JM, et al. A randomized, double-masked, clinical dose, respectively) prior to and during mating did not impair fertility in either gender. 1690 1690 2010 Bausch + Lomb Incorporated. placebo-controlled parallel study of loteprednol etabonate 0.2% in patients If signs and symptoms fail to improve after two days, the patient should be re-evaluated.
Pregnancy: Teratogenic effects: Pregnancy Category C. Loteprednol etabonate has been shown to be embryotoxic (delayed ossification) andisteratogenic (increased incidence of meningocele, left common carotid artery, and limb flexures) when If this product used for 10 days or longer, intraocular pressure shouldabnormal be monitored. administered orally to rabbits during organogenesis at a dose of 3 mg/kg/day (85 times the maximum daily clinical dose), a dose which caused no maternal toxicity. The no-observed-effect-level (NOEL) for these local effects was application. 0.5 mg/kg/day (15 times Fungal infections of the cornea are particularly prone to develop coincidentally with long-term steroid Fungus invasion the daily dose). corneal Oral treatment of ratsa during organogenesis resulted teratogenicity (absent innominate mustmaximum be considered in clinical any persistent ulceration where steroid has been used or is in use.in Fungal cultures should be taken when artery at 5 mg/kg/day doses, and cleft palate and umbilical hernia at 50 mg/kg/day) and embryotoxicity (increased postappropriate. implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with 50 mg/kg/day). Treatment of rats with 0.5 mg/kg/day (15 times the maximum dose) during organogenesis did notnot result in any reproductive toxicity. Loteprednol Information for Patients: This product is sterile clinical when packaged. Patients should be advised to allow the dropper tip to touch any surface, reduced body becomes weight gain during treatment) administered pregnant rats during etabonate maternally toxic (significantly as this maywas contaminate the suspension. If redness or itching aggravated, the patientwhen should be advised toto consult a physician. organogenesis at doses of 5 mg/kg/day. Patients should be advised not to wear a contact lens if their eye is red. ALREX should not be used to treat contact lens related irritation. Oral exposure of female rats to 50 mg/kg/day of loteprednol etabonate the start of the Patients fetal period the end of lenses lactation, a The preservative in ALREX, benzalkonium chloride, may be absorbed by from soft contact lenses. whothrough wear soft contact and maternally toxic regimen body gain), rise to decreased and their survival, and retarded whose eyes are treatment not red, should be (significantly instructed to decreased wait at least tenweight minutes aftergave instilling ALREX before growth they insert contact lenses. 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 have at doses up to conducted 50 mg/kg/day duringthe thecarcinogenic fetal period. Carcinogenesis, mutagenesis, impairment of fertility: Long-term animal studies not been to evaluate potential of loteprednol etabonate. Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma tk assay, There no adequate and welltest controlled studies in pregnant women. Ophthalmic Suspension should be used during pregnancy or in aare chromosome aberration in human lymphocytes, or in vivo inALREX the single dose mouse micronucleus assay. Treatment of male only if the potential justifies the potential risk to the fetus. and female rats withbenefit up to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, (1500 and 750 times the maximum clinical dose, respectively) prior to and during mating did not impair fertility in either gender. Nursing Mothers: It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemic steroids appear in human milk has and could growth, interfere with endogenous Pregnancy: Teratogenic effects: Pregnancy Category C. Loteprednol etabonate been suppress shown to be embryotoxic (delayed oscorticosteroid production, or cause other incidence untoward effects. Caution should be exercised when ALREX is administered a nursing woman. sification) and teratogenic (increased of meningocele, abnormal left common carotid artery, and to limb flexures) when administered orally to rabbits during organogenesis at a dose of 3 mg/kg/day (85 times the maximum daily clinical dose), Pediatric Use: Safety in pediatric patients have not been established. a dose which causedand no effectiveness maternal toxicity. The no-observed-effect-level (NOEL) for these effects was 0.5 mg/kg/day (15 times the maximum daily clinical dose). Oral treatment of rats during organogenesis resulted in teratogenicity (absent innominate ADVERSE artery at REACTIONS: 5 mg/kg/day doses, and cleft palate and umbilical hernia at 50 mg/kg/day) and embryotoxicity (increased postReactions associated includefetal elevated which maywith be associated with optic nerve damage, implantation losses atwith 100 ophthalmic mg/kg/daysteroids and decreased bodyintraocular weight andpressure, skeletal ossification 50 mg/kg/day). Treatment of rats visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes with 0.5 mg/kg/day (15 times the maximum clinical dose) during organogenesis did not result in any reproductive toxicity. Loteprednol simplex, and perforation oftoxic the globe where there is thinning of thegain cornea or sclera. reduced body weight during treatment) when administered to pregnant rats during etabonate was maternally (significantly organogenesis at doses of 5 mg/kg/day. Ocular adverse reactions occurring in 5-15% of patients treated with loteprednol etabonate ophthalmic suspension (0.2% - 0.5%) in clinical studies included vision/blurring, burning on instillation, chemosis, discharge, eyes, epiphora, foreign body sensation, itching, Oral exposure of abnormal female rats to 50 mg/kg/day of loteprednol etabonate from the startdry of the fetal period through the end of lactation, a injection, and photophobia. ocular adverse reactions occurring in lessgain), than 5% of rise patients include conjunctivitis, corneal abnormalities, maternally toxic treatment Other regimen (significantly decreased body weight gave to decreased growth and survival, and retarded eyelid erythema, keratoconjunctivitis, irritation/pain/discomfort, papillae, and uveitis. Some of these events were to the development in the offspring during ocular lactation; the NOEL for these effects was 5 mg/kg/day. Loteprednol etabonate had similar no effect on underlying ocular disease being studied. when administered orally to pregnant rats at doses up to 50 mg/kg/day during the fetal period. the duration of gestation or parturition

References

BY VENDOR and TOthroughout THE HUMAN READABLE INDICATED ON ARTWORK. the first 14 days of treatment.

G.LEGAL: ________________________________ BAUSCH &with seasonal allergic conjunctivitis. LOMB, 8500 HIDDEN RIVER PARKWAY, TAMPA, FLOphthalmology 33637 1999;106:362-9. INDICATIONS AND USAGE: FAX: 813-866-2525 813-866-2485

STERILE OPHTHALMIC SUSPENSION

Rx only DESCRIPTION: ALREX (loteprednol etabonate ophthalmic suspension) contains a sterile, topical anti-inflammatory corticosteroid for ophthalmic use. Loteprednol etabonate is a white to off-white powder. Loteprednol etabonate is represented by the following structural formula:
HO OCH2Cl C=O OCO2C2H5

C24H31ClO7

Mol. Wt. 466.96

Chemical Name: chloromethyl 17-[(ethoxycarbonyl)oxy]-11-hydroxy-3-oxoandrosta-1,4-diene-17-carboxylate Each mL contains: ACTIVE: Loteprednol Etabonate 2 mg (0.2%); INACTIVES: Edetate Disodium, Glycerin, Povidone, Purified Water and Tyloxapol. Hydrochloric Acid and/or Sodium Hydroxide may be added to adjust the pH to 5.4-5.5. The suspension is essentially isotonic with a tonicity of 250 to 310 mOsmol/kg. PRESERVATIVE ADDED: Benzalkonium Chloride 0.01%. CLINICAL PHARMACOLOGY: Corticosteroids 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. It is highly lipid soluble which enhances its penetration into cells. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism to inactive carboxylic acid metabolites. Results from a bioavailability study in normal volunteers established that plasma levels of loteprednol etabonate and 1 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 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 ALREX. Clinical Studies: In two double-masked, placebo-controlled six-week environmental studies of 268 patients with seasonal allergic conjunctivitis, ALREX, when dosed four times per day was superior to placebo in the treatment of the signs and symptoms of seasonal allergic conjunctivitis. ALREX provided reduction in bulbar conjunctival injection and itching, beginning approximately 2 hours after instillation of the first dose and throughout the first 14 days of treatment. INDICATIONS AND USAGE: ALREX Ophthalmic Suspension is indicated for the temporary relief of the signs and symptoms of seasonal allergic conjunctivitis. CONTRAINDICATIONS: ALREX, 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. ALREX is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and to other corticosteroids. WARNINGS: Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and in posterior subcapsular cataract formation. Steroids should be used with caution in the presence of glaucoma. Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. PRECAUTIONS: General: For ophthalmic use only. The initial prescription and renewal of the medication order beyond 14 days should be made by a physician only after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. If signs and symptoms fail to improve after two days, the patient should be re-evaluated. If this product is used for 10 days or longer, intraocular pressure should be monitored. 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 cultures should be taken when appropriate.

Non-ocular adverse reactions occurred in less than in 15% of patients. These include headache, rhinitis and pharyngitis. There are no adequate and well controlled studies pregnant women. ALREX Ophthalmic Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In a summation of controlled, randomized studies of individuals treated for 28 days or longer with loteprednol etabonate, the incidence Nursing Mothers: It is not known whether topical ( ophthalmic administration of corticosteroids could result in sufficient systemic absorption7% to of significant elevation of intraocular pressure 10 mm Hg) was 2% (15/901) among patients receiving loteprednol etabonate, produce detectable quantities in human Systemic acetate steroids and appear in human milk and could suppress growth, interfere with endogenous (11/164) among patients receiving 1%milk. prednisolone 0.5% (3/583) among patients receiving placebo. Among the smaller corticosteroid production, or cause other untoward Cautionof should be exercised when ALREX in is administered toHg) a nursing woman. group of patients who were studied with ALREX, effects. the incidence clinically significant increases IOP (10 mm was 1% (1/133) with ALREX and 1% (1/135) with placebo. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. DOSAGE AND ADMINISTRATION: ADVERSE REACTIONS: SHAKE VIGOROUSLY BEFORE USING. Reactions associated with steroids include One drop instilled into theophthalmic affected eye(s) four times elevated daily. intraocular pressure, which may be associated with optic nerve damage, visual acuity and field 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. HOW SUPPLIED: ALREX (loteprednol etabonate ophthalmic suspension, 0.2%) is supplied in a plastic bottle with a controlled drop tip in the following Ocular adverse reactions occurring in 5-15% of patients treated with loteprednol etabonate ophthalmic suspension (0.2% - 0.5%) in clinical sizes: studies included abnormal vision/blurring, 5 mL (NDC 24208-353-05) - AB35307 burning on instillation, chemosis, discharge, dry eyes, epiphora, foreign body sensation, itching, injection, and 24208-353-10) photophobia. Other ocular adverse reactions occurring in less than 5% of patients include conjunctivitis, corneal abnormalities, 10 mL (NDC - AB35309 eyelid erythema, keratoconjunctivitis, ocular irritation/pain/discomfort, papillae, and uveitis. Some of these events were similar to the underlying ocular disease being studied. DO NOT USE IF NECKBAND IMPRINTED WITH "Protective Seal" AND YELLOW IS NOT INTACT. Non-ocular adverse reactions occurred in less than 15% of patients. These include headache, rhinitis and pharyngitis.
In a summation of controlled, randomized of individuals treated for 28 days or longer with loteprednol etabonate, the incidence Storage: Store upright between 1525C studies (5977F). DO NOT FREEZE. of significant elevation of intraocular pressure (10 mm Hg) was 2% (15/901) among patients receiving loteprednol etabonate, 7% (11/164) patients receiving 1% prednisolone acetate and 0.5% (3/583) among patients receiving placebo. Among the smaller KEEP OUT among OF REACH OF CHILDREN. group of patients who were studied with ALREX, the incidence of clinically significant increases in IOP (10 mm Hg) was 1% (1/133) with ALREX and 1% (1/135) with placebo. Revised August 2008. DOSAGE AND ADMINISTRATION: SHAKE VIGOROUSLY BEFORE USING. One drop instilled into the affected eye(s) four times daily. HOW SUPPLIED: ALREX (loteprednol etabonate ophthalmic suspension, 0.2%) is supplied in a plastic bottle with a controlled drop tip in the following sizes: 5 mL (NDC 24208-353-05) - AB35307 10 mL (NDC 24208-353-10) - AB35309 DO NOT USE IF NECKBAND IMPRINTED WITH "Protective Seal" AND YELLOW Storage: Store upright between 1525C (5977F). DO NOT FREEZE. KEEP OUT OF REACH OF CHILDREN. Revised August 2008. IS NOT INTACT.

Bausch & Lomb Incorporated, Tampa, Florida 33637

U.S. Patent No. 4,996,335 U.S. Patent No. 5,540,930 U.S. Patent No. 5,747,061 Bausch & Lomb Incorporated Alrex is a registered trademark of Bausch & Lomb Incorporated

9007902 (Folded) 9005502 (Flat)

Sponsored by Bausch + Lomb

PH2907, Rev. 6/10

Information for Patients: 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 redness or itching becomes aggravated, the patient should be advised to consult a physician. Patients should be advised not to wear a contact lens if their eye is red. ALREX should not be used to treat contact lens related irritation.