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 option—and my first choice—for 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 one’s 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 glasses—and 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 patient’s history, symptoms, and clinical findings on slit lamp examination. Of course the clinical hallmark of allergic conjunctivitis is ocular itching—if the patient doesn’t 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. RESULTS There 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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source  Shulman DG. the dual-action agents are believed to be quite safe. and antiinflammatory drugs can play a role in managing the condition. and pure mast cell stabilizers do nothing to treat current symptoms. is a type I hypersensitivity reaction. Classic symptoms of seasonal allergic conjunctivitis include itching.4 units versus 3. These agents provide rapid blockade of histamine receptors to stop the histamine-mediated reaction that produces the itch- Double-masked. we have come to realize the degree to which inflammation is involved in symptom formation. At the 2-week evaluation. so one can be comfortable using them for their prophylactic effect in advance of allergy season. NSAIDS are limited in the treatment of allergic conjunctivitis. At the 2-week evaluation. Thus. can be found in either condition. reduce capillary permeability.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. No serious or unexpected adverse events were reported in either treatment group. the mean score for both groups at enrollment was 2. releases intracellularly stored mediators including histamine. tryptase. chymase.2% in patients with seasonal allergic conjunctivitis. due to overlapping symptoms and findings. conclusion  Loteprednol etabonate 0.106(2):362-9. placebo-controlled.7 For this reason. in turn. Sometimes. or baseline pollen counts.7 Nonsteroidal antiinflammatory drugs (NSAIDs) can inhibit part of the inflammatory cascade.Feb. inflammation plays a very significant role in pathogenesis and symptom formation. One hundred thirty-five patients with signs and symptoms of seasonal allergic conjunctivitis participated in the study for a total of 6 weeks. however. Sponsored by Bausch + Lomb . double-masked. Lothringer LL. Patients received loteprednol etabonate 0. It is rare. In allergic conjunctivitis. erythema. effectively blocking both the cyclooxygenase and lipoxygenase pathways. A fourpoint scale was used to evaluate severity (with 0 = none and 4 = severe). iris color. Results The data showed no statistically significant differences between treatment groups with regard to age.6 In addition. in seasonal allergic conjunctivitis.5 units versus 1. As a class. prostaglandins. it is a reaction in which antigen-specific immunoglobulin E (IgE) generates an immune response.0 units for the placebo-treated group. epiphora. and allergic conjunctivitis.4 Allergy and Inflammation: The Role of Steroids As we have learned more about the pathogenesis of common eye conditions.0 units for the placebotreated group. The primary outcome measures were bulbar conjunctival injection and itching over the first 2 weeks of treatment.2% was found to provide clinically and statistically significant improvement in signs and symptoms of seasonal allergic conjunctivitis. and discharge. whitish mucus-like discharge. as in many other common ocular surface conditions. Ophthalmology 1999. chondroitin sulfate. Both treatment groups showed improvement in bulbar conjunctival injection. Diffuse conjunctival injection and chemosis. but they act only on the cyclooxygenase pathway. and photophobia. 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.2% or vehicle four times a day in both eyes for 42 days. race. Corticosteroids. a careful history will often distinguish between it and allergic conjunctivitis. the loteprednol etabonate-treated group showed a reduction in itching of 3. patients with viral conjunctivitis report more or less simultaneous onset and can’t remember either an illness or contact with an affected individual. and stabilize lysosomes.2 Loteprednol Etabonate Technical paper  |  Part III: Seasonal Allergic Conjunctivitis  |  August 2010 ing. In addition. the loteprednol etabonate-treated group showed a reduction in severity of 1. If I am uncertain. While dry eye tends to worsen in winter. for example. corticosteroids suppress inflammatory cell migration and fibroblast function. Placebo-controlled STUDY OF Loteprednol Etabonate for Seasonal Allergic Conjunctivitis This randomized. It is sometimes difficult to distinguish between dry eyes. placebo-controlled parallel study of loteprednol etabonate 0. Both groups also showed improvement in itching. Allergic conjunctivitis. and epiphora at the 2-week evaluation. double-masked. Although the slit lamp examination can often distinguish an allergic from a viral etiology.3. however. parallel-group study compared loteprednol etabonate 0. thromboxanes. they also frequently report having recently had an upper respiratory illness or contact with someone with bacterial conjunctivitis. to encounter a palpable preauricular node or corneal findings such as subepithelial infiltrates. burning. the gold standard for inflammation control. With respect to viral conjunctivitis. I often use an in-office adenovirus detection device (Adeno Detector™.2% with placebo (vehicle) to determine the drug’s safety and efficacy for reducing the signs and symptoms of seasonal allergic conjunctivitis. On a three-point scale used to evaluate severity (with 0 = none and 3 = severe). an allergic etiology has to be questioned. triggering their degranulation which. That is. the loteprednol etabonate-treated group showed statistically significant improvement when compared to placebo with regard to palpebral conjunctival injection. work by preventing the formation of arachidonic acid. RPS Products) to confirm or rule out a viral etiology.2. 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. Their mast cell stabilizing effects may reduce the volume of mediators released at the next antigen exposure. all patients had a +4 score at enrollment. ing and redness characteristic of seasonal ocular allergy. and leukotrienes. puffy swollen lids. or pseudomembranes in allergic conjunctivitis—these findings are more common in viral conjunctivitis. redness. Its safety profile was comparable to that of placebo. discomfort. IgE binds to mast cells in the conjunctiva. et al. papillae or mixed papillofollicular reactions. heparin. conjunctival membranes. its seasonal variability is very different from that of allergy. Randomized. In allergic conjunctivitis the symptoms typically affect both eyes equally and simultaneously. Mast cell stabilization is essentially prophylaxis. sex. Rubin JM. that isn’t always the case. infectious conjunctivitis (particularly viral conjunctivitis).

8.0% to loteprednol etabonate 0.2% and 0. The initial prescription and renewal suspension 0. and refractive surgery. cataract. stabilizer for as long as it takes for symptoms to resolve and allergy and assistant professor of ophthalmology. I may suggest an oral antihistamine as well. For more severe cases. if the patient has significant nasal symptoms. epiphora. intraocular presWith respect to ALREX® (loteprednol etabonate ophthalmic sure should be monitored. gic conjunctivitis. I will typically prescribe a dual-action able using it with the proper patient education and surveillance. I feel very comfortallergic conjunctivitis. and also in mycoknown steroid responders. Loteprednol Etabonate Technical paper  |  Part III: Seasonal Allergic Conjunctivitis  |  August 2010 3 Steroid Selection and Usage When a steroid is to be used. NY. Sometimes. ALREX® is also contraindicated in individuals with In fact. and unwanted concentrated loteprednol etabonate formulation. 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. toms.5% concentrations) has been repeatnea and conjunctiva including epithelial herpes simplex keratitis edly studied. discharge. Rubbing. as it can cause mast cell deand other forms of allergic conjunctivitis granulation. exacerbation or prolongation of viral ocular infections prednisolone acetate 1. of significant elevation of IOP was 2% (15/901) among patients redefects in visual acuity. and I personally have never had a loteprednol etabonateWhen patients present with active symptoms of seasonal related adverse reaction in any of my patients. Finally.5% (3/583) among patients receiving (including herpes simplex). such as seasonal allermay provide the patient with additional solutions. Even when used in non-steroid responders. LOTEMAX® wound healing effects. typically I prescribe it for 7 to 10 days or until the symptoms subside. foreign body Conclusion sensation. I use the steroid in pulse fashion to treat flare-ups— Center.10.5% Isolation from offending antigens also can be very helpful in reducing sympor 0. and even when the higher concentration was used in (dendritic keratitis). 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. and I discuss them with my patients. my patients appreciate the reduction in symptoms that it brings. dividuals treated for 28 days or longer with loteprednol etabonate). 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. 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. New York-Presbyterian Hospital. cataract formation.5% was successful in reducProlonged use of ALREX® is associated with several warnings ing IOP. If this product is used for 10 days or longer. typically ALREX®. gram in ophthalmology.0%. secondary ocular inceiving loteprednol etabonate.8. Important Risk Information for ALREX® However. I talk about palliative measures Christopher E. If patients that may require treatment. Sponsored by Bausch + Lomb . it is often and in my clinical experience. burning on instillation. vaccinia. and varicella.11 structures. Weill Cornell Medical season to pass. cataract formation. including glaucoma with optic nerve damage. Unfortunately.5%). I still counsel Ocular adverse reactions occurring in 5–15% of patients treated patients about the risks and regularly monitor any patient who with loteprednol etabonate ophthalmic suspension (0. tency to quell inflammation and a safety simple measures.2%–0. Bausch + Lomb). the primary (loteprednol etabonate ophthalmic suspension 0. For example. Its safety profile has been demonstrated in multiple Conjunctivitis studies. itching. physician only after examination of the patient with the aid of there was no difference regarding number of patients with IOP magnification.5%) is on a loteprednol etabonate drop for more than a few weeks. they can try cool compresses or chilled artificial tears. These dangers exist with all steroids. the safety data is impressive.2%.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. delay in wound healing and increase placebo (from a summation of controlled. it’s much more etabonate has demonstrated both the podifficult to avoid ubiquitous outdoor antigens like pollen. In repeated studies. chemosis. randomized studies of inin bleb formation. used QID for 42 days. nol etabonate ophthalmic suspension 0. injection. in of the medication order beyond 14 days should be made by a two multicenter clinical trials that were submitted to the FDA. MD FACS. safety concerns involve IOP spikes and cataract formation. I use lotepredneed something to provide immediate relief. like wearing a hat outdoors to keep the pollen out of one’s profile that enables me to recommend its hair or sleeping in an air conditioned room may help.9 Despite its safety profile. however. is counterproductive.2% exclusively. director of I have the patient continue on the topical antihistamine/mast cell the fellowship program in cornea. loteprednol fairly easy to identify the offending substance. Referral to an allergist use in conditions. I may use the more pressure (IOP) rise. and photophobia. is director of the residency prothe patient can take. And antihistamine/mast cell stabilizer and a steroid. the incidence and precautions. Starr. infection. Fungal infections of the cornea may develop with rise of 10 mm Hg or greater between ALREX® and placebo when prolonged use of corticosteroids. the safety of topical loteprednol etabonate ophthalmic ALREX® is contraindicated in most viral diseases of the corsuspension (in both 0. In treating seasonal ocular allergy.2%). that are not inherently vision-threatening. which releases histamine and stimulates further itching. With seasonal allergies triggered by environmental antigens. New York. director of refractive surgery. 7% (11/164) among patients receiving fections. acetate 1. dry eyes. in clinical studies included abnormal vision/blurring. however. and .

etabonate not genotoxic in vitro in the Ames test. Systemic steroids appear in human milk has and could growth. FLwas 33637 potential of loteprednol etabonate. steroids may mask infection or enhance existing infection. J the Ocul Pharmacol Opin Pharmacother . FL 33637 posterior subcapsular cataract formation. A randomized. ALREX provided reduction in bulbar conjunctival injection and itching. eds: Clinical Ocular Pharmacology 2008[5th edition]. PRINTED BAR CODES BEprolong VERIFIED READABLE AND ACCURATE Please see the brief summary below regarding contraindications. 10 mL (NDC . respectively) prior to and during mating did not impair fertility in either gender. ings. In acute purulent conditions of the eye.28(10):1139-43.2%) is supplied in a plastic bottle with a controlled drop tip in the following sizes: 5 mL (NDC 24208-353-05) .7(4):229-37. prednisolone 0. Loteprednol Information for Patients: This product is sterile clinical when packaged. loteprednol etabonate undergoes extensive metabolism to inactive carboxylic acid metabolites.5% (3/583) among patients receiving placebo. TAMPA. Expert G. However. ALREX is also contraindicated in individuals with known or suspected hypersensitivity to any with the use of topical loteprednol etabonate 0. 0. keratoconjunctivitis. perforations have been known to occur with the use of topical steroids. 11. development in the offspring during lactation. Lapidus M. Loteprednol simplex.LEGAL: ________________________________ BY VENDOR TO THE HUMAN READABLE INDICATED ON ARTWORK. Arachidonic acid is released from membrane phospholipids by phospholipase A2. 5 mL (NDC 24208-353-05) . Postolache TT.LEGAL: _____________________________________ BY VENDOR TO THE HUMAN READABLE INDICATED ON ARTWORK. Patent No. capillary dilation. which may be associated with optic nerve damage. its primary. respectively) prior to and during mating did not impair fertility in either gender.AB35309 eyelid erythema.5(9):1135-40. Patent No. 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. DO NOT FREEZE. Mediators In amm 1998. when dosed four times per day was superior to placebo in the treatment of the signs and symptoms of seasonal allergic conjunctivitis. administered orally to rabbits during organogenesis at a dose of 3 mg/kg/day (85 times the maximum daily clinical dose). ALREX. Shulman DG.5(9):1979-94. vaccinia. Dell SJ. impairment of fertility: Long-term animal studies not been to evaluate potential of loteprednol etabonate. group of patients who were studied with ALREX. Laibovitz. intraocular pressure shouldabnormal be monitored. the incidence clinically significant increases IOP (≥10 mm was 1% (1/133) with ALREX and 1% (1/135) with placebo. and uveitis. Corticosteroids are capable of producing a rise in intraocular pressure. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. Allergy Clin 1998. is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis). the patient should be re-evaluated. 8. In a summation of controlled. Pediatric Use: Safety and effectiveness in pediatric patients have not been established. Non-ocular adverse reactions occurred in less than in 15% of patients. sification) and teratogenic (increased of meningocele. Pradhan S. Bartlett JD. Loteprednol etabonate is represented by the following structural formula: HO OCH2Cl C=O OCO2C2H5 C24H31ClO7 Mol. Patients should be advised not to wear a contact lens if their eye is red. rhinitis and pharyngitis. ALREX Ophthalmic Suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. RA: _________________________________________ diseases of ocular structures. dosed MUST four times per VERIFIED day was superior to placebo in AND the treatment of the signs and symptoms of seasonal allergic conjunctivitis. Anti-infl ammatory Drugs. c World Journal ALREX. in Bartlett JD. and female rats with up to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate. 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. PRECAUTIONS: General: For ophthalmic use only. the first 14 days of treatment. 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. defects 1993. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids.102:251-5. Disease ■ SCANNER BAR LOCATION: NA Sub-types. MKT/SALES: __________________________________ PRINTED BAR CODES MUST BE VERIFIED READABLE AND ACCURATE Nov.0.S. Patients should be advised not to wear a contact lens if their eye is red. Results from a bioavailability study in normal volunteers established that plasma levels of loteprednol etabonate and Δ1 cortienic acid etabonate (PJ 91). double-masked. et al.96 O Chemical Name: chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1. and retarded whose eyes are treatment not red. Revised August 2008. the NOEL for these effects was 5 mg/kg/day. preparation and to other corticosteroids. Treatment of male physician only after examination of the patient with the aid of magnification. van der Velden VH. Lowry GM. 466. Treatment of rats with 0. LOMB. burning on instillation. the incidence of clinically significant increases in IOP (≥10 mm Hg) was 1% (1/133) with ALREX and 1% (1/135) with placebo.LEGAL: ________________________________ BAUSCH &with seasonal allergic conjunctivitis. fluorescein staining. papillae. There are no adequate and well controlled studies pregnant women. Clinical Studies: In two double-masked. DO NOT FREEZE. effects. a dose which causedand no effectiveness maternal toxicity. This study suggests that limited (<1 ng/mL) systemic absorption occurs with ALREX. maternally toxic treatment Other regimen (significantly decreased body weight gave to decreased growth and survival. Carcinogenesis. 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. corneal abnormalities. 6. and limb flexures) when If this product used for 10 days or longer. SPECIAL INSTRUCTIONS: ■ DIELINES DOES NOT PRINT ■ PRINT PER SPECIFICATION purulent conditions of the eye. as with other ophthalmic corticosteroids. and perforation of the globe where there is thinning of the cornea or sclera. ALREX is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and to other corticosteroids. discharge. Loteprednol etabonate been suppress shown to be embryotoxic (delayed oscorticosteroid production.540. PRECAUTIONS: BAUSCH & LOMB. rhinitis and pharyngitis. 8500 HIDDEN RIVERLoteprednol PARKWAY. inactive/metabolite. the patient should be advised to consult a physician. 2004 Sep.1(3):127-49. Fungal cultures should be taken when appropriate.2% .4-diene-17β-carboxylate Each mL contains: ACTIVE: Loteprednol Etabonate 2 mg (0. 2003. Abnormal rubbing and keratectasia. 6/10 Information for Patients: This product is sterile when packaged. DESCRIPTION: US0. Cornea 2009 Dec. 1690 1690 ©2010 Bausch + Lomb Incorporated. BAUSCH & LOMB. HOW SUPPLIED: ALREX® (loteprednol etabonate ophthalmic suspension. or in vivo inALREX the single dose mouse micronucleus assay. loteprednol etabonate undergoes extensive metabolism to inactive carboxylic acid metabolites. were below the limit of quantitation (1 ng/mL) at all sampling times. below the limit of quantitation (1 ng/mL) at all sampling times. 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. If signs and symptoms fail to improve after two days. CONTRAINDICATIONS: ALREX. ALREX should not be used to treat contact lens related irritation. Treatment of male only if the potential justifies the potential risk to the fetus. They inhibit the edema. ocular adverse reactions occurring in lessgain). clinical dose.01%. perforations have been known to occur with the use of topical steroids. It is highly lipid soluble which enhances its penetration into cells. Abhishek K. . such as slit lamp biomicroscopy and. 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. injection.2% in the treatment of seasonal and perennial allergic conjunctivitis. organogenesis at doses of ≥5 mg/kg/day. reduced body becomes weight gain during treatment) administered pregnant rats during etabonate maternally toxic (significantly as this maywas contaminate the suspension. Glycerin. Ophthalmic Suspension should be used during pregnancy or in aare chromosome aberration in human lymphocytes.5% loteprednol etabonate 8 times daily for 2 days or 4 times daily 42 days. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. produce detectable quantities in human Systemic acetate steroids and appear in human milk and could suppress growth. MKT/SALES: _____________________________ PRINTED BARwhen CODES BE READABLE ACCURATE ALREX 9. where appropriate. Chapin M. when administered orally to pregnant rats at doses up to 50 mg/kg/day during the fetal period. and also in mycobacterial infection of the eye and fungal 2007 Dec 17. Northcutt JA.2%). FLOphthalmology 33637 1999.930 U. and 24208-353-10) photophobia.335 U. posterior subcapsular cataract formation. Slonim C. 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). The suspension is essentially isotonic with a tonicity of 250 to 310 mOsmol/kg. PRESERVATIVE ADDED: Benzalkonium Chloride 0. the patientwhen should be advised toto consult a physician. Steroids should be used with caution in the presence of glaucoma. may be absorbed by from soft contact lenses. CLINICAL PHARMACOLOGY: Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing.4-5. of significant elevation of intraocular pressure (≥10 mm Hg) was 2% (15/901) among patients receiving loteprednol etabonate. In those diseases causing thinning of the cornea or sclera. Lothringer LL. Prolonged use of corticosteroids may result in glaucoma with damage to optic nerve. posterior subcapsular cataract formation. the mouse lymphoma tk assay. Abelson MB. DOSAGE AND ADMINISTRATION: SHAKE VIGOROUSLY BEFORE USING.2% . mutagenesis. whothrough wear soft contact and maternally toxic regimen body gain). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution.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. leukocyte migration. pp 221-45. These include headache. such as slit lamp biomicroscopy and. 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. Among the smaller KEEP OUT among OF REACH OF CHILDREN.in Fungal cultures should be taken when artery at ≥5 mg/kg/day doses.5 mg/kg/day (15 times the maximum clinical dose) during organogenesis did not result in any reproductive toxicity.S.S. keratoconjunctivitis. 1. Sendrowski DP. foreign body sensation. Oral treatment of rats during organogenesis resulted in teratogenicity (absent innominate ADVERSE artery at REACTIONS: ≥5 mg/kg/day doses. ALREX. placebo-controlled six-week environmental studies of 268 patients with seasonal allergic conjunctivitis. visual acuity and field defects.5% (3/583) among patients receiving placebo. and scar formation associated with inflammation. a injection. reduced body weight during treatment) when administered to pregnant rats during etabonate was maternally (significantly organogenesis at doses of ≥5 mg/kg/day. Loteprednol etabonate had similar no effect on underlying ocular disease being studied. mutagenesis. If redness or itching becomes aggravated. IS NOT INTACT. interfere with endogenous Pregnancy: Teratogenic effects: Pregnancy Category C. Loteprednol etabonate was not genotoxic in vitro in the Ames test. Jaanus SD.106:362-9. and dnol etabonate in known steroid responders. Ocular Allergic Disease: Mechanisms. Rev. 5. Non-ocular adverse reactions occurred in less than 15% of patients. Povidone. In acute Metab Toxicol 2009 Sep. itching. as this may contaminate the suspension. rise to decreased and their survival. fibroblast proliferation. where appropriate. than 5% of rise patients include conjunctivitis. (1500 and 750 times the maximum clinical dose. Pediatric Use: Safety in pediatric patients have not been established. or cause other untoward Cautionof should be exercised when ALREX in is administered toHg) a nursing woman. and varicella. Braswell GR. Tampa. warnEmployment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. The results were obtained following the ocular administration of one drop in each eye of 0. 5. and adverse reactions. epiphora. Glucocorticoids: mechanisms of action and anti-infl amG. the NOEL for these effects was 5 mg/kg/day. Patent No.7:1968-77. double-masked. DO NOT USE IF NECKBAND IMPRINTED WITH "Protective Seal" AND YELLOW IS NOT INTACT. foreign body sensation. Caution should be exercised when ALREX is administered a nursing woman. steroids may mask infection or enhance existing infection. and varicella. placebo-controlled six-week environmental studies of 268 patients with seasonal allergic conjunctivitis. SD. Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. One drop instilled into the affected eye(s) four times daily. randomized of individuals treated for 28 days or longer with loteprednol etabonate. secondary ocular infection from pathogens including herpes simplex. WARNINGS: Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve. and uveitis. 4. 8500 HIDDEN RIVER PARKWAY. Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. benzalkonium chloride. beginning approximately 2 hours after instillation of the first dose RA: ____________________________________ ■ SCANNER BAR LOCATION: NA In two double-masked. a The preservative in ALREX.33(6 Pt 1):265-71.5%) in clinical sizes: studies included abnormal vision/blurring.5 mg/kg/day (15 times the maximum daily clinical dose). plaOphthalmic Suspension is indicated for the temporary relief of the signs and symptoms of seasonal allergic conjunctivitis. In a summation of controlled. placebo-controlled parallel study of loteprednol etabonate 0. or cause other incidence untoward effects. implantation losses atwith 100 ophthalmic mg/kg/daysteroids and decreased bodyintraocular weight andpressure. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). 7% (11/164) patients receiving 1% prednisolone acetate and 0. If redness or itching aggravated. and cleft palate and umbilical hernia at ≥50 mg/kg/day) and embryotoxicity (increased postappropriate. the mouse lymphoma tk assay. Ocular adverse reactions occurring in 5-15% of patients treated with loteprednol etabonate ophthalmic suspension (0. capillary proliferation. dry eyes. and photophobia. left common carotid artery. itching. INDICATIONS AND USAGE: • FAX: 813-866-2525 813-866-2485 STERILE OPHTHALMIC SUSPENSION Rx only DESCRIPTION: ALREX® (loteprednol etabonate ophthalmic suspension) contains a sterile. isJ contraindicated in Immunol most viral diseases of the cornea and conjunctiva including GPE:Scienti ________________________________________ epithelial 10. This study suggests that limited (<1 ng/mL) systemic absorption occurs with ALREX. Ilyas H. 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. 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. precautions. RA: ____________________________________ 5. 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. 0. et al. 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. implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with ≥50 mg/kg/day). Djalilian AR. 7. skeletal ossification ≥50 mg/kg/day). intraocular pressure should be monitored. intraocular pressure. 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. Long-term safety of loteprednol etabonate AW #: 9005502-9007902 SPEC: L-3002 / L-3102 COLORS: Black 4. et al. and in posterior subcapsular cataract formation.30:10-13. eyes. 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. Florida 33637 U. (1500 and 750 times the maximum ALREX is a registered trademark of Bausch + Lomb Incorporated.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. Wt. the incidence Storage: Store upright between 15°–25°C studies (59°–77°F). Based upon in vivo and in vitro preclinical metabolism studies. abnormal left common carotid artery. in 12. Abelson MB. TAMPA. et al. Epinastine: topical ophthalmic second generaAPPROVALS / DATE: 813-866-2485 • FAX: 813-866-2525 Eyeocular infections. collectively called lipocortins. However. ocular irritation/pain/discomfort. beginning approximately 2 hours after instillation of the first dose and throughout the first 14 days of treatment. corticosteroids are thought to act by the induction of phospholipase A2 inhibitory proteins. A randomized. Ocul Surf. or in vivo in the single dose mouse micronucleus assay. 8500 HIDDEN RIVER PARKWAY. the patient should be re-evaluated.9:157-65. Some of these events were to the development in the offspring during ocular lactation. interfere with endogenous (11/164) among patients receiving 1%milk. 0. inactive metabolite. Sander ER. Among the smaller corticosteroid production. Results from a bioavailability study in normal volunteers established that plasma levels of loteprednol etabonate and Δ1 cortienic acid 4 Loteprednol Etabonate Technical paper | etabonate (PJ 91).5% in steroid responders aft er of the ingredients ■ SCANNER BAR LOCATION: NA2. Some of these events were similar to the underlying ocular disease being studied. Rubin JM.5% loteprednol etabonate 8 times daily for 2 days or 4 times daily for 42 days. Other ocular adverse reactions occurring in less than 5% of patients include conjunctivitis.highly lipid soluble which enhances its penetration into cells.0. INACTIVES: Edetate Disodium. chemosis. epiphora. secondary ocular infection from pathogens including herpes with 0. INDICATIONS AND USAGE: ALREX Ophthalmic Suspension is indicated for the temporary relief of the signs and symptoms of seasonal allergic conjunctivitis. DOSAGE AND ADMINISTRATION: ADVERSE REACTIONS: SHAKE VIGOROUSLY BEFORE USING. and female rats withbenefit up to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate.2% in patients If signs and symptoms fail to improve after two days. Patients should be advised to allow the dropper tip to touch any surface. These include headache. the duration of gestation or parturition References BY VENDOR and TOthroughout THE HUMAN READABLE INDICATED ON ARTWORK. The no-observed-effect-level (NOEL) for these local effects was application. McMonnies CW. its primary.AB35309 DO NOT USE IF NECKBAND IMPRINTED WITH "Protective Seal" AND YELLOW Storage: Store upright between 15°–25°C (59°–77°F).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). Purified Water and Tyloxapol. fibrin deposition. Pregnancy: Teratogenic effects: Pregnancy Category C. The no-observed-effect-level (NOEL) for these effects was 0. and perforation oftoxic the globe where there is thinning of thegain cornea or sclera. Sanderson JP. as with other ophthalmic corticosteroids. et al. Bausch & Lomb Incorporated. Carcinogenesis. corneal abnormalities. Steroids should be used with caution in the presence of glaucoma.5 mg/kg/day (15 times the maximum dose) during organogenesis did notnot result in any reproductive toxicity. papillae. 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. Patients should be advised not to allow the dropper tip to touch any surface.AB35307 10 mL (NDC 24208-353-10) . KEEP OUT OF REACH OF CHILDREN. Treatment. group of patients who were studied with ALREX. HOW SUPPLIED: ALREX® (loteprednol etabonate ophthalmic suspension. A review of olopatadine for the treatment of ocular allergy. defects in visual acuity and fields of vision. Loteprednol etabonate is structurally similar to other corticosteroids. Smith L.061 ©Bausch & Lomb Incorporated Alrex® is a registered trademark of Bausch & Lomb Incorporated 9007902 (Folded) 9005502 (Flat) Sponsored by Bausch + Lomb PH2907. Holland EJ. and retarded eyelid erythema. randomized studies of individuals treated for 28 days or longer with loteprednol etabonate. FAX: or in a chromosome aberration test813-866-2525 in human lymphocytes. irritation/pain/discomfort. Loteprednol etabonate has been shown to be embryotoxic (delayed ossification) andisteratogenic (increased incidence of meningocele. Horwitz B. Loteprednol etabonate is a white to off-white powder. 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). seasonal allergic conjunctivitis.5%) in clinical studies included vision/blurring. should be (significantly instructed to decreased wait at least tenweight minutes aftergave instilling ALREX before growth they insert contact lenses. vaccinia. a dose which caused no maternal toxicity. chemosis. Hydrochloric Acid and/or Sodium Hydroxide may be added to adjust the pH to 5. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. respectively. ALREX should not be used to treat contact lens related irritation. deposition of collagen.5. in visual acuity and fields of vision. G. Intraocular pressure response to lotepreWARNINGS: 3. impairment of fertility: Long-term animal studies have not been conducted to evaluate the carcinogenic matory potential in asthma.AB35307 burning on instillation. Attenuation of ocular hypertension SPECIAL INSTRUCTIONS: ■ DIELINES DOES NOT PRINT ■ PRINT PER SPECIFICATION herpes simplex keratitis (dendritic keratitis). Reactions associated with steroids include One drop instilled into theophthalmic affected eye(s) four times elevated daily. Based upon in vivo and in vitro preclinical metabolism studies.747. Revised August 2008. and also in mycobacterial infection of the eye and fungal diseases of ocular structures. If this product is used for 10 days or longer. There no adequate and welltest controlled studies in pregnant women. the number 20 position ketone group is absent. Mah F. fluorescein staining. Treatment of rats visual acuity and field defects. Eye Contact Lens 2007 of thiscorneal transplantation. In those diseases causing thinning of the cornea or sclera. topical anti-inflammatory corticosteroid for ophthalmic use. Expert Opin Drug GPE: ____________________________________ Contact Lens 2004. respectively. TAMPA.996. discharge.

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