`

`Loteprednol etabonatc 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(cid:173)
`related compounds so that it will undergo a predictable tnmsformation to an inactive metabolite.
`Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate w1<iergoes
`extensive metabolism to inactive carboxylic acid metabolites.
`
`Results from a bioavailability study in normal volunteers established that plasma levels of
`lotcprednol etabonate and !11 c:ortienic acid etabonatc (PJ 91), its primary, inactive metabolite,
`~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 nglml) systemic absorption occurs with LOTEMAX.
`
`CliDic:al Studies:
`Post-operative Inflammation: Placebo-controlled clinical studies demonstrated that LOTEMAX
`is effective for the treatment of anterior chamber inflammation as measured by cell and flare.
`
`~ Controlled clinical studies of patients with uveitis demonstrated that LOTEMAX was
`less effective. than prednisolone acetate 1%. Overall, 72% of patients treated with LOTEMAX
`experienced resolution of anterior chamber cell by day 28, compared to 87% of patients treated
`with 1% prednisolone acetate. The incidence of patients with clinically significant increases in
`lOP (~10 DunHg) was I% with LOTEMAX and 6% with 1% prednisolone acetate.
`
`Giant Papillarv Coniunctillitjs: Placebo-controlled clinical studies demonstrated that LOTEMAX
`was effective in reducing the signs and symptoms of giant papillary conjunctiVitis after 1 week of
`treatment and continuing for up to 6 weeks while on treatment.
`
`Seasonal Allergic Conjunctivitis: A placebo-<:ontrolled clinical study demonstrated that
`LOTEMAX was effective in reducing the signs and symptoms of allergic conjunctivitis during
`peak periods of pollen exposure.
`
`INDICATIONS AND USAGE:
`LOTEMAX is indicated for the treatment of steroid responsive 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,
`selected infective conjunctivitides, when the inherent hazard of steroid use is accepted to obtain
`an advisable diminution in edema and inflammation.
`
`L01EMAX is less effective than prednisolone acetate 1% in two 28-day controlled clinical
`studies in acute anterior uveitis, where 72% of patients treated with LOTEMAX experienced
`resolution of anterior chamber cells, compared to 8?0/o of patients treated with prednisolone
`
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`acetate 1%. The incidence of patients with clinically significant increases in lOP(~ 10 mmHg)
`was 1% with LOIEMAX and 6% with prednisolone acetate 1%. LOTEMAX should not be used
`in patients who require a more potent corticosteroid for this indication.
`
`LOTEMAX is also indicated for the treatment of post-operative inflammation following ocular
`surgay.
`
`CONTRAINDICATIONS:
`LOTEMAX, as with other ophthalmic corticosteroids, is contraindicated in most viral diseases of
`the cornea and conjunctiva including epithelial hetpCS simplex keratitis (dendritic keratitis),
`vaccinia. and varicella, and also in mycobacterial infection of the eye and fungal diseases of
`ocular structures. LOTEMA.X 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,
`pezforations ]lave been .known to occur with the use of topical steroids. In acute pmulent
`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-Ul
`the treatment of patients with a history of herpes simplex requires great caution.
`
`The use of steroids after cataract surgery may delay healing and increase the incidence of bleb
`formation.
`
`PRECAUTIONS:
`Geuenl: 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 even
`though it may be difficult in children and uncooperative patients (see WARNINGS).
`
`Fungal infections of the comea are particularly prone to develop coincidentally with long-term
`local steroid application. Fungus invasion must be considered in any persistent comeal
`ulceration where a steroid has been used or is in use. Fungal cultures should be taken when
`appropriate.
`
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`Information for Patients: 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 LO'J'EMAXTM.
`
`Can:inogeacsis, mutagenesis, impairmeat of fertility: Long-term animal studies have not been
`conducted to evaluate the carcinogenic potential ofloteprednol etabonate. Loteprednol etabonate
`was not genotoxic in the Ames test, the mouse lymphoma tk assay, or in a chromosome
`aberration test in human lymphocytes, three in vitro tests. In vivo evidence of genotoxicity, an
`increased frequency of micronucleated immature erythrocytes, was not observed in mice that
`received a single 4 gmlkg dose ofloteprcdnol etabonate (50,000 times the maximum daily
`clinical dose). Treatment of male and female rats with up to 50 mg/kglday and 25 mglkglday of
`loteprednol etabonate, respectively, (600 and 300 times the maximUm clinical dose, respectively)
`prior to and during mating did not impair fertility in either gender.
`
`Pregnancy: Teratogenic effects: Pregnancy Category C. Lotcprednol etabonate has been shown
`to be embryotoxic (delayed ossification) and teratogenic (increased incidence of meningocele,
`abnonnalleft common carotid artery, and limb flexures) when administered orally to rabbits
`during organogenesis ala dose of 3 mg/kglday (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.ikglday (6 times the maximum daily clinical dose). Oral treatment ofrats during
`organogenesis with 50 or 100 mglkglday (600 and 1,200 times the maximum clinical dose)
`resulted in embryotoxicitY (increased post-implantation losses with 100 mglkglday, and
`decreased fetal body weight and skeletal ossification with 50 and 100 mglkg/day ); doses of 5 ( 60
`times the maximum daily clinical dose), 50 and 100 mglkglday caused teratogenicity (absent
`innominale artery a1 all doses, and cleft palate and umbilical hernia at 50 and 100 mglkglday).
`Loteprednol etabonatc was matemally toxic (significantly reduced body weight gain during
`treatment) when administered to pregnant rats during organogenesis at doses of 5 to 100
`mg/kg/day but not at 0.5 mglkglday. The NOELs for the embryotoxic and teratogenic effects in
`rats were 5 mglkglday and 0.5 mglkglday (60 and 6 times the maximlDD. daily clinical dose) for
`embryotoxicity and teratogenicity, respectively.
`
`Oral exposure of pregnant rats to 5 and SO mgllcglday of loteprednol etabonate during the fetal
`period. a maternally toxic treatment regimen (significantly dccrcased body weight gain), resulted
`in teratogenicity (umbilical herniation) and embryotoxicity (dccrcased fetal birth weight); the
`NOEL for these effects was 0.5 mglkglday. Oral exposure offcmale rats to 50 mglkglday 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 mglkglday. Lotcprednol etabonate had no effect on the duration of gestalion
`or parturition when administered orally to pregnant rats at doses up to 50 mglkglday during the
`fetal period.
`.
`
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`Oral treatment of female rats with 25 mglkg/day (300 times the maximum daily clinical dose)
`from prior to mating through parturition increased the duration of gestation.
`
`Naniag Mothen: It is not known whether topical ophthalmic administration of corticosteroids
`could result in sufficient systemic absorption to produce detectable quantities in hwnan milk.
`Systemic steroids appear in human milk and could suppress growth. interfere with endogenous
`corticosteroid production, or cause other untoward effects. Caution should be exercised when
`LOTEMAX is administcrcd to a nursing woman.
`
`Pediatric Use: Safety and effectiveDess in pediatric patients have not been established.
`
`ADVERSE REACTIONS:
`Reactions associated with ophthalmic steroids include elevated 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 bctpCS simplex, and
`perforation of the globe w~ there is thinning of the cornea or sclera.
`
`Ocular adverse reactions occurring in 5-l 5% of patients treated with lotcprednol embonate
`ophthalmic suspension (0.2o/o-0.5%) in clinical studies included abnormal vision/blurring,
`burning on instillation, chemosis, discharge, dry eyes, epiphora, foreign body sensation, itching,
`injection, and photophobia. Other ocular adverse reactions occurring in less than 5% of patients
`include conjunctivitis, comeal abnormalities, eyelid erythema, keratoconjunctivitis, ocular
`irritation/pain/discomfort, papillae, and uveitis. Some of these events were similar to the
`underlying ocular disease being studied.
`
`Non-ocular adverse reactions occwrcd in less than 15% of patients. These include headache,
`rlrinitis and pharyngitis.
`
`In controlled, randomized studies of individuals treated for 28 days or longer with lotcprcdnol
`ctabonate, the incidence of significant elevation of intraocular pressure ~ 10 mm Hg) was 2%
`(15/90 I) among patients receiving lotcprcdnol etabonate, 7% (11/164) among patients receiving
`1% prednisolone acetate and 0.5% (3/583) among patients receiving placebo.
`
`DOSAGE AND ADMINISTRATION:
`SHAKE VIGOROUSLY BEFORE USING.
`
`Steroid Resoonsive Djsea.se Treatment: Apply one to two drops ofLOTEMAX into the
`conjunctival sac of the affected eye(s) four times daily. During the initial treatment within the
`first week, the dosing may be increased, up to 1 drop every ho\U', if necessary. Care should be
`taken not to discontinue therapy prematurely. If signs and symptoms fail to improve after two
`days, the patient should be re-evaluated (Sec PRECAUTIONS).
`
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`Post-Operative Inflammation; Apply one to two drops ofLOTEMAX into the conjunctival sac
`of the operated eye(s) four times daily beginning 24 hours after surgery and continuing
`throughout the first 2 weeks of the postoperative period.
`
`HOW SUPPLIED:
`LOTEMAX"' (loteprednol etabonate ophthalmic suspension) is supplied in a plastic bottle with
`a controlled drop tip in the following sizes:
`2.5 mL (NDC 24208-299-25) .. AB29904
`S mL (NDC 24208-299-05)- AB29907
`10 mL (NDC 24208-299-10)- AB29909
`15 mL (NDC 24208-299-15)- AB299ll
`
`DO NOT USE IF NECKBAND IMPRINTED WITH "Protective Seal" ud yellow (mortar
`ud pestle graphic) IS NOT INTACf.
`
`Stonge: Store upright between ]5°- 2S°C (59° • 777). DO NOT FREEZE.
`
`KEEP OUT OF REACH OF CHILDREN.
`
`Rxoaly
`
`Manufactured by:
`Bausch & Lomb Phannaceuticals, Inc., Tampa, Florida 33637
`under Agreement with Phannos Corporation.
`U.S. Patent No. 4,996,335
`U.S. Patent No. 5,540,930
`C Bausch & Lomb Pharmaceuticals, Inc.
`
`X050317 (Folded)
`XM10039 (Flat)
`Rev. 2198-SB
`
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`B.U.'SCH
`IWtotu•
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`.............. ~~
`LAemax.
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`Z.htL
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`; .. ..,
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`; et'-7l'flOONIHIII£ll.
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`
`CORE 29904 LABEL
`4/C: PMS 197, PMS Violet, Cyan, Black
`DIMENSIONS: 3 1/8" x 13/16"
`3/4" unvarnish area at lett
`l-1605
`ART IS AT 100%
`PHARMACODE#682
`
`---------------------------------------------------------------
`
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