KRAA/u¢\ 4’. ‘(ft ?
`
`LOTEMAXT“
`
`loteprednol etabonate
`ophthalmic suspension, 0.5%
`STERILE OPHTHALMIC SUSPENSION
`
`DESCRIPTION:
`
`LOTEMAX"" (loteprednol etabonate ophthalmic suspension) contains a sterile, topical anti-
`inflammatory corticosteroid for ophthalmic use. Loteprednol etabonatc is a white to off-white
`powder.
`
`Loteprednol etabonate is represented by the following structural formula:
`
`oeuzct
`o
`
`Cal-l,,ClO,
`
`Mol. Wt. 466.96
`
`Chemical name: chloromethyl 17a-[(ethoxycarbonyl)oxy]-1lB-hydroxy-3-oxoandrosta-1,4-
`diene-l7B~carboxylate
`
`Each rnL contains: ACTIVE: Loteprednol Etabonate 5 mg (0.5%);
`INACTIVES: Edetate Disodium, Glycerin, Povidone, Purified Water and Tyloxapol.
`-5.6. The
`Hydrochloric Acid and/or Sodium Hydroxide may be added to adjust the pH to 5.3
`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
`migratiori. 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 A, inhibitory proteins, collectively called lipocortins. It is
`postulated that these proteins control the biosyntbesis of potent mediators of inflammation such
`as prostaglandins and leukotrienes by inhibiting the release of their common precursor
`arachidonic acid. AI‘5¢hid0ni¢ acid is fcleased ficm membrane phospholipids by phospholipase
`A,. Corticosteroids are capable of producing a rise in intraocular pressure.
`
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`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 compotmds so that it will undergo a predictable transformation to an inactive metabolite.
`Based upon in vivo and in virra preclinical metabolisn 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 A‘ cortienic acid etabonate (PI 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 LOTEMAX.
`‘
`
`Clinical Studies:
`
`;
`
`flogtgpgrgfle Inflammation: Placebo-controlled clinical studies donsuated that LOTEMAX
`is efiective 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 effectivethan 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
`I01’ (210 mmHg) was 1% with LOTEMAX and 6% with 1% prednisolone acetate.
`
`Giant Eggjllg Qqgjflctivitg: 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 ueatment.
`
`gasonal Allergic Coniuncn‘viti,s;; A placebo-controlled clinical study demonstrated that
`LOTEMAX was efi‘ective 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 lteratitis, herpes zoster lreratitis, iritis, cyclitis,
`selected infective conjunctivitides, when the inherent hamrd of steroid use is accepted to obtain
`an advisable diminution in edema and inflammation.
`
`LOTEMAX is less efiective 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 87% of patients treated with prednisolone
`
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`acetate 1%. The incidence of patients with clinically significant increases in IOP (2 10 mml-lg)
`was 1% with LOTEMAX and 6% withprednisolone 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
`mrgery.
`
`.
`CONTRAINDICATIONS:
`LOTEMAX, 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 varieella, and also in mycobacterial infection ofthe eye and fungal diseases of
`ocular structures. LOTEMAX is also contraindicated in individuals with known or suspected
`hypersensitivity to any of the ingredits 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 causingthinning 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 medicationin
`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:
`
`General: For ophthalmic use only. The initial prescription and renewal of the medication order
`beyond 14 days should be made by a physician only afier examination of the patient with the aid
`ofmagnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein
`If signs and symptoms fail to improve after two days, the patient should be re-evaluated.
`
`Ifthis product is used for 10 days or longer, intraocular pressure should be monitored even
`though it may be dificult in children and uncooperative patients (see WARNINGS).
`
`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.
`
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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. Ifpain 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 sofi contact lenses when using LOTEMAX“.
`
`Carcinogenesis, mutagenesis, impairment 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 gm/kg dose of loteprednol etabonate (50,000 times the maximum daily
`clinical dose). Treatment of male and female rats with up to 50 mg/kg/day and 25 mg/kg/day 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: Teiatogenic efiects: Pregnancy Category C. Loteprednol etabonate ha been shown
`to be ernbryotoxic (delayed ossification) and tn-atogenic (increased incidence of meningocele,
`abnormal lefi common carotid artery, and limb flexures) when administered orally to rabbits
`during organogenesis at a dose of 3 mg/kyday (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 mgilcg/day (6 times the maximum daily clinical dose). Oral treatment ofrats during
`organogenesis with 50 or_ 100 mg/kg/day (600 and 1,200 times the maximum clinical dose)
`resulted in embryotoxicity (increased post-implantation losses with 100 mg/kg/day, and
`decreased fetal body weight and skeletal ossification with 50 and 100 mykg/day); doses of 5 (60
`times the maximum daily clinical dose), 50 and 100 mg/kg/day caused teratogenicity (absent
`innominate artery at all doses, and cleft palate and umbilical hernia at 50 and 100 mg/kg/day).
`Loteprednol etabonate was maternally 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 mg/kg/day. The NOELS for the embryotoxic and teratogenic efiects in
`rats were 5 mg/kg/day and 0.5 mg/kg/day (60 and 6 times the maximtnn daily clinical dose) for
`embryotoxicity and teratogenicity, respectively.
`
`Oral exposure of pregnant rats to 5 and S0 mg/kyday of loteprednol etabonate during the fetal
`period, a maternally toxic treatment regimen (significantly decreased body weight gain), resulted
`in teratogenicity (umbilical herniation) and bryotoxicity (decreased fetal birth weight); the
`NOEL for these effects was 0.5 mg/kyday. Oral exposure of female rats to 50 mg/kg/day of
`loteprednol etabonate from the start of the fetal period through the end of lactation, a maternally
`toxic treatment regimen (significantly decreased body weight gain), gave rise to decreased
`growth and survival, and retarded development in the offspring during lactation; the NOEL for
`these effects was 5 mg/kg/day. Loteprednol etabonate had no eflect on the duration of gestation
`or parturition when administered orally to pregnant rats at doses up to 50 mg/kg/day during the
`fetal period.
`'
`
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`Oral treatment of female rats with 25 mg/kg/day (300 times the maximum daily clinical dose)
`from prior to mating through parturition increased the duration of gestation.
`
`Nursing Mothers: It is not known whether topical ophthalmic administration of corticosteroids
`could result in suficient systemic absorption to produce detectable quantities in human milk.
`Systemic steroids appear in human milk and could suppress growth, interfere with endogenous
`corticosteroid production, or cause other untoward efiects. Caution should be exercised when
`LOTEMAX is administered to a musing woman.
`
`Pediatric Use: Safety and eficctiveness in pediatric patients have not been established.
`
`ADVERSE REACTIONS:
`
`Reactions associated with ophthalmic steroids include elevated intraocular pressure, which may
`be associated with optic nervedamage, visual acuity and field defects, posterior subcapsular
`cataract formation, secondary ocular infection from pathogens including herpes simplex, and
`perforation ofthe globe where there is thinning ofthe cornea or sclera.
`
`Ocular adverse reactiom occurring in 5-15% of patients treated with loteprednol etabonate
`ophthalmic suspension (0.2%-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, corneal abnormalities, eyelid erytherna, 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 occurred in less than 15% of patients. These include headache,
`rhinitis and pharyngitis.
`
`In controlled, randomized studies of individuals treated for 28 days or longer with loteprednol
`etahonate, the incidence of significant elevation of intraocular pressure (2 10 mm Hg) was 2%
`(15/901) among patients receiving loteprednol etabonate, 7% (11/164) among patients receiving
`1% prednisolone acetate and 0.5% (3/5 83) among patients receiving placebo.
`
`DOSAGE AND ADMINISTRATION:
`SHAKE VIGOROUSLY BEFORE USING.
`
` Apply one to two drops of LOTEMAX into the
`conjunctiva! sac of the afiected eye(s) four times daily. During the initial treatment within the
`first week, the dosing may be increased, up to 1 drop every hour, ifnecessary. Care should be
`taken not to discontinue therapy prematurely. If sips and symptoms fail to improve afier two
`days, the patient should be re-evaluated (See PRECAUTIONS).
`
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`
` @ply one to two drops ofLOTEMAX into the conjunctiva! sac
`ofthe operated eye(s) four times daily beginning 24 hours afier surgery and continuing
`throughout the first 2 weeks of the postoperative period.
`
`_
`HOW SUPPLIED:
`LOTEMAX“ (loteprednol etabonnte ophthalmic suspension) is supplied in a plastic bottle with
`a controlled drop tip in the following sizes:
`2.5 mL (NDC 24208-299-25) s AB29904
`5 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” and yellow (mortar
`and pestle graphic) IS NOT INTACT.
`
`-
`
`Storage: Store upright between 15° - 25°C (59° - 77°F). DO NOT FREEZE.
`
`KEEP OUT OF REACH OF CHILDREN.
`
`Rx only
`
`Manufactured by:
`Bausch & Lomb Phaxmaceuticals, Inc., Tampa, Florida 33637
`under Agreement with Pharmos Corporation.
`'
`U.S. Patent No. 4,996,335
`US. Patent No. 5,540,930
`0 Bausch & Lamb Pharmaceuticals, Inc.
`
`XO503l7 (Folded)
`XMl0O39 (Flat)
`Rev. 2/98-8B
`
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`DIMENSIONS: 3 1/8" x 13/16"
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`DIMENSIONS: 3 1/8" x 13/16"
`3/4" unvamish area at left
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`DIMENSIONS: 3 1/8" x 13/16"
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`DIMENSIONS: 3 3/8" x 0.711"
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`Innopharma EX1038, Page 13
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`Innopharma EX1038, Page 14
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`
`!%%&’#"($" -0$#&+" /143 $)
`Innopharma EX1038, Page 16