of superficial ocular infection is high or where there is an expectation that potentially dangerous numbers of bacteria will be present in the eye. the particular anti-infective drug in this product (tobramycin) is active against the following common bacterial eye pathogens: staphylococci, including s. aureus and s. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains. streptococci, including some of the group a-beta-hemolytic species, some nonhemolytic species, and some streptococcus pneumoniae , pseudomonas aeruginosa, escherichia coli, klebsiella pneumoniae, enterobacter aerogenes, proteus mirabilis, morganella morganii , most proteus vulgaris strains, haemophilus influenzae , and h. aegyptius, moraxella lacunata, acinetobacter calcoaceticus and some neisseria species. zylet is a combination of loteprednol etabonate, a corticosteroid, and tobramycin, an aminoglycoside antibacterial, indicated for steroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where superficial bacterial ocular infection or a risk of bacterial ocular infection exists. ( 1 )

d thus increase the hazard of secondary ocular infection. in acute purulent conditions, steroids may mask infection or enhance existing infection. if signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. ( 5.4 ) • viral infections : employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). ( 5.5 ) • fungal infections : fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. ( 5.6 ) 5.1 intraocular pressure (iop) increase prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. steroids should be used with caution in the presence of glaucoma. if this product is used for 10 days or longer, intraocular pressure should be monitored. 5.2 cataracts use of corticosteroids may result in posterior subcapsular cataract formation. 5.3 delayed healing the use of steroids after cataract surgery may delay healing and increase the incidence of bleb formation. in those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. the initial prescription and renewal of the medication order should be made by a physician only after examination of the patient with the aid of magnification such as a slit lamp biomicroscopy and, where appropriate, fluorescein staining. 5.4 bacterial infections prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. in acute purulent conditions of the eye, steroids may mask infection or enhance existing infection. if signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. 5.5 viral infections employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution. use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). 5.6 fungal infections fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid application. fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. fungal cultures should be taken when appropriate. 5.7 aminoglycoside hypersensitivity sensitivity to topically applied aminoglycosides may occur in some patients. if hypersensitivity develops with this product, discontinue use and institute appropriate therapy. 5.8 risk of contamination do not allow the dropper tip to touch any surface, as this may contaminate the suspension. 5.9 contact lens wear as with all ophthalmic preparations containing benzalkonium chloride, patients should be advised not to wear soft contact lenses when using zylet.

ions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with infrequent optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, delayed wound healing and secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera. in a summation of controlled, randomized studies of individuals treated for 28 days or longer with loteprednol etabonate, the incidence of significant elevation of intraocular pressure (≥10 mm hg) was 2% (15/901) among patients receiving loteprednol etabonate, 7% (11/164) among patients receiving 1% prednisolone acetate and 0.5% (3/583) among patients receiving placebo. tobramycin ophthalmic solution 0.3% the most frequent adverse reactions to topical tobramycin are hypersensitivity and localized ocular toxicity, including lid itching and swelling and conjunctival erythema. these reactions occur in less than 4% of patients. similar reactions may occur with the topical use of other aminoglycoside antibiotics. secondary infection the development of secondary infection has occurred after use of combinations containing steroids and antimicrobials. fungal infections of the cornea are particularly prone to develop coincidentally with long-term applications of steroids. the possibility of fungal invasion must be considered in any persistent corneal ulceration where steroid treatment has been used. secondary bacterial ocular infection following suppression of host responses also occurs. most common adverse reactions reported in patients were injection and superficial punctate keratitis, increased intraocular pressure, burning and stinging upon instillation. ( 6 ) to report suspected adverse reactions, contact bausch & lomb incorporated at 1-800-553-5340 or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

eous injection at 180 times the rhod. tobramycin did not affect fetal development when administered by subcutaneous injection to pregnant rats at doses 450 times the rhod. the background risk of major birth defects and miscarriage for the indicated population is unknown. however, the background risk in the u.s. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. data animal data embryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation days 6 to 18, to target the period of organogenesis. loteprednol etabonate produced fetal malformations at doses ≥ 0.1 mg/kg/day (0.54 times the recommended human ophthalmic dose (rhod) based on body surface area, assuming 100% absorption of loteprednol etabonate). spina bifida (including meningocele) was observed at doses ≥ 0.1 mg/kg/day, and exencephaly and craniofacial malformations were observed at doses ≥ 0.4 mg/kg/day (2.1 times the rhod). at 3 mg/kg/day (16 times the rhod), loteprednol etabonate was associated with increased incidences of abnormal left common carotid artery, limb flexures, umbilical hernia, scoliosis, and delayed ossification. abortion and embryofetal lethality (resorption) occurred at doses ≥ 6 mg/kg/day (32 times the rhod). a noael for developmental toxicity was not established in this study. the noael for maternal toxicity in rabbits was 3 mg/kg/day. embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation days 6 to 15, to target the period of organogenesis. loteprednol etabonate produced fetal malformations, including absent innominate artery at doses ≥ 5 mg/kg/day (13 times the rhod); and cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body weight and decreased skeletal ossification at doses ≥ 50 mg/kg/day (135 times the rhod). embryofetal lethality (resorption) was observed at 100 mg/kg/day (270 times the rhod). the noael for developmental toxicity in rats was 0.5 mg/kg/day (1.3 times the rhod). loteprednol etabonate was maternally toxic (reduced body weight gain) at doses of ≥ 50 mg/kg/day. the noael for maternal toxicity was 5 mg/kg/day. a peri-/postnatal study was conducted in rats administered loteprednol etabonate by oral gavage from gestation day 15 (start of fetal period) to postnatal day 21 (the end of lactation period). at doses ≥ 0.5 mg/kg/day (1.3 times the rhod), reduced survival was observed in live-born offspring. doses ≥ 5 mg/kg/day (13 times the rhod) caused umbilical hernia/incomplete gastrointestinal tract. doses ≥ 50 mg/kg/day (135 times the rhod) produced maternal toxicity (reduced body weight gain, death), decreased number of live-born offspring, decreased birth weight, and delays in postnatal development. a developmental noael was not established in this study. the noael for maternal toxicity was 5 mg/kg/day. an embryofetal study was conducted in pregnant rabbits administered 20 or 40 mg/kg/day tobramycin by subcutaneous injection on gestational days 6 to 18, to target the period of organogenesis. abortions and maternal toxicity (renal nephrosis and cortical tubular necrosis) were observed at both dose levels. the developmental and maternal lowest observed adverse effect level (loael) is 20 mg/kg/day (180 times the rhod based on body surface area, assuming 100% absorption of tobramycin). an embryofetal study was conducted in pregnant rats administered 50 or 100 mg/kg/day tobramycin by subcutaneous injection on gestational days 6 to 15, to target the period of organogenesis. no effects on development, reproduction, or maternal toxicity were reported. the developmental and maternal noael is 100 mg/kg/day (450 times the rhod). 8.2 lactation there are no data on the presence of loteprednol etabonate or tobramycin in human milk, the effects on the breastfed infant, or the effects on milk production. the developmental and health benefits of breastfeeding should be considered, along with the mother’s clinical need for zylet and any potential adverse effects on the breastfed infant from zylet. 8.4 pediatric use two trials were conducted to evaluate the safety and efficacy of zylet (loteprednol etabonate and tobramycin ophthalmic suspension) in pediatric subjects age zero to six years; one was in subjects with lid inflammation and the other was in subjects with blepharoconjunctivitis. in the lid inflammation trial, zylet with warm compresses did not demonstrate efficacy compared to vehicle with warm compresses. patients received warm compress lid treatment plus zylet or vehicle for 14 days. the majority of patients in both treatment groups showed reduced lid inflammation. in the blepharoconjunctivitis trial, zylet did not demonstrate efficacy compared to vehicle, loteprednol etabonate ophthalmic suspension, or tobramycin ophthalmic solution. there was no difference between treatment groups in mean change from baseline blepharoconjunctivitis score at day 15. there were no differences in safety assessments between the treatment groups in either trial. 8.5 geriatric use no overall differences in safety and effectiveness have been observed between elderly and younger patients.

e rhod. tobramycin did not affect fetal development when administered by subcutaneous injection to pregnant rats at doses 450 times the rhod. the background risk of major birth defects and miscarriage for the indicated population is unknown. however, the background risk in the u.s. general population of major birth defects is 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. data animal data embryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation days 6 to 18, to target the period of organogenesis. loteprednol etabonate produced fetal malformations at doses ≥ 0.1 mg/kg/day (0.54 times the recommended human ophthalmic dose (rhod) based on body surface area, assuming 100% absorption of loteprednol etabonate). spina bifida (including meningocele) was observed at doses ≥ 0.1 mg/kg/day, and exencephaly and craniofacial malformations were observed at doses ≥ 0.4 mg/kg/day (2.1 times the rhod). at 3 mg/kg/day (16 times the rhod), loteprednol etabonate was associated with increased incidences of abnormal left common carotid artery, limb flexures, umbilical hernia, scoliosis, and delayed ossification. abortion and embryofetal lethality (resorption) occurred at doses ≥ 6 mg/kg/day (32 times the rhod). a noael for developmental toxicity was not established in this study. the noael for maternal toxicity in rabbits was 3 mg/kg/day. embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation days 6 to 15, to target the period of organogenesis. loteprednol etabonate produced fetal malformations, including absent innominate artery at doses ≥ 5 mg/kg/day (13 times the rhod); and cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body weight and decreased skeletal ossification at doses ≥ 50 mg/kg/day (135 times the rhod). embryofetal lethality (resorption) was observed at 100 mg/kg/day (270 times the rhod). the noael for developmental toxicity in rats was 0.5 mg/kg/day (1.3 times the rhod). loteprednol etabonate was maternally toxic (reduced body weight gain) at doses of ≥ 50 mg/kg/day. the noael for maternal toxicity was 5 mg/kg/day. a peri-/postnatal study was conducted in rats administered loteprednol etabonate by oral gavage from gestation day 15 (start of fetal period) to postnatal day 21 (the end of lactation period). at doses ≥ 0.5 mg/kg/day (1.3 times the rhod), reduced survival was observed in live-born offspring. doses ≥ 5 mg/kg/day (13 times the rhod) caused umbilical hernia/incomplete gastrointestinal tract. doses ≥ 50 mg/kg/day (135 times the rhod) produced maternal toxicity (reduced body weight gain, death), decreased number of live-born offspring, decreased birth weight, and delays in postnatal development. a developmental noael was not established in this study. the noael for maternal toxicity was 5 mg/kg/day. an embryofetal study was conducted in pregnant rabbits administered 20 or 40 mg/kg/day tobramycin by subcutaneous injection on gestational days 6 to 18, to target the period of organogenesis. abortions and maternal toxicity (renal nephrosis and cortical tubular necrosis) were observed at both dose levels. the developmental and maternal lowest observed adverse effect level (loael) is 20 mg/kg/day (180 times the rhod based on body surface area, assuming 100% absorption of tobramycin). an embryofetal study was conducted in pregnant rats administered 50 or 100 mg/kg/day tobramycin by subcutaneous injection on gestational days 6 to 15, to target the period of organogenesis. no effects on development, reproduction, or maternal toxicity were reported. the developmental and maternal noael is 100 mg/kg/day (450 times the rhod).

cturally similar to other corticosteroids. however, the number 20 position ketone group is absent. the anti-infective component in the combination (tobramycin) is included to provide action against susceptible organisms. in vitro studies have demonstrated that tobramycin is active against susceptible strains of the following microorganisms: staphylococci, including s. aureus and s. epidermidis (coagulase-positive and coagulase-negative), including penicillin-resistant strains. streptococci, including some of the group a-beta-hemolytic species, some nonhemolytic species, and some streptococcus pneumoniae . pseudomonas aeruginosa, escherichia coli, klebsiella pneumoniae, enterobacter aerogenes, proteus mirabilis, morganella morganii, most proteus vulgaris strains, haemophilus influenzae and h. aegyptius , moraxella lacunata , acinetobacter calcoaceticus and some neisseria species. 12.3 pharmacokinetics in a controlled clinical study of ocular penetration, the levels of loteprednol etabonate in the aqueous humor were found to be comparable between lotemax ® and zylet treatment groups. results from a bioavailability study in normal volunteers established that plasma levels of loteprednol etabonate and Δ 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 ophthalmic suspension 8 times daily for 2 days or 4 times daily for 42 days. this study suggests that limited (<1 ng/ml) systemic absorption occurs with 0.5% loteprednol etabonate.

orption).