ZYLET- loteprednol etabonate and tobramycin suspension/ drops

Zylet by

Drug Labeling and Warnings

Zylet by is a Prescription medication manufactured, distributed, or labeled by Bausch & Lomb Incorporated, Bausch & Lomb Incoporated. Drug facts, warnings, and ingredients follow.

Drug Details [pdf]

  • 1 INDICATIONS AND USAGE

    ZYLET® (loteprednol etobonate and tobramycin ophthalmic suspension) is a topical anti-infective and corticosteroid combination 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.

    Ocular steroids are indicated in 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, and where the inherent risk of steroid use in certain infective conjunctivitides is accepted to obtain a diminution in edema and inflammation. They are also indicated in chronic anterior uveitis and corneal injury from chemical, radiation or thermal burns, or penetration of foreign bodies.

    The use of a combination drug with an anti-infective component is indicated where the risk 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.

  • 2 DOSAGE AND ADMINISTRATION

    2.1 Recommended Dosing

    Apply one or two drops of ZYLET into the conjunctival sac of the affected eye every four to six hours. During the initial 24 to 48 hours, the dosing may be increased, to every one to two hours. Frequency should be decreased gradually as warranted by improvement in clinical signs. Care should be taken not to discontinue therapy prematurely.

    2.2 Prescription Guideline

    Not more than 20 mL should be prescribed initially and the prescription should not be refilled without further evaluation [see Warnings and Precautions (5.3)].

  • 3 DOSAGE FORMS AND STRENGTHS

    ZYLET (loteprednol etabonate and tobramycin ophthalmic suspension) 0.5%/0.3% contains 5 mg/mL loteprednol etabonate and 3 mg/mL tobramycin.

  • 4 CONTRAINDICATIONS

    4.1 Nonbacterial Etiology

    ZYLET, as with other steroid anti-infective ophthalmic combination drugs, 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.

  • 5 WARNINGS AND PRECAUTIONS

    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.

  • 6 ADVERSE REACTIONS

    Adverse reactions have occurred with steroid/anti-infective combination drugs which can be attributed to the steroid component, the anti-infective component, or the combination.

    ZYLET:

    In a 42-day safety study comparing ZYLET to placebo, ocular adverse reactions included injection (approximately 20%) and superficial punctate keratitis (approximately 15%). Increased intraocular pressure was reported in 10% (ZYLET) and 4% (placebo) of subjects. Nine percent (9%) of ZYLET subjects reported burning and stinging upon instillation.

    Ocular reactions reported with an incidence less than 4% include vision disorders, discharge, itching, lacrimation disorder, photophobia, corneal deposits, ocular discomfort, eyelid disorder, and other unspecified eye disorders.

    The incidence of non-ocular reactions reported in approximately 14% of subjects was headache; all other non-ocular reactions had an incidence of less than 5%.

    Loteprednol etabonate ophthalmic suspension 0.2% - 0.5%:

    Reactions 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.

  • 8 USE IN SPECIFIC POPULATIONS

    8.1 Pregnancy

    Teratogenic effects: Loteprednol etabonate has been shown to be embryotoxic (delayed ossification) and teratogenic (increased incidence of meningocele, abnormal left common carotid artery, and limb fixtures) when administered orally to rabbits during organogenesis at a dose of 3 mg/kg/day (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/kg/day (6 times the maximum daily clinical dose). Oral treatment of rats during organogenesis resulted in teratogenicity (absent innominate artery at ≥5 mg/kg/day doses, and cleft palate and umbilical hernia at ≥50 mg/kg/day) and embryotoxicity (increased post-implantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with ≥50 mg/kg/day). Treatment of rats at 0.5 mg/kg/day (6 times the maximum daily clinical dose) during organogenesis did not result in any reproductive toxicity. Loteprednol etabonate was maternally toxic (significantly reduced body weight gain during treatment) when administered to pregnant rats during organogenesis at doses of ≥5 mg/kg/day.

    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 effect 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.

    Reproductive studies have been performed in rats and rabbits with tobramycin at doses up to 100 mg/kg/day parenterally and have revealed no evidence of impaired fertility or harm to the fetus. There are no adequate and well-controlled studies in pregnant women. ZYLET should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

    8.3 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 that appear in human milk could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when ZYLET is administered to a nursing woman.

    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.

  • 11 DESCRIPTION

    ZYLET (loteprednol etabonate and tobramycin ophthalmic suspension) is a sterile, multiple dose topical anti-inflammatory corticosteroid and anti-infective combination for ophthalmic use. Both loteprednol etabonate and tobramycin are white to off-white powders. The chemical structures of loteprednol etabonate and tobramycin are shown below.

    Loteprednol etabonate:

    structure1.jpg

    Chemical name: chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate

    Tobramycin:

    image2

    Chemical Name:

    O-3-Amino-3-deoxy-α-D-glucopyranosyl-(1→ 4)-O- [2,6-diamino-2,3,6-trideoxy-α-D-ribo-hexopyranosyl- (1→ 6)] -2-deoxystreptamine

    Each mL contains: Actives: Loteprednol Etabonate 5 mg (0.5%) and Tobramycin 3 mg (0.3%). Inactives: Edetate Disodium, Glycerin, Povidone, Purified Water, Tyloxapol, and Benzalkonium Chloride 0.01% (preservative). Sulfuric Acid and/or Sodium Hydroxide may be added to adjust the pH to 5.7-5.9. The suspension is essentially isotonic with a tonicity of 260 to 320 mOsm/kg.

  • 12 CLINICAL PHARMACOLOGY

    12.1 Mechanism of Action

    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.

    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 Δ1 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.

  • 13 NONCLINICAL TOXICOLOGY

    13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

    Long-term animal studies have not been conducted to evaluate the carcinogenic potential of loteprednol etabonate or tobramycin.

    Loteprednol etabonate was not genotoxic in vitro in the Ames test, the mouse lymphoma TK assay, a chromosome aberration test in human lymphocytes, or in an in vivo mouse micronucleus assay.

    Oral treatment of male and female rats at 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, (500 and 250 times the maximum clinical dose, respectively) prior to and during mating did not impair fertility in either gender. No impairment of fertility was noted in studies of subcutaneous tobramycin in rats at 100 mg/kg/day (1700 times the maximum daily clinical dose).

  • 16 HOW SUPPLIED/STORAGE AND HANDLING

    ZYLET (loteprednol etabonate and tobramycin ophthalmic suspension) is supplied in a white low density polyethylene plastic bottle with a white controlled drop tip and a white polypropylene cap in the following sizes:

    5 mL (NDC: 24208-358-05) in a 7.5 mL bottle

    10 mL (NDC: 24208-358-10) in a 10 mL bottle

    USE ONLY IF IMPRINTED NECKBAND IS INTACT.

    Storage: Store upright at 15º to 25ºC (59º to 77ºF). PROTECT FROM FREEZING. SHAKE VIGOROUSLY BEFORE USING.

  • 17 PATIENT COUNSELING INFORMATION

    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 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 ZYLET.

    Distributed by:

    Bausch + Lomb, a division of Bausch Health US, LLC

    Bridgewater, NJ 08807 USA

    ZYLET is a trademark of Bausch & Lomb Incorporated or its affiliates.

    © 2019 Bausch & Lomb Incorporated or its affiliates

    Manufactured by:
    Bausch & Lomb Incorporated
    Tampa, FL 33637 USA

    9007707 (FOLDED)

    9004407 (FLAT)

  • PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC: 24208-358-10 BAUSCH + LOMB Zylet® loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension SterileFOR OPHTHALMIC USE ONLY Rx only 10 mL

    carton.jpg
  • INGREDIENTS AND APPEARANCE
    ZYLET 
    loteprednol etabonate and tobramycin suspension/ drops
    Product Information
    Product TypeHUMAN PRESCRIPTION DRUGItem Code (Source)NDC: 24208-358
    Route of AdministrationOPHTHALMIC
    Active Ingredient/Active Moiety
    Ingredient NameBasis of StrengthStrength
    LOTEPREDNOL ETABONATE (UNII: YEH1EZ96K6) (LOTEPREDNOL - UNII:Z8CBU6KR16) LOTEPREDNOL ETABONATE5 mg  in 1 mL
    TOBRAMYCIN (UNII: VZ8RRZ51VK) (TOBRAMYCIN - UNII:VZ8RRZ51VK) TOBRAMYCIN3 mg  in 1 mL
    Packaging
    #Item CodePackage DescriptionMarketing Start DateMarketing End Date
    1NDC: 24208-358-101 in 1 CARTON12/14/2004
    110 mL in 1 BOTTLE, DROPPER; Type 0: Not a Combination Product
    2NDC: 24208-358-051 in 1 CARTON12/14/2004
    25 mL in 1 BOTTLE, DROPPER; Type 0: Not a Combination Product
    3NDC: 24208-358-011 in 1 CARTON12/14/2004
    31 mL in 1 BOTTLE, DROPPER; Type 0: Not a Combination Product
    Marketing Information
    Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
    NDANDA05080412/14/2004
    Labeler - Bausch & Lomb Incorporated (196603781)
    Establishment
    NameAddressID/FEIBusiness Operations
    Bausch & Lomb Incoporated079587625MANUFACTURE(24208-358) , LABEL(24208-358) , PACK(24208-358)

    • Trademark Results [Zylet]

    Mark Image

    Registration | Serial
    Company
    Trademark
    Application Date
    ZYLET
    ZYLET
    78112937 3002481 Live/Registered
    BAUSCH & LOMB INCORPORATED
    2002-03-06
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