PDR MEMBER LOGIN:
  • PDR Search

    Required field
  • Advertisement
  • CLASSES

    Ophthalmological Corticosteroid and Anti-infective Combinations

    DEA CLASS

    Rx

    DESCRIPTION

    Ophthalmic suspension of a corticosteroid (loteprednol) plus aminoglycoside antibiotic (tobramycin); indicated for steroid-responsive inflammatory conditions associated with superficial bacterial ocular infection or a risk thereof.

    COMMON BRAND NAMES

    Zylet

    HOW SUPPLIED

    Zylet Ophthalmic Susp: 0.5-0.3%

    DOSAGE & INDICATIONS

    For the treatment of corticosteroid-responsive inflammatory ocular conditions for which a corticosteroid is indicated and where a superficial bacterial ophthalmic infection or a risk of bacterial infection exists, including bacterial conjunctivitis, allergic conjunctivitis, acne rosacea, superficial punctate keratitis, herpes zoster ocular infection (keratitis), iritis, cyclitis, and chronic anterior uveitis or corneal injury resulting from chemical, radiation, or thermal ocular burns or from the penetration of foreign bodies.
    NOTE: Care should be taken not to discontinue therapy prematurely. Not more than 20 mL should be prescribed initially and the prescription should not be refilled without further evaluation.
    Ophthalmic dosage (suspension)
    Adults and Geriatric

    Apply 1 to 2 drops into the conjunctival sac of the affected eye(s) every 4 to 6 hours. During the initial 24 to 48 hours, the dose frequency may be increased (e.g., every 1 to 2 hours) if needed. Frequency should be decreased gradually as warranted by improvement in clinical signs. If ocular signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. Intraocular pressure should be monitored after 10 days of therapy and an ophthalmologic exam should be done after 14 days of therapy.

    MAXIMUM DOSAGE

    Adults

    24 drops/day loteprednol 0.5% and tobramycin 0.3% in the affected eye(s).

    Elderly

    24 drops/day loteprednol 0.5% and tobramycin 0.3% in the affected eye(s).

    Adolescents

    Safety and efficacy have not been established.

    Children

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    No dosage adjustment is needed.

    Renal Impairment

    No dosage adjustment is needed.

    ADMINISTRATION

    Ophthalmic Administration

    Zylet (0.5% loteprednol etabonate and 0.3% tobramycin ophthalmic suspension) is administered topically to the eye. Not for injection into the eye.
    Wash hands before and after use.
    Shake well before use. To avoid contamination, do not to touch the tip of the dropper to the eye, fingertips, or other surface.
    Instruct the patient on proper instillation of eye solution. Tilt head back slightly and pull the lower eyelid down with the index finger to form a pouch. Squeeze the prescribed number of drops into the pouch and gently close eyes for 1—2 minutes. Do not blink.
    The patient should not wear contact lenses during the treatment course.

    STORAGE

    Zylet:
    - Protect from freezing
    - Store between 59 to 77 degrees F
    - Store upright

    CONTRAINDICATIONS / PRECAUTIONS

    Aminoglycoside hypersensitivity, corticosteroid hypersensitivity, glycerin hypersensitivity

    Tobramycin should not be used in patients with a history of aminoglycoside hypersensitivity. Cross-sensitivity with other aminoglycoside antibiotics may occur. Loteprednol may mask signs and symptoms of tobramycin hypersensitivity. Loteprednol is also contraindicated in individuals with glycerin hypersensitivity or hypersensitivity to loteprednol, corticosteroid hypersensitivity, or sensitivity to any of the other product ingredients (edetate disodium, povidone, tyloxapol, and benzalkonium chloride). If hypersensitivity develops, discontinue use and institute appropriate therapy.

    Fungal infection, herpes infection, herpes simplex keratitis (dendritic keratitis), mycobacterial infection, ocular infection, varicella, viral infection

    The use of ocular steroids may prolong the course and exacerbate the severity of ocular infections. Ophthalmic steroid use may result in delayed or impaired wound healing of the eye or cornea, or mask the signs of ocular infection. Loteprednol, as with other ophthalmic corticosteroids, is contraindicated in most cases of viral infection of the cornea and conjunctiva including herpes infection, such as epithelial herpes simplex keratitis (dendritic keratitis), and varicella. Loteprednol is also contraindicated in mycobacterial infection of the eye and fungal infection of ocular structures. Fungal infections of the cornea may develop with long-term ocular application of steroids. Fungal invasion should be evaluated in any persistent corneal ulceration where corticosteroid treatment has been used. Fungal cultures should be taken when appropriate. Corticosteroid therapy can also exacerbate purulent bacterial infections of the eye. If signs and symptoms do not improve or appear to worsen, loteprednol and tobramycin therapy should be reevaluated.

    Glaucoma, increased intraocular pressure, open-angle glaucoma

    Intraocular hypertension is most likely to occur in patients receiving prolonged ophthalmic corticosteroids and in patients with glaucoma. Intraocular pressure elevations are usually greater in eyes with open-angle glaucoma. If loteprednol etabonate is used for 10 days or longer, intraocular pressure should be monitored. If ocular signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. Regular ophthalmic examinations are recommended after 14 days of loteprednol and tobramycin therapy to identify corneal abnormalities, lens opacities, and increased intraocular pressure (IOP). Periodic slit-lamp examinations for punctate, herpetic, or fungal keratitis is necessary. Where appropriate, fluorescein staining should be done.

    Cataracts

    The use of steroids immediately after cataract surgery may delay healing and increase the incidence of bleb formation. Use loteprednol and tobramycin with caution in patients who have had cataracts recently removed.

    Diabetes mellitus

    Long-term ocular administration of corticosteroids for several years has been associated with the formation of posterior subcapsular (PSC) cataracts. Patients with diabetes mellitus appear to be more susceptible to developing PSC cataracts during ocular steroid use. Patients should be monitored for the development of lens opacities during long-term loteprednol and tobramycin therapy.

    Corneal abrasion

    In patients with corneal or scleral thinning, administration of topical ophthalmic corticosteroids have caused perforations. Loteprednol should be used with caution in patients with a corneal abrasion.

    Contact lenses

    Patients who wear contact lenses should be aware that benzalkonium chloride, a preservative in loteprednol and tobramycin combination preparations, can be absorbed by soft contact lenses. Patients should not wear contact lenses when using this ophthalmic preparation.

    Pregnancy

    There are no adequate and well-controlled studies regarding the use of loteprednol etabonate; tobramycin in pregnant women. In animal studies, orally administered loteprednol etabonate produced embryotoxicity (delayed ossification) and teratogenicity (meningocele, abnormal left common carotid artery, and limb fixtures) at a dose that was 35-times the maximum daily clinical dose in rabbits. Teratogenicity was also observed when loteprednol was orally administered to pregnant rats at doses of 5 mg/kg/day and greater. The no-observed-effect-level (NOEL) for these effects in rats and rabbits was seen at oral loteprednol doses of 0.5 mg/kg/day (6 times the maximum daily clinical dose). No evidence of fetal harm has been observed at parenteral tobramycin doses up to 100 mg/kg/day in animal reproductive studies involving rats and rabbits. Although loteprednol etabonate; tobramycin is not significantly absorbed following ophthalmic administration with plasma concentrations less than 1 ng/mL, the drug should be used during pregnancy only if the potential benefits outweigh the risks of therapy. To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration.

    Breast-feeding

    According to the manufacturer, it is unknown whether loteprednol; tobramycin ophthalmic solution is sufficiently systemically absorbed to produce detectable quantities in human milk. However, pharmacokinetic studies indicate that loteprednol is not significantly absorbed following ophthalmic administration with plasma concentrations less than 1 ng/mL, and therefore it is unlikely that a significant amount of drug would be excreted into breast-milk. When used in low doses, systemically administered corticosteroids (e.g., prednisone) are distributed into breast milk in quantities not likely to have a deleterious effect on the infant. The American Academy of Pediatrics (AAP) did not evaluate loteprednol in breast-feeding mothers; however, previous AAP recommendations considered the corticosteroids prednisone and prednisolone to be usually compatible with lactation. Aminoglycosides are generally excreted into breast milk in low concentrations. However, they are poorly absorbed from the gastrointestinal tract are not likely to cause adverse events in nursing infants. Tobramycin breast milk concentrations after systemic administration are around 0.52 mcg/mL. Previous AAP recommendations considered several aminoglycosides to be compatible with breast-feeding. To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Children, infants, neonates

    Safety and efficacy of loteprednol; tobramycin ophthalmic suspension in neonates, infants, children, and adolescents have not been established. Two trials have been conducted to evaluate the safety and efficacy in pediatric patients aged 0—6 years. In the first trial, patients with lid inflammation received either loteprednol; tobramycin with warm compresses or vehicle only with warm compresses. The results failed to show increased efficacy with active treatment, as the majority of patients in both treatment groups demonstrated reduced lid inflammation. In the second trial, patients with blepharoconjunctivitis were treated with either loteprednol; tobramycin, vehicle only, loteprednol ophthalmic suspension, or tobramycin ophthalmic suspension. Data from this trial also failed to show increased efficacy with the combination product. There was no difference in safety between the treatment groups in either trial.

    Geriatric

    No overall differences in safety and efficacy of loteprednol; tobramycin have been observed between geriatric and younger adult patients.

    ADVERSE REACTIONS

    Severe

    keratitis / Delayed / 15.0-15.0
    ocular hypertension / Delayed / 10.0-10.0
    visual impairment / Early / Incidence not known

    Moderate

    ocular infection / Delayed / 20.0-20.0
    corneal deposits / Delayed / 0-4.0
    photophobia / Early / 0-4.0
    impaired wound healing / Delayed / Incidence not known
    superinfection / Delayed / Incidence not known
    blepharitis / Early / Incidence not known
    conjunctivitis / Delayed / Incidence not known
    cataracts / Delayed / Incidence not known

    Mild

    headache / Early / 14.0-14.0
    ocular irritation / Rapid / 0-4.0
    ocular discharge / Delayed / 0-4.0
    ocular pain / Early / 0-4.0
    ocular pruritus / Rapid / 0-4.0

    DRUG INTERACTIONS

    There are no drug interactions associated with Loteprednol; Tobramycin products.

    PREGNANCY AND LACTATION

    Pregnancy

    There are no adequate and well-controlled studies regarding the use of loteprednol etabonate; tobramycin in pregnant women. In animal studies, orally administered loteprednol etabonate produced embryotoxicity (delayed ossification) and teratogenicity (meningocele, abnormal left common carotid artery, and limb fixtures) at a dose that was 35-times the maximum daily clinical dose in rabbits. Teratogenicity was also observed when loteprednol was orally administered to pregnant rats at doses of 5 mg/kg/day and greater. The no-observed-effect-level (NOEL) for these effects in rats and rabbits was seen at oral loteprednol doses of 0.5 mg/kg/day (6 times the maximum daily clinical dose). No evidence of fetal harm has been observed at parenteral tobramycin doses up to 100 mg/kg/day in animal reproductive studies involving rats and rabbits. Although loteprednol etabonate; tobramycin is not significantly absorbed following ophthalmic administration with plasma concentrations less than 1 ng/mL, the drug should be used during pregnancy only if the potential benefits outweigh the risks of therapy. To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration.

    According to the manufacturer, it is unknown whether loteprednol; tobramycin ophthalmic solution is sufficiently systemically absorbed to produce detectable quantities in human milk. However, pharmacokinetic studies indicate that loteprednol is not significantly absorbed following ophthalmic administration with plasma concentrations less than 1 ng/mL, and therefore it is unlikely that a significant amount of drug would be excreted into breast-milk. When used in low doses, systemically administered corticosteroids (e.g., prednisone) are distributed into breast milk in quantities not likely to have a deleterious effect on the infant. The American Academy of Pediatrics (AAP) did not evaluate loteprednol in breast-feeding mothers; however, previous AAP recommendations considered the corticosteroids prednisone and prednisolone to be usually compatible with lactation. Aminoglycosides are generally excreted into breast milk in low concentrations. However, they are poorly absorbed from the gastrointestinal tract are not likely to cause adverse events in nursing infants. Tobramycin breast milk concentrations after systemic administration are around 0.52 mcg/mL. Previous AAP recommendations considered several aminoglycosides to be compatible with breast-feeding. To minimize the amount of drug that reaches systemic circulation, apply pressure over the tear duct in the corner of the eye for 1 to 2 minutes after ophthalmic administration. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    Mechanism of Action:•Loteprednol: Corticosteroids inhibit the inflammatory response to chemical, immunologic, or mechanical agents. Although the precise mechanism of action is unknown, the antiinflammatory actions are thought to involve phospholipase A2 inhibitory proteins, collectively called lipocortins. Lipocortins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of the precursor molecule arachidonic acid. Corticosteroids inhibit edema, fibrin deposition, capillary dilatation, and migration of leukocytes and phagocytes in the acute inflammatory response. They may also reduce capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation. They also inhibit the body's immune response against infection and reduce the outflow of aqueous humor, thereby increasing intraocular pressure and inducing or aggravating open-angle glaucoma.•Tobramycin: Tobramycin is a bactericidal aminoglycoside antibiotic. It binds irreversibly to one of two aminoglycoside binding sites on the 30 S ribosomal subunit and inhibits bacterial protein synthesis. However, inhibition of bacterial protein synthesis does not adequately explain tobramycin's bactericidal effects, since other non-aminoglycoside antibiotics that also inhibit protein synthesis are only bacteriostatic. One aspect essential to aminoglycoside lethality is the need to achieve intracellular concentrations in excess of extracellular. Anaerobic bacteria are not susceptible to aminoglycosides due, at least in part, to a lack of an active transport mechanism for aminoglycoside uptake.

    PHARMACOKINETICS

    The combination of loteprednol and tobramycin is administered topically to the eye. The pharmacokinetics of this drug combination have not been studied. The pharmacokinetic information below is based on administration of each agent alone.
    Loteprednol: Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism (primarily by hydrolysis) to inactive carboxylic acid metabolites.

    Other Route(s)

    Ophthalmic Route
    The ocular concentration of loteprednol in combination with tobramycin was found to be comparable to the concentration of loteprednol alone. Loteprednol penetration into the eye is neither increased or decreased with the addition of tobramycin to the preparation.
    Loteprednol: Limited systemic (< 1 ng/ml) absorption of loteprednol occurs following daily administration. Bioavailability data in normal volunteers receiving 0.5% loteprednol etabonate eight times daily for 2 days or four times daily for 42 days demonstrated insignificant plasma levels of loteprednol etabonate and its primary carboxylic acid metabolite at all sampling times.
    Tobramycin: Animal data suggest that tobramycin is absorbed into the aqueous humor after topical administration of an ophthalmic solution containing the drug. It is not known whether tobramycin is absorbed into the vitreous humor. Absorption of tobramycin into the aqueous humor is greatest when the cornea is abraded. One manufacturer of tobramycin states that topically administered tobramycin is cleared from the surface of the eye in approximately 15—30 minutes when administered as a solution.