Zylet
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ZYLET (loteprednol etabonate and tobramycin ophthalmic suspension) safely and effectively. See full prescribing information for ZYLET (loteprednol etabonate and tobramycin ophthalmic suspension, 0.5%/0.3%). Zylet (loteprednol etabonate and tobramycin ophthalmic suspension) 0.5%/0.3%Initial U.S. Approval: 2004INDICATIONS AND USAGEZylet is a topical anti-infective and steroid 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. (1)DOSAGE AND ADMINISTRATIONApply one or two drops of Zylet into the conjunctival sac of the affected eye every four to six hours. (2.1)DOSAGE FORMS AND STRENGTHSZylet contains 5 mg/mL loteprednol etabonate and 3 mg/mL tobramycin. (3)CONTRAINDICATIONSZylet, 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. (4.1)WARNINGS AND PRECAUTIONS •Intraocular pressure (IOP) – Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision. If this product is used for 10 days or longer, IOP should be monitored. (5.1) •Cataracts – Use of corticosteroids may result in posterior subcapsular cataract formation. (5.2) •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 a magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. (5.3) •Bacterial infections – Prolonged use of corticosteroids may suppress the host response and 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) Side EffectsMost common adverse reactions reported in patients were injection and superficial punctuate keratitis, increased intraocular pressure, burning and stinging upon instillation.(6) To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb at 1-800-323-0000 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
FULL PRESCRIBING INFORMATION: CONTENTS*
- 1 ZYLET INDICATIONS AND USAGE
- 2 ZYLET DOSAGE AND ADMINISTRATION
- 3 DOSAGE FORMS AND STRENGTHS
- 4 ZYLET CONTRAINDICATIONS
- 5 WARNINGS AND PRECAUTIONS
- 6 ZYLET ADVERSE REACTIONS
- 8 USE IN SPECIFIC POPULATIONS
- 11 ZYLET DESCRIPTION
- 12 CLINICAL PHARMACOLOGY
- 13 NONCLINICAL TOXICOLOGY
- 16 HOW SUPPLIED/STORAGE AND HANDLING
- 17 PATIENT COUNSELING INFORMATION
- PACKAGE/LABEL PRINCIPAL DISPLAY PANELNDC 24208-358-10 Bausch & Lomb Zylet® loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension Rx only 10 mL Sterile Ophthalmic Suspension
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
Zylet® 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 punctuate 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: Pregnancy Category C. 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:
Chemical name: chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate
Tobramycin:
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,. 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-25º C (59º-77º F).
PROTECT FROM FREEZING
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.
MANUFACTURER INFORMATION
BAUSCH & LOMB INCORPORATED
TAMPA, FLORIDA 33637 USA
©Bausch & Lomb Incorporated
Zylet is a registered trademark of Bausch & Lomb Incorporated.
9007705 (folded)
9004405 (flat)
Revised 08/2013
PACKAGE/LABEL PRINCIPAL DISPLAY PANELNDC 24208-358-10 Bausch & Lomb Zylet® loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension Rx only 10 mL Sterile Ophthalmic Suspension
Zyletloteprednol etabonate and tobramycin SUSPENSION/ DROPS
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