Zylet® loteprednol etabonate 0.5% and tobramycin 0.3%ophthalmic suspension

ZYLET - loteprednol etabonate and tobramycin suspension/ drops 
Bausch & Lomb Incorporated

----------

Zylet®
loteprednol etabonate 0.5%
and tobramycin 0.3%
ophthalmic suspension

STERILE

DESCRIPTION:

Zylet (loteprednol etabonate and tobramycin ophthalmic suspension), is a sterile, multiple dose topical anti-inflammatory corticosteroid and antibiotic 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:

Zylet

C24H31ClO7                         Mol. Wt. 466.96

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

Tobramycin:

Tobramycin

C18H37N5O9                           Mol. Wt. 467.52

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 mOsmol/kg.

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 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. It is highly lipid soluble which enhances its penetration into cells. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism to inactive carboxylic acid metabolites.

The antibiotic 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.

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.

INDICATIONS AND USAGE:

Zylet is 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.

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.

CONTRAINDICATIONS:

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. Zylet is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and to other corticosteroids.

WARNINGS:

NOT FOR INJECTION INTO THE EYE.

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. Sensitivity to topically applied aminoglycosides may occur in some patients. If sensitivity reaction does occur, discontinue use.

Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In those diseases causing thinning 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 medication in 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 after examination of the patient with the aid of magnification, such as slit lamp biomicroscopy and, where appropriate, fluorescein staining.

If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated.

If this product is used for 10 days or longer, intraocular pressure should be monitored even though it may be difficult 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.

As with other antibiotic preparations, prolonged use may result in overgrowth of nonsusceptible organisms, including fungi. If superinfection occurs, appropriate therapy should be initiated.

Cross-sensitivity to other aminoglycoside antibiotics may occur; if hypersensitivity develops with this product, discontinue use and institute appropriate therapy.

Information for Patients:

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.

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 25mg/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).

Pregnancy:

Teratogenic effects

Pregnancy Category C.

Loteprednol etabonate was shown to be teratogenic when administered orally to rats and rabbits during organogenesis at 5 and 3 mg/kg/day, respectively (50 and 30 times the maximum daily clinical dose in rats and rabbits, respectively). An oral dose of loteprednol etabonate in rats at 50 mg/kg/day (500 times the maximum daily clinical dose) during late pregnancy through the weaning period showed a decrease in the growth and survival of pups without dystocia. However, no adverse effect in the pups was observed at 5 mg/kg/day (50 times the maximum daily clinical dose).

Parenteral doses of tobramycin did not show any harm to fetuses up to 100 mg/kg/day (1700 times the maximum daily clinical dose) in rats and rabbits.

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.

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 appear in human milk and 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.

Pediatric Use:

In a trial to evaluate the safety and efficacy of Zylet in pediatric subjects age zero to six years with lid inflammation, 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. There were no differences in safety assessments between the treatment groups.

Geriatric Use:

No overall differences in safety and effectiveness have been observed between elderly and younger patients.

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, the incidence of ocular adverse events reported in greater than 10% of subjects 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 adverse events reported in approximately 14% of subjects was headache; all other non-ocular events 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. Other adverse reactions have not been reported; however, if topical ocular tobramycin is administered concomitantly with systemic aminoglycoside antibiotics, care should be taken to monitor the total serum concentration.

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.

DOSAGE AND ADMINISTRATION:

SHAKE VIGOROUSLY BEFORE USING.

Apply one or two drops of Zylet into the conjunctival sac of the affected eye(s) 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. Not more than 20 mL should be prescribed initially and the prescription should not be refilled without further evaluation as outlined in PRECAUTIONS above.

HOW SUPPLIED:

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:

2.5 mL (NDC 24208-358-25) in a 7.5 mL bottle

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 15°-25°C (59°-77°F). PROTECT FROM FREEZING.

KEEP OUT OF REACH OF CHILDREN.

Rx only

Revised November 2009

Manufactured by:
Bausch & Lomb Incorporated
Tampa, Florida 33637
©Bausch & Lomb Incorporated

U.S. Patent Numbers: 4,996,335; 5,540,930; 5,747,061

Zylet is a registered trademark of Bausch & Lomb Incorporated

9007702 (FOLDED)
9004402 (FLAT)

Principle Display Panel

10 mL Carton

NDC 24208-358-10

Bausch & Lomb

Zylet®

loteprednol etabonate 0.5% and tobramycin 0.3%
ophthalmic suspension

Rx only

10 mL

Sterile Ophthalmic Suspension


ZYLET 
loteprednol etabonate and tobramycin   suspension/ drops
Product Information
Product TypeHUMAN PRESCRIPTION DRUGNDC Product Code (Source)24208-358
Route of AdministrationOPHTHALMICDEA Schedule    
Active Ingredient/Active Moiety
Ingredient NameBasis of StrengthStrength
LOTEPREDNOL ETABONATE (LOTEPREDNOL) LOTEPREDNOL ETABONATE5 mg  in 1 mL
TOBRAMYCIN (TOBRAMYCIN) TOBRAMYCIN3 mg  in 1 mL
Inactive Ingredients
Ingredient NameStrength
No Inactive Ingredients Found
Product Characteristics
Color    Score    
ShapeSize
FlavorImprint Code
Contains    
Packaging
#NDCPackage DescriptionMultilevel Packaging
124208-358-101 BOTTLE In 1 CARTONcontains a BOTTLE, DROPPER
110 mL In 1 BOTTLE, DROPPERThis package is contained within the CARTON (24208-358-10)
224208-358-251 BOTTLE In 1 CARTONcontains a BOTTLE, DROPPER
22.5 mL In 1 BOTTLE, DROPPERThis package is contained within the CARTON (24208-358-25)
324208-358-051 BOTTLE In 1 CARTONcontains a BOTTLE, DROPPER
35 mL In 1 BOTTLE, DROPPERThis package is contained within the CARTON (24208-358-05)

Marketing Information
Marketing CategoryApplication Number or Monograph CitationMarketing Start DateMarketing End Date
NDANDA05080412/14/2004

Labeler - Bausch & Lomb Incorporated (807927397)
Establishment
NameAddressID/FEIOperations
Bausch & Lomb Incorporated807927397MANUFACTURE
Revised: 12/2009Bausch & Lomb Incorporated