ZYLET ® (LOTEPREDNOL ETABONATE 0.5% AND TOBRAMYCIN 0.3% OPHTHALMIC SUSPENSION) TECHNICAL PAPER 1 A CLINICAL DIAGNOSIS Blepharitis is a clinical diagnosis made on the basis of typical signs and symptoms. A thorough history and care- ful ocular examination are essential to appropriate diagnosis and treatment of the condition. e symptoms of blepha- ritis include burning, irritation, tearing, itching, and foreign-body sensation. Ocular signs of blepharitis may or may not correlate with the severity of symptoms. Yellowish crusting of the anterior lid margin is typical of staphy- lococcal overgrowth, the most common cause of anterior blepharitis and associ- ated conjunctivitis, whereas patients with seborrheic blepharitis oſten have scurf or flaking in their lashes or eyebrows. e inflammatory changes I look for on the eyelid include thickening, erythema, tel- angiectasia, scarring, and notching. Eye- Blepharitis—inflammation of the eyelid—is one of the most common disorders eyecare practitioners encoun- ter. 1 Blepharitis can result from many causes and has diverse possible mani- festations. Oſten chronic and recurring, blepharitis is most simply classified anatomically, into two forms: anteri- or (affecting the anterior lid margin and eyelashes) and posterior (affect- ing primarily the meibomian glands). Both anterior and posterior bleph- aritis can have an infectious (predomi- nantly staphylococcal) or inflammatory (eg, seborrheic or allergic) etiology. 1 Especially in clinically significant cases, however, it is oſten difficult to find a sin- gle cause. Indeed, both infectious and in- flammatory mechanisms may contribute simultaneously and may reinforce one another: in addition to directly causing eyelid inflammation, colonizing bacteria produce lipolytic exoenzymes that can affect the quality of meibomian gland secretions, leading to reduced tear film integrity and associated ocular surface inflammation. 1 Blepharitis is characterized by symp- toms of ocular discomfort, which can be significant. Patients with chronic blepharitis may develop other ocular problems including chronic conjuncti- vitis, keratitis, and recurrent hordeolum or chalazion. Untreated blepharitis may over time lead to irreversible structural Blepharitis: A Treatment Approach damage, such as eyelid notching, and vi- sion-threatening sequelae such as corne- al neovascularization and scarring. Ian Benjamin Gaddie, OD, FAAO Characterized by inflammation of the eyelid that is often chronic, blepharitis’ symptoms are important to treat. While seldom vision threatening on its own, blepharitis can cause ocular discomfort and can initiate associated conjunctivitis or even keratitis. Both inflammatory and infectious processes are often implicated in the pathogenesis of blepharitis. Eyelid hygiene is essential in the management of blepharitis but is often insufficient to control the disease, especially in acute presentations. Antiinflammatory and antiinfective therapy, combined with eyelid hygiene, can help in managing the condition and improving patient symptoms, especially for those with disease that affects the conjunctiva or cornea as well. Combining a broadly effective antibiotic with a potent corticosteroid that has a proven safety profile, ZYLET ® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) offers an excellent therapeutic option for patients with blepharitis. INDICATIONS AND USAGE ZYLET ® (loteprednol etabonate 0.5% and tobramycin 0.3% 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. IMPORTANT RISK INFORMATION ZYLET 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. 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 sued for 10 days or longer, intraocular pressure should be monitored. Use of corticosteroids may result in posterior subcapsular cataract formation. 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. Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infections. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated. Employment of 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 exacerbate the severity of many viral infections of the eye (including herpes simplex). Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid applica- tion. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. ADVERSE REACTIONS Most common adverse reactions reported in patients were injection and superficial punctate keratitis, increased intraocular pressure, burning and stinging upon instillation. Sponsored by Bausch + Lomb Please see the full prescribing information for ZYLET ® on pages 3 and 4.
Transcript
ZYLET® (LoTEprEdnoL ETabonaTE 0.5% and TobramYcin 0.3% ophThaLmic suspEnsion) TEchnicaL papEr 1
a CLiniCaL diaGnOsisBlepharitis is a clinical diagnosis
made on the basis of typical signs and symptoms. A thorough history and care-ful ocular examination are essential to appropriate diagnosis and treatment of the condition. Th e symptoms of blepha-ritis include burning, irritation, tearing, itching, and foreign-body sensation.
Ocular signs of blepharitis may or may not correlate with the severity of symptoms. Yellowish crusting of the anterior lid margin is typical of staphy-lococcal overgrowth, the most common cause of anterior blepharitis and associ-ated conjunctivitis, whereas patients with seborrheic blepharitis oft en have scurf or fl aking in their lashes or eyebrows. Th e infl ammatory changes I look for on the eyelid include thickening, erythema, tel-angiectasia, scarring, and notching. Eye-
Blepharitis—infl ammation of the eyelid—is one of the most common disorders eyecare practitioners encoun-ter.1 Blepharitis can result from many causes and has diverse possible mani-festations. Oft en chronic and recurring, blepharitis is most simply classifi ed anatomically, into two forms: anteri-or (aff ecting the anterior lid margin and eyelashes) and posterior (aff ect-ing primarily the meibomian glands).
Both anterior and posterior bleph-aritis can have an infectious (predomi-nantly staphylococcal) or infl ammatory (eg, seborrheic or allergic) etiology.1
Especially in clinically signifi cant cases, however, it is oft en diffi cult to fi nd a sin-gle cause. Indeed, both infectious and in-fl ammatory mechanisms may contribute simultaneously and may reinforce one another: in addition to directly causing eyelid infl ammation, colonizing bacteria produce lipolytic exoenzymes that can aff ect the quality of meibomian gland secretions, leading to reduced tear fi lm integrity and associated ocular surface infl ammation.1
Blepharitis is characterized by symp-toms of ocular discomfort, which can be signifi cant. Patients with chronic blepharitis may develop other ocular problems including chronic conjuncti-vitis, keratitis, and recurrent hordeolum or chalazion. Untreated blepharitis may over time lead to irreversible structural
Blepharitis: A treatment Approach
damage, such as eyelid notching, and vi-sion-threatening sequelae such as corne-al neovascularization and scarring.
ian Benjamin Gaddie, Od, FaaO
Characterized by inflammation of the eyelid that is often chronic,
blepharitis’ symptoms are important to treat. While seldom vision
threatening on its own, blepharitis can cause ocular discomfort and can
initiate associated conjunctivitis or even keratitis. Both inflammatory and
infectious processes are often implicated in the pathogenesis of blepharitis.
eyelid hygiene is essential in the management of blepharitis but is often insufficient
to control the disease, especially in acute presentations. Antiinflammatory and
antiinfective therapy, combined with eyelid hygiene, can help in managing the
condition and improving patient symptoms, especially for those with disease that
affects the conjunctiva or cornea as well. Combining a broadly effective antibiotic
with a potent corticosteroid that has a proven safety profile, Zylet® (loteprednol
etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) offers an excellent
therapeutic option for patients with blepharitis.
Characterized by inflammation of the eyelid that is often chronic,
blepharitis’ symptoms are important to treat. While seldom vision
threatening on its own, blepharitis can cause ocular discomfort and can
initiate associated conjunctivitis or even keratitis. Both inflammatory and
infectious processes are often implicated in the pathogenesis of blepharitis.
INDICAtIONS AND USAGeZYLET® (loteprednol etabonate 0.5% and tobramycin 0.3% 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.
IMPORtANt RISK INFORMAtIONZYLET 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.
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 sued for 10 days or longer, intraocular pressure should be monitored.
Use of corticosteroids may result in posterior subcapsular cataract formation.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.
Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may mask infection or enhance existing infections. If signs and symptoms fail to improve after 2 days, the patient should be re-evaluated.
Employment of 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 exacerbate the severity of many viral infections of the eye (including herpes simplex).
Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid applica-tion. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use.
ADVeRSe ReACtIONSMost common adverse reactions reported in patients were injection and superficial punctate keratitis, increased
intraocular pressure, burning and stinging upon instillation.
Sponsored by Bausch + Lomb Please see the full prescribing information for Zylet® on pages 3 and 4.
2 ZYLET® (LoTEprEdnoL ETabonaTE 0.5% and TobramYcin 0.3% ophThaLmic suspEnsion) TEchnicaL papEr
lash changes such as madarosis, trichia-sis, and poliosis may also present as signs of chronic eyelid infl ammation.
One of the most common symptoms in blepharitis patients is itching, which is also a hallmark symptom of allergic con-junctivitis. To diff erentiate the two, I ask patients to describe whether the itching sensation seems to be concentrated on the conjunctiva—the eye itself—or on the lids. Patients oft en assume they have ocular allergies, but asking where pre-cisely their eyes itch will sometimes re-veal that the root problem is blepharitis.
When tO treatAlthough blepharitis is a very com-
treatMent GUided BY CaUseEyelid hygiene, which consists of
warm compresses, lid massage, and lid scrubs, continues to be a mainstay of blepharitis treatment. While removing bacterial deposits and oily debris is help-ful in reducing signs and symptoms, the practice of lid hygiene alone is oft en in-adequate for disease control and symp-tom resolution.
In my view, the treatment should take aim at the underlying causes of the disease. In many cases, signifi cant infl ammation and infectious bacterial overgrowth both contribute to the signs and symptoms. To address both of these components, I recommend combining lid hygiene measures with antiinfl am-matory and antibiotic therapy in these patients.
aGent seLeCtiOnMy agent of choice for the medi-
cal treatment of blepharitis is ZYLET® (loteprednol etabonate 0.5% and tobra-mycin 0.3% ophthalmic suspension), an agent that combines antiinfl ammatory effi cacy with broad antibacterial cover-age.2,3 A combination agent combines infl ammation control and antibacterial action in a single drop.
Tobramycin, the antiinfective com-ponent of ZYLET®, is a broad-spectrum aminoglycoside antibiotic. Th e agent has an established safety profi le and ex-cellent activity against common ocular pathogens, including the gram-positive bacteria residing on the eyelids that oft en contribute to blepharitis.4
Loteprednol etabonate, an ester cor-ticosteroid, has high therapeutic poten-cy and an established safety profi le. Th e loteprednol etabonate molecule was de-signed for predictable breakdown into inactive metabolites aft er eliciting its therapeutic eff ects.5 Indeed, loteprednol etabonate has a low propensity to cause a signifi cant intraocular pressure ele-vation, even in known steroid respond-ers.4,5 However, if the product is used for 10 days or longer, intraocular pressure should be monitored.
Its safety profi le and clinical effi cacy for patients with acute blepharitis give me confi dence in prescribing ZYLET®.
mon condition, not all patients are symptomatic. In my experience, bleph-aritis associated with rosacea or atopic disease can be asymptomatic until late stages of the disease. Instead of diagnos-ing every single patient with any form of blepharitis, a more practical goal may be to identify those who have more acute, progressed disease and signifi cantly dis-comforting symptoms.
My approach is to look for conjuncti-vitis and other ocular morbidities asso-ciated with blepharitis. Th e presence of such secondary conditions is a defi nite indication for treatment; such patients are nearly always symptomatic and may benefi t noticeably from intervention.
Case stUdY: ChrOniC BLePharOCOnJUnCtiVitis
a 52-year-old woman presented with a chief complaint of blurry vision and irritated, injected eyes. over the previous 3 months, symptoms had gradually progressed from occasional to almost constant. recently, she had been nearly incapacitated due to constant watering and tearing. The symptoms tended to peak in the early morning and late afternoon/evening. occasionally, her eyelids were sticky and crusty in the morning, sometimes requiring a warm washcloth to open.
Entering bcVa was 20/25 in each eye. anterior segment evaluation revealed an oily tear film, plugged meibomian glands, and patchy yellow debris along the lash line on both the
upper and lower eyelids. The orbital skin and adnexa was very oily, with sheen evident on slit lamp examination. The upper lash line had cylindrical dandruff collars around the lashes (Figure 1). The palpebral conjunctiva also showed a mild follicular response.
We diagnosed the patient with chronic blepharoconjunctivitis and started her on ZYLET® (loteprednol etabonate 0.5% and tobramycin 0.3% ophthalmic suspension) four times daily in both eyes. The patient
was instructed to rub any excess drop into her eyelash line. in addition, the patient was instructed to wash her face and scrub her eyelashes with a hot washcloth prior to drop instillation.
at the 2-week follow up visit, the patient’s vision had improved to 20/20 in each eye. The watering and mattering was completely resolved, as were the scurf and yellow debris
(Figure 2). she was still having difficulty with redness, but it had markedly improved.
The medication was reduced to twice daily for two more weeks and a follow up appointment was scheduled. at the next appointment, all symptoms were resolved. The ZYLET® was discontinued and conservative lid scrubs daily were prescribed along with oil based artificial tears. her symptoms have not returned to date.
ChrOniC BLePharOCOnJUnCtiVitis
a 52-year-old woman presented with a chief complaint of blurry vision and irritated, injected eyes. over the previous 3 months, symptoms had gradually progressed from occasional to almost constant. recently, she had been nearly incapacitated due to
Figure 1. Chronic blepharoconjunctivitis with
cylindrical dandruff around the lashes.
Figure 2. Absence of scurf and yellow debris
following 2 weeks of treatment.
Sponsored by Bausch + Lomb Please see Important Risk Information on page 1 and the full prescribing information for Zylet® on pages 3 and 4.
ZYLET® (LoTEprEdnoL ETabonaTE 0.5% and TobramYcin 0.3% ophThaLmic suspEnsion) TEchnicaL papEr 3
Other COnsideratiOns Because blepharitis is often chronic,
clear patient counseling about the role of eyelid hygiene and the use of ZYLET® are paramount. It is not uncommon for patients to stop prescribed therapy upon sign and symptom improvement, only to experience a recurrence soon afterward.
As a combination agent, ZYLET® of-fers patients an antiinflammatory agent and an antiinfective agent in one drop. ZYLET® is a good choice for treating blepharitis.
Along with eyelid hygiene and, where applicable, warm compresses, I dose ZYLET® QID for 1 to 2 weeks and I bring patients back at about 2 weeks to assess treatment efficacy and to check intra-ocular pressure. I take time to instruct patients to shake the bottle well prior to instillation, and to rub any excess onto the lids and lash line with clean hands.
Ian Benjamin Gaddie, OD, FAAO, is owner and director of the Gaddie Eye Centers in Louisville, KY.
Please see Important Risk Information on page 1
and the full prescribing information for Zylet® on
this page and the next.
reFerenCes 1. Jackson WB. Blepharitis: current strategies for
diagnosis and management. Can J Ophthalmol. 2008;43:170-9.
2. White EM, Macy JI, Bateman KM, et al. Com-parison of the safety and efficacy of loteprednol 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of bleph-arokeratoconjunctivitis. Curr Med Res Opin. 2008;24(1):287-96.
3. Chen M, Gong L, Sun X, et al. A multicenter, ran-domized, parallel-group, clinical trial comparing the safety and efficacy of loteprednol etabonate 0.5%/tobramycin 0.3% with dexamethasone 0.1%/tobramycin 0.3% in the treatment of Chi-nese patients with blepharokeratoconjunctivitis. Curr Med Res Opin. 2012;28(3):385-94.
4. Comstock TL, Holland EJ. Loteprednol and to-bramycin in combination: a review of their im-pact on current treatment regimens. Expert Opin Pharmacother. 2010;11(5):843-50.
5. Comstock TL, Decory HH. Advances in cortico-steroid therapy for ocular inflammation: lotepre-dnol etabonate. Int J Inflam. 2012;2012:789623.
®/™ are trademarks of Bausch & Lomb Incorporated or its affiliates. All other product/brand names are trademarks of their respective owners.
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 informa-tion 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: 2004- - - -- - - -- - - -- - - -- INDICATIONS AND USAGE - - - -- - - -- - - -- - - --Zylet 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 ADMINISTRATION- -- - - -- - - -- - - --Apply one or two drops of Zylet into the conjunctival sac of the affected eye every four to six hours. (2.1)- - - -- - - -- - - -- - DOSAGE FORMS AND STRENGTHS -- - - -- - - -- - - -- Zylet contains 5 mg/mL loteprednol etabonate and 3 mg/mL tobramycin. (3)- - - -- - - -- - - -- - - -- - 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. (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 ap-propriate, 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 (includ-ing herpes simplex). (5.5)
• Fungal infections–Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid applica-tion. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. (5.6)
- - - -- - - -- - - -- - - -- - ADVERSE REACTIONS- -- - - -- - - -- - - -- - - --Most common adverse reactions reported in patients were injection and superficial punctate keratitis, increased intraocular pressure, burn-ing 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/medwatchSee 17 for PATIENT COUNSELING INFORMATION
Revised: 08/2013
FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION2.1 Recommended Dosing2.2 Prescription Guideline3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS4.1 Nonbacterial Etiology5 WARNINGS AND PRECAUTIONS5.1 Intraocular Pressure (IOP) Increase5.2 Cataracts5.3 Delayed Healing5.4 Bacterial Infections5.5 Viral Infections5.6 Fungal Infections5.7 Aminoglycoside Hypersensitivity
6 ADVERSE REACTIONS8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are not listed
FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEZylet® 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, Pseu-domonas 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 ADMINISTRATION2.1 Recommended DosingApply 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 GuidelineNot 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 STRENGTHSZylet (loteprednol etabonate and tobramycin ophthalmic suspension) 0.5%/0.3% contains 5 mg/mL loteprednol etabonate and 3 mg/mL tobramycin.4 CONTRAINDICATIONS4.1 Nonbacterial EtiologyZylet, 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) IncreaseProlonged 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 CataractsUse of corticosteroids may result in posterior subcapsular cataract formation.5.3 Delayed HealingThe 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 InfectionsProlonged 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 InfectionsEmployment 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 InfectionsFungal 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 HypersensitivitySensitivity 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.
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Sponsored by Bausch + Lomb
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Sponsored by Bausch + Lomb Please see Important Risk Information for Zylet® on page 1.
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 informa-tion 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: 2004- - - -- - - -- - - -- - - -- INDICATIONS AND USAGE - - - -- - - -- - - -- - - --Zylet 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 ADMINISTRATION- -- - - -- - - -- - - --Apply one or two drops of Zylet into the conjunctival sac of the affected eye every four to six hours. (2.1)- - - -- - - -- - - -- - DOSAGE FORMS AND STRENGTHS -- - - -- - - -- - - -- Zylet contains 5 mg/mL loteprednol etabonate and 3 mg/mL tobramycin. (3)- - - -- - - -- - - -- - - -- - 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. (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 ap-propriate, 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 (includ-ing herpes simplex). (5.5)
• Fungal infections–Fungal infections of the cornea are particularly prone to develop coincidentally with long-term local steroid applica-tion. Fungus invasion must be considered in any persistent corneal ulceration where a steroid has been used or is in use. (5.6)
- - - -- - - -- - - -- - - -- - ADVERSE REACTIONS- -- - - -- - - -- - - -- - - --Most common adverse reactions reported in patients were injection and superficial punctate keratitis, increased intraocular pressure, burn-ing 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/medwatchSee 17 for PATIENT COUNSELING INFORMATION
Revised: 08/2013
FULL PRESCRIBING INFORMATION: CONTENTS*1 INDICATIONS AND USAGE2 DOSAGE AND ADMINISTRATION2.1 Recommended Dosing2.2 Prescription Guideline3 DOSAGE FORMS AND STRENGTHS4 CONTRAINDICATIONS4.1 Nonbacterial Etiology5 WARNINGS AND PRECAUTIONS5.1 Intraocular Pressure (IOP) Increase5.2 Cataracts5.3 Delayed Healing5.4 Bacterial Infections5.5 Viral Infections5.6 Fungal Infections5.7 Aminoglycoside Hypersensitivity
6 ADVERSE REACTIONS8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy8.3 Nursing Mothers8.4 Pediatric Use8.5 Geriatric Use11 DESCRIPTION12 CLINICAL PHARMACOLOGY12.1 Mechanism of Action12.3 Pharmacokinetics13 NONCLINICAL TOXICOLOGY13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility16 HOW SUPPLIED/STORAGE AND HANDLING17 PATIENT COUNSELING INFORMATION*Sections or subsections omitted from the full prescribing information are not listed
FULL PRESCRIBING INFORMATION1 INDICATIONS AND USAGEZylet® 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, Pseu-domonas 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 ADMINISTRATION2.1 Recommended DosingApply 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 GuidelineNot 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 STRENGTHSZylet (loteprednol etabonate and tobramycin ophthalmic suspension) 0.5%/0.3% contains 5 mg/mL loteprednol etabonate and 3 mg/mL tobramycin.4 CONTRAINDICATIONS4.1 Nonbacterial EtiologyZylet, 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) IncreaseProlonged 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 CataractsUse of corticosteroids may result in posterior subcapsular cataract formation.5.3 Delayed HealingThe 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 InfectionsProlonged 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 InfectionsEmployment 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 InfectionsFungal 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 HypersensitivitySensitivity 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.
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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 de-velopment 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 MothersIt is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detect-able 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 UseTwo 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 DESCRIPTIONZylet (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
