LOTEPREDNOL ETABONATE: 1,630 Adverse Event Reports & Safety Profile

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: Structure: Molecular formula: C 24 H 31 ClO 7 Molecular Weight:

466.95 Chemical name: Chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate Or (11β, 17α)-17-[(ethoxycarbonyl)oxy]-11-hydroxy-3-oxoandrosta-1,4-diene-17-carboxylic acid chloromethyl ester Tobramycin: Structure: Molecular formula: C 18 H 37 N 5 O 9 Molecular Weight:

467.51 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)]-2deoxystreptamine Each mL contains: Actives: Loteprednol Etabonate 5 mg (0.5%) and Tobramycin 3 mg (0.3%). Inactives: Edetate Disodium, Glycerin, Tyloxapol, Povidone, Water for Injection and Benzalkonium Chloride 0.01% (preservative).

Sulfuric

Acid and/or Sodium Hydroxide may be added to adjust the pH to 5.5 to 6.2. The suspension is essentially isotonic with a tonicity of 260 to 320 mOsm/kg. loteprednol-structure loteprednol-tobra-structure

AND USAGE Loteprednol Etabonate and Tobramycin Ophthalmic Suspension 0.5%/0.3% 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.

Loteprednol

Etabonate and Tobramycin Ophthalmic Suspension is a combination of loteprednol etabonate, a corticosteroid, and tobramycin, an aminoglycoside antibacterial, 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. ( 1 )

AND ADMINISTRATION Shake for one to two seconds before using. ( 2 ) Instill one to two drops of INVELTYS into the affected eye twice daily beginning the day after surgery and continuing throughout the first 2 weeks of the post-operative period. ( 2 )

2.1 Dosage Information Instill one to two drops of INVELTYS into the affected eye twice daily beginning the day after surgery and continuing throughout the first 2 weeks of the post-operative period.

2.2 Administration Instructions Instruct patient to wash hands well before each use. Shake for one to two seconds before using. If the patient is using other eye drops in addition to INVELTYS , advise the patient to wait at least 5 minutes between instillation of INVELTYS and other eye drops.

2.1 Dosage Information Instill one to two drops of INVELTYS into the affected eye twice daily beginning the day after surgery and continuing throughout the first 2 weeks of the post-operative period.

2.2 Administration Instructions Instruct patient to wash hands well before each use. Shake for one to two seconds before using. If the patient is using other eye drops in addition to INVELTYS , advise the patient to wait at least 5 minutes between instillation of INVELTYS and other eye drops.

LOTEPREDNOL ETABONATE and TOBRAMYCIN ophthalmic suspension, 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 )

4.1 Nonbacterial Etiology Loteprednol etabonate and tobramycin ophthalmic suspension, 0.5%/0.3%, 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.

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. Loteprednol etabonate and tobramycin ophthalmic suspension, 0.5%/0.3% In a 42-day safety study comparing loteprednol etabonate and tobramycin ophthalmic suspension, 0.5%/0.3% to placebo, ocular adverse reactions included injection (approximately 20%) and superficial punctate keratitis (approximately 15%). Increased intraocular pressure was reported in 10% (loteprednol etabonate and tobramycin ophthalmic suspension, 0.5%/0.3%) and 4% (placebo) of subjects. Nine percent (9%) of loteprednol etabonate and tobramycin ophthalmic suspension, 0.5%/0.3%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. Most common adverse reactions reported in patients were injection and superficial punctate keratitis, increased intraocular pressure, burning and stinging upon instillation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Alembic Pharmaceuticals, Inc. at 1-866-210- 9797 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

AND PRECAUTIONS 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. 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 )

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.

5.8 Risk of Contamination Do not allow the dropper tip to touch any surface, as this may contaminate the suspension.

5.9 Contact Lens Wear As with all ophthalmic preparations containing benzalkonium chloride, patients should be advised not to wear soft contact lenses when using loteprednol etabonate and tobramycin ophthalmic suspension, 0.5%/0.3%.

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 two 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. Information for Patients 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 loteprednol etabonate ophthalmic suspension. Carcinogenesis, mutagenesis, impairment of fertility Long-term animal studies have not been conducted to evaluate the carcinogenic potential of loteprednol etabonate. Loteprednol etabonate was not genotoxic in the Ames test, the mouse lymphoma tk assay, or in a chromosome aberration test in human lymphocytes, three in vitro tests. In vivo evidence of genotoxicity, an increased frequency of micronucleated immature erythrocytes, was not observed in mice that received a single 4 gm/kg dose of loteprednol etabonate (50,000 times the maximum daily clinical dose). Treatment of male and female rats with up to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, (600 and 300 times the maximum clinical dose, respectively) prior to and during mating did not impair fertility in either gender.

Pregnancy

Teratogenic effects: Loteprednol etabonate has been shown to be embryotoxic (delayed ossification) and teratogenic (increased incidence of meningocele, abnormal left common carotid artery and limb flexures) 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 with 50 mg/kg/day or 100 mg/kg/day (600 and 1,200 times the maximum clinical dose) resulted in embryotoxicity (increased post-implantation losses with 100 mg/kg/day and decreased fetal body weight and skeletal ossification with 50 mg/kg/day and 100 mg/kg/day); doses of 5 (60 times the maximum daily clinical dose), 50 mg/kg/day and 100 mg/kg/day caused teratogenicity (absent innominate artery at all doses and cleft palate and umbilical hernia at 50 mg/kg/day and 100 mg/kg/day). 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 to 100 mg/kg/day but not at 0.5 mg/kg/day. The NOELs for the embryotoxic and teratogenic effects in rats were 5 mg/kg/day and 0.5 mg/kg/day (60 and 6 times the maximum daily clinical dose) for embryotoxicity and teratogenicity, respectively. Oral exposure of pregnant rats to 5 mg/kg/day and 50 mg/kg/day of loteprednol etabonate during the fetal period, a maternally toxic treatment regimen (significantly decreased body weight gain), resulted in teratogenicity (umbilical herniation) and embryotoxicity (decreased fetal birth weight); the NOEL for these effects was 0.5 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. Oral treatment of female rats with 25 mg/kg/day (300 times the maximum daily clinical dose) from prior to mating through parturition increased the duration of gestation.

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 loteprednol etabonate ophthalmic suspension is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Information for Patients 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 loteprednol etabonate ophthalmic suspension.