Loteprednol Etabonate (Page 2 of 2)

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: 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 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 mg/kg/day (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.

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.

ADVERSE REACTIONS

Reactions associated with ophthalmic steroids include elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, posterior subcapsular cataract formation, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.

Ocular adverse reactions occurring in 5% to 15% of patients treated with loteprednol etabonate ophthalmic suspension (0.2% to 0.5%) in clinical studies included abnormal vision/blurring, burning on instillation, chemosis, discharge, dry eyes, epiphora, foreign body sensation, itching, injection, and photophobia. Other ocular adverse reactions occurring in less than 5% of patients include conjunctivitis, corneal abnormalities, eyelid erythema, keratoconjunctivitis, ocular irritation/pain/discomfort, papillae, and uveitis. Some of these events were similar to the underlying ocular disease being studied.

Non-ocular adverse reactions occurred in less than 15% of patients. These include headache, rhinitis and pharyngitis.
In controlled, randomized studies of individuals treated for 28 days or longer with loteprednol etabonate, the incidence of significant elevation of intraocular pressure (≥10 mmHg) 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.

To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DOSAGE AND ADMINISTRATION

SHAKE VIGOROUSLY BEFORE USING.

Steroid Responsive Disease Treatment: Apply one to two drops of loteprednol etabonate ophthalmic suspension into the conjunctival sac of the affected eye(s) four times daily. During the initial treatment within the first week, the dosing may be increased, up to 1 drop every hour, if necessary. Care should be taken not to discontinue therapy prematurely. If signs and symptoms fail to improve after two days, the patient should be re-evaluated (see PRECAUTIONS).

Post-Operative Inflammation: Apply one to two drops of loteprednol etabonate ophthalmic suspension into the conjunctival sac of the operated eye(s) four times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the post-operative period.

HOW SUPPLIED

Loteprednol etabonate ophthalmic suspension is supplied in a white opaque LDPE plastic dropper bottle with LDPE white opaque plug and HDPE pilfer-proof pink cap as follows:

5 mL (NDC 62756-232-90)

10 mL (NDC 62756-232-55)

15 mL (NDC 62756-232-56)

Storage: Store upright between 20°C-25°C (68°-77°F). DO NOT FREEZE.

KEEP OUT OF REACH OF CHILDREN.
Rx only

Manufactured by:

Sun Pharmaceutical Medicare Ltd.

Baska Ujeti Road, Ujeti,

Halol-389350, Gujarat, India.

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Version Date:

ISS. 08/2020

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-Carton

NDC 62756-232-90
Loteprednol Etabonate Ophthalmic Suspension 0.5%
For Ophthalmic Use Only
Rx only
Sterile
5 mL SUN PHARMA

spl-loteprednol-carton
(click image for full-size original)

spl-loteprednol-carton

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL-Label

NDC 62756-232-90
Loteprednol Etabonate Ophthalmic Suspension 0.5%
For Ophthalmic Use Only5 mL

spl-loteprednol-label
(click image for full-size original)
LOTEPREDNOL ETABONATE loteprednol etabonate suspension/ drops
Product Information
Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:62756-232
Route of Administration OPHTHALMIC DEA Schedule
Active Ingredient/Active Moiety
Ingredient Name Basis of Strength Strength
LOTEPREDNOL ETABONATE (LOTEPREDNOL) LOTEPREDNOL ETABONATE 5 mg in 1 mL
Inactive Ingredients
Ingredient Name Strength
EDETATE DISODIUM
GLYCERIN
POVIDONE, UNSPECIFIED
WATER
TYLOXAPOL
HYDROCHLORIC ACID
SODIUM HYDROXIDE
BENZALKONIUM CHLORIDE 0.2 mg in 1 mL
Packaging
# Item Code Package Description Multilevel Packaging
1 NDC:62756-232-90 1 BOTTLE in 1 CARTON contains a BOTTLE
1 5 mL in 1 BOTTLE This package is contained within the CARTON (62756-232-90)
2 NDC:62756-232-55 1 BOTTLE in 1 CARTON contains a BOTTLE
2 10 mL in 1 BOTTLE This package is contained within the CARTON (62756-232-55)
3 NDC:62756-232-56 1 BOTTLE in 1 CARTON contains a BOTTLE
3 15 mL in 1 BOTTLE This package is contained within the CARTON (62756-232-56)
Marketing Information
Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA212450 05/01/2021
Labeler — Sun Pharmaceutical Industries, Inc. (146974886)
Establishment
Name Address ID/FEI Operations
Sun Pharmaceutical Medicare Limited 725420835 ANALYSIS (62756-232), MANUFACTURE (62756-232)

Revised: 05/2021 Sun Pharmaceutical Industries, Inc.

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