ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Adverse 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.The most common adverse drug reactions reported in the clinical trials (2-5%) were anterior chamber inflammation, eye pain, and foreign body sensation.. The most common adverse drug reactions (2-5%) were anterior chamber inflammation, eye pain, and foreign body sensation.(6)To report SUSPECTED ADVERSE REACTIONS, contact Bausch Lomb Incorporated, at 1-800-321-4576 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1 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 vitroin the Ames test, the mouse lymphoma tk assay, or in chromosome aberration test in human lymphocytes, or in vivoin the single dose mouse micronucleus assay.Treatment of female and male rats with doses >= 25 mg/kg/day of loteprednol etabonate (152 times the RHOD based on body surface area, assuming 100% absorption) prior to and during mating caused preimplantation loss and decreased the number of live fetuses/live births. The NOAEL for fertility in rats was mg/kg/day (30 times the RHOD).

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Corticosteroids inhibit the inflammatory response to 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. While glucocorticoids are known to bind to and activate the glucocorticoid receptor, the molecular mechanisms involved in glucocorticoid/glucocorticoid receptor-dependent modulation of inflammation are not clearly established. However, corticosteroids are thought to inhibit prostaglandin production through several independent mechanisms.. 12.3 Pharmacokinetics. Loteprednol etabonate is lipid soluble and can penetrate into cells. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo predictable transformation to an inactive metabolite. Based upon in vivoand in vitropreclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism to the inactive carboxylic acid metabolites, PJ-91 and PJ-90. The systemic exposure to loteprednol etabonate following ocular administration of LOTEMAX has not been studied in humans.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Adult StudiesIn two randomized, multicenter, double-masked, parallel-group, vehicle-controlled studies in 813 subjects with post-operative inflammation, LOTEMAX was more effective compared to its vehicle in resolving anterior chamber inflammation and pain following cataract surgery. Primary endpoints were complete resolution of anterior chamber cells (cell count of 0) and no pain at post-operative day 8. In these studies, LOTEMAX had statistically significant higher incidence of subjects with complete clearing of anterior chamber cells (31% vs. 14-16%) and were pain-free at post-operative day (73-76% vs. 42-46%).Pediatric StudyThe safety and effectiveness of LOTEMAX were evaluated in pediatric study of patients from birth to less than 11 years of age (mean age of years) undergoing cataract surgery. Patients were randomized to receive either LOTEMAX (54 patients) or prednisolone acetate ophthalmic suspension 1% (53 patients) four times daily for 14 days. At Day 14, the percentages of patients with complete clearing of anterior chamber inflammation were 57% in the LOTEMAX group and 63% in the prednisolone group.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. LOTEMAX is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, in mycobacterial infection of the eye and fungal diseases of ocular structures.. LOTEMAX is contraindicated in most viral diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, in mycobacterial infection of the eye and fungal diseases of ocular structures. (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Loteprednol etabonate is corticosteroid. Its chemical name is chloromethyl 17-[(ethoxycarbonyl)oxy]-11-hydroxy-3-oxoandrosta-1,4-diene-17-carboxylate. Its molecular formula is C24H31ClO7 and its chemical structure is:LOTEMAX (loteprednol etabonate ophthalmic gel) 0.5% contains sterile, topical corticosteroid for ophthalmic use. Loteprednol etabonate is white to off-white powder.Each gram contains:oACTIVE: loteprednol etabonate mg (0.5%)oINACTIVES: boric acid, edetate disodium dihydrate, glycerin, polycarbophil, propylene glycol, sodium chloride, tyloxapol, water for injection, and sodium hydroxide to adjust to pH of between and 7oPRESERVATIVE: benzalkonium chloride 0.003%. oACTIVE: loteprednol etabonate mg (0.5%). oINACTIVES: boric acid, edetate disodium dihydrate, glycerin, polycarbophil, propylene glycol, sodium chloride, tyloxapol, water for injection, and sodium hydroxide to adjust to pH of between and 7. oPRESERVATIVE: benzalkonium chloride 0.003%. Loteprednol etabonate structural formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. Invert closed bottle and shake once to fill tip before instilling drops.Apply one to two drops of LOTEMAX into the conjunctival sac of the affected eye four times daily beginning the day after surgery and continuing throughout the first weeks of the post-operative period. oInvert closed bottle and shake once to fill tip before instilling drops. (2)oApply one to two drops of LOTEMAX into the conjunctival sac of the affected eye four times daily beginning the day after surgery and continuing throughout the first weeks of the postoperative period. (2). oInvert closed bottle and shake once to fill tip before instilling drops. (2). oApply one to two drops of LOTEMAX into the conjunctival sac of the affected eye four times daily beginning the day after surgery and continuing throughout the first weeks of the postoperative period. (2).

DOSAGE FORMS & STRENGTHS SECTION.

3 DOSAGE FORMS AND STRENGTHS. LOTEMAX (loteprednol etabonate ophthalmic gel) is sterile preserved ophthalmic gel containing mg of loteprednol etabonate per gram of gel.. LOTEMAX is sterile preserved ophthalmic gel containing mg of loteprednol etabonate per gram of gel. (3).

GERIATRIC USE SECTION.

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

HOW SUPPLIED SECTION.

16 HOW SUPPLIED/STORAGE AND HANDLING. LOTEMAX(R) (loteprednol etabonate ophthalmic gel) 0.5% is sterile ophthalmic gel supplied in white low density polyethylene plastic bottle with white controlled drop tip and pink polypropylene cap in the following size:5 in 10 mL bottle (NDC 24208-503-07)Storage: Store upright at 15o to 25o (59o to 77o F).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. LOTEMAX(R) is corticosteroid indicated for the treatment of post-operative inflammation and pain following ocular surgery.. LOTEMAX is corticosteroid indicated for the treatment of postoperative inflammation and pain following ocular surgery. (1).

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. AdministrationInvert closed bottle and shake once to fill tip before instilling drops.Risk of ContaminationAdvise patients not to allow the dropper tip to touch any surface, as this may contaminate the gel.Contact Lens WearAdvise patients not to wear contact lenses when using LOTEMAX.Risk of Secondary InfectionAdvise the patient to consult physician if pain develops, redness, itching or inflammation becomes aggravated.Distributed by:Bausch Lomb, division ofBausch Health US, LLCBridgewater, NJ 08807 USAManufactured by:Bausch Lomb Incorporated Tampa, FL 33637 USALOTEMAX is trademark of Bausch Lomb Incorporated or its affiliates.(C) 2020 Bausch Lomb Incorporated or its affiliates9269203 Folded9269103 Flat.

LACTATION SECTION.

8.2 Lactation There are no data on the presence of loteprednol etabonate in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered, along with the mothers clinical need for LOTEMAX and any potential adverse effects on the breastfed infant from LOTEMAX.

MECHANISM OF ACTION SECTION.

12.1 Mechanism of Action. Corticosteroids inhibit the inflammatory response to 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. While glucocorticoids are known to bind to and activate the glucocorticoid receptor, the molecular mechanisms involved in glucocorticoid/glucocorticoid receptor-dependent modulation of inflammation are not clearly established. However, corticosteroids are thought to inhibit prostaglandin production through several independent mechanisms.

NONCLINICAL TOXICOLOGY SECTION.

13 NONCLINICAL TOXICOLOGY. 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility. Long-term animal studies have not been conducted to evaluate the carcinogenic potential of loteprednol etabonate. Loteprednol etabonate was not genotoxic in vitroin the Ames test, the mouse lymphoma tk assay, or in chromosome aberration test in human lymphocytes, or in vivoin the single dose mouse micronucleus assay.Treatment of female and male rats with doses >= 25 mg/kg/day of loteprednol etabonate (152 times the RHOD based on body surface area, assuming 100% absorption) prior to and during mating caused preimplantation loss and decreased the number of live fetuses/live births. The NOAEL for fertility in rats was mg/kg/day (30 times the RHOD).

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL. NDC 24208-503-07BAUSCH LOMBLOTEMAX(R) loteprednol etabonateophthalmic gel 0.5%SterileRx only5 g. lotemax carton.

PEDIATRIC USE SECTION.

8.4 Pediatric Use The safety and effectiveness of LOTEMAX have been established in the pediatric population. Use of LOTEMAX in this population is supported by evidence from adequate and well-controlled trials of LOTEMAX in adults with additional data from safety and efficacy trial in pediatric patients from birth to 11 years of age [see Clinical Studies (14)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Loteprednol etabonate is lipid soluble and can penetrate into cells. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo predictable transformation to an inactive metabolite. Based upon in vivoand in vitropreclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism to the inactive carboxylic acid metabolites, PJ-91 and PJ-90. The systemic exposure to loteprednol etabonate following ocular administration of LOTEMAX has not been studied in humans.

PREGNANCY SECTION.

8.1 Pregnancy. Risk SummaryThere are no adequate and well-controlled studies with loteprednol etabonate in pregnant women.Loteprednol etabonate produced teratogenicity at clinically relevant doses in the rabbit and rat when administered orally during pregnancy. Loteprednol etabonate produced malformations when administered orally to pregnant rabbits at doses >=1.2 times the recommended human ophthalmic dose (RHOD) and to pregnant rats at doses >= 30 times the RHOD. In pregnant rats receiving oral doses of loteprednol etabonate during the period equivalent to the last trimester of pregnancy through lactation in humans, survival of offspring was reduced at doses >=3 times the RHOD. Maternal toxicity was observed in rats at doses >= 304 times the RHOD, and maternal no observed adverse effect level (NOAEL) was established at 30 times the RHOD.The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies.DataAnimal DataEmbryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation days to 18, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations at doses >= 0.1 mg/kg (1.2 times the recommended human ophthalmic dose (RHOD) based on body surface area, assuming 100% absorption). Spina bifida (including meningocele) was observed at doses >= 0.1 mg/kg, and exencephaly and craniofacial malformations were observed at doses >= 0.4 mg/kg (4.9 times the RHOD). At mg/kg (36 times the RHOD), loteprednol etabonate was associated with increased incidences of abnormal left common carotid artery, limb flexures, umbilical hernia, scoliosis, and delayed ossification. Abortion and embryofetal lethality (resorption) occurred at doses >= mg/kg (73 times the RHOD). NOAEL for developmental toxicity was not established in this study. The NOAEL for maternal toxicity in rabbits was mg/kg/day.Embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation days to 15, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations, including absent innominate artery at doses >= mg/kg (30 times the RHOD); and cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body weight and decreased skeletal ossification at doses >= 50 mg/kg (304 times the RHOD). Embryofetal lethality (resorption) was observed at 100 mg/kg (608 times the RHOD). The NOAEL for developmental toxicity in rats was 0.5 mg/kg (3 times the RHOD). Loteprednol etabonate was maternally toxic (reduced body weight gain) at doses of >= 50 mg/kg/day. The NOAEL for maternal toxicity was mg/kg.A peri-/postnatal study was conducted in rats administered loteprednol etabonate by oral gavage from gestation day 15 (start of fetal period) to postnatal day 21 (the end of lactation period). At doses >= 0.5 mg/kg (3 times the clinical dose), reduced survival was observed in live-born offspring. Doses >= mg/kg (30 times the RHOD) caused umbilical hernia/incomplete gastrointestinal tract. Doses >= 50 mg/kg (304 times the RHOD) produced maternal toxicity (reduced body weight gain, death), decreased number of live-born offspring, decreased birth weight, and delays in postnatal development. developmental NOAEL was not established in this study. The NOAEL for maternal toxicity was mg/kg.

SPL UNCLASSIFIED SECTION.

5.1 Intraocular Pressure (IOP) Increase. Prolonged use of corticosteroids, including LOTEMAX, 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.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Risk SummaryThere are no adequate and well-controlled studies with loteprednol etabonate in pregnant women.Loteprednol etabonate produced teratogenicity at clinically relevant doses in the rabbit and rat when administered orally during pregnancy. Loteprednol etabonate produced malformations when administered orally to pregnant rabbits at doses >=1.2 times the recommended human ophthalmic dose (RHOD) and to pregnant rats at doses >= 30 times the RHOD. In pregnant rats receiving oral doses of loteprednol etabonate during the period equivalent to the last trimester of pregnancy through lactation in humans, survival of offspring was reduced at doses >=3 times the RHOD. Maternal toxicity was observed in rats at doses >= 304 times the RHOD, and maternal no observed adverse effect level (NOAEL) was established at 30 times the RHOD.The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies.DataAnimal DataEmbryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation days to 18, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations at doses >= 0.1 mg/kg (1.2 times the recommended human ophthalmic dose (RHOD) based on body surface area, assuming 100% absorption). Spina bifida (including meningocele) was observed at doses >= 0.1 mg/kg, and exencephaly and craniofacial malformations were observed at doses >= 0.4 mg/kg (4.9 times the RHOD). At mg/kg (36 times the RHOD), loteprednol etabonate was associated with increased incidences of abnormal left common carotid artery, limb flexures, umbilical hernia, scoliosis, and delayed ossification. Abortion and embryofetal lethality (resorption) occurred at doses >= mg/kg (73 times the RHOD). NOAEL for developmental toxicity was not established in this study. The NOAEL for maternal toxicity in rabbits was mg/kg/day.Embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation days to 15, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations, including absent innominate artery at doses >= mg/kg (30 times the RHOD); and cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body weight and decreased skeletal ossification at doses >= 50 mg/kg (304 times the RHOD). Embryofetal lethality (resorption) was observed at 100 mg/kg (608 times the RHOD). The NOAEL for developmental toxicity in rats was 0.5 mg/kg (3 times the RHOD). Loteprednol etabonate was maternally toxic (reduced body weight gain) at doses of >= 50 mg/kg/day. The NOAEL for maternal toxicity was mg/kg.A peri-/postnatal study was conducted in rats administered loteprednol etabonate by oral gavage from gestation day 15 (start of fetal period) to postnatal day 21 (the end of lactation period). At doses >= 0.5 mg/kg (3 times the clinical dose), reduced survival was observed in live-born offspring. Doses >= mg/kg (30 times the RHOD) caused umbilical hernia/incomplete gastrointestinal tract. Doses >= 50 mg/kg (304 times the RHOD) produced maternal toxicity (reduced body weight gain, death), decreased number of live-born offspring, decreased birth weight, and delays in postnatal development. developmental NOAEL was not established in this study. The NOAEL for maternal toxicity was mg/kg. 8.2 Lactation There are no data on the presence of loteprednol etabonate in human milk, the effects on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered, along with the mothers clinical need for LOTEMAX and any potential adverse effects on the breastfed infant from LOTEMAX. 8.4 Pediatric Use The safety and effectiveness of LOTEMAX have been established in the pediatric population. Use of LOTEMAX in this population is supported by evidence from adequate and well-controlled trials of LOTEMAX in adults with additional data from safety and efficacy trial in pediatric patients from birth to 11 years of age [see Clinical Studies (14)].. 8.5 Geriatric Use. No overall differences in safety and effectiveness have been observed between elderly and younger patients.

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oIntraocular 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)oCataracts Use of corticosteroids may result in posterior subcapsular cataract formation. (5.2)oDelayed 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 physician only after examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. (5.3) oBacterial 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. (5.4) oViral infections Employment of corticosteroid medication in the treatment of patients with 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) oFungal 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 steroid has been used or is in use. (5.6). oIntraocular 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). oCataracts Use of corticosteroids may result in posterior subcapsular cataract formation. (5.2). oDelayed 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 physician only after examination of the patient with the aid of magnification such as slit lamp biomicroscopy and, where appropriate, fluorescein staining. (5.3) oBacterial 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. (5.4) oViral infections Employment of corticosteroid medication in the treatment of patients with 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) oFungal 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 steroid has been used or is in use. (5.6). 5.1 Intraocular Pressure (IOP) Increase. Prolonged use of corticosteroids, including LOTEMAX, 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 physician only after examination of the patient with the aid of magnification such as 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.. 5.5 Viral Infections. Employment of corticosteroid medication in the treatment of patients with 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 steroid has been used or is in use. Fungal cultures should be taken when appropriate.. 5.7 Contact Lens Wear. Patients should not wear contact lenses during their course of therapy with LOTEMAX.