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1 INDICATIONS AND USAGE LOTEMAX ® (loteprednol etabonate ophthalmic ointment) 0.5% ointment is a corticosteroid indicated for the treatment of post-operative inflammation and pain following ocular surgery. LOTEMAX ointment is a corticosteroid indicated for the treatment of post-operative inflammation and pain following ocular surgery. (1)

2 DOSAGE AND ADMINISTRATION Wash hands prior to using LOTEMAX ointment. Apply a small amount (approximately ½ inch ribbon) into the conjunctival sac(s) four times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the post-operative period. Apply a small amount (approximately ½ inch ribbon) into the conjunctival sac(s) four times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the post-operative period. ( 2 )

4 CONTRAINDICATIONS LOTEMAX ointment, as with other ophthalmic corticosteroids, 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. LOTEMAX ointment, as with other ophthalmic corticosteroids, 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 )

5 WARNINGS 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 even though it may be difficult in children and uncooperative patients. ( 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. ( 5.3 ) • Bacterial Infections : 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 infection. ( 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, IOP should be monitored even though it may be difficult in children and uncooperative patients. 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 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. 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, 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 culture should be taken when appropriate.

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 culture should be taken when appropriate. 5.7 Risk of Contamination Do not touch the eyelid or surrounding areas with the tip of the tube. The cap should remain on the tube when not in use. 5.8 Contact Lens Wear Patients should not wear contact lenses during their course of therapy with LOTEMAX ointment. 5.9 Topical Ophthalmic Use LOTEMAX is not indicated for intraocular administration.

6 ADVERSE REACTIONS Adverse 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. The most common ocular adverse event reported at approximately 25% in subjects in clinical studies with LOTEMAX ointment was anterior chamber inflammation. Other common adverse events, with an incidence of 4-5%, were conjunctival hyperemia, corneal edema, and eye pain. Many of these events may have been the consequence of the surgical procedure. The only non-ocular adverse event occurring at ≥ 1% was headache (1.5%). The most common ocular adverse event, reported in approximately 25% of subjects in clinical studies, is anterior chamber inflammation. Other common adverse events, with an incidence of 4-5%, are conjunctival hyperemia, corneal edema, and eye pain. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb Incorporated at 1‑800-553-5340 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There 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 ≥ 1.6 times the recommended human ophthalmic dose (RHOD) and to pregnant rats at doses ≥ 41 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 ≥ 4 times the RHOD. Maternal toxicity was observed in rats at doses ≥ 405 times the RHOD, and a maternal no observed adverse effect level (NOAEL) was established at 41 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 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. Data Animal Data Embryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation Days 6 to 18, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations at doses ≥ 0.1 mg/kg (1.6 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 (6.5 times the RHOD). At 3 mg/kg (49 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 ≥ 6 mg/kg (97 times the RHOD). A NOAEL for developmental toxicity was not established in this study. The NOAEL for maternal toxicity in rabbits was 3 mg/kg/day. Embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation Days 6 to 15, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations, including absent innominate artery at doses ≥ 5 mg/kg (41 times the RHOD); and cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body weight and decreased skeletal ossification at doses ≥ 50 mg/kg (410 times the RHOD). Embryofetal lethality (resorption) was observed at 100 mg/kg (811 times the RHOD). The NOAEL for developmental toxicity in rats was 0.5 mg/kg (4 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 5 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 (4 times the clinical dose), reduced survival was observed in live-born offspring. Doses ≥ 5 mg/kg (41 times the RHOD) caused umbilical hernia/incomplete gastrointestinal tract. Doses ≥ 50 mg/kg (410 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.

in live-born offspring. Doses ≥ 5 mg/kg (41 times the RHOD) caused umbilical hernia/incomplete gastrointestinal tract. Doses ≥ 50 mg/kg (410 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. A developmental NOAEL was not established in this study. The NOAEL for maternal toxicity was 5 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 mother’s clinical need for LOTEMAX (loteprednol etabonate ophthalmic ointment) 0.5% and any potential adverse effects on the breastfed infant from LOTEMAX. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger adult patients.

8.1 Pregnancy Risk Summary There 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 ≥ 1.6 times the recommended human ophthalmic dose (RHOD) and to pregnant rats at doses ≥ 41 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 ≥ 4 times the RHOD. Maternal toxicity was observed in rats at doses ≥ 405 times the RHOD, and a maternal no observed adverse effect level (NOAEL) was established at 41 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 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. Data Animal Data Embryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation Days 6 to 18, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations at doses ≥ 0.1 mg/kg (1.6 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 (6.5 times the RHOD). At 3 mg/kg (49 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 ≥ 6 mg/kg (97 times the RHOD). A NOAEL for developmental toxicity was not established in this study. The NOAEL for maternal toxicity in rabbits was 3 mg/kg/day. Embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation Days 6 to 15, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations, including absent innominate artery at doses ≥ 5 mg/kg (41 times the RHOD); and cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body weight and decreased skeletal ossification at doses ≥ 50 mg/kg (410 times the RHOD). Embryofetal lethality (resorption) was observed at 100 mg/kg (811 times the RHOD). The NOAEL for developmental toxicity in rats was 0.5 mg/kg (4 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 5 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 (4 times the clinical dose), reduced survival was observed in live-born offspring. Doses ≥ 5 mg/kg (41 times the RHOD) caused umbilical hernia/incomplete gastrointestinal tract. Doses ≥ 50 mg/kg (410 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.

in live-born offspring. Doses ≥ 5 mg/kg (41 times the RHOD) caused umbilical hernia/incomplete gastrointestinal tract. Doses ≥ 50 mg/kg (410 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. A developmental NOAEL was not established in this study. The NOAEL for maternal toxicity was 5 mg/kg.

11 DESCRIPTION LOTEMAX ® (loteprednol etabonate ophthalmic ointment) 0.5% is a sterile, topical corticosteroid for ophthalmic use. Loteprednol etabonate is a white to off-white powder. Loteprednol etabonate is represented by the following structural formula: Chemical name: chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate Each gram contains: Active: Loteprednol etabonate 5 mg (0.5%); Inactives: Mineral Oil and White Petrolatum. CHEM

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. 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 The systemic exposure to loteprednol etabonate following ocular administration of LOTEMAX ointment has not been studied in humans. However, results from a bioavailability study with LOTEMAX suspension in normal volunteers established that plasma concentrations of loteprednol etabonate and Δ¹ cortienic acid etabonate (PJ 91), its primary, inactive metabolite, were below the limit of quantitation (1 ng/mL) at all sampling times. The results were obtained following the ocular administration of one drop in each eye of 0.5% loteprednol etabonate suspension, 8 times daily for 2 days or 4 times daily for 42 days. The maximum systemic exposure to loteprednol following administration of the ointment product dosed 4 times daily is not expected to exceed exposures attained with LOTEMAX suspension dosed up to two drops 4 times daily.

12.1 Mechanism of Action Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. 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 The systemic exposure to loteprednol etabonate following ocular administration of LOTEMAX ointment has not been studied in humans. However, results from a bioavailability study with LOTEMAX suspension in normal volunteers established that plasma concentrations of loteprednol etabonate and Δ¹ cortienic acid etabonate (PJ 91), its primary, inactive metabolite, were below the limit of quantitation (1 ng/mL) at all sampling times. The results were obtained following the ocular administration of one drop in each eye of 0.5% loteprednol etabonate suspension, 8 times daily for 2 days or 4 times daily for 42 days. The maximum systemic exposure to loteprednol following administration of the ointment product dosed 4 times daily is not expected to exceed exposures attained with LOTEMAX suspension dosed up to two drops 4 times daily.

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 vitro in the Ames test, the mouse lymphoma tk assay, or in a chromosome aberration test in human lymphocytes, or in vivo in the single-dose mouse micronucleus assay. Treatment of female and male rats with doses ≥ 25 mg/kg/day of loteprednol etabonate (203 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 5 mg/kg/day (41 times the RHOD).

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 vitro in the Ames test, the mouse lymphoma tk assay, or in a chromosome aberration test in human lymphocytes, or in vivo in the single-dose mouse micronucleus assay. Treatment of female and male rats with doses ≥ 25 mg/kg/day of loteprednol etabonate (203 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 5 mg/kg/day (41 times the RHOD).

14 CLINICAL STUDIES In two independent, randomized, multicenter, double-masked, parallel-group, vehicle-controlled studies in 805 subjects meeting a protocol-specified threshold amount of anterior chamber inflammation, LOTEMAX ointment was more effective compared to its vehicle for complete resolution of post-operative anterior chamber cell, flare, and pain following cataract surgery. Primary endpoint was complete resolution of anterior chamber cells and flare (cell count of 0 and no flare) and no pain at post-operative Day 8. The individual clinical trial results are provided below. In the two studies, LOTEMAX had statistically significant higher incidence of complete clearing of anterior chamber cells and flare at post-operative Day 8 (24-32% vs. 11-14%) and also had a statistically significant higher incidence of subjects that were pain free at post-operative Day 8 (73-78% vs. 41-45%).

16 HOW SUPPLIED/STORAGE AND HANDLING LOTEMAX ® (loteprednol etabonate ophthalmic ointment) 0.5% is a sterile ointment supplied in a tin tube with a pink polypropylene cap in the following size: NDC 24208-443-35 3.5 g tube DO NOT USE IF TAMPER-EVIDENT SKIRT IS VISIBLE ON BOTTOM OF CAP. Storage: Store between 15°C to 25°C (59°F to 77°F). After opening, LOTEMAX can be used until the expiration date on the tube.

17 PATIENT COUNSELING INFORMATION Risk of Contamination Advise patients to wash hands prior to using LOTEMAX ointment. Advise patients not to touch the eyelid or surrounding areas with the tip of the tube. The cap should remain on the tube when not in use. Contact Lens Wear Advise patients not to wear contact lenses during their course of therapy. Risk of Secondary Infection Advise patients to consult a physician if pain, redness, itching or inflammation becomes aggravated [see Warnings and Precautions ( 5.4 )] . Distributed by: Bausch & Lomb Americas Inc. Bridgewater, NJ 08807 USA Manufactured by: Bausch & Lomb Incorporated Tampa, FL 33637 USA LOTEMAX is a trademark of Bausch & Lomb Incorporated or its affiliates. © 2022 Bausch & Lomb Incorporated or its affiliates 9234905 (Folded) 9234805 (Flat)

1 INDICATIONS AND USAGE Loteprednol etabonate ophthalmic gel is a corticosteroid indicated for the treatment of post-operative inflammation and pain following ocular surgery. Loteprednol etabonate ophthalmic gel is a corticosteroid indicated for the treatment of postoperative inflammation and pain following ocular surgery. ( 1 )

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

3 DOSAGE FORMS AND STRENGTHS Loteprednol etabonate ophthalmic gel is a sterile preserved ophthalmic gel 0.5% containing 5 mg of loteprednol etabonate per gram of gel. Loteprednol etabonate ophthalmic gel is a sterile preserved ophthalmic gel containing 5 mg of loteprednol etabonate per gram of gel. ( 3 )

4 CONTRAINDICATIONS Loteprednol etabonate ophthalmic gel 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. Loteprednol etabonate ophthalmic gel 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 )

5 WARNINGS 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 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. ( 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, including loteprednol etabonate ophthalmic gel, 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 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 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.

any 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 Contact Lens Wear Patients should not wear contact lenses during their course of therapy with loteprednol etabonate ophthalmic gel.

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 to 5%) were anterior chamber inflammation, eye pain, and foreign body sensation. The most common adverse drug reactions (2 to 5%) were anterior chamber inflammation, eye pain, and foreign body sensation. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Sentiss at 1-855-473-6847 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There 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 a 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 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. Data Animal Data Embryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation days 6 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 3 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 ≥ 6 mg/kg (73 times the RHOD). A NOAEL for developmental toxicity was not established in this study. The NOAEL for maternal toxicity in rabbits was 3 mg/kg/day. Embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation days 6 to 15, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations, including absent innominate artery at doses ≥ 5 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 5 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 ≥ 5 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.

in live-born offspring. Doses ≥ 5 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. A developmental NOAEL was not established in this study. The NOAEL for maternal toxicity was 5 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 mother's clinical need for loteprednol etabonate ophthalmic gel and any potential adverse effects on the breastfed infant from loteprednol etabonate ophthalmic gel. 8.4 Pediatric Use The safety and effectiveness of loteprednol etabonate ophthalmic gel have been established in the pediatric population. Use of loteprednol etabonate ophthalmic gel in this population is supported by evidence from adequate and well-controlled trials of loteprednol etabonate ophthalmic gel in adults with additional data from a safety and efficacy trial in pediatric palien1s 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.

8.1 Pregnancy Risk Summary There 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 a 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 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. Data Animal Data Embryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation days 6 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 3 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 ≥ 6 mg/kg (73 times the RHOD). A NOAEL for developmental toxicity was not established in this study. The NOAEL for maternal toxicity in rabbits was 3 mg/kg/day. Embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation days 6 to 15, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations, including absent innominate artery at doses ≥ 5 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 5 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 ≥ 5 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.

in live-born offspring. Doses ≥ 5 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. A developmental NOAEL was not established in this study. The NOAEL for maternal toxicity was 5 mg/kg.

8.4 Pediatric Use The safety and effectiveness of loteprednol etabonate ophthalmic gel have been established in the pediatric population. Use of loteprednol etabonate ophthalmic gel in this population is supported by evidence from adequate and well-controlled trials of loteprednol etabonate ophthalmic gel in adults with additional data from a safety and efficacy trial in pediatric palien1s from birth to 11 years of age [see Clinical Studies (14]

11 DESCRIPTION Loteprednol etabonate is a corticosteroid. Its chemical name is chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate. Its molecular formula is C 24 H 31 ClO 7 and its chemical structure is: Loteprednol etabonate ophthalmic gel 0.5% contains a sterile, topical corticosteroid for ophthalmic use. Loteprednol etabonate is a white to off-white powder. Each gram contains: ACTIVE: loteprednol etabonate 5 mg (0.5%) INACTIVES: boric acid, edetate disodium dihydrate, glycerin, polycarbophil, propylene glycol, sodium chloride, tyloxapol, water for injection, and sodium hydroxide to adjust to a pH of between 6 and 7 PRESERVATIVE: benzalkonium chloride 0.003% Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. 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 a predictable transformation to an inactive metabolite. Based upon in vivo and in vitro preclinical 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 loteprednol etabonate ophthalmic gel has not been studied in humans.

12.1 Mechanism of Action Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. 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 a predictable transformation to an inactive metabolite. Based upon in vivo and in vitro preclinical 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 loteprednol etabonate ophthalmic gel has not been studied in humans.

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 vitro in the Ames test, the mouse lymphoma tk assay, or in a chromosome aberration test in human lymphocytes, or in vivo in 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 5 mg/kg/day (30 times the RHOD).

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 vitro in the Ames test, the mouse lymphoma tk assay, or in a chromosome aberration test in human lymphocytes, or in vivo in 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 5 mg/kg/day (30 times the RHOD).

14 CLINICAL STUDIES Adult Studies In two randomized, multicenter, double-masked, parallel-group, vehicle-controlled studies in 813 subjects with post-operative inflammation, loteprednol etabonate ophthalmic gel 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, loteprednol etabonate ophthalmic gel had a statistically significant higher incidence of subjects with complete clearing of anterior chamber cells (31% vs. 14 to 16%) and were pain-free at post-operative day 8 (73 to 76% vs. 42 to 46%). Pediatric Study The safety and effectiveness of loteprednol etabonate ophthalmic gel were evaluated in a pediatric study of patients from birth to less than 11 years of age (mean age of 3 years) undergoing cataract surgery. Patlen1s were randomized to receive either loteprednol etabonate ophthalmic gel (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 lnflammatlon were 57% In the loteprednol etabonate ophthalmic gel group and 63% in the prednisolone group.

16 HOW SUPPLIED/STORAGE AND HANDLING Loteprednol Etabonate Ophthalmic Gel 0.5% is a sterile ophthalmic gel supplied in a white low density polyethylene plastic bottle with a white controlled drop tip and a pink polypropylene cap in the following size: NDC 70244-036-01 5 g in a 10 mL bottle Storage: Store upright at 15º to 25º C (59º to 77º F).

17 PATIENT COUNSELING INFORMATION Administration Invert closed bottle and shake once to fill tip before instilling drops. Risk of Contamination Advise patients not to allow the dropper tip to touch any surface, as this may contaminate the gel. Contact Lens Wear Advise patients not to wear contact lenses when using loteprednol etabonate ophthalmic gel. Risk of Secondary Infection Advise the patient to consult a physician if pain develops, redness, itching or inflammation becomes aggravated. Manufactured tor: Sentiss Pharmaceuticals, LLC, San Clemente, CA 92672 Manufactured by: Ophtapharm AG Riethofstrasse 1, Hettlingen, 8442, Switzerland (CHE) Made in Switzerland Rev. 08/23

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

2 DOSAGE 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.

4 CONTRAINDICATIONS INVELTYS 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. INVELTYS 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 )

5 WARNINGS 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 : 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 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 infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. ( 5.4 ) Viral Infections : Use 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, as well as 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 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 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 Use 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 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.

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 Risk of Contamination Do not to allow the dropper tip to touch any surface, as this may contaminate the suspension. 5.8 Contact Lens Wear The preservative in INVELTYS may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of INVELTYS and may be reinserted 15 minutes following administration.

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 were eye pain (1%) and posterior capsular opacification (1%). These reactions may have been the consequence of the surgical procedure. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Alcon Laboratories, Inc. at 1-800-757-9195 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The most common adverse drug reactions in the clinical trials with INVELTYS were eye pain and posterior capsular opacification, both reported in 1% of patients. These reactions may have been the consequence of the surgical procedure.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary INVELTYS is not absorbed systemically following topical ophthalmic administration and maternal use is not expected to result in fetal exposure to the drug. 8.2 Lactation Risk Summary INVELTYS is not absorbed systemically by the mother following topical ophthalmic administration, and breastfeeding is not expected to result in exposure of the child to INVELTYS . 8.3 Pediatric Use Safety and effectiveness in pediatric patients have not been established. 8.4 Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger patients.

11 DESCRIPTION Loteprednol etabonate is a corticosteroid. Its chemical name is chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate. Its molecular formula is C 24 H 31 ClO 7 and its chemical structure is: C 24 H 31 ClO 7 Mol. Wt. 467.0 INVELTYS (loteprednol etabonate ophthalmic suspension) 1% contains a sterile, topical anti-inflammatory corticosteroid for ophthalmic use. Each mL contains: ACTIVE: loteprednol etabonate 10 mg (1%) INACTIVES: glycerin, sodium citrate dihydrate, Poloxamer 407, sodium chloride, edetate disodium dihydrate, citric acid, and water for injection PRESERVATIVE: benzalkonium chloride 0.01% Chemical Structure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. 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 a predictable transformation to an inactive metabolite. Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism to inactive carboxylic acid metabolites, PJ-91 and PJ-90. Following twice-daily unilateral topical ocular dosing of INVELTYS for 14 days in healthy subjects, the plasma concentrations of loteprednol etabonate were below the limit of quantitation (1 ng/mL) at all timepoints.

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 a predictable transformation to an inactive metabolite. Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism to inactive carboxylic acid metabolites, PJ-91 and PJ-90. Following twice-daily unilateral topical ocular dosing of INVELTYS for 14 days in healthy subjects, the plasma concentrations of loteprednol etabonate were below the limit of quantitation (1 ng/mL) at all timepoints.

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 vitro in the Ames test, the mouse lymphoma thymidine kinase (tk) assay, or in a chromosome aberration test in human lymphocytes, or in vivo in the single dose mouse micronucleus assay.

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 vitro in the Ames test, the mouse lymphoma thymidine kinase (tk) assay, or in a chromosome aberration test in human lymphocytes, or in vivo in the single dose mouse micronucleus assay.

14 CLINICAL STUDIES Clinical efficacy was evaluated in 2 multi-centered, randomized, double-masked, placebo-controlled trials in which patients with an anterior cell grade greater than or equal to "2" (a cell count of 6 or higher using a slit-lamp biomicroscope) after cataract surgery were assigned to INVELTYS or placebo (vehicle) following surgery (NCT # 02163824 and NCT # 02793817). One to two drops of INVELTYS or vehicle was self-administered twice a day for 14 days, beginning the day after surgery. Complete resolution of inflammation (a cell count of 0 maintained through day 15 without rescue medication) and complete resolution of pain (a patient-reported pain grade of 0 maintained through day 15 without rescue medication) was assessed 4, 8, and 15 days post-surgery. In the intent-to-treat analysis of both studies, a significant benefit was seen in the INVELTYS -treated group for complete resolution of ocular inflammation at Days 8 and 15, and complete resolution of pain at Days 4, 8, and 15, when compared with placebo. The consolidated clinical trial results are provided below. Figure 1 Consolidated Clinical Trial Data: Percent of Patients with Complete Resolution of Anterior Chamber Cells (Cell Count = 0) at Days 8 and 15 * p-values < 0.01 for treatment comparisons Figure 2 Consolidated Clinical Trial Data: Percent of Patients Who Were Pain Free at Days 4, 8, and 15 * p-values < 0.01 for treatment comparisons Figure 1 Figure 2

16 HOW SUPPLIED/STORAGE AND HANDLING INVELTYS (loteprednol etabonate ophthalmic suspension) 1% is a sterile ophthalmic suspension. It is supplied in a white low-density polyethylene plastic dropper bottle with a controlled-drop linear low-density polyethylene tip, a pink high-density polyethylene cap, and a white low-density polyethylene tamper-evident overcap in the following size: 2.8 mL in a 5 mL bottle (NDC 71571-121-28) Storage and Handling Do not use if tamper-evident overcap seal is not intact. The white tamper-evident overcap can be thrown away. Retain the pink cap and keep the bottle tightly closed when not in use. Store upright at 15°C to 25°C (59°F to 77°F). Do not freeze.

Storage and Handling Do not use if tamper-evident overcap seal is not intact. The white tamper-evident overcap can be thrown away. Retain the pink cap and keep the bottle tightly closed when not in use. Store upright at 15°C to 25°C (59°F to 77°F). Do not freeze.

17 PATIENT COUNSELING INFORMATION Administration Instruct the patient to shake the bottle 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. Risk of Contamination Advise patients to wash their hands well before each use. Advise patients not to allow the dropper tip to touch any surface, as this may contaminate the suspension. Risk of Secondary Infection Advise the patient to consult a physician if pain develops, or redness, itching, or inflammation becomes aggravated. Contact Lens Wear Advise patients that the preservative in INVELTYS may be absorbed by soft contact lenses. Contact lenses should be removed prior to instillation of INVELTYS and may be reinserted after 15 minutes following administration.

INSTRUCTIONS FOR USE INVELTYS [in-vel-tis] (loteprednol etabonate ophthalmic suspension) 1% for topical ophthalmic use This Instructions for Use contains information on how to properly administer INVELTYS. Important Information You Need to Know Before Using INVELTYS INVELTYS is for use in the eye only. Wash your hands before using INVELTYS. Do not use if the tamper-evident seal is not intact. Do not let the INVELTYS dropper tip touch your eye, fingers, or any other surfaces to avoid contamination or injury to your eye. Use INVELTYS exactly as your healthcare provider tells you to. If you are using INVELTYS with other eye (ophthalmic) medicines, you should wait at least 5 minutes between using INVELTYS and the other medicine. If you wear contact lenses, remove them before using INVELTYS. Put the pink cap back on INVELTYS after each use. Before you use INVELTYS for the first time: There are two caps on your bottle of INVELTYS. Hold the bottle firmly by its neck. Remove the white cap by twisting it clockwise (See Figure A ) . Throw away the white cap. INVELTYS is now ready to use. Figure A Follow Steps 1 to 6 each time you use INVELTYS. Step 1. Wash your hands well. Step 2. Shake the INVELTYS bottle for 1 to 2 seconds (See Figure B ) . Figure B Step 3: Remove the pink cap from the top of the INVELTYS dropper by turning it counterclockwise (See Figure C ) . Keep the pink cap. Do not let the INVELTYS dropper tip touch your eye, fingers, or any other surface. Figure C Step 4: Turn the INVELTYS bottle upside down (See Figure D ) . Figure D Step 5: Tilt your head back. Hold the bottle directly above your affected eye. Squeeze the middle of the INVELTYS bottle gently to put 1 to 2 drops (follow your doctor's recommendation) into the affected eye (See Figure E ) . Figure E Step 6: Place the pink cap back onto the INVELTYS bottle and tighten by turning clockwise (See Figure F ) . Figure F If you use contact lenses, wait for 15 minutes before placing them back in. How should I store INVELTYS? Store INVELTYS upright at 59ºF to 77ºF (15ºC to 25ºC). Do not freeze. Keep INVELTYS and all medicines out of the reach of children. This Instructions for Use has been approved by the U.S. Food and Drug Administration. Manufactured for: Alcon Laboratories, Inc. Fort Worth, TX 76134 USA Revised: 11/2023 figurea figureb figurec figured figuree figuref

<table styleCode="Noautorules" width="100%"><tbody><tr><td align="center"><paragraph><content styleCode="bold">INSTRUCTIONS FOR USE</content></paragraph> <paragraph><content styleCode="bold">INVELTYS [in-vel-tis] (loteprednol etabonate ophthalmic suspension) 1% for topical ophthalmic use</content></paragraph></td></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col align="center" valign="middle" width="100%"/><tbody><tr><td align="center"><paragraph ID="figurea"><renderMultiMedia referencedObject="MM5"/></paragraph><paragraph><content styleCode="bold">Figure A</content></paragraph></td></tr></tbody></table>

<table styleCode="Noautorules" width="100%"><tbody><tr><td align="center"><paragraph><content styleCode="bold">INSTRUCTIONS FOR USE</content></paragraph> <paragraph><content styleCode="bold">INVELTYS [in-vel-tis] (loteprednol etabonate ophthalmic suspension) 1% for topical ophthalmic use</content></paragraph></td></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col align="center" valign="middle" width="100%"/><tbody><tr><td align="center"><paragraph ID="figurea"><renderMultiMedia referencedObject="MM5"/></paragraph><paragraph><content styleCode="bold">Figure A</content></paragraph></td></tr></tbody></table> <table styleCode="Noautorules" width="100%"><col align="left" valign="top" width="7%"/><col align="left" valign="top" width="93%"/><tbody><tr><td><content styleCode="bold">Step 1.</content></td><td>Wash your hands well.</td></tr><tr><td><content styleCode="bold">Step 2.</content></td><td>Shake the INVELTYS bottle for 1 to 2 seconds <content styleCode="bold">(See <linkHtml href="#figureb">Figure B</linkHtml>)</content>. </td></tr><tr><td/><td align="center"><paragraph ID="figureb"><renderMultiMedia referencedObject="MM6"/></paragraph></td></tr><tr><td/><td align="center"><content styleCode="bold">Figure B</content></td></tr><tr><td><content styleCode="bold">Step 3:</content></td><td>Remove the pink cap from the top of the INVELTYS dropper by turning it <content styleCode="bold">counterclockwise (See <linkHtml href="#figurec">Figure C</linkHtml>)</content>. Keep the pink cap. <content styleCode="bold">Do not</content> let the INVELTYS dropper tip touch your eye, fingers, or any other surface. </td></tr><tr><td/><td align="center"><paragraph ID="figurec"><renderMultiMedia referencedObject="MM7"/></paragraph></td></tr><tr><td/><td align="center"><content styleCode="bold">Figure C</content></td></tr><tr><td><content styleCode="bold">Step 4:</content></td><td>Turn the INVELTYS bottle upside down <content styleCode="bold">(See <linkHtml href="#figured">Figure D</linkHtml>)</content>.</td></tr><tr><td/><td align="center"><paragraph ID="figured"><renderMultiMedia referencedObject="MM8"/></paragraph></td></tr><tr><td/><td align="center"><content styleCode="bold">Figure D</content></td></tr><tr><td><content styleCode="bold">Step 5:</content></td><td>Tilt your head back. Hold the bottle directly above your affected eye. Squeeze the middle of the INVELTYS bottle gently to put 1 to 2 drops (follow your doctor&apos;s recommendation) into the affected eye <content styleCode="bold">(See <linkHtml href="#figuree">Figure E</linkHtml>)</content>.</td></tr><tr><td/><td align="center"><paragraph ID="figuree"><renderMultiMedia referencedObject="MM9"/></paragraph></td></tr><tr><td/><td align="center"><content styleCode="bold">Figure E</content></td></tr><tr><td><content styleCode="bold">Step 6:</content></td><td>Place the pink cap back onto the INVELTYS bottle and tighten by turning clockwise <content styleCode="bold">(See <linkHtml href="#figuref">Figure F</linkHtml>)</content>.</td></tr><tr><td/><td align="center"><paragraph ID="figuref"><renderMultiMedia referencedObject="MM10"/></paragraph></td></tr><tr><td/><td align="center"><content styleCode="bold">Figure F</content></td></tr></tbody></table>

1 INDICATIONS AND USAGE LOTEMAX ® SM (loteprednol etabonate ophthalmic gel) 0.38% is a corticosteroid indicated for the treatment of post-operative inflammation and pain following ocular surgery. LOTEMAX ® SM is a corticosteroid indicated for the treatment of post-operative inflammation and pain following ocular surgery. ( 1 )

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

3 DOSAGE FORMS AND STRENGTHS LOTEMAX ® SM (loteprednol etabonate ophthalmic gel) 0.38% is a sterile preserved ophthalmic gel containing 3.8 mg of loteprednol etabonate per gram of gel. LOTEMAX ® SM is a sterile preserved ophthalmic gel containing 3.8 mg of loteprednol etabonate per gram of gel. ( 3 )

4 CONTRAINDICATIONS LOTEMAX ® SM, as with other ophthalmic corticosteroids, 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 ® SM, as with other ophthalmic corticosteroids, 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 )

5 WARNINGS 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. () 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 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 infections. In acute purulent conditions, steroids may mask infection or enhance existing infection. ( 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 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 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.

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 Contact Lens Wear Contact lenses should not be worn when the eyes are inflamed.

6 ADVERSE REACTIONS Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 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. There were no treatment-emergent adverse drug reactions that occurred in more than 1% of subjects in the three times daily group compared to vehicle. There were no treatment-emergent adverse drug reactions that occurred in more than 1% of subjects in the three times daily group compared to vehicle. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb Incorporated at 1-800-553-5340 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There 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 4.2 times the recommended human ophthalmic dose (RHOD) and to pregnant rats at doses 106 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 10.6 times the RHOD. Maternal toxicity was observed in rats at doses 1066 times the RHOD, and a maternal no observed adverse effect level (NOAEL) was established at 106 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 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. Data Animal Data Embryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation days 6 to 18, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations at 0.1 mg/kg (4.2 times the recommended human ophthalmic dose (RHOD) based on body surface area, assuming 100% absorption). Spina bifida (including meningocele) was observed at 0.1 mg/kg, and exencephaly and craniofacial malformations were observed at 0.4 mg/kg (17 times the RHOD). At 3 mg/kg (128 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 6 mg/kg (256 times the RHOD). A NOAEL for developmental toxicity was not established in this study. The NOAEL for maternal toxicity in rabbits was 3 mg/kg/day. Embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation days 6 to 15, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations, including absent innominate artery at 5 mg/kg (106 times the RHOD); and cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body weight and decreased skeletal ossification at 50 mg/kg (1066 times the RHOD). Embryofetal lethality (resorption) was observed at 100 mg/kg (2133 times the RHOD). The NOAEL for developmental toxicity in rats was 0.5 mg/kg (10.6 times the RHOD). Loteprednol etabonate was maternally toxic (reduced body weight gain) at 50 mg/kg/day. The NOAEL for maternal toxicity was 5 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 0.5 mg/kg (10.6 times the clinical dose), reduced survival was observed in live-born offspring. Doses ≥ 5 mg/kg (106 times the RHOD) caused umbilical hernia/incomplete gastrointestinal tract. Doses ≥ 50 mg/kg (1066 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. A developmental NOAEL was not established in this study.

) caused umbilical hernia/incomplete gastrointestinal tract. Doses ≥ 50 mg/kg (1066 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. A developmental NOAEL was not established in this study. The NOAEL for maternal toxicity was 5 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 mother’s clinical need for LOTEMAX ® SM and any potential adverse effects on the breastfed infant from LOTEMAX ® SM. 8.4 Pediatric Use Safety and effectiveness of LOTEMAX ® SM in pediatric patients have not been established. 8.5 Geriatric Use No overall differences in safety and effectiveness have been observed between elderly and younger patients.

8.1 Pregnancy Risk Summary There 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 4.2 times the recommended human ophthalmic dose (RHOD) and to pregnant rats at doses 106 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 10.6 times the RHOD. Maternal toxicity was observed in rats at doses 1066 times the RHOD, and a maternal no observed adverse effect level (NOAEL) was established at 106 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 2 to 4%, and of miscarriage is 15 to 20%, of clinically recognized pregnancies. Data Animal Data Embryofetal studies were conducted in pregnant rabbits administered loteprednol etabonate by oral gavage on gestation days 6 to 18, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations at 0.1 mg/kg (4.2 times the recommended human ophthalmic dose (RHOD) based on body surface area, assuming 100% absorption). Spina bifida (including meningocele) was observed at 0.1 mg/kg, and exencephaly and craniofacial malformations were observed at 0.4 mg/kg (17 times the RHOD). At 3 mg/kg (128 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 6 mg/kg (256 times the RHOD). A NOAEL for developmental toxicity was not established in this study. The NOAEL for maternal toxicity in rabbits was 3 mg/kg/day. Embryofetal studies were conducted in pregnant rats administered loteprednol etabonate by oral gavage on gestation days 6 to 15, to target the period of organogenesis. Loteprednol etabonate produced fetal malformations, including absent innominate artery at 5 mg/kg (106 times the RHOD); and cleft palate, agnathia, cardiovascular defects, umbilical hernia, decreased fetal body weight and decreased skeletal ossification at 50 mg/kg (1066 times the RHOD). Embryofetal lethality (resorption) was observed at 100 mg/kg (2133 times the RHOD). The NOAEL for developmental toxicity in rats was 0.5 mg/kg (10.6 times the RHOD). Loteprednol etabonate was maternally toxic (reduced body weight gain) at 50 mg/kg/day. The NOAEL for maternal toxicity was 5 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 0.5 mg/kg (10.6 times the clinical dose), reduced survival was observed in live-born offspring. Doses ≥ 5 mg/kg (106 times the RHOD) caused umbilical hernia/incomplete gastrointestinal tract. Doses ≥ 50 mg/kg (1066 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. A developmental NOAEL was not established in this study.

) caused umbilical hernia/incomplete gastrointestinal tract. Doses ≥ 50 mg/kg (1066 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. A developmental NOAEL was not established in this study. The NOAEL for maternal toxicity was 5 mg/kg.

11 DESCRIPTION LOTEMAX ® SM (loteprednol etabonate ophthalmic gel) 0.38% contains a sterile, topical corticosteroid for ophthalmic use. Loteprednol etabonate is a white to off-white powder. Loteprednol etabonate is represented by the following structural formula: Chemical Name: chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate Each gram contains: Active: loteprednol etabonate 3.8 mg (0.38%); Inactives: boric acid, edetate disodium dihydrate, glycerin, hypromellose, poloxamer, polycarbophil, propylene glycol, sodium chloride, water for injection, and sodium hydroxide to adjust to a pH of between 6 and 7. Preservative: benzalkonium chloride 0.003% chemstructure

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Loteprednol etabonate is a corticosteroid. Corticosteroids have been shown to inhibit the inflammatory response to a variety of inciting agents. 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 The pharmacokinetic exposure to loteprednol etabonate following topical bilateral ocular administration of one drop three times daily of LOTEMAX ® SM for up to two weeks (Day 15) was evaluated in 18 healthy adult subjects. Plasma concentrations of loteprednol etabonate were analyzed using a validated LC/MS/MS method and the lower limit of quantitation for loteprednol etabonate was 0.05 ng/mL. The mean (± SD) C max values for loteprednol etabonate in plasma were 0.13 (± 0.06) ng/mL on Day 1 after a single dose and 0.16 (± 0.06) ng/mL after the last dose on Day 15 of the study. The mean (± SD) AUC t values for loteprednol etabonate in plasma were 0.15 (± 0.15) hr•ng/mL on Day 1 after a single dose and 0.35 (± 0.32) hr•ng/mL after the last dose on Day 15.

12.1 Mechanism of Action Loteprednol etabonate is a corticosteroid. Corticosteroids have been shown to inhibit the inflammatory response to a variety of inciting agents. 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 The pharmacokinetic exposure to loteprednol etabonate following topical bilateral ocular administration of one drop three times daily of LOTEMAX ® SM for up to two weeks (Day 15) was evaluated in 18 healthy adult subjects. Plasma concentrations of loteprednol etabonate were analyzed using a validated LC/MS/MS method and the lower limit of quantitation for loteprednol etabonate was 0.05 ng/mL. The mean (± SD) C max values for loteprednol etabonate in plasma were 0.13 (± 0.06) ng/mL on Day 1 after a single dose and 0.16 (± 0.06) ng/mL after the last dose on Day 15 of the study. The mean (± SD) AUC t values for loteprednol etabonate in plasma were 0.15 (± 0.15) hr•ng/mL on Day 1 after a single dose and 0.35 (± 0.32) hr•ng/mL after the last dose on Day 15.

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 the chromosomal aberration test in human lymphocytes, or in vivoin the mouse micronucleus assay. Treatment of male and female rats with 25 mg/kg/day of loteprednol etabonate (533 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 5 mg/kg/day (106 times the RHOD).

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 the chromosomal aberration test in human lymphocytes, or in vivoin the mouse micronucleus assay. Treatment of male and female rats with 25 mg/kg/day of loteprednol etabonate (533 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 5 mg/kg/day (106 times the RHOD).

14 CLINICAL STUDIES In two randomized, multicenter, double-masked, parallel group, vehicle-controlled trials in patients who underwent cataract extraction with intraocular lens implantation, LOTEMAX ® SM administered three times daily to the affected eye beginning the day after cataract surgery was more effective compared to its vehicle in resolving anterior chamber inflammation and pain following surgery. In these studies, LOTEMAX ® SM had statistically significantly higher rates of subjects with complete clearing of anterior chamber cells and of subjects who were pain free at post-operative Day 8 compared to vehicle. Results are shown in the following table. Proportion of Subjects with Complete Clearing of Anterior Chamber Cells and Proportion of Subjects with Complete Resolution of Pain at Post-Operative Day 8. Outcome Study 1 Study 2 LOTEMAX ® SM N=171 n (%) Vehicle N=172 n (%) Difference (95 CI) % LOTEMAX ® SM N=200 n (%) Vehicle N=199 n (%) Difference (95% CI) % Cells 49 (29%) 16 (9%) 19 (11, 27) 61 (31%) 40 (20%) 10 (2, 19) Pain 125 (73%) 82 (48%) 25 (15, 35) 151 (76%) 99 (50%) 26 (17, 35)

<table ID="_RefID0EVEAE" width="100%"><caption>Proportion of Subjects with Complete Clearing of Anterior Chamber Cells and Proportion of Subjects with Complete Resolution of Pain at Post-Operative Day 8.</caption><col width="10%"/><col width="16%"/><col width="16%"/><col width="15%"/><col width="14%"/><col width="15%"/><col width="15%"/><tbody><tr><td align="center" rowspan="2" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Outcome</content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Study 1</content></paragraph></td><td align="center" colspan="3" styleCode="Rrule Botrule Lrule Toprule " valign="middle"><paragraph><content styleCode="bold">Study 2</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">LOTEMAX ^&#xAE;SM </content> <content styleCode="bold">N=171</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Vehicle</content> <content styleCode="bold">N=172</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Difference</content> <content styleCode="bold">(95 CI)</content> <content styleCode="bold">%</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">LOTEMAX ^&#xAE;SM </content> <content styleCode="bold">N=200</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Vehicle</content> <content styleCode="bold">N=199</content> <content styleCode="bold">n (%)</content></paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph><content styleCode="bold">Difference</content> <content styleCode="bold">(95% CI)</content> <content styleCode="bold">%</content></paragraph></td></tr><tr><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>Cells</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>49</paragraph><paragraph>(29%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>16</paragraph><paragraph>(9%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>19 (11, 27)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>61</paragraph><paragraph>(31%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>40</paragraph><paragraph>(20%)</paragraph></td><td align="center" styleCode="Rrule Lrule Botrule " valign="middle"><paragraph>10 (2, 19)</paragraph></td></tr><tr><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>Pain</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>125</paragraph><paragraph>(73%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>82</paragraph><paragraph>(48%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>25 (15, 35)</p

de="Rrule Botrule Lrule " valign="middle"><paragraph>125</paragraph><paragraph>(73%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>82</paragraph><paragraph>(48%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>25 (15, 35)</p aragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>151</paragraph><paragraph>(76%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>99</paragraph><paragraph>(50%)</paragraph></td><td align="center" styleCode="Rrule Botrule Lrule " valign="middle"><paragraph>26 (17, 35)</paragraph></td></tr></tbody></table>

16 HOW SUPPLIED/STORAGE AND HANDLING LOTEMAX ® SM (loteprednol etabonate ophthalmic gel) 0.38% is a sterile ophthalmic submicron gel supplied in a white low-density polyethylene plastic bottle with a white controlled drop tip and a pink polypropylene cap in the following size: NDC 24208-507-07 5g in a 10 mL bottle Use only if imprinted neckband is intact. Storage: Store upright at 15ºC to 25ºC (59ºF to 77ºF). After opening, LOTEMAX ® SM can be used until the expiration date on the bottle.

17 PATIENT COUNSELING INFORMATION Administration Invert closed bottle and shake once to fill tip before instilling drops. Risk of Contamination Advise patients not to allow the dropper tip to touch any surface, as this may contaminate the gel. Contact Lens Wear Advise patients contact lenses should not be worn when the eyes are inflamed. Risk of Secondary Infection Advise the patient to consult a physician if pain develops, redness, itching or inflammation becomes aggravated. Distributed by: Bausch & Lomb Americas Inc. Bridgewater, NJ 08807 USA Manufactured by: Bausch & Lomb Incorporated Tampa, FL 33637 USA Patented. See https://patents.bausch.com. LOTEMAX is a trademark of Bausch & Lomb Incorporated or its affiliates. © 2023 Bausch & Lomb Incorporated or its affiliates 9669602 (Folded) 9669702 (Flat)

DESCRIPTION ALREX ® (loteprednol etabonate ophthalmic suspension, 0.2%) contains a sterile, topical anti-inflammatory corticosteroid for ophthalmic use. Loteprednol etabonate is a white to off-white powder. Loteprednol etabonate is represented by the following structural formula: Chemical Name: chloromethyl 17α-[(ethoxycarbonyl)oxy]-11β-hydroxy-3-oxoandrosta-1,4-diene-17β-carboxylate Each mL contains: ACTIVE: Loteprednol Etabonate 2 mg (0.2%); INACTIVES: Edetate Disodium, Glycerin, Povidone, Purified Water and Tyloxapol. Hydrochloric Acid and/or Sodium Hydroxide may be added to adjust the pH. The suspension is essentially isotonic with a tonicity of 250 to 310 mOsmol/kg. PRESERVATIVE ADDED: Benzalkonium Chloride 0.01%. Alrex chemical formula

CLINICAL PHARMACOLOGY Corticosteroids inhibit the inflammatory response to a variety of inciting agents and probably delay or slow healing. They inhibit the edema, fibrin deposition, capillary dilation, leukocyte migration, capillary proliferation, fibroblast proliferation, deposition of collagen, and scar formation associated with inflammation. There is no generally accepted explanation for the mechanism of action of ocular corticosteroids. However, corticosteroids are thought to act by the induction of phospholipase A 2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A 2 . Corticosteroids are capable of producing a rise in intraocular pressure. Loteprednol etabonate is structurally similar to other corticosteroids. However, the number 20 position ketone group is absent. It is highly lipid soluble which enhances its penetration into cells. Loteprednol etabonate is synthesized through structural modifications of prednisolone-related compounds so that it will undergo a predictable transformation to an inactive metabolite. Based upon in vivo and in vitro preclinical metabolism studies, loteprednol etabonate undergoes extensive metabolism to inactive carboxylic acid metabolites. Results from a bioavailability study in normal volunteers established that plasma levels of loteprednol etabonate and Δ 1 cortienic acid etabonate (PJ 91), its primary, inactive metabolite, were below the limit of quantitation (1 ng/mL) at all sampling times. The results were obtained following the ocular administration of one drop in each eye of 0.5% loteprednol etabonate 8 times daily for 2 days or 4 times daily for 42 days. This study suggests that limited (<1 ng/mL) systemic absorption occurs with ALREX. Clinical Studies: In two double-masked, placebo-controlled six-week environmental studies of 268 patients with seasonal allergic conjunctivitis, ALREX, when dosed four times per day was superior to placebo in the treatment of the signs and symptoms of seasonal allergic conjunctivitis. ALREX provided reduction in bulbar conjunctival injection and itching, beginning approximately 2 hours after instillation of the first dose and throughout the first 14 days of treatment.

Clinical Studies: In two double-masked, placebo-controlled six-week environmental studies of 268 patients with seasonal allergic conjunctivitis, ALREX, when dosed four times per day was superior to placebo in the treatment of the signs and symptoms of seasonal allergic conjunctivitis. ALREX provided reduction in bulbar conjunctival injection and itching, beginning approximately 2 hours after instillation of the first dose and throughout the first 14 days of treatment.

CONTRAINDICATIONS ALREX, as with other ophthalmic corticosteroids, 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. ALREX is also contraindicated in individuals with known or suspected hypersensitivity to any of the ingredients of this preparation and to other corticosteroids.

WARNINGS Prolonged use of corticosteroids may result in glaucoma with damage to the optic nerve, defects in visual acuity and fields of vision, and in posterior subcapsular cataract formation. Steroids should be used with caution in the presence of glaucoma. Prolonged use of corticosteroids may suppress the host response and thus increase the hazard of secondary ocular infections. In those diseases causing thinning of the cornea or sclera, perforations have been known to occur with the use of topical steroids. In acute purulent conditions of the eye, steroids may mask infection or enhance existing infection. Use of ocular steroids may prolong the course and may exacerbate the severity of many viral infections of the eye (including herpes simplex). Employment of a corticosteroid medication in the treatment of patients with a history of herpes simplex requires great caution.

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. 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: This product is sterile when packaged. Patients should be advised not to allow the dropper tip to touch any surface, as this may contaminate the suspension. If redness or itching becomes aggravated, the patient should be advised to consult a physician. Patients should be advised not to wear a contact lens if their eye is red. ALREX should not be used to treat contact lens related irritation. The preservative in ALREX, benzalkonium chloride, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red , should be instructed to wait at least ten minutes after instilling ALREX before they insert their contact lenses. 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 vitro in the Ames test, the mouse lymphoma tk assay, or in a chromosome aberration test in human lymphocytes, or in vivo in the single dose mouse micronucleus assay. Treatment of male and female rats with up to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, (1,500 and 750 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 (85 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 (15 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 postimplantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with ≥50 mg/kg/day). Treatment of rats with 0.5 mg/kg/day (15 times the maximum 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.

eatment of rats with 0.5 mg/kg/day (15 times the maximum 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 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. There are no adequate and well controlled studies in pregnant women. ALREX ophthalmic suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Nursing Mothers: It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemic steroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when ALREX is administered to a nursing woman. Pediatric Use: Safety and effectiveness in pediatric patients have not been established.

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. 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: This product is sterile when packaged. Patients should be advised not to allow the dropper tip to touch any surface, as this may contaminate the suspension. If redness or itching becomes aggravated, the patient should be advised to consult a physician. Patients should be advised not to wear a contact lens if their eye is red. ALREX should not be used to treat contact lens related irritation. The preservative in ALREX, benzalkonium chloride, may be absorbed by soft contact lenses. Patients who wear soft contact lenses and whose eyes are not red , should be instructed to wait at least ten minutes after instilling ALREX before they insert their contact lenses.

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 vitro in the Ames test, the mouse lymphoma tk assay, or in a chromosome aberration test in human lymphocytes, or in vivo in the single dose mouse micronucleus assay. Treatment of male and female rats with up to 50 mg/kg/day and 25 mg/kg/day of loteprednol etabonate, respectively, (1,500 and 750 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 (85 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 (15 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 postimplantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with ≥50 mg/kg/day). Treatment of rats with 0.5 mg/kg/day (15 times the maximum 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 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. There are no adequate and well controlled studies in pregnant women. ALREX ophthalmic suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

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 (85 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 (15 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 postimplantation losses at 100 mg/kg/day and decreased fetal body weight and skeletal ossification with ≥50 mg/kg/day). Treatment of rats with 0.5 mg/kg/day (15 times the maximum 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 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. There are no adequate and well controlled studies in pregnant women. ALREX ophthalmic suspension should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers: It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Systemic steroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. Caution should be exercised when ALREX is administered to a nursing woman.

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 5-15% of patients treated with loteprednol etabonate ophthalmic suspension (0.2-0.5%) 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 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. Among the smaller group of patients who were studied with ALREX, the incidence of clinically significant increases in IOP (≥10 mm Hg) was 1% (1/133) with ALREX and 1% (1/135) with placebo. To report SUSPECTED ADVERSE REACTIONS, contact Bausch & Lomb Incorporated at 1-800-553-5340 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

HOW SUPPLIED ALREX ® (loteprednol etabonate ophthalmic suspension, 0.2%) is supplied in a plastic bottle with a controlled drop tip in the following sizes: NDC 24208-353-05 5 mL in a 7.5 mL bottle NDC 24208-353-10 10 mL in a 10 mL bottle

Distributed by: Bausch & Lomb Americas Inc. Bridgewater, NJ 08807 USA Manufactured by: Bausch & Lomb Incorporated Tampa, FL 33637 USA ALREX is a trademark of Bausch & Lomb Incorporated or its affiliates. © 2022 Bausch & Lomb Incorporated or its affiliates Revised: 03/2022 9007907 (Folded) 9005507 (Flat)