Difluprednate

1 INDICATIONS AND USAGE Difluprednate ophthalmic emulsion is a topical corticosteroid that is indicated for: The treatment of inflammation and pain associated with ocular surgery (1.1) The treatment of endogenous anterior uveitis (1.2) 1.1 Ocular Surgery Difluprednate ophthalmic emulsion 0.05%, a topical corticosteroid, is indicated for the treatment of inflammation and pain associated with ocular surgery. 1.2 Endogenous Anterior Uveitis Difluprednate ophthalmic emulsion is also indicated for the treatment of endogenous anterior uveitis.

1.1 Ocular Surgery Difluprednate ophthalmic emulsion 0.05%, a topical corticosteroid, is indicated for the treatment of inflammation and pain associated with ocular surgery.

1.2 Endogenous Anterior Uveitis Difluprednate ophthalmic emulsion is also indicated for the treatment of endogenous anterior uveitis.

2 DOSAGE AND ADMINISTRATION • For the treatment of inflammation and pain associated with ocular surgery, instill one drop into the conjunctival sac of the affected eye 4 times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the postoperative period, followed by 2 times daily for a week and then a taper based on the response. ( 2.1 ) • For the treatment of endogenous anterior uveitis instill one drop into the conjunctival sac of the affected eye 4 times daily for 14 days followed by tapering as clinically indicated. ( 2.2 ) 2.1 Ocular Surgery Instill one drop into the conjunctival sac of the affected eye 4 times daily beginning 24 hours after surgery and continuing throughout the first 2 weeks of the postoperative period, followed by 2 times daily for a week and then a taper based on the response. 2.2 Endogenous Anterior Uveitis Instill one drop into the conjunctival sac of the affected eye 4 times daily for 14 days followed by tapering as clinically indicated. 2.3 Prescribing Guidelines The initial prescription and renewal of the medication order beyond one bottle 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 reevaluated. Not more than one bottle should be prescribed initially, and the prescription should not be refilled without further evaluation.

3 DOSAGE FORMS AND STRENGTHS Difluprednate ophthalmic emulsion contains 0.05% difluprednate as a sterile preserved emulsion for topical ophthalmic administration. Difluprednate ophthalmic emulsion contains 0.05% difluprednate, as a sterile preserved ophthalmic emulsion for topical ophthalmic use only. ( 3 )

4 CONTRAINDICATIONS The use of difluprednate ophthalmic emulsion, as with other ophthalmic corticosteroids, is contraindicated in most active 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 disease of ocular structures. Difluprednate ophthalmic emulsion, as with other ophthalmic corticosteroids, is contraindicated in most active 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 )

6 ADVERSE REACTIONS The following serious reactions are found elsewhere in the labeling: Elevated intraocular pressure [see Warnings and Precautions (5.1) ] Posterior subcapsular cataract formation [see Warnings and Precautions (5.2) ] Secondary ocular infection [see Warnings and Precautions (5.4) ] Perforation of the globe [see Warnings and Precautions (5.3) ] 6.1 Ocular Surgery Ocular adverse reactions occurring in 5-15% of subjects in clinical studies with difluprednate ophthalmic emulsion included corneal edema, ciliary and conjunctival hyperemia, eye pain, photophobia, posterior capsule opacification, anterior chamber cells, anterior chamber flare, conjunctival edema, and blepharitis. Other ocular adverse reactions occurring in 1-5% of subjects included reduced visual acuity, punctate keratitis, eye inflammation, and iritis. Ocular adverse reactions occurring in < 1% of subjects included application site discomfort or irritation, corneal pigmentation and striae, episcleritis, eye pruritis, eyelid irritation and crusting, foreign body sensation, increased lacrimation, macular edema, sclera hyperemia, and uveitis. Most of these reactions may have been the consequence of the surgical procedure. 6.2 Endogenous Anterior Uveitis A total of 200 subjects participated in the clinical trials for endogenous anterior uveitis, of which 106 were exposed to difluprednate ophthalmic emulsion. The most common adverse reactions of those exposed to difluprednate ophthalmic emulsion occurring in 5-10% of subjects included blurred vision, eye irritation, eye pain, headache, increased IOP, iritis, limbal and conjunctival hyperemia, punctate keratitis, and uveitis. Adverse reactions occurring in 2-5% of subjects included anterior chamber flare, corneal edema, dry eye, iridocyclitis, photophobia, and reduced visual acuity.

6.1 Ocular Surgery Ocular adverse reactions occurring in 5-15% of subjects in clinical studies with difluprednate ophthalmic emulsion included corneal edema, ciliary and conjunctival hyperemia, eye pain, photophobia, posterior capsule opacification, anterior chamber cells, anterior chamber flare, conjunctival edema, and blepharitis. Other ocular adverse reactions occurring in 1-5% of subjects included reduced visual acuity, punctate keratitis, eye inflammation, and iritis. Ocular adverse reactions occurring in < 1% of subjects included application site discomfort or irritation, corneal pigmentation and striae, episcleritis, eye pruritis, eyelid irritation and crusting, foreign body sensation, increased lacrimation, macular edema, sclera hyperemia, and uveitis. Most of these reactions may have been the consequence of the surgical procedure.

6.2 Endogenous Anterior Uveitis A total of 200 subjects participated in the clinical trials for endogenous anterior uveitis, of which 106 were exposed to difluprednate ophthalmic emulsion. The most common adverse reactions of those exposed to difluprednate ophthalmic emulsion occurring in 5-10% of subjects included blurred vision, eye irritation, eye pain, headache, increased IOP, iritis, limbal and conjunctival hyperemia, punctate keratitis, and uveitis. Adverse reactions occurring in 2-5% of subjects included anterior chamber flare, corneal edema, dry eye, iridocyclitis, photophobia, and reduced visual acuity.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Risk Summary There are no available data on difluprednate ophthalmic emulsion use in pregnant women to evaluate for a drug- associated risk of major birth defects, miscarriage or other adverse maternal or fetal outcomes. Systemic exposure to difluprednate ophthalmic emulsion following ocular administration is low [see Clinical Pharmacology ( 12.3 )]. Consequently, the systemic exposure of a pregnant woman to difluprednate is expected to be minimal following topical ocular administration. In animal reproductive studies, subcutaneous administration of difluprednate to pregnant rabbits and rats throughout organogenesis produced maternal toxicity, embryo-fetal toxicity and teratogenicity in rabbits and fetotoxicity in rats. Administration of difluprednate to rats during late gestation through lactation did not produce adverse maternal, fetal or neonatal effects at clinically relevant doses. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively. Data Animal Data In embryofetal development studies, subcutaneous administration of difluprednate to pregnant rats during the period of organogenesis decreased the placental weight, at doses greater than or equal to 10 mcg/kg/day (approximately 0.48-fold higher than the maximum recommended human ophthalmic dose [MRHOD] of 0.2 mg/day, on a mg/m 2 basis and assuming 100% absorption of the dose). Decreased weight gain and delayed ossification of the fetus were observed at a dose of 100 mcg/kg/day (approximately 4.8-fold higher than the MRHOD). The no-observed-effect level (NOEL) for teratogenic effects was 10 mcg/kg/day. In rabbits, subcutaneous administration of difluprednate during the period of organogenesis produced maternal toxicity, embryofetal lethality, fetal growth retardation and teratogenicity (cleft palate, cerebral hernia, exencephaly, hypogenesis of the first digit of the forelimbs, club hand, umbilical hernia and others) at 10 mcg/kg/day (approximately 0.97-fold the MRHOD on a mg/m 2 basis and assuming 100% absorption of the dose). The NOEL was 1 mcg/kg/day. In a peri- or pre-/postnatal study in rats, subcutaneous administration of difluprednate during late gestation through lactation resulted in no abnormalities in postnatal development, growth and behavior or reproductive potential. The NOEL was greater than or equal to 10 mcg/kg/day (the highest dose tested; approximately 0.48-fold higher than the MRHOD on a mg/m 2 basis and assuming 100% absorption of the dose). 8.2 Lactation Risk Summary There are no data on the presence of difluprednate ophthalmic emulsion in human milk, the effects on the breastfed infants, or the effects on milk production to inform risk of difluprednate ophthalmic emulsion to an infant during lactation. Systemically administered corticosteroids appear in human milk and could suppress growth, interfere with endogenous corticosteroid production, or cause other untoward effects. The systemic exposure of a breastfeeding woman to difluprednate is expected to be minimal following topical ocular administration, however, the possibility of harm to the breastfed child cannot be ruled out. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for difluprednate ophthalmic emulsion and any potential adverse effects on the breast-fed child from difluprednate ophthalmic emulsion or from the underlying maternal condition. 8.3 Nursing Mothers It is not known whether topical ophthalmic administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in breast milk. Systemically administered corticostero …

12.1 Mechanism of Action Corticosteroids inhibit the inflammatory response to a variety of inciting agents and may delay or slow healing. They inhibit 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 A2 inhibitory proteins, collectively called lipocortins. It is postulated that these proteins control the biosynthesis of potent mediators of inflammation, such as prostaglandins and leukotreines by inhibiting the release of their common precursor arachidonic acid. Arachidonic acid is released from membrane phospholipids by phospholipase A2. Difluprednate is structurally similar to other corticosteroids.

11 DESCRIPTION Difluprednate ophthalmic emulsion 0.05% is a sterile, white opaque to slightly translucent topical anti-inflammatory corticosteroid for topical ophthalmic use. The chemical name is 6α, 9-difluoro-11β,17,21-trihydroxypregna-1,4-diene-3,20-dione 21-acetate 17-butyrate (CAS number 23674-86-4). Difluprednate is represented by the following structural formula: Difluprednate has a molecular weight of 508.55 g/mol, and the empirical formula is C 27 H 34 F 2 O 7 . Each mL of difluprednate ophthalmic emulsion contains: Active: difluprednate 0.5 mg (0.05%); Inactive: boric acid, castor oil, glycerin, polysorbate 80, water for injection, sodium acetate, edetate disodium, sodium hydroxide (to adjust the pH to 5.2 to 5.8). Preservative: sorbic acid 0.1%. The emulsion is essentially isotonic with a tonicity of 304 to 411 mOsm/kg. Difluprednate Structural Formula

16 HOW SUPPLIED/STORAGE AND HANDLING Difluprednate ophthalmic emulsion 0.05% is a sterile, aqueous topical ophthalmic emulsion supplied in a white, LDPE bottle with a nozzle and a pink cap in the following sizes: 5 mL in a 5 mL bottle NDC 46708-750-05 Storage and Handling Store at 20°C to 25°C (68°F to 77°F), excursions permitted between 15°C and 30°C (59°F and 86°F) [see USP Controlled Room Temperature]. Do not freeze. Protect from light. When not in use, keep the bottles in the protective carton.After opening, difluprednate ophthalmic emulsion can be used until the expiration date on the bottle.