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`Filed:
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`UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`AKORN, INC.
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`Petitioner
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`V.
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`SENJU PHARMACEUTICAL CO., LTD.
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`MITSUBISHI CHEMICAL CORPORATION
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`Patent Owner
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`Case IPR2015-01205
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`Patent 6,114,319
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`DECLARATION OF DIANE PANG REGARDING AUTHENTICATION OF
`DUREZOL® LABEL FROM 2008
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`SENJU-MITSUBISHI 2082
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`IPR2015—01205
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`U.S. Patent No. 6,114,319
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`Declaration of Diane Pang
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`Exhibits Referenced In This Declaration
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`Exhibit #
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`Printout of “durezol” search results from “Drugs@FDA”
`database
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` Description
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`Label for Durezol from 2008
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`IPR2015—012U5
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`Declaration of Diane Pang
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`US. Patent No. 6,114,319
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`1.
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`2.
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`1, Diane Pang, am an attorney at O’Me1veny & Myers LLP.
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`Exhibit A is a true and correct copy of the search results for “durezol”
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`that I obtained from the “Drugs@FDA” database on June 22, 2016.
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`3.
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`Exhibit B is a true and correct copy of the Durezo1® Label with an
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`“Action Date” of 06/23/2008, that I obtained from the “Drugs@FDA” database o_n
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`June 22, 2016.
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`4.
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`I declare under penalty of perjury under the laws of the United States
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`that the foregoing is true and correct. This declaration is executed this 22"” day of
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`June, 2016, at Newport Beach, California.
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`WW Pagg
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`Exhibit A
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`Drug§'@FDA: FDA Approved Drug Products
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`_ 3 E-er»=ir’ : ~; rt ;‘ Health 9. Human Services
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`Atozlnriax
`|Fullav.-FDA EEnEspanoI
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`U5. FOOH and Dflig Administration —
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`Protecting and Promoting Your Health
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`FD/.—\5
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`“M”
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`Food Drugs
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`Medical Devices
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`Radiation-Emitting Products Vaccines, Blood 8: Biologlcs Animal 8: Veterinary Cosmetics Tobacco Products
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`is FDA Home Eli Drug Databases tit Drogsr§ajJF£lA
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`FDA Approved mug Products
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`FAQ | Instructions | Glossary | Contact Us
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`pg‘. L;
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`Qiimail Link
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`Back to Details
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`Label and Approval History
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`Drug Name(s)
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`DUHEZOL
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`FDA Application No.
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`(NDA] 022212
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`Active lngredienl(s) DIFLUPREDNATE
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`ALCON PHARMS LTD
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`Label Information
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`Go to Approval History
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`What information does a label include?
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`Note: Not all labels are available in electronic format from FDA.
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`The supplement type of the 04/11/2016 approval does not usually require new labeling.
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`Vlewlhe label approved on nsits/2913 (PDF) for NDA no. 022212
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`e To see if other previously-approved labels are available on this site, go to the "Approval History" section of this
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`page. Older Iab__e-_l_s__are for historical i__r_r_f_o_rrpation only_and_sbouId not beused f
`Approval History
`NDA 022212
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`Note: Not all reviews are available in electronic format from FDA.
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`Older labels are for historical information only, and should not be used for clinical purposes.
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`Approval dates can only be verilied from 1984 to the present.
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`This supplement type does
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`notusuallyrequirenewlabeling.
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`This supplement type does
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`not usually require new labeling.
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`Label is not available
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`Click on a column header to re-sort the table:
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`Supplement Approval
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`3 Manulaciuring Change or Addition
`Labeling Revision
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`Efficacy Supplement with Clinical Data to Support
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`Label (PDF)
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`Drugs@FDA: FDA Approved Drug Products
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`Note: if you need help accessing information in different file formats. see Instructions for Downloading Viewers and Players
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`‘,3 There are no Therapeutic Equivalents 7
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`Back to Top | Back to Previous Page | Back to Drugs@FDA Home
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`-,,_.t_,i,i,;w,,;~._
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`g U.S.Department of Heatth & Human services
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`Note: if you need help accessing information in dilferent file tormats, see instructions for Downloading Viewers and Players.
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`.. .- god and Drug Administration
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`r0555 ii... Hampshire Avenue
`_ Silver Spring, MD 20993
`Ph. 1-BBB-iNFO-FDA {1-888-4636332)
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`E?"
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`Exhibit B
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`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all of the information needed to use Durezol
`safely and effectively. See full prescribing information for Durezol.
`Durezol (difluprednate ophthalmic emulsion) 0.05%
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`Initial U.S. approval: 2008
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`--——---------------------INDICATIONS AND USAGE--------------------------------
`Durezol is a topical corticosteroid that is indicated for the treatment of
`inflammation and pain associated with ocular surgery. (1)
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`0
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`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 beyond 28 clays 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. If signs and symptoms fail to improve after 2. days, the
`patient should be re-evaluated. (5.4)
`Viral infections- Employment of a corticosteroid medication in the
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`treatment of patients with a history of herpes simplex requires great
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`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 infecIions- 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)
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`----------------------DOSAGE AND ADMINISTRATION--------------------------
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`Instill one drop into the conjunetival sac of the affected eye(s) 4 times daily
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`beginning 24 hours after surgery and continuing throughout the first 2 weeks of
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`the postoperative period, followed by 2 times daily for a week and then a taper
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`based on the response. (2)
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`-----------------------DOSAGE FORMS AND STRENGTHS-----------------------
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`Durezol contains tl.tl5% difluprednate, as a sterile preserved ophtlialmic
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`emulsion for topical ophthalmic use only. (3)
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`--------------------—
`---------------------------CONTRAINDICA'l'IONS-------------
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`Durezol, as with other ophthalmic corticosteroids, is contraindicated in most
`viral diseases of the cornea and conjunctiva including epithelial herpes simplex
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`keratitis (dendritic keratitis), vaccinia, and varicella, and also in mycobacterial
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`infection of the eye and fungal diseases of ocular structures. (4)
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`To report SUSPECTED ADVERSE REACTIONS, contact Sirion
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`Therapeutics at (TBD) or FDA at 1-800-FDA-1088 or
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`www.fdn.gnv[medwatcIt.
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`Revised date: June 2008
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`--------------------—-WARNINGS AND PRECAUTIONS----------------------------
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`lntraocular pressure (IOP) increase-Prolonged use of corticosteroids may
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`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).
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`8.4 Pediatric Use
`8.5 Geriatric Use
`FULL PRESCRIBING INFORMATION: CONTENTS*
`11 DESCRIPTION
`INDICATIONS AND USAGE
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`12 CLINICAL PHARMACOLOGY
`DOSAGE AND ADMINISTRATION
`12.1 Mechanism of Action
`DOSAGE FORMS AND STRENGTHS
`12.3 Pharmacokinetics
`CONTRAINDICATIONS
`13 NONCLINICAL TOXICOLOGY
`WARNINGS AND PRECAUTIONS
`[OP increase
`13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
`5.2 Cataracts
`13.2 Animal Toxicology and/or Pharmacology
`14 CLINICAL STUDIES
`5.3 Delayed Healing
`5.4 Bacterial infections
`14.E Postoperative Ocular Inflammation and Pain
`5.5 Viral infections
`16 HOW SUPPLIED]STORAGE AND HANDLING
`17 PATIENT COUNSELING INFORMATION
`5.6 Fungal infections
`5.7 Topical ophthalmic use only
`ADVERSE REACTIONS
`USE IN SPECIFIC POPULATIONS
`8.1 Pregnancy
`8.3 Nursing Mothers
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`See 17 for PATIENT COUNSELING INFORMATION.
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`*Seclions or subsections omitted from the full prescribing information are not
`listed.
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`pigmentation and striae, eplscleritis, eye pruritis, eyelid irritation and crusting,
`foreign body sensation, increased lacrimation, macular edema, scleral
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`hyperemia, and uveitis. Most ofthese events may have been the consequence of
`the surgical procedure.
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`Use in Specific Populations
`8
`Pregnancy
`8.1
`Teratogenie Effects
`Pregnancy Category C. Difluprednate has been shown to be embryotoxic
`(decrease in embryonic body weight and a delay in embryonic ossification) and
`teratogenic (cleft palate and skeletal anomalies when administered
`subcutaneously to rabbits during organogenesis at a dose of I-10 pgfkglday.
`The no-observed—effect-level (NOEL) for these effects was I pg/kgjday, and
`I0 pglkgJday was considered to be a teratogenic dose that was concurrently
`found in the toxic dose range for fetuses and pregnant females. Treatment of rats
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`with 10 pglkglday subcutaneously during organogenesis did not result in any
`reproductive toxicity, I1or was it maternally toxic. At 100 pg/lcgfday after
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`subcutaneous administration in rats, there was a decrease in fetal weights and
`delay in ossification, and effects on weight gain in the pregnant females. It is
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`difficult to extrapolate these doses of ditluprednate to maximum daily human
`doses of Durezol, since Durezol is administered topically with minimal systemic
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`absorption, and difluprednate blood levels were not measured in the
`reproductive animal studies. l-lowever, since use of difluprednate during human
`pregnancy has not been evaluated and cannot rule out the possibility of harm,
`Durezol should be used during pregnancy only if the potential benefit justifies
`the potential risk to the embryo or fetus.
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`Nursing Mothers
`8.3
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`it is not known whether topical ophthalmic administration of corticosteroids
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`could result in Sufficient systemic absorption to produce detectable quantities in
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`breast milk. Systemically administered corticosteroids appear in human milk and
`could suppress growth, interfere with endogenous corticosteroid production, or
`cause other untoward effects. Caution should be exercised when Durezol is
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`administered to a nursing woman.
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`Pediatric Use
`8.4
`Safety and effectiveness in pediatric patients has not been established.
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`Geriatric Use
`8.5
`No overall differences in safety or effectiveness have been observed between
`elderly and younger patients.
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`Description
`11
`Durezol (difluprednate ophthalmic emulsion) 0.05% is a sterile, topical anti-
`inflammatory corticosteroid for ophthalmic use. The chemical name is 6t1,9-
`difluoro-l1[3,l7,21—trihydroxypregna-1,4-diene-3,20-dione 21-acetate 17-
`butyrate (CAS number 23674-86-4). Ditluprednate is represented by the
`following structural formula:
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`
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`Difluprednate has a molecular weight of 508.56, and the empirical formula is
`Cz1H34F207-
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`Each mL contains: ACTIVE: difluprednate 0.5 mg (0.05%); INACTIVES: boric
`acid, castor oil, glycerin, polysorbate 80, purified water, sodium acetate, sodium
`EDTA, sodium hydroxide (to adjust the pl-I to 5.2 to 5.8). The emulsion is
`essentially isotonic with a tonicity of 304 to 411 mOsm/kg. PRESERVATIVE:
`sorbic acid 0.1%.
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`Clinical Pharmacology
`12
`Mechanism of Action
`12.1
`Corticosteroids inhibit the inflammatory response to a variety of inciting agents
`that 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
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`FULL PRESCRIBING INFORMATION
`Indications and Usage
`Durczol (difluprednate ophthalmic emulsion) 0.05%, a topical corticosteroid, is
`indicated forthe treatment of inflammation and pain associated with ocular
`’
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`Dosage and Administration
`Instill one drop into the conjunctival sac ofthe affected eye(s) 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)
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`Dosage Forms and Strengths
`Durezol contains 0.05% ditluprednate as a sterile preserved emulsion for topical
`ophthalmic administration.
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`Contraindications
`The use of Durezol, 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.
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`Warnings and Precautions
`101’ 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.
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`Cataracts
`Use of corticosteroids may result in posterior subcapsular cataract formation.
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`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 ofthe medication order béyond 28 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,
`fluorcscein staining.
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`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.
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`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).
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`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 oris in use.
`Fungal culture should be taken when appropriate.
`
`Topical ophthalmic use only
`Durezol is not indicated for intraocular administration.
`
`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.
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`Ocular adverse reactions occurring in 5—l 5% of subjects in clinical studies with
`Durezol 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 l~5% of subjects included reduced visual acuity, punctate
`keratitis, eye inflammation, and iritis. Ocular adverse events occurring in < 1%
`ofsubjects included application site discomfort or irritation, corneal
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`Storage
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`Store at IS-25”C (59-7'l"‘F). Do not freeze. Protect from light. when not in use
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`keep the bottles in the protective carton and the unused vials in the protective
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`foil pouch.
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`Revised: June 2008
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`inflammation such as prostaglandins and leukotreines by inhibiting the release
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`of their common precursor arachidonic acid. Arachidonic acid is released from
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`membrane phospholipids by phospholipase A2.
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`Difluprednate is structurally similar to other corticosteroids.
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`Pharmacokinetics
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`Diflupretlnate undergoes deacetylation iI1 vivo to 611,‘)-difluoroprecinisolone 17-
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`butyrate (DFB), an active metabolite of difluprednate.
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`Clinical pharrnacoltinetic studies of dillupretlnate after repeat ocular instillation
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`of 2 drops of ditlupretlnate (0.0l% or 0.05%) QID for 7 days showed that DFB
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`levels in blood were below the quantification limit (50 ng/mL) at all time points
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`for all subjects. indicating the systemic absorption of difluprednate after ocular
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`instillation of Durezol is limited.
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`Patient Counseling Information
`17
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`This product is sterile when packaged. Patients should be advised not to allow
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`the dropper tip to touch any surface, as this may contaminate the emulsion. lf
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`pain develops or if redness, itching, or inflammation becomes aggravated, the
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`patient should be advised to consult a physician. As with alt ophthalmic
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`preparations containing a preservative, patients should be advised not to wear
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`contact tenses when using Durezol.
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`Nonclinical Toxicology
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`Carcinogenesis, Mutagenesis, and Impairment of Fertility
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`Difluprednate was not genoloxic in vitro in the Ames test, and in cultured
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`mammalian cells Cl‘lL/lU (a fibroblastic cell line derived from the lungs of
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`newborn female Chinese hamsters). An in viva micronucleus test of
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`difluprednate in mice was also negative. Treatment of male and female rats with
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`subcutaneous diflupretlnate up to 10 pg/kg/day prior to and during mating did
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`not impair fertility in either gender. Long term studies have not been conducted
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`to evaluate the carcinogenic potential of difluprednate.
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`Animal Toxicology and/or Pharmacology
`In multiple studies performed in rodents and non-rodents, subchronic and
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`chronic toxicity tests of tlifluprednate showed systemic effects such as
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`suppression of body weight gain; a decrease in lymphocyte count; atrophy of the
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`lymphatic glands and adrenal gland; and for local effects, thinning of the skin;
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`all of which were due to the pharrnacologic action of the molecule and are well
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`known glucocorticosteroid effects. Most, if not all of these effects were
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`reversible after drug withdrawal. The NOEL for the subchronic and chronic
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`toxicity tests were consistent between species and ranged from l—l .25 uglkg per
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`Clinical Studies
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`Postoperative Ocular Inflammation and Pain
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`Clinical efficacy was evaluated in 2 randomized, double—masked,
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`placebo-controlled trials in which subjects with an anterior chamber cell grade
`2 “2" (a cell count of ID or higher) after cataract surgery were assigned to
`Durezol or placebo (vehicle) following surgery. One drop of Durezol or vehicle
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`was self instilled either 2 (BID) or 4 (QID) times per day for 14 days, beginning
`the day after surgery. The presence of complete clearing (a cell count of U) was
`assessed 8 and 15 days post-surgery using a slit lamp binocular microscope. In
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`the intent-to-treat analyses of both studies, a significant benefit was seen in the
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`QID Durezol-treated group in ocular inflammation and reduction of pain when
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`compared with placebo. The consolidated clinical trial results are provided
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`Ocular Inflammation and Pain End oints (Studies Pooled)
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`t
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` Durezol QID
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`N .—. 107
`If
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`24
`44
`17
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`(4l%)’“
`(22%)*
`(7%)
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`Pain free (% subjects)
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`(27%
`58% "‘
`(63% *
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`* Statistically significantly better than vehicle, p<tl.t)l
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`Anterior Chamber cell
`clearing (% subjects)
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`How Supplied/‘Storage and Handling
`Durezol (difluprednate ophthalmic emulsion) 0.05”/o is a sterile, aqueous topical
`ophthalmic emulsion supplied in an opaque plastic bottle with a controlled drop
`tip and a pink cap in the following sizes:
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`— 2.5 ml. in a 5 mL bottle (NDC 42826-601-25)