DIFUPREDNATE) OPHTHALMIC EMULSION 0.05%
DRUG DESCRIPTION
DUREZOL (DIFUPREDNATE OPHTHALMIC EMULSION) 0.05% IS A STERILE, TOPICAL ANTI-INFAMMATORY CORTICOSTEROID FOR OPHTHALMIC USE. THE CHEMICAL NAME IS 6?,9-DIFUORO-11?,17,21-TRIHYDROXYPREGNA-1,4-DIENE-3,20-DIONE 21-ACETATE 17-BUTYRATE (CAS NUMBER 23674-86-4).
EACH ML CONTAINS: ACTIVE: DIFUPREDNATE 0.5 MG (0.05%) INACTIVE: BORIC ACID, CASTOR OIL, GLYCERIN, POLYSORBATE 80, PURIFED WATER, SODIUM ACETATE, SODIUM EDTA, AND SODIUM HYDROXIDE (TO ADJUST THE PH 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%.
INDICATIONS
DUREZOL (DIFUPREDNATE OPHTHALMIC EMULSION) 0.05%, A TOPICAL CORTICOSTEROID, IS INDICATED FOR THE TREATMENT OF INFAMMATION AND PAIN ASSOCIATED WITH OCULAR SURGERY.
DOSAGE AND ADMINISTRATION
INSTILL ONE DROP INTO THE CONJUNCTIVAL SAC OF THE AFFECTED EYE(S) 4 TIMES DAILY BEGINNING 24 HOURS AFTER SURGERY AND CONTINUING THROUGHOUT THE FRST 2 WEEKS OF THE POSTOPERATIVE PERIOD, FOLLOWED BY 2 TIMES DAILY FOR A WEEK AND THEN A TAPER BASED ON THE RESPONSE.
SIDE EFFECTS
ADVERSE REACTIONS ASSOCIATED WITH OPHTHALMIC STEROIDS INCLUDE ELEVATED INTRAOCULAR PRESSURE, WHICH MAY BE ASSOCIATED WITH OPTIC NERVE DAMAGE, VISUAL ACUITY AND FELD 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 5β15% OF SUBJECTS IN CLINICAL STUDIES WITH DUREZOL INCLUDED CORNEAL EDEMA, CILIARY AND CONJUNCTIVAL HYPEREMIA, EYE PAIN, PHOTOPHOBIA, POSTERIOR CAPSULE OPACIFCATION, ANTERIOR CHAMBER CELLS, ANTERIOR CHAMBER FARE, CONJUNCTIVAL EDEMA, AND BLEPHARITIS. OTHER OCULAR ADVERSE REACTIONS OCCURRING IN 1β5% OF SUBJECTS INCLUDED REDUCED VISUAL ACUITY, PUNCTATE KERATITIS, EYE INFAMMATION, AND IRITIS. OCULAR ADVERSE EVENTS 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, SCLERAL HYPEREMIA, AND UVEITIS. MOST OF THESE EVENTS MAY HAVE BEEN THE CONSEQUENCE OF THE SURGICAL PROCEDURE.
DRUG INTERACTIONS
NO INFORMATION PROVIDED.
WARNINGS
INCLUDED AS PART OF THE PRECAUTIONS SECTION.
PRECAUTIONS
IOP INCREASE
PROLONGED USE OF CORTICOSTEROIDS MAY RESULT IN GLAUCOMA WITH DAMAGE TO THE OPTIC NERVE, DEFECTS IN VISUAL ACUITY AND FELDS 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.
CATARACTS
USE OF CORTICOSTEROIDS MAY RESULT IN POSTERIOR SUBCAPSULAR CATARACT FORMATION.
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 DAYS SHOULD BE MADE BY A PHYSICIAN ONLY AFTER EXAMINATION OF THE PATIENT WITH THE AID OF MAGNIFCATION SUCH AS SLIT LAMP BIOMICROSCOPY AND, WHERE APPROPRIATE, FUORESCEIN STAINING.
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.
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).
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.
TOPICAL OPHTHALMIC USE ONLY
DUREZOL IS NOT INDICATED FOR INTRAOCULAR ADMINISTRATION.
NONCLINICAL TOXICOLOGY
CARCINOGENESIS, MUTAGENESIS, AND IMPAIRMENT OF FERTILITY
DIFUPREDNATE WAS NOT GENOTOXIC IN VITRO IN THE AMES TEST, AND IN CULTURED MAMMALIAN CELLS CHL/IU (A FBROBLASTIC CELL LINE DERIVED FROM THE LUNGS OF NEWBORN FEMALE CHINESE HAMSTERS). AN IN VIVO MICRONUCLEUS TEST OF DIFUPREDNATE IN MICE WAS ALSO NEGATIVE. TREATMENT OF MALE AND FEMALE RATS WITH SUBCUTANEOUS DIFUPREDNATE UP TO 10 ?G/KG/DAY PRIOR TO AND DURING MATING DID NOT IMPAIR FERTILITY IN EITHER GENDER. LONG TERM STUDIES HAVE NOT BEEN CONDUCTED TO EVALUATE THE CARCINOGENIC POTENTIAL OF DIFUPREDNATE.
USE IN SPECIFIC POPULATIONS
PREGNANCY
TERATOGENIC EFFECTS
PREGNANCY CATEGORY C. DIFUPREDNATE HAS BEEN SHOWN TO BE EMBRYOTOXIC (DECREASE IN EMBRYONIC BODY WEIGHT AND A DELAY IN EMBRYONIC OSSIFCATION) AND TERATOGENIC (CLEFT PALATE AND SKELETAL) ANOMALIES WHEN ADMINISTERED SUBCUTANEOUSLY TO RABBITS DURING ORGANOGENESIS AT A DOSE OF 1β10 ?G/KG/DAY. THE NO-OBSERVED-EFFECT-LEVEL (NOEL) FOR THESE EFFECTS WAS 1 ?G/KG/DAY, AND 10 ?G/KG/DAY WAS CONSIDERED TO BE A TERATOGENIC DOSE THAT WAS CONCURRENTLY FOUND IN THE TOXIC DOSE RANGE FOR FETUSES AND PREGNANT FEMALES. TREATMENT OF RATS WITH 10 ?G/KG/DAY SUBCUTANEOUSLY DURING ORGANOGENESIS DID NOT RESULT IN ANY REPRODUCTIVE TOXICITY, NOR WAS IT MATERNALLY TOXIC. AT 100 ?G/KG/DAY AFTER SUBCUTANEOUS ADMINISTRATION IN RATS, THERE WAS A DECREASE IN FETAL WEIGHTS AND DELAY IN OSSIFCATION, AND EFFECTS ON WEIGHT GAIN IN THE PREGNANT FEMALES. IT IS DIFFCULT TO EXTRAPOLATE THESE DOSES OF DIFUPREDNATE TO MAXIMUM DAILY HUMAN DOSES OF DUREZOL, SINCE DUREZOL IS ADMINISTERED TOPICALLY WITH MINIMAL SYSTEMIC ABSORPTION, AND DIFUPREDNATE BLOOD LEVELS WERE NOT MEASURED IN THE REPRODUCTIVE ANIMAL STUDIES. HOWEVER, SINCE USE OF DIFUPREDNATE 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 BENEFT JUSTIFES THE POTENTIAL RISK TO THE EMBRYO OR FETUS.
NURSING MOTHERS
IT IS NOT KNOWN WHETHER TOPICAL OPHTHALMIC ADMINISTRATION OF CORTICOSTEROIDS COULD RESULT IN SUFFCIENT SYSTEMIC ABSORPTION TO PRODUCE DETECTABLE QUANTITIES IN 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 ADMINISTERED TO A NURSING WOMAN.
PEDIATRIC USE
SAFETY AND EFFECTIVENESS IN PEDIATRIC PATIENTS HAS NOT BEEN ESTABLISHED.
GERIATRIC USE
NO OVERALL DIFFERENCES IN SAFETY OR EFFECTIVENESS HAVE BEEN OBSERVED BETWEEN ELDERLY AND YOUNGER PATIENTS.
OVERDOSE
NO INFORMATION PROVIDED.
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.
CLINICAL PHARMACOLOGY
MECHANISM OF ACTION
CORTICOSTEROIDS INHIBIT THE INFAMMATORY RESPONSE TO A VARIETY OF INCITING AGENTS THAT MAY DELAY OR SLOW HEALING. THEY INHIBIT EDEMA, FBRIN DEPOSITION, CAPILLARY DILATION, LEUKOCYTE MIGRATION, CAPILLARY PROLIFERATION, FBROBLAST PROLIFERATION, DEPOSITION OF COLLAGEN, AND SCAR FORMATION ASSOCIATED WITH INFAMMATION. 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 INFAMMATION SUCH AS PROSTAGLANDINS AND LEUKOTRIENES BY INHIBITING THE RELEASE OF THEIR COMMON PRECURSOR ARACHIDONIC ACID. ARACHIDONIC ACID IS RELEASED FROM MEMBRANE PHOSPHOLIPIDS BY PHOSPHOLIPASE A2.
DIFUPREDNATE IS STRUCTURALLY SIMILAR TO OTHER CORTICOSTEROIDS.
PHARMACOKINETICS
DIFUPREDNATE UNDERGOES DEACETYLATION IN VIVO TO 6?,9-DIFUOROPREDNISOLONE 17-BUTYRATE (DFB), AN ACTIVE METABOLITE OF DIFUPREDNATE.
CLINICAL PHARMACOKINETIC STUDIES OF DIFUPREDNATE AFTER REPEAT OCULAR INSTILLATION OF 2 DROPS OF DIFUPREDNATE (0.01% OR 0.05%) QID FOR 7 DAYS SHOWED THAT DFB LEVELS IN BLOOD WERE BELOW THE QUANTIFCATION LIMIT (50 NG/ML) AT ALL TIME POINTS FOR ALL SUBJECTS, INDICATING THE SYSTEMIC ABSORPTION OF DIFUPREDNATE AFTER OCULAR INSTILLATION OF DUREZOL IS LIMITED.
ANIMAL TOXICOLOGY AND/OR PHARMACOLOGY
IN MULTIPLE STUDIES PERFORMED IN RODENTS AND NON-RODENTS, SUBCHRONIC AND CHRONIC TOXICITY TESTS OF DIFUPREDNATE SHOWED SYSTEMIC EFFECTS SUCH AS SUPPRESSION OF BODY WEIGHT GAIN; A DECREASE IN LYMPHOCYTE COUNT; ATROPHY OF THE LYMPHATIC GLANDS AND ADRENAL GLAND; AND FOR LOCAL EFFECTS, THINNING OF THE SKIN; ALL OF WHICH WERE DUE TO THE PHARMACOLOGIC ACTION OF THE MOLECULE AND ARE WELL KNOWN GLUCOCORTICOSTEROID EFFECTS. MOST, IF NOT ALL OF THESE EFFECTS WERE REVERSIBLE AFTER DRUG WITHDRAWAL. THE NOEL FOR THE SUBCHRONIC AND CHRONIC TOXICITY TESTS WERE CONSISTENT BETWEEN SPECIES AND RANGED FROM 1β1.25 ?G/KG PER DAY.
CLINICAL STUDIES
POSTOPERATIVE OCULAR INFAMMATION AND PAIN
CLINICAL EFFCACY WAS EVALUATED IN 2 RANDOMIZED, DOUBLE-MASKED, PLACEBO-CONTROLLED TRIALS IN WHICH SUBJECTS WITH AN ANTERIOR CHAMBER CELL GRADE = β2β (A CELL COUNT OF 11 OR HIGHER) AFTER CATARACT SURGERY WERE ASSIGNED TO DUREZOL OR PLACEBO (VEHICLE) FOLLOWING SURGERY. ONE DROP OF DUREZOL OR VEHICLE 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 0) WAS ASSESSED AT 8 DAYS AND 15 DAYS POST-SURGERY USING A SLIT LAMP BINOCULAR MICROSCOPE. IN THE INTENT-TO-TREAT ANALYSES OF BOTH STUDIES, A SIGNIFCANT BENEFT WAS SEEN IN THE QID DUREZOL-TREATED GROUP IN OCULAR INFAMMATION AND REDUCTION OF PAIN WHEN COMPARED WITH PLACEBO. THE CONSOLIDATED CLINICAL TRIAL RESULTS ARE PROVIDED BELOW.
OCULAR INFAMMATION AND PAIN ENDPOINTS (STUDIES POOLED)
Β
DUREZOL QID
(N=107)
VEHICLE
(N=220)
DAY
8
15
8
15
ANTERIOR CHAMBER CELL CLEARING (% SUBJECTS)
24 (22%)*
44 (41%)*
17 (7%)
25 (11%)
PAIN FREE (% SUBJECTS)
62 (58%)*
67 (63%)*
59 (27%)
76 (35%)
* STATISTICALLY SIGNIFCANTLY BETTER THAN VEHICLE, P < 0.01