OZURDEX
HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use OZURDEX safely and effectively. See full prescribing information for OZURDEX.OZURDEX (dexamethasone intravitreal implant) Initial U.S. Approval: 1958 INDICATIONS AND USAGE OZURDEX ® is a corticosteroid indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) (1.1) and for the treatment of non-infectious uveitis affecting the posterior segment of the eye. (1.2) DOSAGE AND ADMINISTRATION For ophthalmic intravitreal injection only. (2.1) The intravitreal injection procedure should be carried out under controlled aseptic conditions. (2.2) Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. (2.2) DOSAGE FORMS AND STRENGTHS Intravitreal implant containing dexamethasone 0.7 mg in the NOVADUR ® solid polymer drug delivery system. (3) CONTRAINDICATIONS Ocular or periocular infections (4.1) Advanced glaucoma (4.2) Aphakic eyes with rupture of the posterior lens capsule (4.3) ACIOL and rupture of the posterior lens capsule (4.4) Hypersensitivity (4.5) WARNINGS AND PRECAUTIONS Intravitreal injections have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments. Patients should be monitored following the injection. (5.1) Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses. (5.2) The implant may migrate to the anterior chamber if the posterior lens capsule is not intact. (5.3) Side EffectsIn controlled studies, the most common adverse reactions reported by ≥ 20% of patients were increased intraocular pressure and conjunctival hemorrhage. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-433-8871 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .
FULL PRESCRIBING INFORMATION: CONTENTS*
- 1 OZURDEX INDICATIONS AND USAGE
- 2 OZURDEX DOSAGE AND ADMINISTRATION
- 3 DOSAGE FORMS AND STRENGTHS
- 4 OZURDEX CONTRAINDICATIONS
- 5 WARNINGS AND PRECAUTIONS
- 6 OZURDEX ADVERSE REACTIONS
- 8 USE IN SPECIFIC POPULATIONS
- 11 OZURDEX DESCRIPTION
- 12 CLINICAL PHARMACOLOGY
- 13 NONCLINICAL TOXICOLOGY
- 14 CLINICAL STUDIES
- 16 HOW SUPPLIED/STORAGE AND HANDLING
- 17 PATIENT COUNSELING INFORMATION
FULL PRESCRIBING INFORMATION
1 INDICATIONS AND USAGE
1.1 Retinal Vein Occlusion
OZURDEX ® (dexamethasone intravitreal implant) is indicated for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO).
1.2 Posterior Segment Uveitis
OZURDEX ® is indicated for the treatment of non-infectious uveitis affecting the posterior segment of the eye.
2 DOSAGE AND ADMINISTRATION
2.1 General Dosing Information
For ophthalmic intravitreal injection only.
2.2 Administration
The intravitreal injection procedure should be carried out under controlled aseptic conditions which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). Adequate anesthesia and a broad-spectrum microbicide applied to the periocular skin, eyelid and ocular surface are recommended to be given prior to the injection.
Remove the foil pouch from the carton and examine for damage. Then, open the foil pouch over a sterile field and gently drop the applicator on a sterile tray. Carefully remove the cap from the applicator. Hold the applicator in one hand and pull the safety tab straight off the applicator. Do not twist or flex the tab. The long axis of the applicator should be held parallel to the limbus, and the sclera should be engaged at an oblique angle with the bevel of the needle up (away from the sclera) to create a shelved scleral path. The tip of the needle is advanced within the sclera for about 1 mm (parallel to the limbus), then re-directed toward the center of the eye and advanced until penetration of the sclera is completed and the vitreous cavity is entered. The needle should not be advanced past the point where the sleeve touches the conjunctiva.
Slowly depress the actuator button until an audible click is noted. Before withdrawing the applicator from the eye, make sure that the actuator button is fully depressed and has locked flush with the applicator surface. Remove the needle in the same direction as used to enter the vitreous.
Following the intravitreal injection, patients should be monitored for elevation in intraocular pressure and for endophthalmitis. Monitoring may consist of a check for perfusion of the optic nerve head immediately after the injection, tonometry within 30 minutes following the injection, and biomicroscopy between two and seven days following the injection. Patients should be instructed to report any symptoms suggestive of endophthalmitis without delay.
Each applicator can only be used for the treatment of a single eye. If the contralateral eye requires treatment, a new applicator must be used, and the sterile field, syringe, gloves, drapes, and eyelid speculum should be changed before OZURDEX ® is administered to the other eye.
3 DOSAGE FORMS AND STRENGTHS
Intravitreal implant containing dexamethasone 0.7 mg in the NOVADUR ® solid polymer drug delivery system.
4 CONTRAINDICATIONS
4.1 Ocular or Periocular Infections
OZURDEX ® (dexamethasone intravitreal implant) is contraindicated in patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases.
4.2 Advanced Glaucoma
OZURDEX ® is contraindicated in patients with advanced glaucoma.
4.3 Aphakic Eyes with Rupture of the Posterior Lens Capsule
OZURDEX ® is contraindicated in patients who have aphakic eyes with rupture of the posterior lens capsule.
4.4 ACIOL and Rupture of the Posterior Lens Capsule
OZURDEX ® is contraindicated in eyes with ACIOL (Anterior Chamber Intraocular Lens) and rupture of the posterior lens capsule.
4.5 Hypersensitivity
OZURDEX ® is contraindicated in patients with known hypersensitivity to any components of this product.
5 WARNINGS AND PRECAUTIONS
5.1 Intravitreal Injection-related Effects
Intravitreal injections, including those with OZURDEX ®, have been associated with endophthalmitis, eye inflammation, increased intraocular pressure, and retinal detachments.
Patients should be monitored regularly following the injection [see Patient Counseling Information (17)].
5.2 Potential Steroid-related Effects
Use of corticosteroids may produce posterior subcapsular cataracts, increased intraocular pressure, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses.
Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex.
5.3 Risk of Implant Migration
Patients in whom the posterior capsule of the lens is absent or has a tear are at risk of implant migration into the anterior chamber.
6 ADVERSE REACTIONS
6.1 Clinical Studies Experience
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies 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 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 following information is based on the combined clinical trial results from 3 initial, randomized, 6-month, sham-controlled studies (2 for retinal vein occlusion and 1 for posterior segment uveitis):
|
MedDRA Term
|
OZURDEX
®
N=497 (%) |
Sham
N=498 (%) |
| Intraocular pressure increased | 125 (25%) | 10 (2%) |
| Conjunctival hemorrhage | 108 (22%) | 79 (16%) |
| Eye pain | 40 (8%) | 26 (5%) |
| Conjunctival hyperemia | 33 (7%) | 27 (5%) |
| Ocular hypertension | 23 (5%) | 3 (1%) |
| Cataract | 24 (5%) | 10 (2%) |
| Vitreous detachment | 12 (2%) | 8 (2%) |
| Headache | 19 (4%) | 12 (2%) |
Increased IOP with OZURDEX ® peaked at approximately week 8. During the initial treatment period, 1% (3/421) of the patients who received OZURDEX ® required surgical procedures for management of elevated IOP.
Following a second injection of OZURDEX ® in cases where a second injection was indicated, the overall incidence of cataracts was higher after 1 year.
6.2 Postmarketing Experience
The following reactions have been identified during post-marketing use of OZURDEX ® in clinical practice. Because they are reported voluntarily from a population of unknown size, estimates of frequency cannot be made. The reactions, which have been chosen for inclusion due to either their seriousness, frequency of reporting, possible causal connection to OZURDEX ®, or a combination of these factors, include: complication of device insertion (implant misplacement), device dislocation with or without corneal edema, endophthalmitis, hypotony of the eye (associated with vitreous leakage due to injection), and retinal detachment.
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Teratogenic Effects: Pregnancy Category C
Topical dexamethasone has been shown to be teratogenic in mice producing fetal resorptions and cleft palate. In the rabbit, dexamethasone produced fetal resorptions and multiple abnormalities involving the head, ears, limbs, palate, etc. Pregnant rhesus monkeys treated with dexamethasone sodium phosphate intramuscularly at 1 mg/kg/day every other day for 28 days or at 10 mg/kg/day once or every other day at 3 or 5 days between gestation days 23 and 49 had fetuses with minor cranial abnormalities. A 1 mg/kg/dose in pregnant rhesus monkeys would be approximately 85 times higher than an OZURDEX ® injection in humans (assuming 60 kg body weight).
There are no adequate and well-controlled studies in pregnant women. OZURDEX ® (dexamethasone intravitreal implant) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
8.3 Nursing Mothers
It is not known whether ocular administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human 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 corticosteroids are administered to a nursing woman.
8.4 Pediatric Use
Safety and effectiveness of OZURDEX ® in pediatric patients have not been established.
8.5 Geriatric Use
No overall differences in safety or effectiveness have been observed between elderly and younger patients.
11 DESCRIPTION
OZURDEX ® is an intravitreal implant containing 0.7 mg (700 mcg) dexamethasone in the NOVADUR ® solid polymer drug delivery system. OZURDEX ® is preloaded into a single-use, specially designed DDS ® applicator to facilitate injection of the rod-shaped implant directly into the vitreous. The NOVADUR ® system contains poly (D,L-lactide-co-glycolide) PLGA intravitreal polymer matrix without a preservative. The chemical name for dexamethasone is Pregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-, (11β,16α)-. Its structural formula is:
MW 392.47; molecular formula: C22H29FO5
Dexamethasone occurs as a white to cream-colored crystalline powder having not more than a slight odor, and is practically insoluble in water and very soluble in alcohol.
The PLGA matrix slowly degrades to lactic acid and glycolic acid.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by inhibiting multiple inflammatory cytokines resulting in decreased edema, fibrin deposition, capillary leakage and migration of inflammatory cells.
12.3 Pharmacokinetics
Plasma concentrations were obtained from 21 patients in two 6 month studies prior to dosing and on Days 1, 7, 30, 60, and 90 following the intravitreal implant containing 0.35 mg or 0.7 mg dexamethasone. In both studies, the majority of plasma dexamethasone concentrations were below the lower limit of quantitation (LLOQ = 50 pg/mL). Plasma dexamethasone concentrations from 10 of 73 samples in the 0.7 mg dose group and from 2 of 42 samples in the 0.35 mg dose group were above the LLOQ, ranging from 52 pg/mL to 94 pg/mL. The highest plasma concentration value of 94 pg/mL was observed in one subject from the 0.7 mg group. Plasma dexamethasone concentration did not appear to be related to age, body weight, or sex of patients.
In an in vitro metabolism study, following the incubation of [14C]-dexamethasone with human cornea, iris-ciliary body, choroid, retina, vitreous humor, and sclera tissues for 18 hours, no metabolites were observed.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No adequate studies in animals have been conducted to determine whether OZURDEX ® (dexamethasone intravitreal implant) has the potential for carcinogenesis.
Although no adequate studies have been conducted to determine the mutagenic potential of OZURDEX ®, dexamethasone has been shown to have no mutagenic effects in bacterial and mammalian cells in vitro or in the in vivo mouse micronucleus test.
14 CLINICAL STUDIES
Retinal Vein Occlusion
The efficacy of OZURDEX ® for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) was assessed in two, multicenter, double-masked, randomized, parallel studies.
Following a single injection, OZURDEX ® demonstrated the following clinical results for the percent of patients with ≥ 15 letters of improvement from baseline in best-corrected visual acuity (BCVA):
|
*P-values were based on the Pearson's chi-square test. |
||||||
| Study 1 | Study 2 | |||||
| Study Day |
DEX 700
N=201 |
Sham
N=202 |
p-value* |
DEX 700
N=226 |
Sham
N=224 |
p-value* |
| Day 30 | 40 (20%) | 15 (7%) | < 0.01 | 51 (23%) | 17 (8%) | < 0.01 |
| Day 60 | 58 (29%) | 21 (10%) | < 0.01 | 67 (30%) | 27 (12%) | < 0.01 |
| Day 90 | 45 (22%) | 25 (12%) | < 0.01 | 48 (21%) | 31 (14%) | 0.039 |
| Day 180 | 39 (19%) | 37 (18%) | 0.780 | 53 (24%) | 38 (17%) | 0.087 |
In each individual study and in a pooled analysis, time to achieve ≥ 15 letters (3-line) improvement in BCVA cumulative response rate curves were significantly faster with OZURDEX ® compared to sham (p < 0.01), with OZURDEX ® treated patients achieving a 3-line improvement in BCVA earlier than sham-treated patients.
The onset of a ≥ 15 letter (3-line) improvement in BCVA with OZURDEX ® occurs within the first two months after implantation in approximately 20-30% of subjects. The duration of effect persists approximately one to three months after onset of this effect.
Posterior Segment Uveitis
The efficacy of OZURDEX ® was assessed in a single, multicenter, masked, randomized study of 153 patients with non-infectious uveitis affecting the posterior segment of the eye.
After a single injection, the percent of patients reaching a vitreous haze score of 0 (where a score of 0 represents no inflammation) was statistically significantly greater for patients receiving OZURDEX ® versus sham at week 8 (primary time point) (47% versus 12%). The percent of patients achieving a 3-line improvement from baseline BCVA was 43% for patients receiving OZURDEX ® versus 7% for sham at week 8.
16 HOW SUPPLIED/STORAGE AND HANDLING
OZURDEX ® (dexamethasone intravitreal implant) 0.7 mg is supplied in a foil pouch with 1 single-use plastic applicator, NDC 0023-3348-07.
Storage: Store at 15°-30°C (59°-86°F).
17 PATIENT COUNSELING INFORMATION
In the days following intravitreal injection of OZURDEX ®, patients are at risk for potential complications including in particular, but not limited to, the development of endophthalmitis or elevated intraocular pressure. If the eye becomes red, sensitive to light, painful, or develops a change in vision, advise patient to seek immediate care from an ophthalmologist.
Patients may experience temporary visual blurring after receiving an intravitreal injection. Advise patients not to drive or use machines until this has been resolved.
© 2014 Allergan, Inc.
Irvine, CA 92612, U.S.A.
® marks owned by Allergan, Inc.
Patented. See: www.allergan.com/products/patent_notices
Made in Ireland
72212US16
Ozurdex
®
(dexamethasone
intravitreal implant) 0.7 mg
Contents include:
One Sterile, Single-Use Applicator
NDC 0023-3348-07
For Intravitreal Injection Only
Rx only
ALLERGAN
OZURDEXdexamethasone IMPLANT
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