Ozurdex

OZURDEX Intravitreal implant containing dexamethasone 0.7 mg in the NOVADUR solid polymer drug delivery system.
OZURDEX is an intravitreal implant containing 0.7 mg (700 μg) 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. OZURDEX is preservative-free. The chemical name for dexamethasone is pregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydoxy-16-methyl-,(11 β,16α). Its MW is 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.

Pharmacology: Pharmacodynamics: Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by inhibiting multiple inflammatory cytokines resulting in decreased edema, fibrin deposition, capillary leakage and phagocytic migration of inflammatory cells. Vascular endothelial growth factor (VEGF) is a cytokine which is expressed at increased concentrations in the setting of macular edema. It is a potent promoter of vascular permeability. Corticosteroids have been shown to inhibit the expression of VEGF. Additionally, corticosteroids prevent the release of prostaglandins, some of which have been identified as mediators of cystoid macular edema.
OZURDEX contains 0.7 mg micronized dexamethasone in a biodegradable polymer matrix that is injected directly into the posterior segment of the eye with an applicator. The polymer degrades into water and carbon dioxide over time, gradually releasing dexamethasone to the vitreous, allowing for sustained drug levels in the target area with a smaller total amount of drug administered than via other routes of corticosteroid administration. Furthermore, delivery of OZURDEX directly into the vitreous cavity reduces the potential for systemic effects compared to other routes of administration.
The dose of dexamethasone delivered by OZURDEX every 6 months is less than the usual single daily physiologic replacement dose (0.75 mg).
Pharmacokinetics: Plasma concentrations were obtained from 21 patients with macular edema due to branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO), and 21 patients with diabetic macular edema (DME) prior to dosing and at 4 to 5 additional post-dose timepoints on Days 1, 7, 21, 30, 45, 60, and 90 following the administration of the first intravitreal implant containing 0.7 mg dexamethasone. In RVO and DME patients, the majority of plasma dexamethasone concentrations were below the lower limit of quantitation (LLOQ=50 pg/mL). Plasma dexamethasone concentrations from 12% of the 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 102 pg/mL. 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.
These results show that systemic exposure of dexamethasone was minimal but dose dependent in patients who had received one administration of dexamethasone 0.7 mg.
Renal impairment: No formal studies have been conducted to examine the pharmacokinetics of OZURDEX in patients with renal impairment.
Hepatic impairment: No formal studies have been conducted to examine the pharmacokinetics of OZURDEX in patients with hepatic impairment.
Nonclinical Toxicology: 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.
Adequate fertility studies have not been conducted in animals.
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) (Table 1): See Table 1.

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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.
Diabetic Macular Edema: The efficacy of OZURDEX for the treatment of diabetic macular edema was assessed in two, multicenter, masked, randomized, sham-controlled studies. Subjects were to be evaluated for retreatment eligibility every three months starting from Month 6 but could only receive successive treatments at least 6 months apart. Retreatment was based on physician's discretion after examination including Optical Coherence Tomography. Patients in the OZURDEX arm received an average of 4 treatments during the 36 months.
The primary endpoint was the proportion of patients with 15 or more letters improvement in BCVA from baseline at Month 39 or final visit for subjects who exited the study at or prior to Month 36. The Month 39 extension was included to accommodate the evaluation of safety and efficacy outcomes for subjects who received re-treatment at Month 36. Only fourteen percent of the study patients completed the Month 39 visit (16.8% from OZURDEX and 12.2% from Sham). (See Table 2.)

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Visual acuity outcomes by lens status (Phakic or Pseudophakic) at different visits are presented in Figure 1 and Figure 2. The occurrence of cataracts impacted visual acuity during the study. The visual acuity improvement from baseline increases during a treatment cycle, peaks at approximately 3 Months post-treatment and diminishes thereafter. Patients who were pseudophakic at baseline achieved greater mean BCVA change from baseline at the final study visit. (See Figures 1 and 2.)

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The best corrected visual acuity outcomes for the Pseudophakic and Phakic subgroups from Studies 1 and 2 at Month 39 are presented in Table 3. (See Table 3.)

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OZURDEX (dexamethasone intravitreal implant) is indicated for the treatment of adult patients with macular edema due to Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO).
OZURDEX is indicated for the treatment of non-infectious uveitis affecting the posterior segment of the eye.
OZURDEX is indicated for the treatment of diabetic macular edema.

Recommended Dose: For ophthalmic intravitreal injection only. The recommended dose for the treatment of macular edema following BRVO or CRVO and for the treatment of non-infectious uveitis affecting the posterior segment of the eye and for the treatment of diabetic macular edema is 0.7 mg per eye (entire contents of a single-use OZURDEX 0.7 mg device). Re-injection of OZURDEX 0.7 mg for macular edema due to BRVO or CRVO is recommended when there is reoccurrence of macular edema or vascular leakage in the macula.
Mode of Administration: The intravitreal injection procedure should be carried out under controlled aseptic conditions, which include the use of surgical hand disinfection, sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent). The patient's medical history for hypersensitivity reactions should be carefully evaluated before performing the intravitreal procedure. The periocular skin, eyelid and ocular surface should be disinfected (for example, drops of povidone iodine 5% solution on the conjunctiva) and adequate local anesthesia and a broad-spectrum topical microbicide should be administered before the injection. Aseptic technique should be maintained at all times before and during the injection procedure.
Remove the foil pouch from the carton and examine for damage. Then, in a sterile field, open the foil pouch and gently place 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. With the long axis of the applicator parallel to the limbus, enter the sclera at a shallow oblique angle with the bevel of the needle up (away from the sclera) to create a partial thickness tract 1-2 mm in length parallel to the limbus (no more than the length of the needle bevel). Re-direct the needle perpendicularly towards the center of the vitreous cavity; this creates a bi-planar self-sealing sclera puncture.
Advance the needle until the vitreous cavity is entered and the silicone sleeve is against the conjunctiva. Do not advance the needle past the point where the sleeve touches the conjunctiva. When re‐directing into the vitreous cavity, allow for the fact that the DDS can be up to 6.5 mm long. Slowly depress the actuator button on the applicator until an audible or palpable click is noted. (Note: On occasion, a smaller, softer click is heard or felt while the button is only partially depressed).
Before withdrawing the applicator from the eye, ensure that the button is fully depressed and has locked flush with the applicator surface. The speed of the DDS injection is proportional to the speed that the button is depressed. Withdraw the needle from the eye back‐tracking along the original entry path if possible.
Following the intravitreal injection, patients should be treated with antibiotics and should be monitored. 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.
Each applicator can only be used for the treatment of a single eye.

Overdose with OZURDEX has not been reported in clinical trials and would not be expected due to its method of administration.

Ocular or Periocular Infections: OZURDEX (dexamethasone intravitreal implant) is contraindicated in patients with active or suspected ocular or periocular infection including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections and fungal diseases.
Advanced Glaucoma: OZURDEX is contraindicated in patients with advanced glaucoma.
Aphakic eyes: OZURDEX is contraindicated in patients with aphakic eyes with ruptured posterior lens capsule.
Anterior Chamber Intraocular Lens: OZURDEX is contraindicated in patients with eyes with ACIOL, iris or transscleral fixated IOLs and ruptured posterior lens capsule.
Hypersensitivity: OZURDEX is contraindicated in patients with known hypersensitivity to dexamethasone or to any components of this product.

Treatment with OZURDEX is for intravitreal injection only.
Intravitreal Injection-related Effects: Intravitreal injections, including those with OZURDEX, have been associated with endophthalmitis, intraocular inflammation, increased intraocular pressure, and retinal detachment. Proper aseptic injection techniques must always be used. In addition, patients should be monitored following the injection to permit early treatment if an infection or increased intraocular pressure occur. Patients should be instructed to report any symptoms suggestive of endophthalmitis or any of the previously mentioned events without delay.
Risk of Implant Migration: Patients who had a tear in the posterior lens capsule (e.g., due to cataract surgery), or who had an iris opening to the vitreous cavity (e.g., due to iridectomy) are at risk of implant migration into the anterior chamber. Implant migration to the anterior chamber might lead to corneal edema. Persistent severe corneal edema could progress to the need of corneal transplantation. Regular monitoring of such patients allows for early diagnosis of device migration.
Potential Steroid-related Effects: Use of corticosteroids, including those with OZURDEX, have been associated with posterior subcapsular cataracts, increased intraocular pressure, and glaucoma. Use of corticosteroids may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses.
Ocular Herpes Simplex: Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex. Corticosteroids should not be used in active ocular herpes simplex.
Effects on Ability to Drive and Use Machines: Patients may experience temporary visual blurring after receiving an intravitreal injection. They should not drive or use machines until this has resolved.
Use in Children: Safety and effectiveness of OZURDEX in pediatric patients have not been established.
Use in the Elderly: No overall differences in safety or effectiveness have been observed between elderly and younger patients.

Pregnancy: Safety for use in pregnancy and lactation has not been established. There are no adequate data from the use of dexamethasone in pregnant women. Corticosteroids are generally teratogenic in laboratory animals when administered systemically at relatively low dosage levels. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. OZURDEX should not be used during pregnancy unless clearly necessary, under the supervision of a physician.
Lactation: It is not known whether intraocular administration of corticosteroids could result in sufficient systemic absorption to produce detectable quantities in human milk. Low level dexamethasone systemic exposure was detected following intraocular implantation of OZURDEX in non-pregnant rabbits and monkeys. OZURDEX should not be used during lactation unless clearly necessary, under the supervision of a physician.

Clinical Studies Experience: Treatment of Macular Edema due to BRVO or CRVO: Clinical Studies 206207‐008 and 206207‐009 (Initial 6‐month Treatment Period): The clinical safety of OZURDEX was assessed in 2 phase 3 randomized, double‐masked, sham-controlled studies in patients with macular edema following BRVO or CRVO. In both studies, a total of 421 patients were randomized and received OZURDEX and 423 received sham. (See Table 4).

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The most frequently reported adverse reactions considered to be related to the intravitreal injection procedure rather than the dexamethasone implant, included vitreous hemorrhage and conjunctival edema. (See Table 5).

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Intraocular Pressure in the Initial 6‐month Treatment Period of Studies 008 and 009: See Table 6.

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The proportion of patients with increases from baseline IOP ≥10 mmHg in the study eye was significantly greater with OZURDEX compared to sham at days 7, 30, 60, and 90. At day 180, there were no significant differences between OZURDEX and sham as shown in Table 7: See Table 7.

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The proportion of patients experiencing increased IOP with OZURDEX peaked at day 60 and returned to baseline levels by day 180. Elevations of IOP either did not require treatment or were managed with topical IOP‐lowering medications in the vast majority of patients. During the initial treatment period, only 0.7% (3/421) of the patients who received OZURDEX required laser or surgical procedures for management of elevated IOP in the study eye compared with 0.2% (1/423) with sham.
Systemic effects with OZURDEX would be expected to be negligible due to low systemic levels (below the lower level of quantitation). The adverse event profile for BRVO patients was generally similar to that observed for CRVO patients, and to the overall population. The overall incidence of adverse events was higher for the subgroup of patients with CRVO, which is consistent with the nature of the disease as patients with CRVO are more likely to develop ocular adverse events than patients with BRVO, even when not treated.
Clinical Studies 206207‐008 and 206207‐009 (6‐month Open‐label Extension): The clinical safety of OZURDEX was further assessed in a 6‐month open‐label (OL) extension of both phase 3 studies. Patients were eligible for re‐treatment if the BCVA was <84 letters or retinal thickness was >250 μm in the central 1 mm macular subfield and the investigator considered that the procedure would not put the patient at significant risk. The re‐treated population consisted of patients who received OZURDEX, or sham as their first injection, completed the initial treatment period at day 180, and then received OZURDEX as their second injection. A total of 997 patients received the OZURDEX injection in the open‐label phase of both studies.
For those events reported at a rate of ≥1%, the types of events and their incidence following the second injection were similar to those seen following the first injection with the exception of subcapsular cataract which were higher in patients who had received OZURDEX as their first injection followed by OZURDEX as the second injection. More specifically, subcapsular cataracts in the study eye were notably more common in the OZURDEX/OZURDEX group (12.9%) compared to either Sham/OZURDEX (3.4%).
For events reported in ≤1% of patients, mostly in only 1 or 2 patients per group, some differences between the first and second injection were seen. Review of these differences does not suggest a safety signal associated with repeat treatments.
The incidence of IOP increased was comparable between patients receiving either 1 or 2 doses of OZURDEX.
CONSTANCE 206207-025 (24-Month Post Approval Observational Study): The clinical safety of OZURDEX was assessed in a multicentre, 24-month real world observational study in the treatment of macular edema following RVO and non-infectious uveitis affecting the posterior segment of the eye. The most frequent adverse reactions observed in this study were consistent with the most frequent adverse reactions from clinical trials. Stratifications by injection frequency revealed increases in the incidence of adverse reactions among patients who received >2 injections compared to patients who received ≤2 injections. The most frequent adverse reactions for patients who received >2 injections included cataract [(24.7%, 44/178) for cataract formation and (32.0%, 57/178) for cataract progression] based on eyes with phakic lens status at baseline, vitreous hemorrhage (6.0%, 17/283), and increased IOP (24.0%, 68/283).
Treatment of Uveitis: Clinical Study 206207‐014: The clinical safety of OZURDEX was assessed in a multi-center, masked, and randomized, 26‐week phase 3 study in the treatment of non‐infectious uveitis affecting the posterior segment of the eye. A total of 76 patients were treated with OZURDEX and 75 were treated with sham. (See Table 8.)

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Intraocular Pressure in Study‐014: As shown in Table 9, there were no clinically meaningful differences in the proportions of OZURDEX and sham patients who experienced IOP at ≥25 mmHg or ≥35 mmHg in the study eye, at any visit. At week 26, no OZURDEX patients and 3 sham patients had an IOP ≥25 mmHg; no patients had an IOP ≥35 mmHg. (See Table 9.)

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Table 10 shows the proportion of patients with increases from baseline IOP ≥10 mmHg in the study eye was similar between OZURDEX and sham, except at week 8 where significantly higher percentages were observed with OZURDEX (9.6%) compared to sham (0.0%), p=0.013. At week 26, only 1 OZURDEX patient and 2 sham patients showed an increase from baseline IOP ≥10 mmHg. (See Table 10.)

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The proportion of OZURDEX-treated patients with increased IOP (≥25 mmHg) peaked at week 3 and returned to baseline by week 26. During the treatment period, no patients required incisional surgery for glaucoma. Three patients required laser iridotomies in the study eye for the treatment of pupillary block, iris bombe, and raised IOP.
CONSTANCE 206207-025 (24-Month Post Approval Observational Study): Refer to CONSTANCE Study Results under RVO as previously mentioned.
Treatment of Diabetic Macular Edema: The following information is based on the combined clinical trial results from 2 randomized, 3-year, sham-controlled studies in patients with diabetic macular edema. Discontinuation rates due to the adverse reactions listed in Table 11 were 3% in the OZURDEX group and 1% in the Sham group. The most common ocular (study eye) and non-ocular adverse reactions are shown in Tables 11 and 12: See Table 11.

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Increased Intraocular Pressure: See Table 12.

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The increase in mean IOP was seen with each treatment cycle, and the mean IOP generally returned to baseline between treatment cycles (at the end of the 6 month period) shown as follows: See Figure 3.

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Cataracts and Cataract Surgery: At baseline, 243 of the 324 OZURDEX subjects were phakic; 230 of 328 sham-controlled subjects were phakic. The incidence of cataract development in patients who had a phakic study eye was higher in the OZURDEX group (68%) compared with Sham (21%). The median time of cataract being reported as an adverse event was approximately 15 months in the OZURDEX group and 12 months in the Sham group. Among these patients, 61% of OZURDEX subjects vs. 8% of sham-controlled subjects underwent cataract surgery, generally between Month 18 and Month 39 (Median Month 21 for OZURDEX group and 20 for Sham) of the studies.
Postmarketing Experience: The following adverse reactions have been identified during postmarketing use of OZURDEX in clinical practice. Because postmarketing reporting of these reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate the frequency of these reactions. The reactions have been chosen for inclusion due to a combination of the frequency of reporting and/or possible causal connection to OZURDEX.
Eye disorders: Endophthalmitis, hypotony of eye (associated with vitreous leakage due to injection), retinal detachment.
General disorders and administration site conditions: Complication of device insertion resulting in ocular tissue injury (implant misplacement), device dislocation with or without corneal edema.

No interaction studies have been performed.

Store below 30°C (86°F).

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, the patients should seek immediate care from an ophthalmologist. Patients may experience temporary visual blurring after receiving an intravitreal injection. They should not drive or use machines until this has resolved.

Eye Corticosteroids

S01BA01 - dexamethasone ; Belongs to the class of corticosteroids. Used in the treatment of inflammation of the eye.

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