Consumer medicine information

Ozurdex

Dexamethasone

BRAND INFORMATION

Brand name

Ozurdex

Active ingredient

Dexamethasone

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Ozurdex.

What is in this leaflet

This leaflet answers some common questions about OZURDEX®. It does not contain all the available information. It does not take the place of talking to your doctor or pharmacist.

All medicines have risks and benefits. Your doctor has weighed the risks of you receiving OZURDEX® against the benefits they expect it will have for you.

If you have any concerns about using this medicine, ask your doctor or pharmacist.

Keep this leaflet. You may need to read it again.

What OZURDEX® is used for

OZURDEX® is contained within a small implant injected into the back of the eye by your doctor using a specially designed applicator.

OZURDEX® is used to treat adult patients with Diabetic Macular Oedema (DME), which is a swelling of the light-sensitive layer at the back of the eye called the macula. DME is a condition that affects some people with diabetes.

OZURDEX® is used to treat vision loss caused by a blockage of veins in the eye. This blockage leads to a build up of fluid causing swelling in the area of the retina (the light-sensitive layer at the back of the eye) called the macula. The swelling may lead to damage to the macula which affects your central vision which is used for tasks like reading.

OZURDEX® is also used to treat adult patients with Uveitis, which is an inflammation affecting the choroid (the layer of blood vessels and connective tissue between the white of the eye and retina at the back of the eye). Uveitis is a chronic disease with a high risk of permanent vision loss.

The active ingredient in OZURDEX® is dexamethasone. Dexamethasone belongs to a group of medicines called corticosteroids. OZURDEX® works by reducing the swelling which helps to lessen or prevent more damage to the macula.

Before you use OZURDEX®

When you must not use it

Do not use OZURDEX® if:

  • you have an allergy to dexamethasone or any of the ingredients listed at the end of this leaflet
  • you have an infection of any kind in or around your eyes (bacterial, viral, or fungal)
  • you have advanced glaucoma or high pressure inside your eye that cannot be controlled by medications alone
  • the eye to be treated does not have a lens and the back of the lens capsule (“the bag”) has been ruptured
  • the eye to be treated has a man-made lens, which was implanted in the front compartment of the eye (anterior chamber intraocular lens) after cataract surgery, and the back of the lens capsule (“the bag”) has been ruptured.

Before you start to use it

Tell your doctor if:

  • you have had cataract surgery, iris surgery (the coloured part of the eye that controls the amount of light that enters into the eye) or surgery to remove the gel (called the vitreous) from within the eye.
  • you are taking any medicines to thin the blood.
  • you are taking any steroid or non-steroidal anti-inflammatory medicines by mouth or applied to the eye
  • you have had a herpes simplex infection in your eye in the past (an ulcer on the eye that has been there a long time, or sores on the eye).
  • you are pregnant or intend to become pregnant.
    Like most medicines, OZURDEX® should not be used during pregnancy, unless clearly necessary.
  • you are breast-feeding or intend to breast-feed.

Before you receive OZURDEX® treatment, your doctor should tell you to immediately report any eye pain, change in vision, red eyes or sensitivity to light that occurs post-procedure.

Taking other medicines

Tell your doctor if you are taking any other medicines, including any that you buy without a prescription from your pharmacy, supermarket or health food shop.

How OZURDEX® is used

All OZURDEX® injections will be administered by an appropriately qualified eye doctor.

OZURDEX® is administered as a single injection into your eye under sterile conditions. Before the injection your doctor will use antibiotic eye drops and clean the surface of your eye carefully to help prevent infection. Your doctor will also give you a local anaesthetic to reduce or prevent any pain you might have with the injection. You may hear a “click” during the injection of OZURDEX®; this is normal.

Afterwards your doctor may perform some additional tests to make sure there are no signs of inflammation or infection of the eye and will monitor your vision and the pressure in your eye.

If your condition is found to be worsening, your doctor may administer OZURDEX® again.

Follow all directions given to you by your doctor carefully. The directions may differ from the information contained in this leaflet.

The injection of OZURDEX® into both eyes at the same time has not been studied and is not recommended. Your doctor should not inject OZURDEX® into both eyes at the same time.

How long to use it

Your doctor will advise you and decide how long you should be treated with OZURDEX®.

If a dose is missed

If you miss an OZURDEX® appointment, you need to contact your doctor as soon as possible to arrange another appointment.

While you are using OZURDEX®

Things you must do

Tell your doctor immediately if you develop symptoms such as the following after injection of OZURDEX®:

  • blurred, decreased vision or other visual disturbances
  • eye pain or increased discomfort
  • worsening eye redness
  • a feeling of spots in front of the eye (sometimes called “floaters”)
  • increased sensitivity to light
  • any discharge from the eye

In some patients the pressure in the eye may increase for a short period after the injection, or patients may also develop an eye infection.

Increase in pressure in the eye can also occur at any time following injection, this is something you may not notice so your doctor will monitor you regularly after treatment.

Before stopping OZURDEX® treatment

If you decide not to receive a repeat OZURDEX® treatment, please go to your next appointment and discuss this with your doctor. Your doctor will advise you and decide how long you should be treated with OZURDEX®.

Things you must not do

You may experience temporarily reduced vision after being treated with OZURDEX®. You should not drive or operate machinery until your vision has returned to normal.

Side effects

Tell your doctor as soon as possible if you have any problems while being treated with OZURDEX®, even if you do not think the problems are connected with the medicine or are not listed in this leaflet.

Like all medicines, OZURDEX® can cause side effects, although not everybody gets them.

Tell your doctor immediately if you experience any of the following side effects associated with OZURDEX® treatment:

Common side effects:

  • vision decrease caused byclouding of the lens (cataract) which may need a cataract surgery
  • increased pressure in the eye (as determined by the doctor) which may need to be treated with medicines or in a rare case with a surgical procedure
  • bleeding on the surface of the eye*
  • vision decrease or seeing floaters due to bleeding inside of the eye*
  • eye pain*
  • seeing flashes of light due to detachment of the jelly inside the eye from the light-sensitive layer at the back of the eye
  • perception of having something floating in the eye (floaters)*
  • swelling on the surface of the eye*
  • inflammation in the front part of the eye*
  • redness of the eye

Uncommon side effects:

headache, tear of the light-sensitive layer at the back of the eye (retinal tear), severe inflammation at the back of the eye (usually due to viral infection), increased protein in the front of the eye due to inflammation, inflammation or infection inside the eye, glaucoma, eyelid itching, migraine, blurred vision (difficulties in seeing clearly).

* some of these side effects may be caused by the injection procedure and not the OZURDEX® implant itself.

Complications may result from insertion of the device, including implant misplacement.

Ask your doctor any questions you may have.

Product description

What OZURDEX® looks like:

OZURDEX® is a sterile rod shaped implant containing 700 µg of dexamethasone, located in the stainless steel needle of a disposable applicator.

Ingredients

Active ingredient:
Dexamethasone 700µg

Inactive ingredients:
Polyglactin, 50:50 PLGA ester
Polyglactin, 50:50 PLGA acid

Manufacturer/Supplier

AbbVie Pty Ltd
241 O'Riordan Street
Mascot NSW 2020
AUSTRALIA
Ph: 1800 043 460

AbbVie Limited
6th Floor, 156-158 Victoria St
Wellington, 6011
NEW ZEALAND
PH: 0800 900 030

OZURDEX® can be identified by registration number:

AUST R 222392

Date of preparation:

17 Aug 2023

© 2023 AbbVie. All rights reserved.
OZURDEX and its design are trademarks of Allergan, Inc., an AbbVie company.
NOVADUR and its design are trademarks of Allergan, Inc., an AbbVie company.

Published by MIMS October 2023

BRAND INFORMATION

Brand name

Ozurdex

Active ingredient

Dexamethasone

Schedule

S4

 

1 Name of Medicine

Dexamethasone.

2 Qualitative and Quantitative Composition

Ozurdex is a biodegradable intravitreal implant containing 700 microgram dexamethasone in a solid polymer drug delivery system (DDS).
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Intravitreal implant.

4 Clinical Particulars

4.1 Therapeutic Indications

Ozurdex is indicated for the treatment of:
diabetic macular oedema (DME);
macular oedema due to branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO);
non-infectious uveitis affecting the posterior segment of the eye.

4.2 Dose and Method of Administration

The safety and efficacy of Ozurdex administered to both eyes on the same day has not been studied; and is not recommended.
Ozurdex must be administered by a qualified ophthalmologist, experienced in intravitreal insertions.
Treatment with Ozurdex for diabetic macular oedema, macular oedema following BRVO or CRVO, and non-infectious uveitis affecting the posterior segment of the eye is 700 microgram per eye (entire contents of a single-use Ozurdex device).
If, in the physician's opinion, visual and anatomic parameters indicate that the patient is not benefitting from continued treatment, Ozurdex should be discontinued.

DME.

In clinical trials, the majority of retreatments were administered between 5 and 7 months after a prior treatment (see Section 5.1, Clinical trials). Patients in the Ozurdex arm of the pivotal trials received an average of 4 implants over 3 years. The protocol in the pivotal trials specified a 6-monthly dosing interval. There is currently no experience of the efficacy and safety of repeat administrations in DME beyond 7 implants.

RVO and uveitis.

Ozurdex should be used in BRVO or CRVO patients with reduced visual acuity only when other treatments are considered inappropriate or ineffective.
Monitoring and treatment intervals should be determined by the physician and should be based on disease activity, as assessed by visual acuity and/or anatomical parameters and in the physician's opinion may benefit from retreatment without being exposed to significant risk.
Patients who experience and retain improved vision should not be retreated. Patients who experience deterioration in vision, which is not slowed by Ozurdex, should not be retreated.
There is only very limited information on repeat dosing intervals less than 6 months. There is currently no experience of repeat administrations in posterior segment non-infectious uveitis or beyond 2 implants in RVO.
Patients should be monitored following the injection to permit early treatment if an infection or increased intraocular pressure occurs.

Method of administration.

The intravitreal injection procedure should be carried out under 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 and adequate local anaesthesia 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). Redirect the needle perpendicularly towards the center of the vitreous cavity; this creates a biplanar self-sealing scleral 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 redirecting 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 (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 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 may be treated with antibiotics.
Patients 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 2 and 7 days following the injection.
Each applicator can only be used for the treatment of a single eye.

4.3 Contraindications

Ozurdex is contraindicated in the following:
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;
patients with advanced glaucoma;
aphakic eyes with rupture of the posterior lens capsule;
eyes with an anterior chamber intraocular lens (ACIOL), iris or transscleral fixated IOLs, and rupture of the posterior lens capsule;
patients with hypersensitivity to dexamethasone or to any other components of the product.

4.4 Special Warnings and Precautions for Use

Treatment with Ozurdex is for intravitreal injection only.
Intravitreal injections, including those with Ozurdex, have been associated with endophthalmitis, intraocular inflammation, increased IOP, and retinal detachment.

Monitoring.

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 IOP occur. 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 or any of the abovementioned 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 into the anterior chamber might lead to corneal oedema. Persistent severe corneal oedema could progress to the need for corneal transplantation. Regular monitoring of such patients allows for early diagnosis and management of device migration.

Potential steroid-related effects.

Use of corticosteroids, including Ozurdex, have been associated with posterior subcapsular cataracts, increased IOP, glaucoma, and may enhance the establishment of secondary ocular infections due to bacteria, fungi, or viruses.

Visual disturbance.

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presents with symptoms such as blurred vision or other visual disturbances, the patient should be considered for referral to an ophthalmologist for evaluation of possible causes which may include cataract, glaucoma or rare diseases such as central serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical corticosteroids.

Cataract.

The incidence of cataract increases after multiple corticosteroid injections.

IOP increase.

As expected with ocular steroid treatment and intravitreal injections, IOP increases may be seen. The rise in IOP is normally manageable with IOP lowering medication (see Section 4.8 Adverse Effects (Undesirable Effects)). Of the patients experiencing an increase of IOP of ≥ 10 mmHg from baseline, the greatest proportion showed this IOP increase between 45 and 60 days following an injection. Therefore, regular monitoring of IOP, irrespective of baseline IOP, is required and any elevation should be managed appropriately postinjection as needed. Patients of less than 45 years of age with macular oedema following RVO or non-infectious uveitis affecting the posterior segment of the eyes are more likely to experience increases in IOP.

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.
The safety and efficacy of Ozurdex administered to both eyes on the same day has not been studied.
A limited number of subjects with Type 1 diabetes were investigated in the Phase 3 DME studies, and the response to Ozurdex in these subjects was not significantly different to those subjects with Type 2 diabetes.

Anti-coagulant therapy.

In DME, anticoagulant therapy was used in 8% of patients. Among patients who used anticoagulant therapy, the frequency of haemorrhagic adverse events was similar in the Ozurdex and sham groups (29% vs 32%). Among patients who did not use anticoagulant therapy, 27% of Ozurdex treated patients reported haemorrhagic adverse events compared to 20% in the sham group. Vitreous haemorrhage was reported in a higher proportion of patients treated with Ozurdex who received anticoagulant therapy (11%) compared with those not receiving anticoagulant therapy (6%).
In RVO1 and RVO2, anticoagulant therapy was used in 2% of patients receiving Ozurdex; there were no reports of haemorrhagic adverse events in these patients.

Anti-platelet therapy.

Antiplatelet medicinal products, such as clopidogrel, were used at some stage during the clinical studies in up to 56% of patients. For patients using concomitant and antiplatelet medication, haemorrhagic adverse events were reported in a slightly higher proportion of patients injected with Ozurdex (up to 29%) compared with the sham group (up to 23%), irrespective of indication or number of treatments. The most common haemorrhagic adverse event reported was conjunctival haemorrhage (up to 24%).
Ozurdex should be used with caution in patients taking anticoagulant or antiplatelet medicinal products.

Use in hepatic impairment.

Ozurdex has not been studied in patients with hepatic impairment; however no special considerations are needed in this population.

Use in renal impairment.

Ozurdex has not been studied in patients with renal impairment; however no special considerations are needed in this population.

Use in the elderly.

No overall differences in safety and efficacy have been observed between elderly and younger patients.

Paediatric use.

The safety and efficacy of Ozurdex in paediatric patients has not been established.

Effects on laboratory tests.

There are no data available regarding the effects on laboratory tests.

4.5 Interactions with Other Medicines and Other Forms of Interactions

No interaction studies have been performed.

4.6 Fertility, Pregnancy and Lactation

Effects on fertility.

There are no fertility data available.
(Category B3)
Studies in animals have shown teratogenic effects following topical ophthalmic administration. There are no adequate data from the use of intravitreally administered dexamethasone in pregnant women. Long-term systemic treatment with glucocorticoids during pregnancy increases the risk for intrauterine growth retardation and adrenal insufficiency of the newborn child. Therefore, although the systemic exposure of dexamethasone would be expected to be very low after local, intraocular treatment, Ozurdex is not recommended during pregnancy unless the potential benefit justifies the potential risk to the foetus.
 Dexamethasone is excreted in breast milk. No effects on the child are anticipated due to the route of administration and the resulting systemic levels. Ozurdex should not be used by breastfeeding women unless clearly necessary.

4.7 Effects on Ability to Drive and Use Machines

Patients may experience temporary visual blurring after receiving Ozurdex by intravitreal injection. They should not drive or use machines until this has resolved.

4.8 Adverse Effects (Undesirable Effects)

Clinical trials.

DME.

The clinical safety of Ozurdex was assessed in two Phase 3 randomised, masked, sham controlled studies in patients with diabetic macular oedema. In both studies, a total of 347 patients were randomised and received Ozurdex and 350 received sham.
The most frequent adverse reactions (dexamethasone or injection procedure) were defined as adverse reactions that occurred with a higher frequency in the Ozurdex group compared to the sham group and had a plausible mechanism of action as shown in Table 1.
Uncommon adverse reactions included endophthalmitis (0.6% - injection procedure related), glaucoma (0.9%) and necrotising retinitis (0.3%).

Cataract and raised intraocular pressure.

The most frequently reported adverse reactions across the entire study period in the study eye of patients who received Ozurdex were cataract and elevated IOP (see below).
In the three year DME clinical studies, at baseline, 87% of patients with a phakic study eye treated with Ozurdex had some degree of lens opacification/ early cataract. The incidence of all observed cataract types (i.e. cataract cortical, cataract diabetic, cataract nuclear, cataract subcapsular, cataract lenticular, cataract) was 68% in Ozurdex treated patients with a phakic study eye across the three-year studies. 59% of patients with a phakic study eye required cataract surgery by the three year final visit, with the majority performed in the 2nd and 3rd years.
Mean IOP in the study eye at baseline was the same in both treatment groups (15.3 mmHg). The mean increase from baseline IOP did not exceed 3.2 mmHg across all visits in the Ozurdex group with the mean IOP peaking at the 1.5 month visit postinjection, and returning to approximately baseline levels by month 6 following each injection. The rate and magnitude of IOP elevation following Ozurdex treatment did not increase upon repeated injection of Ozurdex.
28% of patients treated with Ozurdex had a ≥ 10 mmHg IOP increase from baseline at one or more visits during the study. At baseline 3% of patients required IOP lowering medication(s). Overall, 42% of patients required IOP-lowering medications in the study eye at some stage during the three-year studies, with the majority of these patients requiring more than one medication. Peak usage (33%) occurred during the first 12 months and remained similar from year to year.
A total of 4 patients (1%) treated with Ozurdex had procedures in the study eye for the treatment of IOP elevation. One patient treated with Ozurdex required incisional surgery (trabeculectomy) to manage the steroid-induced IOP elevation, 1 patient had a trabeculectomy owing to anterior chamber fibrin blocking the aqueous outflow leading to increased IOP, 1 patient had an iridotomy for narrow angle glaucoma and 1 patient had iridectomy due to cataract surgery. No patient required removal of the implant by vitrectomy to control IOP.

RVO.

The clinical safety of Ozurdex was assessed in three Phase 3 randomised, double masked, sham-controlled studies in patients with macular oedema following BRVO or CRVO. In Study RVO3, a total of 129 patients were randomised and received Ozurdex and 130 received sham. In Studies RVO1 and RVO2, a total of 421 patients were treated with Ozurdex and 423 received sham.
The most frequent adverse reactions (dexamethasone or injection procedure) were defined as adverse reactions in the initial masked treatment period, that occurred with a higher frequency in the Ozurdex group compared to the sham group or had a plausible mechanism of action as shown in Table 2.
Uncommon adverse reactions occurring in pooled studies RVO1 and RVO2 included anterior chamber flare (0.7% - injection procedure related) and retinal tear (0.5% - injection procedure related).
Increased intraocular pressure (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 the temporary use of topical IOP-lowering medicinal products. Over the initial treatment and open-label extension periods of the 1 year studies, IOP medications in the study eye were reported for 39.3% of patients in the Ozurdex group and 32.7% in the sham group. Less than 1% of patients who received Ozurdex required laser or surgical procedures for management of elevated IOP in the study eye.
In the RVO clinical studies (RVO1 and RVO2), cataract was reported more frequently in patients with a phakic study eye receiving a second injection of Ozurdex. Two patients had lenticular opacities and there was no cataract adverse reaction or cataract surgery reported in Study RVO3.
In Studies RVO1 and RVO2, only 1 patient out of 368 with a phakic study eye required cataract surgery in the study eye during the first treatment and 3 patients out of 302 with a phakic study eye during the second treatment.
The adverse reaction profile of 341 patients analysed following a second injection of Ozurdex in the open-label extension phase of Studies RVO1 and RVO2, was similar to that following the first injection. The incidence of increased IOP (32.6%) was similar to that seen following the first injection and likewise returned to baseline by open-label day 180. The overall incidence of cataracts was higher after 1 year compared to the initial 6 months.

Uveitis.

The clinical safety of Ozurdex was assessed in a single, multi-center, masked and randomised, 26-week Phase 3 study for 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.
The most frequent adverse reactions (dexamethasone or injection procedure) were defined as adverse reactions that occurred with a higher frequency in the Ozurdex group compared to the sham group or had a plausible mechanism of action as shown in Table 3.
The proportion of Ozurdex-treated patients with increased IOP (≥ 25 mmHg) peaked at week 3 and returned to baseline by week 26. IOP medications in the study eye were reported for 33.8% of patients in the Ozurdex group and 13.2% in the sham group. During the treatment period, no patients required incisional surgery for raised IOP. Two patients in the Ozurdex treatment group required laser iridotomies in the study eye for the treatment of iris bombe, and raised IOP compared to 0 patients in sham group.
One patient out of the 62 with a phakic study eye underwent cataract surgery in the study eye after a single injection of Ozurdex.
The clinical safety of Ozurdex was assessed in a multicentre, 24-month real world observational study in the treatment of macular oedema 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 [(44/178), for cataract formation and (57/178) for cataract progression] based on eyes with phakic lens status at baseline, vitreous haemorrhage (17/283), and increased IOP (68/283).

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, central serous chorioretinopathy, vision blurred.

General disorders and administration site conditions.

Complication of device insertion resulting in ocular tissue injury (implant misplacement).
Device dislocation with or without corneal oedema.

Reporting suspected adverse effects.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at www.tga.gov.au/reporting-problems.

4.9 Overdose

Overdose with Ozurdex has not been reported in clinical trials and would not be expected due to its method of administration.
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia).

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Mechanism of action.

Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by inhibiting multiple inflammatory cytokines resulting in decreased oedema, fibrin deposition, capillary leakage, and migration of the inflammatory cells. Vascular endothelial growth factor (VEGF) is a cytokine which is expressed at increased concentrations in the setting of macular oedema. It is a potent promoter of vascular permeability. Corticosteroids have been shown to inhibit the expression of VEGF and modulate VEGF-mediated responses. Additionally, corticosteroids prevent the release of prostaglandins, some of which have been identified as mediators of cystoid macular oedema.
Ozurdex contains 700 microgram micronised 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 700 microgram directly into the vitreous cavity reduces the potential for systemic effects compared to other routes of administration. The dose of dexamethasone delivered by Ozurdex 700 microgram every 6 months is less than the usual single daily physiologic replacement dose (0.75 mg).

Clinical trials.

DME. The clinical efficacy of Ozurdex was assessed in two Phase 3 randomised, masked, sham-controlled studies in patients with diabetic macular oedema. A total of 1,048 patients (351 Ozurdex [700 microgram], 347 dexamethasone 350 microgram, and 350 sham) were evaluated as the intent-to-treat (ITT) population and received up to 7 treatments during the 3-year study period.
The primary endpoint in both studies was best corrected visual acuity (BCVA) using early treatment diabetic retinopathy study (ETDRS) method in the study eye at the qualification/ baseline visit and each follow-up visit.
Patients were eligible for retreatment based upon central subfield retinal thickness > 175 microns by optical coherence tomography (OCT) or upon physician's interpretation for any evidence of residual retinal oedema consisting of intraretinal cysts or any regions of increased retinal thickening within or outside of the central subfield.

BCVA average change from baseline (area under the curve [AUC] approach).

In Study DME1, the mean BCVA average change from baseline during the study was significantly greater with Ozurdex compared to sham (4.1 letters versus 1.9 letters, p = 0.016).
In Study DME2, the mean BCVA average change from baseline during the study was 2.9 letters with Ozurdex compared to 2.0 letters with sham; the difference was not statistically significant (p = 0.366).
In the pooled analysis, the mean BCVA average change from baseline during the study was significantly greater with Ozurdex compared to sham (3.5 letters versus 2.0 letters, p = 0.023).

BCVA improvement ≥ 15 letters from baseline.

In Study DME1 the proportion of patients with 15 or more letters improvement in BCVA from baseline was significantly higher with Ozurdex (22.1%) compared with sham (13.3%) at the year 3 final visit, p = 0.038.
In Study DME2, the proportion of patients with 15 or more letters improvement in BCVA from baseline was significantly higher with Ozurdex (22.3%) compared with sham (10.8%) at the year 3 final visit, p = 0.003.
In the pooled analysis, the proportion of patients with 15 or more letters improvement from baseline was significantly higher with Ozurdex (22.2%) compared to sham (12.0%) at the year 3 final visit (p < 0.001) and significantly higher with Ozurdex compared to sham at 15 of the 17 study visits. The treatment benefit of Ozurdex in vision improvement was seen throughout the 3-year study period. See Figure 1.

BCVA improvement of 10 or more letters from baseline.

In Study DME1, the proportion of patients with 10 or more letters improvement in BCVA was significantly higher with Ozurdex compared to sham at 14 of the 17 study visits. At the end of the study, significantly greater proportions of patients receiving Ozurdex (38.7%) showed a 10 letter improvement compared to sham (23.0%), p = 0.002.
In Study DME2, the proportion of patients with 10 or more letters improvement in BCVA was significantly higher with Ozurdex compared to sham at 10 of the 17 study visits. At the end of the 3-year study, a significantly greater proportion of patients receiving Ozurdex (34.6%) showed a ≥ 10 letter improvement compared to sham (24.9%), p = 0.040.
In the pooled analysis, the proportion of patients with 10 or more letters improvement in BCVA was significantly higher with Ozurdex compared with sham at 16 of the 17 study visits. By the end of the 3-year study, 36.5% of patients receiving Ozurdex showed a 10 letter improvement compared to 24.0% of patients receiving sham (p < 0.001). See Figure 2.

BCVA 20/40 or better.

In the pooled analysis, the proportion of patients achieving a BCVA of 20/40 or better in the study eye was significantly greater with Ozurdex compared to sham at 10 of the 17 study visits. At the year 3/ final visit, the proportion of patients achieving BCVA 20/40 or better was significantly higher with Ozurdex (28.8% [101/351]) compared to sham (21.4% [75/350]), p = 0.025.

Time to BCVA ≥ 15 letters improvement.

In each of the Phase 3 studies and the pooled analysis, Ozurdex was shown to have a rapid onset of action, as demonstrated by the time to BCVA 15 letter improvement from baseline in the study eye. The response time distributions in the Ozurdex group was significantly earlier compared with sham, indicating an earlier onset of BCVA improvement in the Ozurdex group, with separation of curves at the first efficacy visit and no crossover during the study.

Retinal thickness in the center subfield using OCT.

In Study DME1, the mean average decrease from baseline during the study in central subfield retinal thickness was significantly greater with Ozurdex (101.1 micrometre) versus sham (37.8 micrometre), p < 0.001.
In Study DME2, the mean average decrease from baseline during the study in central subfield retinal thickness was significantly greater with Ozurdex (120.7 micrometre) versus sham (45.8 micrometre), p < 0.001.
In the pooled studies, the improvement in vision with Ozurdex during the 3-year study was associated with a rapid and sustained improvement in anatomical outcomes, as demonstrated by OCT. The mean average decrease from baseline during the study in the central subfield retinal thickness was significantly greater with Ozurdex (111.6 micrometre) compared to sham (41.9 micrometre), p < 0.001.
In the pooled studies, mean decreases in retinal thickness at the center subfield were consistently greater with Ozurdex than with sham throughout the studies. Statistically significant mean improvements with Ozurdex compared to sham were observed at every visit during the 3-year study.

Retreatment intervals.

In the pooled Phase 3 studies, during the course of the 3-year study period, a total of 1080 study retreatments for Ozurdex were administered. Approximately 80% of the retreatments were administered between 5 to 7 months after the prior treatment and 19.9% were after 7 months.

Discontinuations.

A total of 35.9% of Ozurdex treated patients discontinued study participation for any reason during the study compared with 56.6% of sham patients. Discontinuation rates due to adverse events were similar across treatment and sham groups (12.8% vs 11.1%). Discontinuation due to lack of efficacy was higher in the sham group (6.6% vs 24.0%).
RVO. A branch retinal vein occlusion (BRVO) is a blockage of the portion of the circulation that drains the retina of blood. Central retinal vein occlusion (CRVO) is closure of the central retinal vein (located at the optic nerve) which collects all of the blood after it passes through the capillaries. The clinical efficacy of a single administration of Ozurdex in patients with macular oedema following CRVO or BRVO was assessed in three Phase 3 randomised, masked, sham-controlled studies with masked treatment for 6 months. Study enrolment included male or female patients, at least 18 years or age with macular oedema due to BRVO or CRVO, best-corrected visual acuity (BCVA) baseline score between 34 and 68 letters by ETDRS, and retinal thickness of ≥ 300 micrometer by optical coherence tomography (OCT). Patients were eligible to receive a second treatment during open-label extensions for 2 to 6 months. In Study RVO3 a total of 259 patients (129 Ozurdex and 130 sham) were treated. In Studies RVO1 and RVO2, a total of 1,267 patients (427 Ozurdex, 414 dexamethasone 350 microgram, and 426 sham) were treated.
Primary efficacy endpoints were the following:
the time to achieve a response of 15 or more letters improvement in BCVA from baseline in the study eye during the initial treatment period from day 0 to day 180 using the Kaplan-Meier survival analysis (Studies RVO3 and RVO1);
the proportion of patients with a BCVA improvement of 15 or more letters from baseline in the study eye at initial treatment day 180 (Study RVO2).

Time to achieve ≥ 15 letters improvement in BCVA.

Ozurdex was shown to have a rapid onset of action, as demonstrated by the time to BCVA 15-letter improvement from baseline in the study eye. The time to achieve ≥ 15 letters improvement in BCVA was significantly improved with Ozurdex compared to sham. The cumulative response rates of patients achieving a 3-line improvement were consistently higher with Ozurdex starting from day 30 (month 1) to the end of the initial treatment period for the RVO3 study (see Figure 3), and consistently higher with Ozurdex starting from day 30, further separated at day 60, with the treatment difference maintained through the end of day 180, for pooled RVO1 and RVO2 studies (see Figure 4).

Proportion of patients with BCVA ≥ 15 letters improvement.

In all three studies, the proportion of patients with ≥ 15 letters improvement in BCVA from baseline was significantly higher with Ozurdex compared to sham at days 30, 60, and 90 (p < 0.001), as shown in Table 4. A treatment effect was seen at the first observation time point of day 30. The maximum treatment effect was observed at day 60 and the difference in response rates was statistically significant favouring Ozurdex compared with sham at all time-points to day 90 following injection. There continued to be a numerically greater proportion of responders for a ≥ 15 letter improvement from baseline in BCVA in patients treated with Ozurdex compared with sham at day 180.

Mean change from baseline in BCVA.

In Study RVO3, the mean changes from baseline BCVA in the study eye peaked at day 60, and were significantly greater with Ozurdex compared to sham at initial treatment days 30, 60, and 90 (p < 0.001) (see Table 5).
For the pooled analysis of Studies RVO1 and RVO2, the mean change from baseline BCVA was significantly greater with Ozurdex compared to sham at days 30, 60, 90, and 180 (see Table 5). The magnitude of improvement peaked at day 60 with nearly 10 letters with Ozurdex compared to approximately 3 letters with sham. At day 90, improvements of more than 7 letters increase were maintained with Ozurdex compared to the nearly constant change to 3 letters at every visit with sham.

Retinal thickness in the center subfield using OCT.

In Study RVO3, mean decreases in retinal thickness at the center subfield were significantly greater with Ozurdex than with sham at days 30, 60, and 90 (p < 0.001), though not at day 180. In the pooled RVO1 and RVO2 studies, the mean decrease in retinal thickness was significantly greater with Ozurdex (207.9 micrometre) than with sham (95.0 micrometre) at day 90 (p < 0.001), though not at day 180.
6-month open-label extension (studies RVO1 and RVO2).

Eligibility criteria for second injection.

While remaining masked of the initial randomised treatment, patients were eligible for an Ozurdex treatment at day 180 if they had a BCVA score of < 84 or retinal thickness > 250 micrometre by OCT. 98% received an Ozurdex injection between 5 and 7 months after the initial treatment. Of the 427 patients who received an initial treatment of Ozurdex, 341 patients were retreated at day 180.
Peak BCVA improvement was seen at day 60 in the open-label phase.
The cumulative response rates were higher throughout the open-label phase in those patients receiving two consecutive Ozurdex injections compared with those patients who had not received an Ozurdex injection in the initial phase. The proportion of responders at each time point was always greater after the second treatment compared with the first treatment. Whereas, delaying treatment for 6 months (i.e. patients who received sham as their first treatment) resulted in a lower proportion of responders at all timepoints in the open label phase when compared with those first receiving Ozurdex.
Uveitis. The clinical efficacy of Ozurdex has been assessed in a single, multicentre, masked, randomised Phase 3 study for the treatment of non-infectious uveitis affecting the posterior segment of the eye. Study enrolment included male or female patients, at least 18 years of age, vitreous haze ≥ +1.5 at both screening and baseline visits in the study eye, BCVA in the study eye of 10 to 75 letters using ETDRS method.
A total of 229 patients were randomised to receive a single treatment of Ozurdex, dexamethasone 350 microgram or sham. Of these, a total of 77 were randomised to receive Ozurdex, 76 to dexamethasone 350 microgram and 76 to sham, and evaluated as the ITT population.
The primary endpoint was the proportion of patients with vitreous haze score of 0 in the study eye at week 8. Vitreous haze was graded by assigning scores ranging from 0 = no inflammation to +4 = optic nerve head not visible.
The proportion of patients with vitreous haze score of 0 in the study eye at week 8 (primary endpoint) was 4-fold higher with Ozurdex (46.8%) compared to sham (11.8%), p < 0.001. Statistical superiority was observed at week 6 and maintained up to and including week 26 (p ≤ 0.014) as shown in Table 6.
Secondary endpoints included the time to vitreous haze score of 0, and patients demonstrating at least 15 letters improvement from baseline BCVA throughout the 26-week period.
Time to vitreous haze score of 0 was significantly different for the Ozurdex group compared to sham group (p < 0.001), with patients receiving dexamethasone showing an earlier onset and greater treatment response.
The reduction in vitreous haze was accompanied by an improvement in visual acuity. The proportion of patients with at least 15 letters improvement from baseline BCVA in the study eye at week 8 was more than 6-fold higher with Ozurdex (42.9%) compared to sham (6.6%), p < 0.001. Statistical superiority was achieved at week 3 and maintained up to and including week 26 (p < 0.001) as shown in Table 6.
The percent of patients requiring escape medications from baseline to week 8 was nearly 3-fold less with Ozurdex (7.8%) compared to sham (22.4%), p = 0.012.

5.2 Pharmacokinetic Properties

Absorption and distribution.

In two Phase 3 diabetic macular oedema studies (DME1 and DME2), adult patients with a diagnosis of Type 1 or Type 2 diabetes mellitus and clinically observable macular oedema associated with diabetic retinopathy were randomised in a 1:1:1 ratio to Ozurdex, 350 microgram dexamethasone, or sham DEX PS DDS needleless applicator. Blood samples were obtained from a subgroup of patients at predose, days 1, 7, and 21, and months 1.5 and 3 to determine plasma dexamethasone concentrations. In both studies, the majority of concentrations were below the lower limit of quantitation (LLOQ) of 0.05 nanogram/mL. Plasma dexamethasone concentrations from 5 of 52 samples in the Ozurdex group and from 0 of 60 samples in the dexamethasone 350 microgram group were above the LLOQ, ranging from 0.0599 nanogram/mL to 0.102 nanogram/mL. The highest plasma concentration value of 0.102 nanogram/mL was observed in one subject from the 0.7 mg group. Plasma dexamethasone concentration did not appear to be related to age, bodyweight, or sex of patients.
In the Phase 3 retinal vein occlusion Studies RVO1 and RVO2, blood samples were obtained from a subgroup of patients at predose and days 1, 7, 30, 60, and 90 to determine plasma dexamethasone concentrations. In both studies, the majority of concentrations were below the LLOQ of 0.05 nanogram/mL. Both studies showed that plasma concentrations from 10 of 73 samples in the Ozurdex group and from 2 of 42 samples in the dexamethasone 350 microgram group were above the LLOQ, ranging from 0.0521 nanogram/mL to 0.0940 nanogram/mL.
In monkeys, following single bilateral intravitreal implantation of Ozurdex, dexamethasone was released in two phases. The first phase provided high concentrations of dexamethasone, with peak concentrations of dexamethasone observed in the vitreous humour and retina 60 days postinjection. This was followed by a second phase in which low concentrations of dexamethasone were released, extending the therapeutic period to 6 months.

Metabolism.

In an in vitro metabolism study, following the incubation of [14C]-dexamethasone with human cornea, iris ciliary body, choroid, retina, vitreous humour, and sclera tissues for 18 hours, no metabolites were observed. This is consistent with results from rabbit and monkey ocular metabolism studies. Systemically, dexamethasone is subject to metabolism by CYP3A4 in the liver.

Excretion.

Dexamethasone is predominantly cleared from the vitreous humour by diffusion into the retina/ choroid/ sclera membrane. Dexamethasone is ultimately metabolised to lipid and water soluble metabolites that can be excreted in bile and urine.

5.3 Preclinical Safety Data

Genotoxicity.

Studies evaluating the mutagenic potential of dexamethasone in bacteria and mammalian cells in vitro have been negative. Assays for clastogenicity conducted in vitro and in vivo (mouse bone marrow micronucleus test) have returned mixed results, but the observed positive findings are considered likely to be confounded by the drug's pharmacological activity. The available data support that dexamethasone, as well as the polymeric component of Ozurdex, do not pose a genotoxic hazard to patients.

Carcinogenicity.

No studies on the carcinogenic potential of Ozurdex have been conducted.

6 Pharmaceutical Particulars

6.1 List of Excipients

Ozurdex is preloaded into a single use, specially designed DDS applicator to facilitate injection of the rod-shaped implant directly into the vitreous. The polymer DDS contains polyglactin [poly (D,L-lactide-coglycolide)] PLGA biodegradable polymer matrix.
Ozurdex is preservative-free.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

36 months.

6.4 Special Precautions for Storage

Store below 25°C. Protect from excessive heat.

6.5 Nature and Contents of Container

1 pack contains: 1 sustained-release sterile implantable rod-shaped implant containing 700 microgram of dexamethasone, located in the needle (stainless steel) of a disposable applicator.
The applicator containing the implant is packaged in a sealed foil pouch containing desiccant.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of in accordance with local requirements.

6.7 Physicochemical Properties

Chemical structure.


Chemical name: pregna-1,4-diene-3,20-dione, 9-fluoro-11,17,21-trihydroxy-16-methyl-(11β,16α).
Molecular weight: 392.47.
Empirical formula: C22H29FO5.
Dexamethasone is a white to cream coloured crystalline powder with not more than a slight odour and is practically insoluble in water and very soluble in alcohol.

CAS number.

50-02-2.

7 Medicine Schedule (Poisons Standard)

S4 Prescription Only Medicine.

Summary Table of Changes