OZURDEX 700mcg implant medication leaflet

OZURDEX 700 micrograms intravitreal implant in applicator

One implant contains 700 micrograms of dexamethasone.

For the full list of excipients, see section 6.1.

Intravitreal implant in applicator.

Disposable injection device, containing a rod-shaped implant. which is not visible. The implant isapproximately 0.46 mm in diameter and 6 mm in length.

OZURDEX is indicated for the treatment of adult patients with:

- visual impairment due to diabetic macular oedema (DME) who are pseudophakic or who areconsidered insufficiently responsive to, or unsuitable for non-corticosteroid therapy

- macular oedema following either Branch Retinal Vein Occlusion (BRVO) or Central Retinal

Vein Occlusion (CRVO) (see section 5.1)

- inflammation of the posterior segment of the eye presenting as non-infectious uveitis

OZURDEX must be administered by a qualified ophthalmologist experienced in intravitreal injections.

The recommended dose is one OZURDEX implant to be administered intra-vitreally to the affectedeye. Administration to both eyes concurrently is not recommended (see section 4.4).

Patients treated with OZURDEX who have experienced an initial response and in the physician’sopinion may benefit from retreatment without being exposed to significant risk should be consideredfor retreatment.

Retreatment may be performed after approximately 6 months if the patient experiences decreasedvision and/or an increase in retinal thickness, secondary to recurrent or worsening diabetic macularoedema.

There is currently no experience of the efficacy or safety of repeat administrations in DME beyond7 implants.

RVO and uveitis

Repeat doses should be considered when a patient experiences a response to treatment followedsubsequently by a loss in visual acuity and in the physician’s opinion may benefit from retreatmentwithout being exposed to significant risk (see section 5.1).

Patients who experience and retain improved vision should not be retreated. Patients who experiencedeterioration 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 (see section 5.1).

For information concerning the current safety experience of repeat administrations beyond 2 implantsin posterior segment non-infectious uveitis and Retinal Vein Occlusion, see section 4.8.

Patients should be monitored following the injection to permit early treatment if an infection orincreased intraocular pressure occurs (see section 4.4).

No dose adjustment is required for elderly patients.

OZURDEX has not been studied in patients with renal impairment however no special considerationsare needed in this population.

OZURDEX has not been studied in patients with hepatic impairment; however no specialconsiderations are needed in this population.

There is no relevant use of OZURDEX in the paediatric population in

- diabetic macular oedema

- macular oedema following either Branch Retinal Vein Occlusion (BRVO) or Central Retinal

Vein Occlusion (CRVO)

The safety and efficacy of OZURDEX in uveitis in the paediatric population have not beenestablished. No data are available.

OZURDEX is a single-use intravitreal implant in applicator for intravitreal use only.

Each applicator can only be used for the treatment of a single eye.

The intravitreal injection procedure should be carried out under controlled aseptic conditions whichinclude the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent).

The patient should be instructed to self-administer broad spectrum antimicrobial drops daily for 3 daysbefore and after each injection. Before the injection, the periocular skin, eyelid and ocular surfaceshould be disinfected (using for example drops of povidone iodine 5% solution on the conjunctiva as itwas done in the clinical trials for the approval of OZURDEX) and adequate local anaesthesia shouldbe administered. Remove the foil pouch from the carton and examine for damage (see section 6.6).

Then, in a sterile field, open the foil pouch and gently place the applicator on a sterile tray. Carefullyremove the cap from the applicator. Once the foil pouch is opened the applicator should be usedimmediately. Hold the applicator in one hand and pull the safety tab straight off the applicator. Do nottwist or flex the tab. With the bevel of the needle up away from the sclera, advance the needle about1 mm into the sclera then redirect toward the centre of the eye into the vitreous cavity until the siliconesleeve is against the conjunctiva. Slowly press the actuator button until an audible click is noted.

Before withdrawing the applicator from the eye, make sure that the actuator button is fully pressed andhas locked flush with the applicator surface. Remove the needle in the same direction as used to enterthe vitreous.

For instructions on the administration of the intravitreal implant, see section 6.6

Immediately after injecting OZURDEX, use indirect ophthalmoscopy in the quadrant of injection toconfirm successful implantation. Visualisation is possible in the large majority of cases. In cases inwhich the implant cannot be visualised, take a sterile cotton bud and lightly depress over the injectionsite to bring the implant into view.

Following the intravitreal injection patients should continue to be treated with a broad spectrumantimicrobial.

- Hypersensitivity to the active substance or to any of the excipients as listed in section 6.1.

- Active or suspected ocular or periocular infection including most viral diseases of the corneaand conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis),vaccinia, varicella, mycobacterial infections, and fungal diseases.

- Advanced glaucoma which cannot be adequately controlled by medicinal products alone.

- Aphakic eyes with ruptured posterior lens capsule.

- Eyes with Anterior Chamber Intraocular Lens (ACIOL), iris or transscleral fixated intraocularlens and ruptured posterior lens capsule.

Intravitreous injections, including those with OZURDEX, can be associated with endophthalmitis,intraocular inflammation, increased intraocular pressure and retinal detachment. Proper asepticinjection techniques must always be used. In addition, patients should be monitored following theinjection to permit early treatment if an infection or increased intraocular pressure occurs. Monitoringmay consist of a check for perfusion of the optic nerve head immediately after the injection, tonometrywithin 30 minutes following the injection, and biomicroscopy between two and seven days followingthe injection.

Patients must be instructed to report any symptoms suggestive of endophthalmitis or any of the abovementioned events without delay, e.g. eye pain, blurred vision etc. (see section 4.8).

All patients with posterior capsule tear, such as those with a posterior lens (e.g. due to cataractsurgery), and/or those who have an iris opening to the vitreous cavity (e.g. due to iridectomy) with orwithout a history of vitrectomy, are at risk of implant migration into the anterior chamber. Implantmigration to the anterior chamber may lead to corneal oedema. Persistent severe corneal oedemacould progress to the need for corneal transplantation. Other than those patients contraindicated (seesection 4.3) where OZURDEX should not be used, OZURDEX should be used with caution and onlyfollowing a careful risk benefit assessment. These patients should be closely monitored to allow forearly diagnosis and management of device migration.

Use of corticosteroids, including OZURDEX, may induce cataracts (including posterior subcapsularcataracts), increased IOP, steroid induced glaucoma and may result in secondary ocular infections.

In the 3 year DME clinical studies, 59% of patients with a phakic study eye treated with OZURDEXunderwent cataract surgery in the study eye (see section 4.8).

After the first injection the incidence of cataract appears higher in patients with non-infectious uveitisof the posterior segment compared with BRVO/CRVO patients. In BRVO/CRVO clinical studies,cataract was reported more frequently in patients with phakic lens receiving a second injection (seesection 4.8). Only 1 patient out of 368 required cataract surgery during the first treatment and3 patients out of 302 during the second treatment. In the non-infectious uveitis study, 1 patient out ofthe 62 phakic patients underwent cataract surgery after a single injection.

The prevalence of conjunctival haemorrhage in patients with non-infectious uveitis of the posteriorsegment appears to be higher compared with BRVO/CRVO and DME. This could be attributable tothe intravitreous injection procedure or to concomitant use of topical and/or systemic corticosteroid or

Non-steroidal anti-inflammatory medications. No treatment is required since spontaneous resolutionoccurs.

As expected with ocular steroid treatment and intravitreal injections, increases in intraocular pressure(IOP) may be seen. The rise in IOP is normally manageable with IOP lowering medication (seesection 4.8). Of the patients experiencing an increase of IOP of ≥10 mmHg from baseline, the greatestproportion 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 bemanaged appropriately post-injection as needed. Patients of less than 45 years of age with macularoedema following Retinal Vein Occlusion or inflammation of the posterior segment of the eyepresenting as non-infectious uveitis are more likely to experience increases in IOP.

Corticosteroids should be used cautiously in patients with a history of ocular viral (e.g. herpessimplex) infection and not be used in active ocular herpes simplex.

The safety and efficacy of OZURDEX administered to both eyes concurrently have not been studied.

Therefore administration to both eyes concurrently is not recommended.

OZURDEX has not been studied in patients with macular oedema secondary to RVO with significantretinal ischemia. Therefore OZURDEX is not recommended.

A limited number of subjects with Type 1 diabetes were investigated in the Phase 3 studies, and theresponse to OZURDEX in these subjects was not significantly different to those subjects with Type 2diabetes.

In RVO, anti-coagulant therapy was used in 2% of patients receiving OZURDEX; there were noreports of haemorrhagic adverse events in these patients. In DME, anti-coagulant therapy was used in8% of patients. Among patients who used anti-coagulant therapy, the frequency of haemorrhagicadverse events was similar in the OZURDEX and sham groups (29% vs 32%). Among patients whodid not use anti-coagulant therapy, 27% of OZURDEX treated patients reported haemorrhagic adverseevents compared to 20% in the sham group. Vitreous haemorrhage was reported in a higherproportion of patients treated with OZURDEX who received anti-coagulant therapy (11%) comparedwith those not receiving anticoagulant therapy (6%).

Anti-platelet medicinal products, such as clopidogrel, were used at some stage during the clinicalstudies in up to 56% of patients. For patients using concomitant and anti-platelet 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 ornumber of treatments. The most common haemorrhagic adverse event reported was conjunctivalhaemorrhage (up to 24%).

OZURDEX should be used with caution in patients taking anti-coagulant or anti-platelet medicinalproducts.

Visual disturbance

Visual disturbance may be reported with systemic and topical corticosteroid use. If a patient presentswith symptoms such as blurred vision or other visual disturbances, consider evaluating for possiblecauses 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.

No interaction studies have been performed.

Systemic absorption is minimal and no interactions are anticipated.

Studies in animals have shown teratogenic effects following topical ophthalmic administration (seesection 5.3). There are no adequate data from the use of intravitreally administered dexamethasone inpregnant women. Long-term systemic treatment with glucocorticoids during pregnancy increases therisk for intra-uterine 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 benefitjustifies the potential risk to the foetus.

Dexamethasone is excreted in breast milk No effects on the child are anticipated due to the route ofadministration and the resulting systemic levels. However OZURDEX is not recommended duringbreast feeding unless clearly necessary.

There are no fertility data available.

OZURDEX may have a moderate influence on the ability to drive and use machines. Patients mayexperience temporarily reduced vision after receiving OZURDEX by intravitreal injection (seesection 4.8). They should not drive or use machines until this has resolved.

The most commonly-reported adverse events reported following treatment with OZURDEX are thosefrequently observed with ophthalmic steroid treatment or intravitreal injections (elevated IOP, cataractformation and conjunctival or vitreal haemorrhage respectively).

Less frequently reported, but more serious, adverse reactions include endophthalmitis, necrotizingretinitis, retinal detachment and retinal tear.

With the exception of headache and migraine, no systemic adverse drug reactions were identified withthe use of OZURDEX.

The adverse reactions considered related to OZURDEX treatment from the Phase III clinical trials(DME, BRVO/CRVO and uveitis) and spontaneous reporting are listed by MedDRA System organclass in the table below using the following convention:

Very common (≥ 1/10); common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000to <1/1,000); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presentedin order of decreasing seriousness.

Table 1 Adverse reactions

System organ class Frequency Adverse reaction

Nervous system disorders Common Headache

Uncommon Migraine

Eye disorders Very common Intraocular pressure increased**, cataract**,conjunctival haemorrhage*

Common Ocular hypertension, cataract subcapsular, vitreoushaemorrhage**, visual acuity reduced*, visualimpairment/ disturbance, vitreous detachment*,vitreous floaters*, vitreous opacities*, blepharitis,eye pain*, photopsia*, conjunctival oedema*conjunctival hyperaemia*

Uncommon Necrotizing retinitis, endophthalmitis*, glaucoma,retinal detachment*, retinal tear*, hypotony of theeye*, anterior chamber inflammation*, anteriorchamber cells/ flares*, abnormal sensation in eye*,eyelids pruritus, scleral hyperaemia*

General disorders and Uncommon Device dislocation* (migration of implant) with oradministration site without corneal oedema (see also section 4.4),conditions complication of device insertion resulting in oculartissue injury* (implant misplacement)

* indicates adverse reactions considered to be related to the intravitreal injection procedure (the frequency ofthese adverse reactions is proportional to the number of treatments given).

** in a 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 these adverse events were reported more frequentlyamong patients who received >2 injections vs patients who received ≤2 injections; cataract formation (24.7% vs17.7%), cataract progression (32.0% vs 13.1%), vitreous haemorrhage (6.0% vs 2.0%), and increased IOP(24.0% vs 16.6%).

Diabetic Macular Oedema

The clinical safety of OZURDEX in patients with diabetic macular oedema was assessed in twophase 3 randomized, double-masked, sham-controlled studies. In both studies, a total of 347 patientswere randomized and received OZURDEX and 350 patients received sham.

The most frequently reported adverse reactions across the entire study period in the study eye ofpatients who received OZURDEX were cataract and elevated IOP (see below).

In the 3 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 observedcataract types (i.e. cataract cortical, cataract diabetic, cataract nuclear, cataract subcapsular, cataractlenticular, cataract) was 68% in OZURDEX treated patients with a phakic study eye across the 3 yearstudies. 59% of patients with a phakic study eye required cataract surgery by the 3 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). Themean increase from baseline IOP did not exceed 3.2 mmHg across all visits in the OZURDEX groupwith the mean IOP peaking at the 1.5 month visit post injection, and returning to approximatelybaseline levels by month 6 following each injection. The rate and magnitude of IOP elevationfollowing OZURDEX treatment did not increase upon repeated injection of OZURDEX.

28% of patients treated with OZURDEX had a ≥ 10 mm Hg IOP increase from baseline at one or morevisits 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 3 yearstudies, 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) tomanage the steroid-induced IOP elevation, 1 patient had a trabeculectomy owing to anterior chamberfibrin blocking the aqueous outflow leading to increased IOP, 1 patient had an iridotomy for narrowangle glaucoma and 1 patient had iridectomy due to cataract surgery. No patient required removal ofthe implant by vitrectomy to control IOP.

BRVO/CRVO

The clinical safety of OZURDEX in patients with macular oedema following central or branch retinalvein occlusion has been assessed in two Phase III randomised, double-masked, sham-controlledstudies. A total of 427 patients were randomised to receive OZURDEX and 426 to receive sham in thetwo Phase III studies. A total of 401 patients (94 %) randomised and treated with OZURDEXcompleted the initial treatment period (up to day 180).

A total of 47.3 % of patients experienced at least one adverse reaction. The most frequently reportedadverse reactions in patients who received OZURDEX were increased intraocular pressure (24.0 %)and conjunctival haemorrhage (14.7 %).

The adverse reaction profile for BRVO patients was similar to that observed for CRVO patientsalthough the overall incidence of adverse reactions was higher for the subgroup of patients with

CRVO.

Increased intraocular pressure (IOP) with OZURDEX peaked at day 60 and returned to baseline levelsby day 180. Elevations of IOP either did not require treatment or were managed with the temporaryuse of topical IOP-lowering medicinal products. During the initial treatment period, 0.7 % (3/421) ofthe patients who received OZURDEX required laser or surgical procedures for management ofelevated IOP in the study eye compared with 0.2 % (1/423) with sham.

The adverse reaction profile of 341 patients analysed following a second injection of OZURDEX, wassimilar to that following the first injection. A total of 54 % of patients experienced at least one adversereaction. The incidence of increased IOP (24.9 %) was similar to that seen following the first injectionand likewise returned to baseline by open-label day 180. The overall incidence of cataracts was higherafter 1 year compared to the initial 6 months.

The clinical safety of OZURDEX in patients with inflammation of the posterior segment of the eyepresenting as non-infectious uveitis, has been assessed in a single, multicentre, masked, randomisedstudy.

A total of 77 patients were randomised to receive OZURDEX and 76 to receive Sham. A total of73 patients (95%) randomised and treated with OZURDEX completed the 26-week study.

The most frequently reported adverse reactions in the study eye of patients who received OZURDEXwere conjunctival haemorrhage (30.3%), increased intraocular pressure (25.0%) and cataract (11.8%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

If an overdose occurs, intraocular pressure should be monitored and treated, if deemednecessary by the attending physician.

Pharmacotherapeutic group: Ophthalmologicals, antiinflammatory agents, ATC code: S01BA01

Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by inhibitingoedema, fibrin deposition, capillary leakage, and phagocytic migration of the inflammatoryresponse. Vascular Endothelial Growth Factor (VEGF) is a cytokine which is expressed at increasedconcentrations in the setting of macular oedema. It is a potent promoter of vascular permeability.

Corticosteroids have been shown to inhibit the expression of VEGF. Additionally, corticosteroidsprevent the release of prostaglandins, some of which have been identified as mediators of cystoidmacular oedema.

Diabetic Macular Oedema

The efficacy of OZURDEX was assessed in two 3 year, multicentre, double-masked, randomised,sham-controlled, parallel studies of identical design which together comprised 1,048 patients(studies 206207-010 and 206207-011). A total of 351 were randomised to OZURDEX, 347 todexamethasone 350 µg and 350 patients to sham.

Patients were eligible for retreatment based upon central subfield retinal thickness >175 microns byoptical coherence tomography (OCT) or upon investigators interpretation of the OCT for anyevidence of residual retinal edema consisting of intraretinal cysts or any regions of increased retinalthickening within or outside of the central subfield. Patients received up to 7 treatments at intervalsno more frequently than approximately every 6 months.

Escape therapy was permitted at the investigators discretion at any stage but led to subsequentwithdrawal from the studies.

A total of 36% of OZURDEX treated patients discontinued study participation for any reason duringthe study compared with 57% of sham patients. Discontinuation rates due to adverse events weresimilar across treatment and sham groups (13% vs 11%). Discontinuation due to lack of efficacywas lower in the OZURDEX group compared to sham (7% vs 24%).

The primary and key secondary endpoints for studies 206207-010 and 011 are presented in Table 2.

The vision improvement in the DEX700 group was confounded by cataract formation. Visionimprovement was re-established upon removal of cataract.

Table 2. Efficacy in studies 206207-010 and 206207-011 (ITT population)

Study Study Pooled Studies206207-010 206207-011 206207-010 and206207-011

DEX Sham DEX Sham DEX Sham

Endpoint 700 700 700

N = 163 N = 165 N = 188 N = 185 N = 351 N = 350

Mean BCVA average change over3 years, AUC approach (letters) 4.1 1.9 2.9 2.0 3.5 2.0

P-value0.016 0.366 0.023

BCVA ≥ 15-letter improvementfrom baseline at Year 3/Final (%) 22.1 13.3 22.3 10.8 22.2 12.0

P-value0.038 0.003 < 0.001

Mean BCVA change from baselineat year 3/final visit (letters) 4.1 0.8 1.3 -0.0 2.6 0.4

P-value0.020 0.505 0.054

OCT retinal thickness at centersubfield mean average change over -101.1 -37.8 -120.7 -45.8 -111.6 -41.93 years, AUC approach (µm)

P-value<0.001 < 0.001 < 0.001

The primary and key secondary endpoints for the pooled analysis for pseudophakic patients arepresented in Table 3.

Table 3. Efficacy in pseudophakic patients (pooled studies 206207-010 and 206207-011)

DEX 700 Sham

Endpoint N = 86 N = 101 P-value

Mean BCVA average change over 3 years, AUC 6.5 1.7 < 0.001approach (letters)

BCVA ≥ 15-letter improvement from baseline at 23.3 10.9 0.024

Year 3/Final visit (%)

Mean BCVA change from baseline at year 3/Final visit 6.1 1.1 0.004

OCT retinal thickness at center subfield mean average -131.8 -50.8 < 0.001change over 3 years, AUC approach (µm)

The primary and key secondary endpoints for the pooled analysis for patients with any priortreatment are presented in Table 4.

Table 4. Efficacy in patients with any prior treatment (pooled studies 206207-010 and 206207-011)

DEX 700 Sham

Endpoint N = 247 N = 261 P-value

Mean BCVA average change over 3 years, AUC3.2 1.5 0.024approach (letters)

BCVA ≥ 15-letter improvement from baseline at21.5 11.1 0.002

Year 3/Final visit (%)

Mean BCVA change from baseline at year 3/Final2.7 0.1 0.055visit

OCT retinal thickness at center subfield mean average

- 126.1 -39.0 < 0.001change over 3 years, AUC approach (µm)

BRVO/CRVO

The efficacy of OZURDEX was assessed in two multicentre, double-masked, randomised,sham-controlled, parallel studies of identical design which together comprised 1,267 patients whowere randomized to receive treatment with dexamethasone 350 µg or 700 µg implants or sham(studies 206207-008 and 206207-009). A total of 427 were randomised to OZURDEX, 414 todexamethasone 350 µg and 426 patients to sham.

Based on the pooled analysis results, treatment with OZURDEX implants showed statisticallysignificantly greater incidence of responders, defined as patients achieving a ≥ 15 letterimprovement from baseline in Best Corrected Visual Acuity (BCVA) at 90 days following injectionof a single implant, when compared with sham (p < 0.001).

The proportion of patients achieving the primary efficacy measure of ≥ 15 letter improvement frombaseline in BCVA following injection of a single implant is shown in Table 5. A treatment effect wasseen at the first observation time point of day 30. The maximum treatment effect was observed atday 60 and the difference in the incidence of responders was statistically significant favouring

OZURDEX compared with sham at all time points to day 90 following injection. There continued tobe 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.

Table 5. Proportion of patients with ≥ 15 letters improvement frombaseline best corrected visual acuity in the study eye(pooled, ITT population)

OZURDEX Sham

Visit N = 427 N = 426

Day 30 21.3 % a 7.5%

Day 60 29.3% a 11.3%

Day 90 21.8% a 13.1%

Day 180 21.5% 17.6%a Proportion significantly higher with OZURDEX compared to sham (p < 0.001)

The mean change from baseline BCVA was significantly greater with OZURDEX compared to shamat all time points.

In each Phase III study and the pooled analysis, the time to achieve ≥ 15 letters (3-line) improvementin BCVA cumulative response curves were significantly different with OZURDEX compared to sham(p < 0.001) with OZURDEX treated patients achieving a 3-line improvement in BCVA earlier thansham treated patients.

OZURDEX was numerically superior to sham in preventing vision loss as shown by a lower ofproportion of patients experiencing deterioration of vision of ≥ 15 letters in the OZURDEX groupthroughout the 6-month assessment period.

In each of the phase III studies and the pooled analysis, mean retinal thickness was significantly less,and the mean reduction from baseline was significantly greater, with OZURDEX (-207.9 microns)compared to sham (-95.0 microns) at day 90 (p < 0.001, pooled data). The treatment effect as assessedby BCVA at day 90 was thus supported by this anatomical finding. By Day 180 the mean retinalthickness reduction (-119.3 microns) compared with sham was not significant.

Patients who had a BCVA score of <84 OR retinal thickness > 250 microns by optical coherencetomography OCT and in the investigator’s opinion treatment would not put the patient at risk; wereeligible to receive an OZURDEX treatment in an open label extension. Of the patients who weretreated in the open label phase, 98% received an OZURDEX injection between 5 and 7 months afterthe initial treatment.

As for the initial treatment, peak response was seen at Day 60 in the open label phase. The cumulativeresponse 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 inthe initial phase.

The proportion of responders at each time point was always greater after the second treatmentcompared with the first treatment. Whereas, delaying treatment for 6 months results in a lowerproportion of responders at all time points in the open label phase when compared with those receivinga second OZURDEX injection.

The clinical efficacy of OZURDEX has been assessed in a single, multicentre, masked, randomisedstudy for the treatment of non-infectious ocular inflammation of the posterior segment in patients withuveitis.

A total of 229 patients were randomised to receive dexamethasone 350 µg or 700 µg implants orsham. Of these, a total of 77 were randomised to receive OZURDEX, 76 to dexamethasone 350 µgand 76 to sham. A total of 95% of patients completed the 26-week study.

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. Statisticalsuperiority was maintained up to and including week 26 (p ≤ 0.014) as shown in Table 6.

The cumulative response rate curves (time to vitreous haze score of 0) were significantly different forthe OZURDEX group compared to the Sham group (p < 0.001), with patients receivingdexamethasone showing an earlier onset and greater treatment response.

The reduction in vitreous haze was accompanied by an improvement in visual acuity. Theproportion of patients with at least 15 letters improvement from baseline BCVA in thestudy 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 andincluding 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 lesswith OZURDEX (7.8%) compared to Sham (22.4%), p = 0.012.

Table 6. Proportion of patients with vitreous haze score of zero and ≥ 15 letters improvementfrom baseline best corrected visual acuity in the study eye (ITT population)

Visit Vitreous Haze Score of Zero BCVA improvement from baselineof ≥15 letters

DEX 700 Sham DEX 700 Sham

N = 77 N = 76 N = 77 N = 76

Week 3 23.4% 11.8% 32.5%a 3.9%

Week 6 42.9%a 9.2% 41.6%a 7.9%

Week 8 46.8%a 11.8% 42.9%a 6.6%

Week 12 45.5%a 13.2% 41.6%a 13.2%

Week 16 40.3%b 21.1% 39.0%a 13.2%

Week 20 39.0%c 19.7% 40.3%a 13.2%

Week 26 31.2%d 14.5% 37.7%a 13.2%a p < 0.001; b p = 0.010; c p = 0.009; d p = 0.014

The European Medicines Agency has waived the obligation to submit the results of studies with

OZURDEX in all subsets of the paediatric population for retinal vascular occlusion and also fordiabetic macular oedema (see section 4.2 for information on paediatric use).

Plasma concentrations were obtained from a subset of 21 patients in the two RVO, 6-month efficacystudies prior to dosing and on days 7, 30, 60 and 90 following intravitreal injection of a singleintravitreal implant containing 350 µg or 700 µg dexamethasone. Ninety-five percent of the plasmadexamethasone concentration values for the 350 µg dose group and 86% for the 700 µg dose groupwere below the lower limit of quantitation (0.05 ng/mL). The highest plasma concentration value of0.094 ng/mL was observed in one subject from the 700 µg group. Plasma dexamethasoneconcentration did not appear to be related to age, body weight, or sex of patients.

Plasma concentrations were obtained from a subgroup of patients in the two DME pivotal studies priorto dosing and on days 1, 7, and 21, and months 1.5 and 3 following intravitreal injection of a singleintravitreal implant containing 350 µg or 700 µg dexamethasone. One hundred percent of the plasmadexamethasone concentration values for the 350 µg dose group and 90% for the 700 µg dose groupwere below the lower limit of quantitation (0.05 ng/mL). The highest plasma concentration value of0.102 ng/mL was observed in 1 subject from the 700 µg group. Plasma dexamethasone concentrationdid not appear to be related to age, body weight, or sex of patients.

In a 6-month monkey study following a single intravitreal injection of OZURDEX the dexamethasonevitreous humour Cmax was 100 ng/mL at day 42 post-injection and 5.57 ng/mL at day 91.

Dexamethasone remained detectable in the vitreous at 6 months post-injection. The rank order ofdexamethasone concentration was retina > iris > ciliary body > vitreous humour > aqueous humour >plasma.

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 wereobserved. This is consistent with results from rabbit and monkey ocular metabolism studies.

Dexamethasone is ultimately metabolised to lipid and water soluble metabolites that can be excreted inbile and urine.

The OZURDEX matrix slowly degrades to lactic acid and glycolic acid through simple hydrolysis,then further degrades into carbon dioxide and water.

Effects in non-clinical studies were observed only at doses considered sufficiently in excess of themaximum dose for human indicating little relevance to clinical use.

No mutagenicity, carcinogenicity, reproductive or developmental toxicity data are available for

OZURDEX. Dexamethasone has been shown to be teratogenic in mice and rabbits following topicalophthalmic application.

Dexamethasone exposure to the healthy/untreated eye via contralateral diffusion has been observed inrabbits following delivery of the implant to the posterior segment of the eye.

Ester terminated 50:50 poly D,L-lactide-co-glycolide.

Acid terminated 50:50 poly D,L-lactide-co-glycolide.

Not applicable.

3 years.

This medicinal product does not require any special storage conditions.

Each pack contains:

One sustained release sterile implantable rod shaped implant containing 700 micrograms ofdexamethasone, located in the needle (stainless steel) of a disposable applicator.

The applicator consists of a plunger (stainless steel) within a needle where the implant is held in placeby a sleeve (silicone). The plunger is controlled by a lever on the side of the applicator body. Theneedle is protected by a cap and the lever by a safety tab.

The applicator containing the implant is packaged in a sealed foil pouch containing desiccant.

OZURDEX is for single use only.

Each applicator can only be used for the treatment of a single eye.

If the seal of the foil pouch containing the applicator is damaged, the applicator must not be used.

Once the foil pouch is opened the applicator should be used immediately.

Administering OZURDEX1) Hold the long axis of the applicator parallel to the limbus.

2) Allow the applicator to meet the sclera at an oblique angle withthe bevel of the needle facing up, away from the sclera. Pushthe tip about 1 mm into the sclera, keeping it parallel to thelimbus.

3) Redirect towards the centre of the eye into the vitreous cavity.

This will create a shelved scleral path.

Advance the needle until you enter the vitreous cavity.

Do not advance the needle past the point where the sleeve ofthe applicator touches the conjunctiva.

4) Depress the actuator button slowly until you hear a click.

Before withdrawing the applicator from the eye, make surethat the actuator button is fully depressed and has locked flushwith the applicator surface.

5) Withdraw the applicator in the same direction that you used toenter the vitreous.

6) Dispose of the applicator safely immediately after treatment.

The OZURDEX applicator is for single use only.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Allergan Pharmaceuticals Ireland

Castlebar Road,

Co. Mayo

Westport

Ireland

EU/1/10/638/001

Date of first authorisation: 27/07/2010

Date of latest renewal: 23/03/2015

MM/YYYY

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu/.