Ozurdex

Section Number

Subject

Change

4.1

Therapeutic indications

Text Added

OZURDEX is indicated for the treatment of adult patients with macular oedema following either Branch Retinal Vein Occlusion (BRVO) or Central Retinal Vein Occlusion (CRVO) (see section 5.1).

OZURDEX is indicated for the treatment of adult patients with inflammation of the posterior segment of the eye presenting as non-infectious uveitis.

4.2

Posology and method of administration

Text added

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

Posology

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

Repeat doses should be considered when a patient experiences a response to treatment followed subsequently by a loss in visual acuity and in the physician’s opinion may benefit from retreatment without being exposed to significant risk (see section 5.1).

Patients who experience and retain improved vision should not be retreated. Patients who experience a 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 (see section 5.1). There is currently no experience of repeat administrations in posterior segment non-infectious uveitis or beyond 2 implants in Retinal Vein Occlusion.

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

Special populations

Elderly (≥65 years old)

No dose adjustment is required for elderly patients.

Renal impairment

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

Hepatic impairment

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

Paediatric population

There is no relevant use of OZURDEX in the paediatric population in 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 been established. No data are available.

Method of administration

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 which include the use of sterile gloves, a sterile drape, and a sterile eyelid speculum (or equivalent).

A broad spectrum topical antimicrobial should be given prior to and on the day of the injection procedure.  Adequate local anaesthesia should be 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. Carefully remove the cap from the applicator. Once the foil pouch is opened the applicator should be used immediately.

Hold the applicator in one hand and pull the safety tab straight off the applicator. Do not twist or flex the tab. With the bevel of the needle up away from the sclera, advance the needle about 1 mm into the sclera then redirect toward the centre of the eye into the vitreous cavity until the silicone sleeve 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 and has locked flush with the applicator surface. Remove the needle in the same direction as used to enter the vitreous.

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

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

4.4

Special warnings and precautions for use

Text added

Monitoring

Any intravitreous injection can be 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 occurs. 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 must be instructed to report any symptoms suggestive of endophthalmitis or any of the above mentioned events without delay (see section 4.8).

Adverse reactions

Use of corticosteroids may produce posterior subcapsular cataracts, glaucoma and may result in secondary ocular infections.

After the first injection the incidence of cataract appears higher in patients with non-infectious uveitis of 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 (see section 4.8). with oOnly 1 patient out of 368 requireding cataract surgery during the first treatment and 3 patients out of 302 during the second treatment. In the non‑infectious uveitis study, 1 patient out of the 62 phakic patients underwent cataract surgery after a single injection.

The prevalence of conjunctival haemorrhage in patients with non-infectious uveitis of the posterior segment appears to be higher compared with BRVO/CRVO.   This could be attributable to the 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 resolution occurs.

As expected with ocular steroid treatment and intravitreal injections, increases in intraocular pressure (IOP) may be seen. Of the patients experiencing an increase of IOP of ≥10 mmHg from baseline, the greatest proportion showed this IOP increase at around 60 days following an injection.  Therefore, regular monitoring of IOP, irrespective of baseline IOP, is required and any elevation should be managed appropriately post‑injection as needed.   Patients of less than 45 years of age with macular oedema following Retinal Vein Occlusion or inflammation of the posterior segment of the eye presenting as non‑infectious uveitis are more likely to experience increases in IOP. 

Other warnings and precautions

Corticosteroids should be used cautiously in patients with a history of ocular herpes simplex 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 aphakic patients Therefore OZURDEX should be used with caution in these patients.

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

Anti-coagulant therapy was used in 1.7% of patients receiving OZURDEX; there were no reports of hemorrhagic adverse events in these patients. Anti‑platelet medicinal products, such as clopidogrel, were used at some stage during the clinical studies in over 40% of patients.  In clinical trial patients receiving anti-platelet therapy, haemorrhagic adverse events were reported in a higher proportion of patients injected with OZURDEX (27%) compared with the control group (20%). The most common haemorrhagic adverse reaction reported was conjunctival haemorrhage (24%). OZURDEX should be used with caution in patients taking anti-coagulant or anti-platelet medicinal products.

4.8

Undesirable effects

Text Removed/Text Added

BRVO/CRVO

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

          A total of 47.3 % of patients experienced at least one adverse reaction. The most frequently reported adverse 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 patients although the overall incidence of adverse reactions was higher for the subgroup of patients with CRVO.

b)      The following adverse reactions, considered related to OZURDEX treatment were reported during the two Phase III clinical trials.

Very Common (≥ 1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very Rare (<1/10,000) adverse reactions are presented according to MedDRA System organ class in Table 1. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1.    Adverse reactions– BRVO/CRVO

* Adverse reactions considered to be related to the intravitreous injection procedure rather than the dexamethasone implant

c)      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. During the initial treatment period, 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. 

The adverse reaction profile of 341 patients analysed following a second injection of OZURDEX, was similar to that following the first injection. A total of 54 % of patients experienced at least one adverse reaction.  The incidence of increased IOP(24.9 %) 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

a)      The clinical safety of OZURDEX in patients with inflammation of the posterior segment of the eye presenting as non-infectious uveitis, has been assessed in a single, multicentre, masked, randomised study .

A total of 77 patients were randomised to receive OZURDEX and 76 to receive Sham. A total of 73 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 OZURDEX were conjunctival haemorrhage (30.3%), increased intraocular pressure (25.0%) and cataract (11.8%).

b)      The following adverse reactions, considered related to OZURDEX treatment were reported during the Phase III clinical trial.

Very Common (≥ 1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1,000 to <1/100); Rare (≥1/10,000 to <1/1,000); Very Rare (<1/10,000) adverse reactions are presented according to MedDRA System organ class in Table 2. Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2.    Adverse reactions - Uveitis

* Adverse reactions considered to be related to the intravitreous injection procedure rather than the dexamethasone implant

Post-Marketing Experience

The following adverse reaction has been identified from post-marketing experience with OZURDEX:

Eye disorders            Endophthalmitis (injection related)           (see also section 4.4)

5.1

Pharmacodynamic properties

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

Dexamethasone, a potent corticosteroid, has been shown to suppress inflammation by inhibiting oedema, fibrin deposition, capillary leakage, and phagocytic migration of the inflammatory response. 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. Additionally, corticosteroids prevent the release of prostaglandins, some of which have been identified as mediators of cystoid macular oedema.

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 who were randomized to received 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 to dexamethasone 350 µg and 426 patients to sham.

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

The proportion of patients achieving the primary efficacy measure of ≥ 15 letter improvement from baseline in BCVA following injection of a single implant is shown in Table 32. 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 the incidence of responders 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.

Table 32. Proportion of Patients with ≥ 15 Letters Improvement from
                        Baseline Best Corrected Visual Acuity in the Study Eye
                        (Pooled, ITT Population)

^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 sham at all time points.

In each Phase III study and the pooled analysis, the time to achieve ≥ 15 letters (3-line) improvement in 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 than sham treated patients.

OZURDEX was numerically superior to sham in preventing vision loss as shown by a lower of proportion of patients experiencing deterioration of vision of ≥ 15 letters in the OZURDEX group throughout 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 assessed by BCVA at day 90 was thus supported by this anatomical finding.  By Day 180 the mean retinal thickness 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 coherence tomography OCT and in the investigator’s opinion treatment would not put the patient at risk; were eligible to receive an OZURDEX treatment in an open label extension.  Of the patients who were treated in the open label phase, 983% received an OZURDEX injection between 5 and 7 months after the initial treatment.

As for the initial treatment, peak response 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 results in a lower proportion of responders at all time points in the open label phase when compared with those receiving a second OZURDEX injection.

Uveitis

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

A total of 229 patients were randomised to receive dexamethasone 350 µg or 700 µg implants or sham.  Of these, a total of 77 were randomised to receive OZURDEX, 76 to dexamethasone 350 µg and 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. Statistical superiority was maintained up to and including week 26 (p ≤ 0.014) as shown in Table 4.

The cumulative response rate curves (time to vitreous haze score of 0) were significantly different for the OZURDEX group compared to the 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 4.

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.

Table 4.    Proportion of Patients with Vitreous Haze Score of Zero and ≥ 15 Letters Improvement from Baseline Best Corrected Visual Acuity in the Study Eye
                 (ITT Population)

^a  p < 0.001;  ^b p = 0.010;  ^c p = 0.009;  ^d p = 0.014

Paediatric population

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. See section 4.2 for information on paediatric use.

10

DATE OF REVISION OF THE TEXT

Text Removed/Added

07/2010 06/2011