A patient guide to OZURDEX therapy
- 1. Name of the medicinal product
- 2. Qualitative and quantitative composition
- 3. Pharmaceutical form
- 4. Clinical particulars
- 4.1 Therapeutic indications
- 4.2 Posology and method of administration
- 4.3 Contraindications
- 4.4 Special warnings and precautions for use
- 4.5 Interaction with other medicinal products and other forms of interaction
- 4.6 Fertility, pregnancy and lactation
- 4.7 Effects on ability to drive and use machines
- 4.8 Undesirable effects
- 4.9 Overdose
- 5. Pharmacological properties
- 5.1 Pharmacodynamic properties
- 5.2 Pharmacokinetic properties
- 5.3 Preclinical safety data
- 6. Pharmaceutical particulars
- 6.1 List of excipients
- 6.2 Incompatibilities
- 6.3 Shelf life
- 6.4 Special precautions for storage
- 6.5 Nature and contents of container
- 6.6 Special precautions for disposal and other handling
- 7. Marketing authorisation holder
- 8. Marketing authorisation number(s)
- 9. Date of first authorisation/renewal of the authorisation
- 10. Date of revision of the text
PosologyThe 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).
DMEPatients treated with OZURDEX who have experienced an initial response and in the physician's opinion may benefit from retreatment without being exposed to significant risk should be considered for retreatment. Retreatment may be performed after approximately 6 months if the patient experiences decreased vision and/or an increase in retinal thickness, secondary to recurrent or worsening diabetic macular oedema. There is currently no experience of the efficacy or safety of repeat administrations in DME beyond 7 implants.
RVO and uveitisRepeat 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 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).
Elderly (≥65 years old)No dose adjustment is required for elderly patients.
Renal impairmentOZURDEX has not been studied in patients with renal impairment however no special considerations are needed in this population.
Hepatic impairmentOZURDEX has not been studied in patients with hepatic impairment; however no special considerations are needed in this population.
Paediatric populationThere 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 been established. No data are available.
Method of administrationOZURDEX 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 which include 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 days before and after each injection. Before the injection, the periocular skin, eyelid and ocular surface should be disinfected (using for example drops of povidone iodine 5% solution on the conjunctiva as it was done in the clinical trials for the approval of OZURDEX) and 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.
PregnancyStudies in animals have shown teratogenic effects following topical ophthalmic administration (see section 5.3). 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 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 benefit justifies the potential risk to the foetus.
Breast-feedingDexamethasone is excreted in breast milk No effects on the child are anticipated due to the route of administration and the resulting systemic levels. However OZURDEX is not recommended during breast feeding unless clearly necessary.
FertilityThere are no fertility data available.
Summary of the safety profileThe most commonly-reported adverse events reported following treatment with OZURDEX are those frequently observed with ophthalmic steroid treatment or intravitreal injections (elevated IOP, cataract formation and conjunctival or vitreal haemorrhage respectively).Less frequently reported, but more serious, adverse reactions include endophthalmitis, necrotizing retinitis, retinal detachment and retinal tear.With the exception of headache and migraine, no systemic adverse drug reactions were identified with the use of OZURDEX.
Tabulated list of adverse reactionsThe 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 organ class 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 (≥1/10,000 to <1/1,000); very rare (<1/10,000). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Table 1 Adverse reactions
|System organ class||Frequency||Adverse reaction|
|Nervous system disorders||Common||Headache|
|Eye disorders||Very common||Intraocular pressure increased, cataract, conjunctival haemorrhage*|
|Common||Ocular hypertension, cataract subcapsular, vitreous haemorrhage*, visual acuity reduced*, visual impairment/ 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 the eye*, anterior chamber inflammation*, anterior chamber cells/ flares*, abnormal sensation in eye*, eyelids pruritus, scleral hyperaemia*|
|General disorders and administration site conditions||Uncommon||Device dislocation* (migration of implant) with or without corneal oedema (see also section 4.4), complication of device insertion* (implant misplacement)|
Description of selected adverse reactions
Diabetic Macular OedemaThe clinical safety of OZURDEX in patients with diabetic macular oedema was assessed in two phase 3 randomized, double-masked, sham-controlled studies. In both studies, a total of 347 patients were randomized and received OZURDEX and 350 patients received sham.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 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 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 3 year studies. 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). 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 post injection, 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 mm Hg 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 3 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.
BRVO/CRVOThe 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. 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.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.
UveitisThe 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%).
Reporting of suspected adverse reactionsReporting suspected adverse reactions after authorisation 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 via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.
Clinical efficacy and safety
Diabetic Macular OedemaThe 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 to dexamethasone 350 µg and 350 patients to sham. Patients were eligible for retreatment based upon central subfield retinal thickness >175 microns by optical coherence tomography (OCT) or upon investigators interpretation of the OCT for any evidence of residual retinal edema consisting of intraretinal cysts or any regions of increased retinal thickening within or outside of the central subfield. Patients received up to 7 treatments at intervals no more frequently than approximately every 6 months. Escape therapy was permitted at the investigators discretion at any stage but led to subsequent withdrawal from the studies. A total of 36% of OZURDEX treated patients discontinued study participation for any reason during the study compared with 57% of sham patients. Discontinuation rates due to adverse events were similar across treatment and sham groups (13% vs 11%). Discontinuation due to lack of efficacy was 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. Vision improvement was re-established upon removal of cataract.Table 2. Efficacy in studies 206207-010 and 206207-011 (ITT population)
|Endpoint||Study 206207-010||Study 206207-011||Pooled Studies 206207-010 and 206207-011|
|DEX 700 N = 163||Sham N = 165||DEX 700 N = 188||Sham N = 185||DEX 700 N = 351||Sham N = 350|
|Mean BCVA average change over 3 years, AUC approach (letters)||4.1||1.9||2.9||2.0||3.5||2.0|
|BCVA ≥ 15-letter improvement from baseline at Year 3/Final (%)||22.1||13.3||22.3||10.8||22.2||12.0|
|Mean BCVA change from baseline at year 3/final visit (letters)||4.1||0.8||1.3||-0.0||2.6||0.4|
|OCT retinal thickness at center subfield mean average change over 3 years, AUC approach (µm)||-101.1||-37.8||-120.7||-45.8||-111.6||-41.9|
|P-value||<0.001||< 0.001||< 0.001|
|Endpoint||DEX 700 N = 86||Sham N = 101||P-value|
|Mean BCVA average change over 3 years, AUC approach (letters)||6.5||1.7||< 0.001|
|BCVA ≥ 15-letter improvement from baseline at Year 3/Final visit (%)||23.3||10.9||0.024|
|Mean BCVA change from baseline at year 3/Final visit||6.1||1.1||0.004|
|OCT retinal thickness at center subfield mean average change over 3 years, AUC approach (µm)||-131.8||-50.8||< 0.001|
|Endpoint||DEX 700 N = 247||Sham N = 261||P-value|
|Mean BCVA average change over 3 years, AUC approach (letters)||3.2||1.5||0.024|
|BCVA ≥ 15-letter improvement from baseline at Year 3/Final visit (%)||21.5||11.1||0.002|
|Mean BCVA change from baseline at year 3/Final visit||2.7||0.1||0.055|
|OCT retinal thickness at center subfield mean average change over 3 years, AUC approach (µm)||-126.1||-39.0||< 0.001|
BRVO/CRVOThe 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 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 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 5. 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 5. Proportion of patients with ≥ 15 letters improvement from baseline best corrected visual acuity in the study eye (pooled, ITT population)
|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%|
UveitisThe 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 6.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 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.Table 6. 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)
|Visit||Vitreous Haze Score of Zero||BCVA improvement from baseline of ≥15 letters|
|DEX 700 N = 77||Sham N = 76||DEX 700 N = 77||Sham N = 76|
Paediatric populationThe 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 for diabetic macular oedema (see section 4.2 for information on paediatric use).
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An Injector's Guide to OZURDEX
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