1. Name Of The Medicinal Product
OZURDEX
2. Qualitative And Quantitative Composition
One implant contains 700 micrograms of dexamethasone.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Intravitreal implant in applicator.
Disposable injection device, containing a rod-shaped implant. which is not visible. The implant is approximately 0.46 mm in diameter and 6 mm in length.
4. Clinical Particulars
4.1 Therapeutic Indications
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
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 (
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.
4.3 Contraindications
OZURDEX is contraindicated in
• Hypersensitivity to the active substance or to any of the excipients.
• Active or suspected ocular or periocular infection including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases.
• Advanced glaucoma which cannot be adequately controlled by medicinal products alone.
4.4 Special Warnings And Precautions For Use
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). Only 1 patient out of 368 required 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
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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
No interaction studies have been performed.
Systemic absorption is minimal and no interactions are anticipated.
4.6 Pregnancy And Lactation
Pregnancy
Studies 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 feeding
Dexamethasone 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.
Fertility
There are no fertility data available.
4.7 Effects On Ability To Drive And Use Machines
Patients may experience temporarily reduced vision after receiving OZURDEX by intravitreal injection (see section 4.8). They should not drive or use machines until this has resolved.
4.8 Undesirable Effects
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. 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 (
Table 1. Adverse reactions– BRVO/CRVO
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* 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 (
Table 2. Adverse reactions - Uveitis
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* 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)
4.9 Overdose
If an overdose occurs, intraocular pressure should be monitored and treated, if deemed necessary by the attending physician.
5. Pharmacological Properties
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 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
The proportion of patients achieving the primary efficacy measure of
Table 3. Proportion of Patients with Baseline Best Corrected Visual Acuity in the Study Eye (Pooled, ITT Population)
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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
OZURDEX was numerically superior to sham in preventing vision loss as shown by a lower of proportion of patients experiencing deterioration of vision of
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, 98% 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
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 (ITT Population)
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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.
5.2 Pharmacokinetic Properties
Plasma concentrations were obtained from a subset of 21 patients in the two, 6-month efficacy studies prior to dosing and on day 7, 30, 60, and 90 following the intravitreal implant containing 350 µg or 700 µg dexamethasone. Ninety-five percent of the plasma dexamethasone concentration values for the 350 µg dose group and 86% for the 700 µg dose group were below the lower limit of quantitation (0.05 ng/ml). The highest plasma concentration value of 0.094 ng/ml was observed in one subject from the 700 µg group. Plasma dexamethasone concentration did 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 dexamethasone vitreous 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 of dexamethasone 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 were observed. 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 in bile and urine.
The OZURDEX matrix slowly degrades to lactic acid and glycolic acid through simple hydrolysis, then further degrades into carbon dioxide and water.
5.3 Preclinical Safety Data
Effects in non-clinical studies were observed only at doses considered sufficiently in excess of the maximum 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 topical ophthalmic application.
Dexamethasone exposure to the healthy/untreated eye via contralateral diffusion has been observed in rabbits following delivery of the implant to the posterior segment of the eye.
6. Pharmaceutical Particulars
6.1 List Of Excipients
• Ester terminated 50:50 poly D,L-lactide-co-glycolide.
• Acid terminated 50:50 poly D,L-lactide-co-glycolide.
6.2 Incompatibilities
Not applicable.
6.3 Shelf Life
3 years.
6.4 Special Precautions For Storage
This medicinal product does not require any special storage conditions.
6.5 Nature And Contents Of Container
1 pack contains:
1 sustained release sterile implantable rod shaped implant containing 700 micrograms of dexamethasone, 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 place by a sleeve (silicone). The plunger is controlled by a lever on the side of the applicator body. The needle 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.
6.6 Special Precautions For Disposal And Other Handling
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, do not use. Once the foil pouch is opened the applicator should be used immediately.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
7. Marketing Authorisation Holder
Allergan Pharmaceuticals Ireland
Castlebar Road,
Co. Mayo
Westport
Ireland
8. Marketing Authorisation Number(S)
EU/1/10/638/001
9. Date Of First Authorisation/Renewal Of The Authorisation
27/07/2010
10. Date Of Revision Of The Text
06/2011
Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu/.
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