The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION. 19 September 2012

Transcription

1 The legally binding text is the original French version TRANSPARENCY COMMITTEE OPINION 19 September 2012 OZURDEX 700 micrograms, intravitreal implant in applicator Box of 1 sachet with applicator (CIP: ) Applicant: ALLERGAN FRANCE SAS dexamethasone ATC code: S01BA01 List I. Prescription-only medicine restricted to ophthalmologists. Date of Marketing Authorisation: 27 July 2010 (centralised procedure) Amendment to Marketing Authorisation: 16 June 2011 (exteion of indication to the treatment of adults with inflammation of the posterior segment of the eye presenting as non-infectious uveitis) Reason for request: Request for inclusion on the list of medicines refundable by National Health Iurance and approved for hospital use in the exteion of indication to the treatment of adults with inflammation of the posterior segment of the eye presenting as noninfectious uveitis. Medical, Economic and Public Health Assessment Division 1/12

2 1 CHARACTERISTICS OF THE MEDICINAL PRODUCT 1.1. Active ingredient dexamethasone 1.2. Indication 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). OZURDEX is indicated for the treatment of adults with inflammation of the posterior segment of the eye presenting as non-infectious uveitis Dosage OZURDEX must be administered by an ophthalmologist experienced in intravitreal injectio. Dosage 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 of the SPC). A repeat dose may be coidered when a patient experiences a respoe 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 of the SPC). 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 of less than 6 months (see section 5.1 of the SPC). There is currently no experience of repeat administratio in non-infectious uveitis or beyond two 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 of the SPC). Special populatio 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 coideratio are needed in this population. Hepatic impairment OZURDEX has not been studied in patients with hepatic impairment. However, no special coideratio are needed in this population. 2/12

3 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). Method of administration Single-use intravitreal implant in applicator for intravitreal use only. Each applicator can only be used once for the treatment of a single eye. The intravitreal injection procedure should be carried out under controlled aseptic conditio 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 agait 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 area around the injection site to bring the implant into view. Following the intravitreal injection patients should continue to be treated with a broad spectrum antimicrobial. 3/12

4 2 SIMILAR MEDICINAL PRODUCTS 2.1. ATC Classification (2011) S Seory orga S01 Ophthalmologicals S01B Antiinflammatory agents S01BA Corticosteroids, plain S01BA01 Dexamethasone 2.2. Medicines in the same therapeutic category OZURDEX is the first dexamethasone-based implant, administered by intravitreal injection with an applicator, indicated in the treatment of inflammation of the posterior segment of the eye secondary to non-infectious uveitis. There is no other topical medicinal product with marketing authorisation in the same indication Medicines with a similar therapeutic aim No other medicinal product has marketing authorisation in this indication, but topical or periocular corticosteroids or corticosteroids administered by intravitreal injection are used. Systemic treatments (corticosteroids, immunosuppressants) are used when there is an underlying systemic disease. 3 ANALYSIS OF AVAILABLE DATA The pharmaceutical company supplied a phase III clinical study (the HURON study) that evaluated the efficacy and safety of dexamethasone as an intravitreal implant in comparison with sham injectio Efficacy HURON study: This randomised, double-blind, phase III study compared the administration of an intravitreal implant of dexamethasone in doses of 350 µg and 700 µg with sham injectio in patients with inflammation of the posterior segment of the eye associated with non-infectious posterior or intermediate uveitis. The treatments were evaluated 8 weeks after the injection. Patients were then followed up for 26 weeks. Inclusion criteria: - age 18 years, - inflammation of the posterior segment of the eye associated with posterior or intermediate uveitis, based on a standardised nomenclature, in at least one eye, - vitreous haze score of at least +1.5 (on a scale of 0 to 4) at the selection and inclusion visit, 4/12

5 - a best corrected visual acuity (BCVA) score of between 10 (approximately equivalent to 20/640 1 on the Snellen chart or 1/30 on the Monoyer chart) and 75 letters (approximately equivalent to 20/32 on the Snellen chart or 6/10 on the Monoyer chart 2 ) at the eye examination, measured on inclusion by the ETDRS method, - a patient can be treated with: o topical corticosteroids and NSAIDs if the doses were stable for at least 2 weeks before the selection visit and remained so throughout the study, o immunosuppressants (ciclosporin, methotrexate) if the doses were stable for at least o 3 months before the selection visit and remained so throughout the study, oral corticosteroids if the doses were less than 20 mg prednisone (or equivalent) and at a cotant dose for at least 1 month before the selection visit and then remained so throughout the study. The use of topical cyclopegics (homatropine, atropine) was left to the discretion of the investigator. Main exclusion criteria: - any uncontrolled systemic disease or HIV infection, - anticoagulant use within 2 weeks before inclusion, - known allergy to the study treatment or one of the cotituents of the device or of the agents used for the study (fluorescein, drops for dilating the eye), - previous treatment with OZURDEX, - intraocular pressure greater than 21 mmhg or less than 5 mmhg, - history of elevated intraocular pressure (IOP) after corticosteroid treatment (increase of more than 10 mmhg or IOP > 25 mmhg), - history of elevated intraocular pressure, - use of antiglaucoma treatment, - history of serious central chorioretinopathy in one or other eye, - any active infection of the eye, - inactive or active toxoplasmosis of the eye, - contraindication to dilatation of the eye, - any eye disorder that could interfere with the evaluation, - periocular injectio into the studied eye within 8 days before inclusion, - history of intravitreal injection of corticosteroid into the studied eye (except on use of triamcinolone and injection more than 26 weeks ago and total doses < 4 mg), - any use of Retisert (intravitreal implant of fluocinolone acetonide) in the studied eye, - intraocular surgery (including cataract and laser) within 90 days before inclusion, - aphakia or intraocular lees, - history of pars plana vitrectomy, herpetic infection of the eye or the ocular adnexae, - best corrected visual acuity (BCVA) score of < 34 letters (approximately equivalent to a Snellen score of 20/200 or 1/10) for the contralateral eye, - uveitis expected to be unrespoive to corticosteroid therapy, - pre-phthisis. Treatments studied: - intravitreal administration of an implant containing 700 µg of dexamethasone (OZURDEX), - intravitreal administration of an implant containing 350 µg of dexamethasone (dose not validated by the marketing authorisation), 1 Snellen scale: on this scale, a person s visual acuity is normal, i.e. 20/20, if the person can read the last line on the Snellen scale at a distance of 20 feet (about 6 metres). A visual acuity of 20/200 indicates that the person can read only the first line at a distance of 20 feet whereas a person with no deficiency can read that same line at a distance of 200 feet. According to the WHO, the term poor vision is used with a corrected vision of 20/70 onwards. 2 Monoyer scale: on this scale, visual acuity is measured in tenths: 1 to 10. An acuity of 10/10ths corresponds to nornal vision in which it is possible to make out a 7.3 mm object at 5 m. The term poor vision is used for a corrected visual acuity of between 3/10 and 1/20. 5/12

6 - a sham injection corresponding to the application of an injector without injection. NB: only the results for the dexamethasone dose validated by the marketing authorisation (700 µg) will be presented. Co-treatments: Before the intervention, all patients received ocular antibiotic treatment for 3 days before the intervention. All treatments that could affect the evaluation of the study treatments had to be taken in a cotant dose. Investigators were free to treat ocular hyperteion so that it could be controlled. If a cataract occurred during the study, the decision on surgery was left to the discretion of the doctor. Primary efficacy endpoint: proportion of patients with a vitreous haze score in the studied eye equal to 0 (no inflammation) in week 8. Ocular inflammation in the studied eye was measured using the vitreous haze score rated from 0 to +4, based on a colorimetric scale (Nussemblat et al ) modified by adding a score of +1.5: Grade Description 0 No inflammation +0.5 Trace of inflammation (slight blurring of the margi of the optic disc and/or loss of reflex of the nerve fibre layer (NFL)) +1 Slight blurring of the retinal vessels and the optic nerve +1.5 Blurred image of the head of the optic nerve and the posterior retina, greater than +1, but less than Moderate blurring of the head of the optic nerve +3 Marked blurring of the head of the optic nerve +4 Head of the optic nerve not visible Among the secondary endpoints: - Proportion of patients with an improvement in their best corrected visual acuity (BCVA) of at least 15 letters (very significant improvement perceptible by the patient 4 ) measured on the ETDRS scale in week 8. - Proportion of patients with an improvement in their BCVA of at least 10 letters (significant improvement perceptible by the patient) measured on the ETDRS scale in week 8. Results: A total of 229 patients were randomised to receive dexamethasone 700 µg (n = 77), dexamethasone 350 µg (n = 76) or a sham injection (n = 76). The number of patients who dropped out of the study (before 26 weeks) was four in the dexamethasone 700 µg group, three in the dexamethasone 350 µg group and five in the sham injection group. The demographic characteristics of the patients were similar in the two groups. The mean age of the patients in the study was between 44.3 and 45.9 years depending on the groups. Most of the patients included had intermediate uveitis (76.3% to 84.2% depending on the groups) and 15.8 to 23.7% had posterior uveitis. The patients included had on average been suffering from uveitis for 3.5 to 5 years depending on the groups. 3 Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory activity in intermediate and posterior uveitis. Ophthalmology Apr; 92(4): BCVA stages with the ETDRS scale: Normal vision: 85 letters Possible/minimum reading level needed to drive in France: 70 letters Normal reading level impossible: 55 letters Legal threshold for blindness in France: 20 letters 6/12

7 The main conditio reported in the history of eye disease were cataract (37.6% of patients) and macular oedema (17.5%). Among the patients included, 40.3% to 47.4% (depending on the groups) had previously been treated uuccessfully for their uveitis with a pharmacological treatment, of which about 15% of them were treated with an oral corticosteroid. About 8 of the patients in each group received concomitant treatments for the studied eye during the study; these were oral corticosteroid therapy (22.4 to 31.6%), topical corticosteroid therapy (50.0 to 65.8%), a topical beta-blocker (6.6% in the sham injection group with 21.1 and 27.3% in the dexamethasone groups), topical antibiotic therapy (3.9 to 13.2%) and other topical non-corticosteroid treatment (7.8 to 21.6%). Primary efficacy endpoint (ITT population using the last available value that met the conditio of the study): In week 8, the percentage of patients with no ocular inflammation (vitreous haze score = 0) was higher in the dexamethasone 700 µg group (46.8%) than in the sham injection group (11.8%) (p < 0.001). Secondary endpoints: Gain of 15 letters (ETDRS): In week 8, the percentage of patients with an improvement of at least 15 letters in their BCVA was higher in the dexamethasone 700 µg group (42.9%) than in the sham injection group (6.6%) (p < 0.001). Gain of 10 letters (ETDRS): In week 8, the percentage of patients with an improvement of at least 10 letters in their BCVA was higher in the dexamethasone 700 µg group (59.7%) than in the sham injection group (17.1%) (p < 0.001). The results for the follow-up phase show that the differences observed in terms of the percentages of patients with a vitreous haze score of = 0 and in terms of a gain in visual acuity of at least 15 letters, although smaller, are still statistically significant at 26 weeks: - % of patients with a vitreous haze score = 0: 31.2% with OZURDEX versus 14.5% with the sham injection (p = 0.014), - % of patients with a gain in BCVA of 15 letters: 37.7% with OZURDEX versus 13.2% with the sham injection (p < 0.001) Adverse effects Safety data from the HURON study The patients included in the safety analysis were randomised patients who received treatment. The adverse events linked to treatment with a frequency of more than 5% were local and reversible. In the treated eye, an increase in intraocular pressure was observed in 25. of patients in the OZURDEX group and 6.7% in the placebo group and conjunctival haemorrhage in 30.3% of patients in the OZURDEX group and 21.3% of patients in the placebo group. The percentage of patients who developed a cataract during the study was 11.8% with OZURDEX and 5.3% with the sham injection. A total of four patients received surgical treatment for their cataract: one patient in the OZURDEX group in the treated eye and three patients in the placebo group, two of them in the studied eye and one in the contralateral eye. 7/12

8 Intraocular pressure (IOP): During the study, patients received antiglaucoma treatment if they had an increase in intraocular pressure. The increase in IOP was evaluated on the basis of (see Table 2): - the proportion of patients with an elevation in IOP of 10 mmhg at each follow-up visit in comparison with the start of the study, - the proportion of patients with an IOP of in comparison with the start of the study, - the proportion of patients with an IOP of in comparison with the start of the study, In week 8, the percentage of patients with an IOP of 10 mmhg in comparison with on inclusion was higher in the OZURDEX group than in the placebo group (9.6% vs, p = 0.012). In week 26, this percentage was 1.4% in the OZURDEX group and 2.8% in the placebo group. Serious adverse events: No death occurred during the study. Seven patients in the OZURDEX group and five in the placebo group had a serious adverse event. Seven were regarded as possibly linked to the study treatment: four retinal detachment (two in the OZURDEX group and two in the placebo group), two cataracts (one in the dexamethasone 350 group, one in the placebo group), one endophthalmitis (OZURDEX group). Residues from the device: In week 26, residues from the device were present in 23.7% of the patients in the OZURDEX group. 8/12

9 Table 2: Proportion of patients with an increase in IOP of more than 10 mmhg, and patients with an IOP of 25 or 35 mmhg in the studied eye Intraocular OZURDEX Placebo p value Visit pressure n = 77 n = 76 Inclusion - - nd Week 3 6/70 (8.6%) 5/70 (7.1%) 1/70 (1.4%) 1/70 (1.4%) 1/70 (1.4%) Week 6 8/71 (11.3%) 5/70 (7%) 1/66 (1.5%) 1/66 (1.5%) Week 8 7/73 (9.6%) 3/73 (4.1%) 2/73 (2.7%) Week 12 6/73 (8.2%) 5/73 (6.8%) 3/73 (4.1%) 1/70 (1.4%) 1/70 (1.4%) Week 16 2/69 (2.9%) 2/69 (2.9%) Week 20 3/71 (4.2%) 3/71 (4.2%) 4/72 (5.6%) 2/72 (2.8%) 1/72 (1.4%) Week 26 : difference not statistically significant nd: not determined 1/74 (1.4%) 2/72 (2.8%) 3/72 (4.2%) Summary of product characteristics The adverse effects rated as very common ( 1) are: increased intraocular pressure, cataract, conjunctival haemorrhage. The adverse effects rated as common ( 1/100 to < 1/10) are: retinal detachment, myodesopsia, vitreous opacities, blepharitis, scleral hyperaemia, impairment of vision, abnormal seation in the eye, eyelid pruritus, migraine Pharmacovigilance data Pharmacovigilance data in the treatment of uveitis are available for the period from 1 January 2011 to 31 December During this period, exposure in this indication can be estimated at 873 patients-year in France and 2011 patients-year in the world. Seventeen pharmacovigilance cases were reported, six of them serious: one case of ocular hypotony (an unexpected effect), three cases of migration of the implant, one case of complication at the time of implantation (unexpected effect) and one case of sterile endophthalmitis. 9/12

10 Additional studies Two studies are in progress to evaluate, in particular, the long-term safety of OZURDEX (2 years): - a study requested by the EMA as part of the risk management plan in patients with non-infectious uveitis and patients with retinal vein occlusion - a study requested by the Traparency Committee as part of the evaluation of OZURDEX in retinal vein occlusio Conclusion OZURDEX was assessed in a randomised double-blind study comparing an intravitreal implant of dexamethasone in doses of 350 µg and 700 µg (the latter in the dose recorded in the marketing authorisation) with a sham injection in 229 patients with inflammation of the posterior segment of the eye associated with non-infectious posterior or intermediate uveitis. The evaluation was made 8 weeks later, then the patients were followed up for 26 weeks. In week 8, - the percentage of patients who no longer had eye inflammation, defined as a vitreous haze score = 0 (primary efficacy endpoint), was higher in the dexamethasone 700 µg group than in the sham injection group (46.8% vs 11.8%, p < 0.001). - the percentage of patients with an improvement in their best corrected visual acuity (BCVA) of at least 15 letters (ETDRS scale) was higher in the dexamethasone 700 µg group than in the sham injection group (42.9% vs 6.6%, p < 0.001); - the percentage of patients with an improvement in their BCVA of at least 10 letters was higher in the dexamethasone 700 µg group than in the sham injection group (59.7% vs 17.1%, p < 0.001). At 26 weeks, the differences observed in terms of the percentages of patients with a vitreous haze score = 0 and a gain in visual acuity of at least 15 letters, although smaller, are still statistically significant. The adverse events associated with treatment were mainly local and reversible. In the treated eye, the following were more common in the dexamethasone 700 µg group than in the sham injection group: increase in intraocular pressure (25. versus 6.7%), conjunctival haemorrhage (30.3% versus 21.3%) and cataract (11.8% versus 5.3%). During the study, patients received antiglaucoma treatment if they had an increase in intraocular pressure. In week 8, the percentage of patients with an IOP of 10 mmhg in comparison with on inclusion was higher in the dexamethasone 700 µg group than in the sham injection group (9.6% vs, p = 0.012). In week 26, this percentage was similar in the dexamethasone 700 µg group and in the sham injection group (1.4% vs 2.8%). The safety profile of OZURDEX in this indication is similar to that observed in the treatment of retinal vein occlusio. 10/12

11 4 TRANSPARENCY COMMITTEE CONCLUSIONS 4.1. Actual benefit Inflammation of the posterior segment of the eye linked to non-infectious uveitis and its complicatio (cystoid macular oedema, cataract, glaucoma, retinal detachment) is characterised by painful symptoms and a reduction in visual acuity, which may be abrupt and severe and may even result in blindness, leading to functional disability and a marked deterioration in the quality of life. This proprietary medicinal product is intended as symptomatic treatment. Public health benefit: The public health burden of inflammatio of the posterior segment of the eye presenting as non-infectious uveitis is low. In the absence of other alternatives with marketing authorisation in this indication and in view of the short-term data available, the proprietary medicinal product OZURDEX is expected to have a moderate impact on morbidity associated with these conditio in terms of maintaining visual acuity. In the medium to long term, OZURDEX does not seem to have an impact on visual acuity and, in the absence of any data, it is not possible to quantify its impact on quality of life. It is uncertain whether the results of these studies could be traposed to clinical practice (uncertainty about the optimal number of injectio, about repeat treatment criteria and about compliance with the injection procedure in particular). The proprietary medicinal product OZURDEX provides a partial respoe to a therapeutic need. Coequently, it is not expected that the proprietary medicinal product OZURDEX will benefit public health in this indication. The efficacy/safety ratio is high. This medicinal product is a first-line therapy. There is no treatment alternative. The actual benefit of OZURDEX 700 micrograms, intravitreal implant in applicator, is substantial in this indication Improvement in actual benefit (IAB) OZURDEX 700 µg, intravitreal implant in applicator, provides a moderate improvement in actual benefit (IAB III) in the management of adult patients with inflammation of the posterior segment of the eye presenting as non-infectious uveitis Therapeutic use The aim of the management of non-infectious uveitis of the posterior segment is to treat the inflammation, firstly at a local level to avoid the complicatio of the cystoid macular oedema type respoible for blindness, and secondly at a systemic level in patients with an underlying systemic or autoimmune disease. The usual topical treatment of non-infectious uveitis of the posterior segment normally coists of corticosteroids given in topical, periocular form or by intravitreal injection. However, these treatments do not have marketing authorisation in this indication. 11/12

12 In patients with a diagnosed systemic disease, systemic corticosteroids and immuno-suppressants can be used, with the treatment chosen according to the underlying disease. OZURDEX is the first topical corticosteroid treatment with marketing authorisation for non-infectious uveitis of the posterior segment. It is a first-line therapy Target population The target population for OZURDEX is adult patients with inflammation of the posterior segment presenting as non-infectious uveitis. When the orphan medicinal product status of OZURDEX was examined by the EMA, the prevalence of non-infectious uveitis of the posterior segment was estimated at between 0.3 and 1/10,000 inhabitants in Europe. Applying these data to the French population (French National Ititute for Demographic Studies (INED), 2011), the population of patients with this condition in France would be between 1960 and 6535 patients. Since the adult population accounts for about 75% of the French population and assuming a uniform prevalence across the different age groups, the target population for OZURDEX can be estimated to be in the range of 1470 to 4900 patients Traparency Committee recommendatio The traparency Committee recommends inclusion on the list of medicines refundable by National Health Iurance and on the list of medicines approved for hospital use and various public services in the indicatio and at the dosages given in the Marketing Authorisation. Request for a study: The Committee requests that patients treated with OZURDEX in this new indication be included in the post-inclusion study requested in 2011 in macular oedema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO), and that the following information be provided: - characteristics of the patients treated with OZURDEX - the characteristics of the prescribing doctors (type of practice, any training before use of the product, etc.) - the methods by which these patients are treated (conditio under which the procedure is performed, different treatments undertaken, number of patients undergoing repeated treatment and the interval between repeat procedures) - the adverse effects experienced by patients treated with OZURDEX, with the frequency of discontinuation of treatment and the reaso for this, - change in visual acuity and quality of life. Packaging: Appropriate for the prescription conditio. Reimbursement rate: 65% 12/12