Adverse reactions : תופעות לוואי

4.8   Undesirable effects

Summary of the safety profile
The 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 reactions

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 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
Uncommon            Migraine
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                Uncommon            Device dislocation* (migration of implant) with or administration site conditions                           without corneal oedema (see also section 4.4), complication of device insertion resulting in ocular tissue injury* (implant misplacement)

* indicates adverse reactions considered to be related to the intravitreal injection procedure (the frequency of these 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 frequently among patients who received >2 injections vs patients who received ≤2 injections; cataract formation (24.7% vs 17.7%), cataract progression (32.0% vs 13.1%), vitreous haemorrhage (6.0% vs 2.0%), and increased IOP (24.0% vs 16.6%).

Description of selected adverse reactions
Diabetic Macular Oedema

The 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/CRVO
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.

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
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%).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form: https://sideeffects.health.gov.il