6.1Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse reactions associated with ophthalmic steroids including ILUVIEN include cataract formation and subsequent cataract surgery, elevated intraocular pressure, which may be associated with optic nerve damage, visual acuity and field defects, secondary ocular infection from pathogens including herpes simplex, and perforation of the globe where there is thinning of the cornea or sclera.
Diabetic Macular Edema ILUVIEN was studied in two multicenter, randomized, sham-controlled, double-masked trials in which patients with diabetic macular edema (DME) were treated with either ILUVIEN (n=375) or sham (n=185). Table 1 summarizes safety data available when the last subject completed the last 36 month follow up visit for the two primary ILUVIEN trials. In these trials, subjects were eligible for retreatment no earlier than 12 months after study entry.
Over the three year follow up period, approximately 75% of the ILUVIEN treated subjects received only one ILUVIEN implant. The most common ocular (study eye) and non-ocular adverse reactions are shown in Tables 1 and 2 : Table 1: Ocular Adverse Reactions Reported by ≥1% of DME Patients and Non-ocular Adverse Reactions Reported by ≥5% of DME Patients 1 Includes cataract, cataract nuclear, cataract subcapsular, cataract cortical and cataract diabetic in patients who were phakic at baseline.
Among these patients, 80% of ILUVIEN subjects vs. 27% of sham-controlled subjects underwent cataract surgery. 2 235 of the 375 ILUVIEN subjects were phakic at baseline; 121 of 185 sham-controlled subjects were phakic at baseline. Adverse Reactions ILUVIEN (N=375) n (%) Sham (N=185) n (%) Ocular Cataract 1 192/235 2 (82%) 61/121 2 (50%) Myodesopsia 80 (21%) 17 (9%) Eye pain 57 (15%) 25 (14%) Conjunctival haemorrhage 50 (13%) 21 (11%) Posterior capsule opacification 35 (9%) 6 (3%) Eye irritation 30 (8%) 11 (6%) Vitreous detachment 26 (7%) 12 (7%) Conjunctivitis 14 (4%) 5 (3%) Corneal oedema 13 (4%) 3 (2%) Foreign body sensation in eyes 12 (3%) 4 (2%) Eye pruritus 10 (3%) 3 (2%) Ocular hyperaemia 10 (3%) 3 (2%) Optic atrophy 9 (2%) 2 (1%) Ocular discomfort 8 (2%) 1 (1%) Photophobia 7 (2%) 2 (1%) Retinal exudates 7 (2%) 0 (0%) Anterior chamber cell 6 (2%) 1 (1%) Eye discharge 6 (2%) 1 (1%) Non-ocular Anemia 40 (11%) 10 (5%) Headache 33 (9%) 11 (6%) Renal Failure 32 (9%) 10 (5%) Pneumonia 28 (7%) 8 (4%) Increased Intraocular Pressure (IOP) in DME Patients Table 2: Summary of Elevated IOP Related Adverse Reactions in DME Patients Event ILUVIEN (N=375) n (%) Sham (N=185) n (%) IOP elevation ≥ 10 mmHg from Baseline 127 (34%) 18 (10%) IOP elevation ≥ 30 mmHg 75 (20%) 8 (4%) Any IOP-lowering medication 144 (38%) 26 (14%) Any surgical intervention for elevated intraocular pressure 18 (5%) 1 (1%) Figure 1: Mean IOP in DME Patients Cataracts and Cataract Surgery in DME Patients In the DME studies at baseline, 235 of the 375 ILUVIEN subjects were phakic; 121 of 185 sham-controlled subjects were phakic.
The incidence of cataract development in patients who had a phakic study eye was higher in the ILUVIEN group (82%) compared with Sham (50%). The median time of cataract being reported as an adverse event was approximately 12 months in the ILUVIEN group and 19 months in the Sham group. Among these patients, 80% of ILUVIEN subjects vs. 27% of sham-controlled subjects underwent cataract surgery, generally within the first 18 months (Median Month 15 for both ILUVIEN group and for Sham) of the studies.
Chronic Non-Infectious Uveitis Affecting the Posterior Segment of the Eye Studies 1 and 2 were multicenter, randomized, sham injection-controlled, double-masked trials in which patients with non-infectious uveitis affecting the posterior segment of the eye were treated once with either fluocinolone acetonide intravitreal implant or sham injection, and then received standard care for the duration of the study. Study 3 was a multicenter, randomized, masked trial in which patients with non-infectious uveitis affecting the posterior segment of the eye were all treated once with fluocinolone acetonide intravitreal implant, administered by one of two different applicators, and then received standard care for the duration of the study.
Table 3 summarizes data available from studies 1, 2 and 3 through 12 months for study eyes treated with fluocinolone acetonide intravitreal implant (n=226) or sham injection (n=94). The most common ocular (study eye) and non-ocular adverse reactions in patients with non-infectious uveitis are shown in Table 3 and Table 4 . Table 3: Ocular Adverse Reactions Reported in ≥ 1% of Subject Eyes and Non-Ocular Adverse Reactions Reported in ≥ 2% of Patients with Non-Infectious Uveitis 1 Includes cataract, cataract subcapsular and lenticular opacities in study eyes that were phakic at baseline. 113 of the 226 fluocinolone acetonide study eyes were phakic at baseline; 56 of 94 sham-controlled study eyes were phakic at baseline.
Ocular ADVERSE REACTIONS Fluocinolone acetonide intravitreal implant (N=226 Eyes) n (%) Sham Injection (N=94 Eyes) n (%) Cataract 1 63/113 (56%) 13/56 (23%) Visual Acuity Reduced 33 ( 15%) 11 (12%) Macular Edema 25 ( 11%) 33 (35%) Uveitis 22 ( 10%) 33 ( 35%) Conjunctival Hemorrhage 17 ( 8%) 5 ( 5%) Eye Pain 17 ( 8%) 12 (13%) Hypotony Of Eye 16 ( 7%) 1 ( 1%) Anterior Chamber Inflammation 12 ( 5%) 6 ( 6%) Dry Eye 10 ( 4%) 3 ( 3%) Vitreous Opacities 9 ( 4%) 8 ( 9%) Conjunctivitis 9 ( 4%) 5 ( 5%) Posterior Capsule Opacification 8 ( 4%) 3 ( 3%) Ocular Hyperemia 8 ( 4%) 7 ( 7%) Vitreous Haze 7 ( 3%) 4 ( 4%) Foreign Body Sensation In Eyes 7 ( 3%) 2 ( 2%) Vitritis 6 ( 3%) 8 ( 9%) Vitreous Floaters 6 ( 3%) 5 ( 5%) Eye Pruritus 6 ( 3%) 5 ( 5%) Conjunctival Hyperemia 5 ( 2%) 2 ( 2%) Ocular Discomfort 5 ( 2%) 1 ( 1%) Macular Fibrosis 5 ( 2%) 2 ( 2%) Glaucoma 4 ( 2%) 1 ( 1%) Photopsia 4 ( 2%) 2 ( 2%) Vitreous Hemorrhage 4 ( 2%) 0 Iridocyclitis 3 ( 1%) 7 ( 7%) Eye Inflammation 3 ( 1%) 2 ( 2%) Choroiditis 3 ( 1%) 1 ( 1%) Eye Irritation 3 ( 1%) 1 ( 1%) Visual Field Defect 3 ( 1%) 0 Lacrimation Increased 3 ( 1%) 0 Non-ocular ADVERSE REACTIONS Fluocinolone acetonide intravitreal implant (N=214 Patients) n (%) Sham Injection (N=94 Patients) n (%) Nasopharyngitis 10 ( 5%) 5 ( 5%) Hypertension 6 ( 3%) 1 ( 1%) Arthralgia 5 ( 2%) 1 ( 1%) Table 4: Summary of Elevated IOP Related Adverse Reactions in Patients with Non-Infectious Uveitis ADVERSE REACTIONS Fluocinolone acetonide intravitreal implant (N=226 Eyes) n (%) Sham (N=94 Eyes) n (%) IOP elevation ≥ 10 mmHg from Baseline 50 (22%) 11 (12%) IOP elevation > 30 mmHg 28 (12%) 3 (3%) Any IOP-lowering medication 98 (43%) 39 (41%) Any surgical intervention for elevated IOP 5 (2%) 2 (2%) Figure 2: Mean IOP in Patients with Non-Infectious Uveitis iluvien-figure-1 iluvien-figure-2
