6 ADVERSE REACTIONS

6.1 Clinical 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
Cataract1	192/2352 (82%)	61/1212 (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

iluvien-figure-1

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 (%)
Cataract1	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-2

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of ILUVIEN. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency or establish a causal relationship to drug exposure. These reactions include reports of drug administration error and reports of the drug being ineffective.