igration of inflammatory cells.
12.3 Pharmacokinetics
Plasma concentrations were obtained from 21 patients with macular edema due to branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO), and 21 patients with diabetic macular edema (DME) prior to dosing and at 4 to 5 additional post-dose timepoints on Days 1, 7, 21, 30, 45, 60, and 90 following the administration of the first intravitreal implant containing 0.7 mg dexamethasone. In RVO and DME patients, the majority of plasma dexamethasone concentrations were below the lower limit of quantitation (LLOQ = 50 pg/mL). Plasma dexamethasone concentrations from 12% of samples were above the LLOQ, ranging from 52 pg/mL to 102 pg/mL. Plasma dexamethasone concentration did not appear to be related to age, body weight, or sex of patients.
In an in vitro metabolism study, following the incubation of [14C]-dexamethasone with human cornea, iris-ciliary body, choroid, retina, vitreous humor, and sclera tissues for 18 hours, no metabolites were observed.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
No adequate studies in animals have been conducted to determine whether OZURDEX® (dexamethasone intravitreal implant) has the potential for carcinogenesis.
Although no adequate studies have been conducted to determine the mutagenic potential of OZURDEX®, dexamethasone has been shown to have no mutagenic effects in bacterial and mammalian cells in vitro or in the in vivo mouse micronucleus test.
Adequate fertility studies have not been conducted in animals.
14 CLINICAL STUDIES
Retinal Vein Occlusion
The efficacy of OZURDEX® for the treatment of macular edema following branch retinal vein occlusion (BRVO) or central retinal vein occlusion (CRVO) was assessed in two, multicenter, double-masked, randomized, parallel studies.
Following a single injection, OZURDEX® demonstrated the following clinical results for the percent of patients with ≥ 15 letters of improvement from baseline in best-corrected visual acuity (BCVA):
Table 4: Number (Percent) of Patients with ≥ 15 Letters Improvement from Baseline in BCVA
*P-values were based on the Pearson's chi-square test.
Study Day Study 1 Study 2
OZURDEX® N=201 Sham
N=202
p-value* OZURDEX® N=226 Sham
N=224
p-value*
Day 30 40 (20%) 15 (7%) < 0.01 51 (23%) 17 (8%) < 0.01
Day 60 58 (29%) 21 (10%) < 0.01 67 (30%) 27 (12%) < 0.01
Day 90 45 (22%) 25 (12%) < 0.01 48 (21%) 31 (14%) 0.039
Day 180 39 (19%) 37 (18%) 0.780 53 (24%) 38 (17%) 0.087
In each individual study and in a pooled analysis, time to achieve ≥ 15 letters (3-line) improvement in BCVA cumulative response rate curves were significantly faster with OZURDEX® compared to sham (p < 0.01), with OZURDEX® treated patients achieving a 3-line improvement in BCVA earlier than sham-treated patients.
The onset of a ≥ 15 letter (3-line) improvement in BCVA with OZURDEX® occurs within the first two months after implantation in approximately 20-30% of subjects. The duration of effect persists approximately one to three months after onset of this effect.
Posterior Segment Uveitis
The efficacy of OZURDEX® was assessed in a single, multicenter, masked, |
