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Triamcinolone Acetonide for the Treatment of Diabetic Macular Oedema


However, a substantial group of patients are unresponsive to laser therapy and fail to improve after photocoagulation. It has been reported that three years after initial grid treatment visual acuity improved in 14.5 % of eyes, did not change in 60.9 % and decreased in 24.6 % of patients with DMO.26


Therefore, TA has been tested for the


treatment of DMO, either naïve or diffuse and refractory to laser therapy. In most cases, TA has been administered intravitreally. However, other delivery routes have been tested, such as sub-Tenon, juxtascleral and sub-conjuntival administration. The current commercial preparations of TA include products that received dermatologic and orthopaedic indications and are considered off-label for the intraocular use, products registered as devices for assisting the visualisation of the vitreous during vitreoretinal procedures and products that are registered for intraocular use in uveitis and other ocular inflammatory conditions. Kenalog-40 (40 mg/ml, Bristol-Myers Squibb, NJ) is the most common intraocular steroid and has been widely used as intravitreal injections since 2004 for the treatment of several retinal diseases. This formulation is US Food and Drug Administration (FDA)-approved only for intramuscular and intra-articular use and is currently employed off-label for intraocular injections. Trivaris™ (80 mg/ml, Allergan Inc., Irvine, CA) and Triesence® (40 mg/ml, Alcon Inc., Fort Worth, TX) are preservative-free brands of TA recently FDA approved for ophthalmic use in the treatment of sympathetic ophthalmia, temporal arteritis, uveitis and other ocular inflammatory diseases unresponsive to topical corticosteroids. Vitreal S (Sooft s.p.a., Fermo, Italy) is a medical device used in endocular surgery to stain the vitreous during vitrectomy and it is not registered as drug for intraocular use. There are some issues regarding the formulation of TA used for intraocular administration. A previous phase-contrast microscopy study showed a notable difference of crystal size depending upon the drug formulation.27


Very large and irregular crystals, with a significant heterogeneity in crystal size, were occasionally found in the off-label commercially available, benzyl-alcohol-preserved TA, whereas the crystals of a preservative-free in-label commercially available TA suspension appeared to be relatively uniform in size. These morphologic aspects may have a significant impact on the half-life of the drug both in vivo and in vitro. This hypothesis is based on the fact that smaller crystals have a superior surface-area-to-volume ratio, allowing them to be dissolved more rapidly. The formulations containing crystals that widely vary in size and, thus, including larger crystals may theoretically generate a wider time–drug concentration curve because of their slower dissolution rate.27–29


In the DRCR.net study, 840 study eyes with DMO were randomised to either focal or grid laser photocoagulation (n=330), 1 mg TA (n=256) or 4 mg TA (n=254). At year three, the mean change in the visual acuity from baseline was +5 letters in the laser group and 0 letters in both the TA groups. For the three two-group comparisons, mean difference adjusted for baseline visual acuity and prior macular photocoagulation and 95 % confidence interval (CI) were as follows: +5.6 (95 % CI, +0.8 to +10.4) for laser versus 1 mg TA groups; +4.7 (95 % CI, 0.0 to +9.5) for laser versus 4 mg TA groups; and -0.8 (95 % CI, -6.0 to +4.3) for 1 mg TA versus 4 mg TA groups. A worsening of visual acuity of three or more lines occurred in 8 %, 17 % and 16% of eyes, respectively, and an improvement in visual acuity by


A carefully designed prospective randomised trial conducted by the Diabetic Retinopathy Clinical Research Network (DRCR.net) investigated the efficacy and safety of 1 mg and 4 mg doses of preservative-free intravitreal TA in comparison with focal or grid laser photocoagulation.30


EUROPEAN ENDOCRINOLOGY


three or more lines occurred in 26 %, 20 % and 21 % of eyes, respectively. Mean (±SD) reductions in central macular thickness were 175 ± 149 μm in the laser group, 124 ± 184 μm in the 1 mg TA group and 126 ± 159 μm in the 4 mg TA group. The mean number of treatments at the end of the follow-up was 3.1 for the laser group, 4.2 for the 1 mg and 4.1 for the 4 mg TA groups. At the four-month visit, mean visual acuity improvement was higher in the 4 mg TA group (4 ± 12 letters improvement) than in either the laser group (0 ± 13 letters change) or the 1 mg TA group (0 ± 13 letters change). By 12 months, there were no significant differences among groups in mean visual acuity. Therefore, in this study, photocoagulation was shown to be more effective over time and had fewer side effects than TA. This was considered in support of focal/grid photocoagulation. However, it must be noted that during the 36 months of follow-up, patients received only four treatments with intravitreal TA, which is a low reinjection rate based on common experience and pharmacokinetic (PK) data. Recently, a new, large, randomised DRCR.net study investigated the efficacy of intravitreal TA in combination with laser photocoagulation in comparison with intravitreal ranibizumab with prompt or deferred laser photocoagulation or laser photocoagulation alone. At two-year visit, compared with the sham + prompt laser group, the mean change in the visual acuity letter score from baseline was 3.7 letters greater in the ranibizumab + prompt laser group (p=0.03), 5.8 letters greater in the ranibizumab + deferred laser group (p<0.01) and 1.5 letters worse in the TA + prompt laser group (p=0.35). A worsening of visual acuity of three or more lines occurred in 10 %, 4 %, 2 % and 13 % of eyes, respectively, and an improvement in visual acuity by three or more lines occurred in 18 %, 29 %, 28 % and 22 % of eyes, respectively. Compared with the sham + prompt laser group, the mean change in central macular thickness from baseline was 31 μm worse in the ranibizumab + prompt laser group (p=0.03), 28 μm worse in the ranibizumab + deferred laser group (p=0.01) and 10 μm worse in the TA + prompt laser group (p=0.37). These results showed that intravitreal ranibizumab with prompt or deferred laser is more effective than prompt laser alone or intravitreal TA combined with laser for the treatment of diabetic macular oedema involving the central macula. Among the eyes that were pseudophakic at baseline, the mean change in visual acuity letter score from baseline to the two-year visit was 1.6 letters greater in the TA + prompt laser group compared with the sham + prompt laser group and was similar to difference in outcomes between the ranibizumab + prompt laser group (+0.5 letters) and the ranibizumab + deferred laser group (+3.5 letters) compared with the sham + prompt laser group. Cataract surgery was required in 12 % of phakic eyes in the sham + prompt laser and in the ranibizumab + prompt laser groups, in 13 % of phakic eyes in the ranibizumab + deferred laser group and in 55 % of patients of the TA + laser group. An intraocular pressure (IOP)-lowering medication was required in 5 % of eyes in the sham + prompt laser and ranibizumab + prompt laser groups, in 3 % of eyes in the ranibizumab + deferred laser group and in 28 % of patients of the TA + laser group.31


Other studies


demonstrated promising results of combination therapy with intravitreal injection of TA and laser photocoagulation for the treatment of proliferative diabetic retinopathy (PDR) with clinically significant macular oedema (CSMO).32–36


In a 12-month randomised


clinical trial conducted by Maia et al., 44 eyes with PDR and CSMO were enrolled and randomised to treatment with combined 4 mg of intravitreal TA and laser photocoagulation (n=22) or to laser photocoagulation alone (n=22). Mean best corrected visual acuity (BCVA) improved significantly (p<0.001) in the TA and laser group


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