Others and Fluocinolone, Dexamethasone, Triamcinolone, chapCorticosteroids:• 30

Table 30.1  Relative anti-inflammatory strength of various corticosteroids

CH3 CH3

F

O

Figure 30.3  Dexamethasone. The molecular weight for dexamethasone is 392.47 Da. It is designated chemically as 9-fluoro-11b,17,21-trihydroxy-16α-methylpregna-1,4-diene-3,20- dione. The empirical formula is C22H29FO5.

The prolonged duration of action of triamcinolone acetonide is due to the fact that it is an insoluble form and therefore, it acts as a depot injection when injected into a sequestered body cavity such as in the vitreous.

The relative anti-inflammatory strength of various corticosteroids is as given in Table 30.1.16

METABOLISM

In ophthalmic practice triamcinolone acetonide is used in its injectable form. The biologic half-life of parenterally administered triamcinolone acetonide is 18–36 hours. The most commonly used intravitreal dosages include 4 and 20 mg. Serum levels after intravitreal injection of triamcinolone acetonide 20–25 mg are mostly undetectable.

Clearance of intravitreal triamcinolone acetonide in a rabbit model showed that normal eyes had the longest retention of 41 days. Eyes that were post vitrectomy cleared the steroid in an average of 17 days. Eyes that were post lensectomy and vitrectomy cleared the steroid fastest, in an average 6.5 days.17

Beer and colleagues18 examined the pharmacokinetics of triamcinolone acetonide after a 4-mg intravitreal injection for macular edema in nonvitrectomized eyes. The mean elimination half-life was 18.6 days, suggesting that triamcinolone acetonide would be present in measurable concentrations in nonvitrectomized eyes for approximately 3 months. The peak aqueous humor concentration ranged from 2.15 to 7.20 µg/ml.

Dexamethasone

The molecular weight for dexamethasone (Figure 30.3) is 392.47 Da. It is designated chemically as 9-fluoro-11b,17,21-trihydroxy-16α- methylpregna-1,4-diene-3,20-dione. The empirical formula is C22H29FO5.

The plasma half-life of parenterally administered dexamethasone is 3–4 hours. The intravitreal dose is typically 350–400 µg.

O

F H

Figure 30.4  Fluocinolone acetonide has an empirical formula of C24H30F2O6 and a molecular weight of 452.49 Da.

Fluocinolone

Fluocinolone acetonide (Figure 30.4) has an empirical formula of C24H30F2O6 and a molecular weight of 452.49 Da. In a study of pigmented rabbits, 0.59 mg fluocinolone acetonide intravitreal implant (Retisert) was inserted and the vitreous concentration of the drug was determined at various time points. The concentration of fluocinolone acetonide19 was found to be relatively constant from the first time point, 2 hours, through 1 year. Concentrations of fluocinolone acetonide were generally higher in the vitreous (11–18 ng/g) and retina (42–87 ng/g) than in the aqueous humor (0.21–1.1 ng/g). Urine and plasma values were below the lower limit of quantitation (200 pg/ml) for all observations.

USAGE OF STEROIDS IN

OCULAR DISEASES

CYSTOID MACULAR EDEMA

Intravitreal injection of triamcinolone acetonide for refractory cystoid macular edema after cataract extraction improves visual acuity and central macular thickness (CMT) by optical coherence tomography (OCT).20 The doses used have ranged from 1 to 25 mg. However, the effects may be transient and patients may require reinjection, typically after 4 months.21

DIABETIC MACULAR EDEMA

Intravitreal triamcinolone acetonide is a useful treatment modality for diabetic macular edema. However, the high risk of secondary glaucoma and cataract has made it somewhat less popular, especially with the advent of anti-VEGF agents. Pharmacologic attenuation of the effects of VEGF is one of the rationales for the use of corticosteroids in the treatment of macular edema associated with diabetic retinopathy. Corticosteroids, a class of substances with anti-inflammatory properties, have been demonstrated to inhibit the expression of the VEGF gene. Initial studies focused on the use of corticosteroids for macular edema that failed to respond to conventional laser photocoagulation.10,11,22 More recent studies have included using triamcinolone acetonide as primary therapy.23

Martidis et al.11 studied 16 eyes with clinically significant diabetic macular edema that failed to respond to at least two previous sessions of laser photocoagulation and observed a decrease in the CMT by OCT24 of 55%, 57.5%, and 38%, at the 1-, 3-, and 6-month follow-up intervals after a 0.1-ml intravitreal injection of 4 mg triamcinolone acetonide. Intravitreal triamcinolone acetonide was effective in improving vision, reducing macular thickness, and inducing reabsorption of hard exudates in diffuse diabetic macular edema.

However, there can be recurrence of macular edema once the effect of triamcinolone wanes. Reports of time to recurrence range from 8 to 36 weeks.23,25

Audren et al.25 studied diffuse diabetic macular edema refractory to laser photocoagulation in 17 patients. Each patient had bilateral disease so one eye received a single 4-mg injection of triamcinolone acetonide and the second eye was used as control. The main outcome measure was CMT measured by OCT (preinjection, 4, 12, and 24 weeks). The mean CMT prior to injection was 566.4 in injected eyes. The mean CMT at follow-up week 24 was 358.5. The measured outcome, ETDRS vision, was significantly improved at all visits.

In another prospective, placebo-controlled, randomized, interventional study which included 40 eyes (38 patients) with diabetic macular edema, 28 (70%) eyes were randomized to treatment and 12 (30%) eyes randomized to receive a placebo injection. The treatment group received an intravitreal injection of approximately 20 mg triamcinolone acetonide. Visual acuity increased significantly in the study group by 3.4 lines. Difference in change of best visual acuity was significant (P < 0.001) between both groups. At 6 months after baseline, 11 (11/23; 48%) eyes and 9 (9/23; 39%) eyes, respectively, improved by at least 2 and 3 lines, respectively, in the study group, versus 0 (0%) eyes improved in the control group.26

The results of a large, multicenter, randomized controlled study comparing triamcinolone acetonide and laser photocoagulation for diabetic macular edema has recently been published by the Diabetic Retinopathy Clinical Research network (DRCRnet). The study showed that, over a 2-year period, focal/grid laser photocoagulation was more effective and had fewer adverse effects than preservative-free intravitreal triamcinolone.27 The study enrolled 840 eyes (693 subjects) at 88 clinical sites. Patients were randomized in a 1 : 1 : 1 ratio into one of three treatment groups: laser (n = 330); intravitreal triamcinolone acetonide 1 mg (n = 256); and intravitreal triamcinolone acetonide 4 mg (n = 254). Patients were retreated every 4 months as needed and followed for 2 years. Initially, groups treated with intravitreal triamcinolone acetonide, particularly the 4-mg group, appeared to have better visual outcomes at 4 (statistically significant) and 8 months (no longer statistically significant), but by 1 year there were no differences between groups. By 16 months onward, laser was statistically superior to 4 mg intravitreal triamcinolone acetonide in terms of visual outcomes. At the primary endpoint of 2 years, eyes treated with laser had a mean best corrected visual acuity (BCVA) improvement of 1 letter, whereas eyes treated with 1 mg intravitreal triamcinolone acetonide had a mean vision loss of 2 letters and eyes treated with 4 mg intravitreal triamcinolone acetonide had a mean loss of 3 letters. Decreases in macular thickness as assessed by OCT thickness followed this same pattern, with a mean decrease in central foveal subfield thickness at 2 years of 139 m in the laser group, 86 m in the 1-mg intravitreal triamcinolone acetonide group, and 77 m in the 4-mg intravitreal triamcinolone acetonide group. Additionally, the incidence of cataracts and increased intraocular pressure (IOP) was significantly greater in the intravitreal triamcinolone acetonide groups than in the laser groups. By 2 years, the percentage of eyes with increase of at least 10 mmHg from baseline was 4% in the laser group, 16% in the 1-mg intravitreal triamcinolone acetonide group, and 33% in the 4-mg intravitreal triamcinolone acetonide group. Cataract extraction was performed by 2 years in 13% of the eyes in the laser group, 23% of eyes in the 1-mg intravitreal triamcinolone acetonide group, and 51% of eyes in the 4-mg intravitreal triamcinolone acetonide group.

RETINAL VEIN OCCLUSION

Intravitreal triamcinolone acetonide has been shown to improve visual acuity, reduce angiographic leakage, and decrease CMT in the management of persistent macular edema as a result of nonischemic central retinal vein occlusion (CRVO).

Park et al.28 studied 10 eyes of 9 patients with perfused CRVO with visual acuity of 20/50 or worse. Triamcinolone acetonide (4 mg in 0.1 ml) was injected intravitreally. The study outcomes included measuring BCVA, IOP, fluorescein angiography, and OCT. The mean dura-

tion from the time of diagnosis to the intravitreal injection was 15.4 months. The study demonstrated biomicroscopic improvement in cystoid macular edema in all 10 eyes with corresponding improvement in volumetric OCT measurements from a mean of 4.2 mm3 preinjection to a mean of 2.6 mm3 at last follow-up (P < 0.001). In addition, the mean BCVA improved from 58 letters (range, 37–72) at baseline to 78 letters (range, 50–100 letters) at last follow-up (average, 4.8 months, P = 0.01). Three eyes (30%) without previous history of glaucoma required initiation of topical aqueous suppressant therapy for IOP elevation at last follow-up and one eye with a previous history of open-angle glaucoma required a trabeculectomy.

Ip et al.29 studied 13 eyes with macular edema associated with CRVO treated with an injection of intravitreal triamcinolone acetonide (4 mg). They found that eyes with nonischemic CRVO (n = 5) demonstrated a significant improvement in visual acuity, whereas eyes with ischemic CRVO (n = 8) demonstrated a nonsignificant visual acuity improvement. During the follow-up no patient had a decrease in visual acuity. OCT analysis showed mean baseline foveal thickness of 590 m. At the 6-month follow-up examination, mean foveal thickness as measured by OCT for 13 patients was 281 m. Four patients developed a recurrence of macular edema between months 4 and 6 of follow-up. Three of the 4 patients were retreated with a second injection of triamcinolone acetonide and 2 of these patients experienced an improvement in visual acuity following retreatment.

Bashshur et al.30 studied 20 patients with a 3–4-month history of persistent macular edema resulting from CRVO. According to the authors, 75% of patients treated with intravitreal triamcinolone acetonide (4 mg) had complete resolution of macular edema on clinical exam using Goldmann contact lens at 10–12 months of follow-up. In addition, at the final follow-up examination the treated group had a mean visual acuity of 20/37 versus 20/110 in the observation group.

A study assessing the Ozurdex implant for the treatment of retinal vein occlusion was recently completed (ClinicalTrials.gov identifier NCT00168298). The primary efficacy endpoint of the study was visual acuity at 6 months with safety and secondary efficacy endpoints out to 12 months. The exact number of patients enrolled has not been announced. Patients were randomly assigned to observation, 350 g Ozurdex, or 700 g Ozurdex in a 1 : 1 : 1 allocation. Allergan recently completed the initial analysis of data for this trial, but to date has only released the following top-line data from the Allergan website, accessed March 22, 2009:

Patients receiving either the 350 microgram or the 700 microgram dose of OZURDEX® had a statistically significant increase in vision based on a 3-line or better improvement in visual acuity compared to a sham treatment. In addition, both doses of OzURDEX® were well tolerated in the studies. Less than 7% of patients receiving 700 or 350 micrograms of OzURDEX® experienced an elevation of intraocular pressure (IOP) greater than

35 mmHg at any time during the 6 month study, and at 6 months less than 1% of patients had an IOP above

25 mmHg. In the fourth quarter, Allergan completed filing the last module of its new drug application (NDA) with the US Food and Drug Administration (FDA) for the approval of OzURDEX® to treat macular edema associated with RVO.

The Standard of Care vs. Corticosteroid for Retinal Vein Occlusion (SCORE) study – the National Eye Institute-sponsored study of triamcinolone for macular edema secondary to central or branch retinal vein occlusion (BRVO) – will be discussed later in the chapter.

EXUDATIVE AGE-RELATED MACULAR DEGENERATION (AMD)

The antiangiogenic property of triamcinolone acetonide has been studied in the treatment of exudative AMD.31,32 Various uncontrolled studies have been conducted.

Diseases Retinal in Mechanisms and Drugs • 4 section

Others and Fluocinolone, Dexamethasone, Triamcinolone, chapCorticosteroids:• 30

In a prospective, comparative nonrandomized clinical interventional study by Jonas et al., all patients had shown an increase or stabilization of visual acuity after a first intravitreal injection of 25 mg triamcinolone acetonide.32 In the study, the mean visual acuity increased significantly (P = 0.005 and P = 0.003, respectively) from 0.17 to 0.32 and from 0.15 to 0.23, respectively, after the first and second injections. An increase in visual acuity was found for 10 patients (77%) after the first and second injections. In the control group, visual acuity did not vary significantly during follow-up (P = 0.81). The peak in visual acuity and, in a chronologically parallel manner, the peak in IOP elevation occurred 2–5 months after each injection.

In another study, 67 patients (71 eyes) who presented with exudative AMD of predominantly or total occult type (n = 68) or classic type (n = 3) received intravitreal injection of 25 mg crystalline triamcinolone acetonide. Visual acuity increased significantly (P < 0.001) from 0.16 to a mean maximum of 0.23. Postinjection visual acuity was highest 1–3 months after the injection. Forty-seven (66.2%) eyes gained in maximal visual acuity and 11 (15.5%) eyes lost in visual acuity. IOP increased significantly (P < 0.001) from 15.1 mmHg at baseline to a maximal value of 23.0 mmHg. Owing to a decrease in visual acuity after an initial increase, 6 patients received a second intravitreal triamcinolone acetonide injection, after which visual acuity increased again in three eyes.33

A randomized clinical trial of a single injection of 4 mg triamcinolone acetonide was performed in 27 patients followed up for 6 months. The study by Danis et al.14 included exudative AMD with subfoveal or occult CNV, and visual acuity between 20/40 and 20/400. Visual acuity was significantly better in the treated group compared with control subjects at both 3 and 6 months (P < 0.005). IOP elevation was seen in 25% of treated patients, but was controlled with topical medications. Progression of cataract was more frequently seen in the treated group.

A double-masked, placebo-controlled, randomized clinical trial was performed by Gillies et al.34 on patients with CNV for less than 1 year, and a visual acuity of 20/200 or better. A single 4-mg intravitreal injection was administered. A total of 151 eyes were randomized into the study, and follow-up data were obtained for 73 (97%) of the 75 eyes in the treated group and for 70 (92%) of the 76 eyes in the control group. Using severe vision loss (30 letters) as the main outcome measure, Gillies et al. found that there was no difference between the two groups during the first year of the study. In addition, although the change in size of the neovascular membranes was significantly less in eyes receiving triamcinolone acetonide than in those receiving placebo 3 months after treatment (P = 0.01), no difference was noted after 12 months. After 12 months, treated eyes had a significantly higher risk of an elevated IOP determined by increase of 5 mmHg or more (31/75 (41%) versus 3/76 (4%); P < 0.001), but not of cataract progression (P = 0.29).34 Currently, corticosteroids have a very limited primary role in the management of neovascular AMD. Prior to the advent of anti-VEGF agents for neovascular AMD, intravitreal triamcinolone was frequently used in combination with photodynamic therapy (PDT) for the treatment of CNV associated with AMD.35–38 More recently, Augustin and others39,40 have proposed the use of intravitreal dexamethasone in combination with PDT and anti-VEGF therapy to provide so-called “triple therapy” for CNV/AMD. Additionally, studies looking at steroid-based drug delivery implants such as Ozurdex in combination with anti-VEGF therapy are under way. However, steroids as sole therapy for CNV/ AMD are not currently considered a viable option.

COMPLICATIONS OF OCULAR

STEROID THERAPY

The common adverse effects of ocular steroid therapy are glaucoma and cataract.41–43 Additionally, given that the commonly used formulation of triamcinolone acetonide, Kenalog, is not formulated for the eye, there is a known risk of pseudoendophthalmitis and a hypothethical potential for clinical retinal toxicity from the vehicle when injected intravitreally.44–46 There have been reports of toxicity of triamcinolone acetonide on retinal pigment epithelial cells in vitro47,48 whereas ex vivo49 and in vivo50 studies have failed to show any significant toxicity on the retina. Triamcinolone acetonide also causes phototoxicity of erythro-

cytes in vitro and may also have weak photosensitizing properties in vivo.19

Raised intraocular pressure

Corticosteroid-induced IOP elevation is a common occurrence that resembles open-angle glaucoma. Patient selection is an important factor when considering the possibility of steroid-induced glaucoma, especially in the setting of a long-acting steroid such as triamcinolone acetonide. A history of chronic open-angle glaucoma or family history of glaucoma is a significant risk factor for the development of steroidinduced elevation of IOP. Other patients at risk for developing steroidinduced IOP elevation are high myopes, diabetics, and patients with connective tissue diseases.51,52

Elevated IOP in association with intravitreal triamcinolone acetonide has been reported in several recent studies.53 One study reported an increase in IOP to over 21 mmHg in 52% of eyes 2 months after a 25-mg injection.41 However, two other studies of 4-mg injections showed similar incidences of IOP increase over different time periods. One study by Bakri and Beer retrospectively reviewed cases receiving a single dosage of 4 mg. Their study showed over a 4-week period an incidence of 48.8% of eyes demonstrating an IOP increase of 5 mmHg or greater, and 27.9% showing an increase in IOP of 10 mmHg or greater at a mean time of 6.6 weeks. The study concluded with a followup time of 12 weeks.43

The second study by Smithen and colleagues followed patients for a mean of 40 weeks and defined a pressure elevation as an IOP of 24 mmHg or greater. In this study, 40.6% of eyes experienced a pressure elevation at a mean time of 14 weeks with the longest duration of pressure elevation present at 42 weeks. In nonglaucomatous patients with a baseline IOP of 15 mmHg or greater, 60% experienced a pressure elevation compared to only 22.7% of patients with baseline pressures below 15 mmHg. Pressure elevation in both studies was controllable with topical glaucoma medications. In rare instances surgical glaucoma intervention has been necessary with vitrectomy to remove the residual triamcinolone acetonide for intractable cases or glaucoma fistulization procedure.54

The increase in IOP following intravitreal steroid injection is higher than those reported for topical and posterior sub-Tenon steroids. In a retrospective study of 202 consecutive posterior sub-Tenon steroid injections in 63 eyes of 55 patients, the highest reported IOP was 27 mmHg.55 That study showed no statistical difference between preand postinjection IOP measurements. Anterior sub-Tenon steroids are much more likely to increase IOP and cases have been reported necessitating surgical removal of the steroid depot secondary to intractable IOP elevation.

Infectious, sterile, and pseudoendophthalmitis associated with triamcinolone acetonide

Infectious, sterile, and pseudoendophthalmitis may all be seen following intravitreal triamcinolone acetonide. Two specific areas of concern after intravitreal triamcinolone acetonide are the potential for decreased local immunity induced by the corticosteroid that may increase infection risk and the anti-inflammatory action of the steroid masking the symptoms of endophthalmitis.

Moshfeghi and coworkers reported a retrospective multicenter study in which 8 of 922 eyes (0.87%) developed infectious endophthalmitis following intravitreal triamcinolone acetonide. The median time of diagnosis was 7.5 days postinjection. All 8 patients presented with iritis, vitritis, and hypopyon. Five of the 8 experienced decreased vision as an initial complaint. One eye had no culture growth but demonstrated intracellular Gram-positive cocci with polymorphonuclear cells on Gram stain. The remaining cases were culture-positive with coagulasenegative staphylococcus (n = 2), Streptobacillus parasanguis (n = 2),

Mycobacterium chelonae (n = 1), Streptobacillus species (n = 1) and

Streptobacillus intermedius (n = 1). Despite aggressive intervention with vitreal tap and injection of antibiotics (6 of 8 patients) or pars plana vitrectomy with intravitreal antibiotics (2 of 8 patients), 3 patients