Drug Safety Evaluation

1.

Introduction

2.

Pharmacological properties of FA and its delivery formulations

3.

Pharmacokinetic and

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pharmacodynamic properties of FA insert 4.

Sustained-release fluocinolone acetonide intravitreal insert for macular edema: clinical pharmacology and safety evaluation Mohammad Ali Sadiq, Aniruddha Agarwal, Mohamed K Soliman, Mostafa Hanout, Salman Sarwar, Diana V Do & Quan Dong Nguyen† †

Data from published and ongoing clinical trials for FAi

5.

Safety evaluation of FAi

6.

Conclusion

7.

Expert opinion

Ocular Imaging Research and Reading Center (OIRRC), Stanley M. Truhlsen Eye Institute, University of Nebraska Medical Center, Omaha, NE, USA

Introduction: Inflammation plays a key role in the pathological processes leading to macular edema. Sustained release, low-dose intraocular corticosteroid delivery devices provide long-term anti-inflammatory therapy. Recently, a novel fluocinolone acetonide intravitreal insert (FAi, Iluvien), has been introduced with promising long-term results in the treatment of macular edema. Areas covered: An extensive review of the literature in the English language was performed to provide comprehensive information on the pharmacological properties of FAi and its safety and efficacy data from various multi-center randomized clinical trials. Expert opinion: The FAc, Retisert is a sustained-release device that is surgically implanted in the vitreous and has been approved by the US FDA for the treatment of non-infectious intermediate, posterior or panuveitis. FAi was developed after FAc and is an intravitreal corticosteroid delivery system that allows controlled release of therapeutic levels of fluocinolone acetonide (FA). Initial efficacy and safety data suggest that this delivery system maintains clinical effectiveness for up to 3 years after a single delivery of the device. This second-generation fluocinolone delivery device has shown superior safety results in clinical trials compared to the previous version of the higher dose FAc (0.59 mg). Sustained delivery preparations may help to reduce the treatment burden and its associated risks by decreasing the frequency of intravitreal injections. However, much needs to be learnt from additional clinical trials, post-marketing surveillance and results of extension studies. Concerns of intravitreal corticosteroids, such as cataract and increase in intraocular pressure, remain major challenges for this therapeutic strategy. Keywords: fluocinolone acetonide, implant, intraocular injection, intravitreal steroid, macular edema, steroid, sustained release Expert Opin. Drug Saf. (2015) 14(7):1147-1156

1.

Introduction

Macular edema (ME) is a condition characterized by accumulation of extravascular fluid in the central retina secondary to a breakdown in the blood--retina barrier [1]. ME is a leading cause of visual impairment [2--4] that can be associated with a number of different disorders including diabetic retinopathy, retinal vascular occlusions, post-operative intraocular surgery and uveitis (anterior, intermediate or posterior) among others [5]. Presently, therapy for ME secondary to retinal vascular diseases such as diabetic retinopathy or retinal vein occlusion (RVO) mainly consists of 10.1517/14740338.2015.1041916 © 2015 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X All rights reserved: reproduction in whole or in part not permitted

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Box 1. Drug summary.

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Drug name (generic) Phase (for indication under discussion)

Indication (specific to discussion) Pharmacology description/mechanism of action Route of administration Chemical structure Molecular weight Pivotal trial(s)

Fluocinolone acetonide Phase II/III; FDA approved for the treatment of diabetic macular edema for patients that have been previously treated with corticosteroids and did not experience a significant rise in intraocular pressure Diabetic macular edema

Pharmacological properties of FA and its delivery formulations

2.

Fluocinolone acetonide FA is a medium potency, synthetic, fluorinated glucocorticoid that has a well-established role in suppressing inflammatory responses in the body. It has been used for the past several years as a dermal anti-inflammatory product. The chemical name for FA is (6a,11b, 16a)-6,9-difluoro-11,21-dihydroxy-16,17-[(1methylethylidene)bis-(oxy)]-pregna-1,4-diene-3,20-dione. The molecular weight of the structure is approximately 452.50 g/mol and the molecular formula is C24H30F206 [10]. The molecule occurs as an odorless, white, crystalline powder and is insoluble in water. FA has a low aqueous solubility (1/24th of dexamethasone); this particular property allows slow release of the drug over a longer period of time [11], which makes it a favorable choice for the treatment of ME. Drug safety and pharmacokinetics of FA was tested in pigmented rabbits prior to designing devices for clinical studies involving human subjects [12]. 2.1

Medium potency glucocorticoid

Intravitreal C24H30F2O6 452.49 FAME A and FAME B [26]

frequent, often monthly injections of anti- VEGF agents. Cost of 1 year of monthly ranibizumab for RVO or diabetic macular edema (DME) alone may be more than US $20,000 for a single patient [6]. Thus, economic burden of therapy combined with burgeoning disease prevalence has resulted in search for alternate, long-term therapies to effectively manage these conditions. With the increased understanding of the role of inflammation in ME, sustained-release, low-dose corticosteroid implants may be a promising viable long-term solution for patients diagnosed with ME [7]. These implants ensure constant linear, long-lasting delivery of the drug reducing the need for re-injections and therefore, the risk of ocular side effects associated with intravitreal injections [8]. Both dexamethasone and FA are available as intravitreal depot delivery systems. Dexamethasone (Ozurdex) is a 0.7 mg intravitreal implant that is inserted through a preloaded 22-gauge injector (Allergan Inc., Irvine, CA) for RVO, uveitis or DME. The fluocinolone acetonide implant (FAc) (Box 1) is a surgically implanted device that is placed near the pars plana (Bausch & Lomb, Rochester, NY), for uveitis, and FAi is a small insert that is injected using a 25-gauge system (Alimera Science, Alpharetta, GA). With its potential advantages of lower dose, smaller size and possibly fewer complications, the newer version of FA device has been employed in the treatment of various retinal pathologies, including ME. Using the FAME study DME population, analysis of healthcare and productivity costs and outcomes has been performed using a Markov model. From the study population, the mean healthcare costs were derived after accounting for costs of monitoring, lasers and caregiver expenses. Based on the treatment regimen followed in the FAME trials, it has been calculated that administration of FA implants and inserts to patients with DME may be a more cost-effective option with an incremental cost-effectiveness ratio of $38,763 for the implant [9]. Detailed cost-effectiveness analysis of dexamethasone implant is not available. Alimera Sciences has received marketing 1148

authorization of FAi for DME in more than 15 countries, spread across Europe, America and Asia at the time of this review. FAi is now commercially available in the US (Table 1). The index review focuses on clinical pharmacology of FAi and its safety profile compared to other available therapies.

2.2

FA intraocular delivery systems FA intravitreal implant

2.2.1

The FAc (Bausch & Lomb, Rochester, NY) is a non-biodegradable, 0.59 mg, sustained-release device that has been developed by Control Delivery Systems, Inc. (now pSivida Inc.). It is surgically implanted in the eye through a 3--4 mm pars plana incision after conjunctival peritomy and is designed to release the drug over a period of approximately 2.5 years [11,13]. The device is placed at the pars plana which allows the release of the drug near the ciliary processes (Figure 1). It is approved for the treatment of chronic non-infectious posterior uveitis. Studies evaluating FAc in patients with uveitis have reported improved visual acuity, reduction of inflammation and a decrease in recurrence of uveitis [14--16]. Similarly, Phase II studies evaluating FAc for treatment of DME reported improved visual and anatomic outcomes [17,18]. However, the implant has been associated with a high rate of cataract progression and elevated intraocular pressure (IOP). Due to the larger size of sclerotomy and need for wound closure, implantation of FAc may expose the patient to serious adverse events such as retinal detachment, endophthalmitis and hypotony. FA intravitreal insert The FAi (Alimera Science, Alpharetta, GA) is an injectable, non-erodible, non-biodegradable intravitreal insert that is designed to release 0.19 mg FAc for up to 36 months (releasing approximately 0.2 µg of FAc per day -- equivalent to the low-dose insert used in the two pivotal multicenter trials of 2.2.2

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Safety evaluation of FA

Table 1. Details of formulation, pharmacology and indications of intraocular sustained-release steroid implants. Fluocinolone acetonide Retisert

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Manufacturer Dimensions Release controlling matrix Procedure Technique of implantation Total dose (µg) Daily release (µg/day) Duration of action (months) Biodegradability Explantation FDA labeled indications



Iluvien

Triamcinolone acetonide



Dexamethasone

I-Vation (MK0140)*

Ozurdex Allergan, Inc. Irvine, CA

Bausch & Lomb Inc. Rochester, NY 5  2  1.5 mm Silicone/PVA

Alimera Sciences, Inc. Alpharetta, GA 3.5  0.37 mm rod Polyimide/PVA

SurModics, Inc., Eden Prairie, MN 0.4  0.21 mm helical PMMA/EVA

Operating room Surgical implantation through scleral incision 590 0.59

Out-patient clinics Injectable using 25-gauge needle 190 0.19

Operating room Out-patient clinics Scleral implantation through pars Injectable using 22-gauge plana sclerotomy needle 925 700 N/A 6.25

30

36

24

4

Non-biodegradable May be required NIPU

Non-biodegradable Not required DME

Non-biodegradable May be required Not approved by US-FDAz

Biodegradable Not required Macular edema in RVO, DME and NIPU

6.5  0.45 mm rod PLGA

*I-Vation is not available commercially; Phase III studies have not been conducted using this device. z The study was terminated before completion due to very high rate of complications. DME: Diabetic macular edema; EVA: Ethylene-vinyl acetate; NIPU: Non-infectious posterior uveitis; PLGA: Poly(lactic-co-glycolic acid); PMMA: Polymethyl methacrylate; PVA: Polyvinyl alcohol; RVO: Retinal vascular occlusion.

FAi). Each device consists of a light brown implant (3.5 mm  0.37 mm) that contains 0.19 mg of FA and the following ingredients: silicone adhesive, polyvinyl alcohol, polyimide tube and water for injection [10]. The device, which uses the MedidurTM (Alimera sciences, Inc.) technology is inserted using a 25-gauge pre-loaded injector system in a minimally invasive outpatient procedure [19]. The insertion does not require any sutures to close the wound hence can be done as an office procedure. The dimensions of FAi are smaller than the dexamethasone implant, which measures approximately 6.5  0.45 mm and is injected using a 22-gauge injection system (Figure 2). FAi has been recently approved by the US-FDA for the treatment of DME in patients who have previously been treated with corticosteroids and have not experienced a significant rise in IOP [13].

Pharmacokinetic and pharmacodynamic properties of FA insert

3.

Pharmacokinetics Data of ocular pharmacokinetics has been generated from studies of FAi in comparison to FAc [20]. Preclinical ocular pharmacokinetic studies of FA have been performed in pigmented rabbits using the FAc [21]. A 24-month repeat-dose toxicity study was performed in rabbits with FAi which demonstrated that exposure of the drug was highest in the choroid and pigmented epithelium followed by the lens or retina. No systemic effects or metabolite effects were reported in this study [22]. 3.1

The FAMOUS study was a 36-month, Phase II, pharmacokinetic, open-label study designed to assess the systemic exposure, safety and efficacy of FA after administration of FAi in patients with DME [23]. Subsequently, pharmacokinetics of FAi in 37 patients with DME enrolled in the FAMOUS study was compared to that of FAc administered in patients with uveitis [20]. Among the 37 DME patients, 20 subjects received the low dose (0.2 µg/day), and 17 subjects received the high dose (0.5 µg/day) of FAi. FA plasma concentration levels were found to be below the lower limit of quantification of the assay (100 pg/ml) at all time-points from day 1 to month 36 suggesting minimal systemic exposure. Therefore, no drug metabolism/elimination and excretion studies have been performed for FAi. For subjects receiving a single, low-dose FA insert, who were not re-treated, the highest mean level of FA occurred at week 1. The mean aqueous (aq.) FA levels in these subjects were 2.17 ± 0.93 ng/ml and 1.76 ± 0.88 ng/ml, respectively, at months 1 and 3. The mean aq. FA values were 0.70 ± 0.37 ng/ml and 0.55 ± 0.45 ng/ml, respectively, at months 12 and 36. In subjects receiving a single highdose FAi, the mean FA levels were 3.03 ± 1.60 ng/ml at month 1 and 2.15 ± 1.07 ng/ml at month 3. The mean aq. FA values were 1.33 ± 0.47 ng/ml and 0.15 ± 0.30 ng/ml, respectively, at months 12 and 36 (Figure 3) [20,23]. Study has reported that FAi inserts provide stable, longterm delivery of FA. Peak levels were achieved early on after administration of the insert, followed by a decline in the concentration over the next 3--6 months. Steady state levels were achieved between months 6 and 9 for both low-dose and high-dose inserts. Low-dose inserts had stable values until

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be used when combination intraocular therapy is planned. The drug device contains polyimide similar to an intraocular lens haptic. Hence, it is expected to remain inert inside the eye [22]. 3.3

Pharmacodynamics Glucocorticoid actions

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3.3.1

Figure 1. Ultra-wide field fundus photograph (Optos P200Tx, Scotland, UK) view of the fluocinolone acetonide implant (white asterisk) that has been surgically placed in the vitreous cavity, near the pars plana, in a patient diagnosed with non-infectious posterior uveitis.

Corticosteroids are thought to reduce retinal edema through their anti-inflammatory role. FA binds to cytosolic glucocorticoid receptor and the newly formed ligand-receptor complex translocates to the cell nucleus. This complex binds to glucocorticoid response elements in the promoter region of the DNA and causes downstream effects on protein transcription. There may be induction of lipocortin-1 synthesis along with diminished eicosanoid production and cyclooxygenase expression. Steroids are also known to inhibit several processes associated with inflammation, including but not limited to capillary dilation, edema formation, leukocyte migration, fibroblast proliferation, fibrin deposition and collagen deposition. Corticosteroids are thought to exert their antiinflammatory effect through the inhibition of phospholipase A2, an enzyme that is necessary for the production of arachidonic acid. Inhibiting this step prevents the formation of several pro-inflammatory mediators such as prostaglandins and leukotrienes [24]. Anti-VEGF actions FA may also reduce VEGF levels, hence reducing edema formation in the macula. An in vitro study with cultured retinal pigment epithelial cells treated with varying concentrations of FA, it was observed that VEGF expression was inhibited by FA by the virtue of its glucocorticoid activity [25]. Thus, FA may affect multiple downstream pathways in reducing ME in vivo, much of which needs to be still learnt. 3.3.2

Data from published and ongoing clinical trials for FAi

4.

Figure 2. Fundus photograph of the retinal periphery shows the long-acting dexamethasone implant injected in the vitreous cavity of a patient with diabetic macular edema.

month 36, whereas high-dose inserts had stable aq. values until month 24 [22]. Pharmacokinetic clearance of the drug is not known in vitrectomized eyes. Theoretically, drug clearance could be accelerated following vitrectomy; however, steady-state concentration may not be affected. The duration of action of the insert may thus be shortened. Further studies are required to clarify this possibility [22]. Drug interactions There have been no studies evaluating drug interactions with FA performed to date. Hence, precautionary measures must 3.2

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Two pivotal Phase III clinical trials, FA in DME (FAME A and B) studies have provided key efficacy data leading to the approval of the FAi by the US-FDA for this indication [26]. Nine hundred and fifty-three patients were enrolled in the FAME trials and patients were randomized into three groups with 1:2:2 ratios: sham injection, low dose (0.2 µg/day) and high dose (0.5 µg/day), respectively. At month 36, the percentage of patients who gained ‡ 15 in letters was 28.7% (low dose) and 27.8% (high dose) in the FAi groups compared with 18.9% (p = 0.018) in the sham group. Almost all phakic patients developed cataract. The incidence of incisional glaucoma surgery at month 36 was 4.8% in the lowdose group and 8.1% in the high-dose insert group. Table 2 provides safety and efficacy of various sustained delivery intravitreal steroids in DME based on Evidence level 1. Additional studies are underway that will provide safety and efficacy data of FAi in subsets of patients with ME due

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Safety evaluation of FA

9 8 7

FAC-ng/ml

6 5

FAC insert 0.2 µg/day FAC insert 0.5 µg/day

4

FAC implant

3

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2 1 0

1

3

6

9

12

15

18

21

24

30

36

Figure 3. Figure shows mean aqueous levels of fluocinolone acetonide after delivery of the fluocinolone acetonide insert at different time points as seen in the Fluocinolone Acetonide in Human Aqueous [FAMOUS] Study and fluocinolone acetonide levels after the fluocinolone acetonide implant in patients with uveitis. Patients with diabetic macular edema (DME) received either 0.2 µg/day or 0.5 µg/day fluocinolone acetonide insert. Data for the implant is available up to 18 months only, whereas the aqueous levels of the insert were measured up to 36 months. The graph has been adapted from the pharmacokinetic data obtained from subsequent analysis of subjects enrolled in the FAMOUS study and uveitis patients who underwent fluocinolone acetonide implant placement [19]. DME: Diabetic macular edema; FAc: Fluocinolone acetonide; FAMOUS: Fluocinolone acetonide in human aqueous.

to causes other than diabetes. Table 3 summarizes various ongoing clinical trials that aim to evaluate these parameters of FAi in edema of the macula secondary to various ocular pathologies. Apart from these indications, FAi is also being tested for potential applications in geographic atrophy and neovascular age-related macular degeneration. 5.

Safety evaluation of FAi

Safety data from published clinical trials and previous reports

5.1

Safety profile of the previous FA implant has been a concern in the literature due to its local ocular adverse effects. Clinical trials involving the use of FAi provide information about local ocular and systemic adverse events related to the drug delivery device. FAi is contraindicated in the presence of active or suspected intraocular or periocular infection such as viral diseases of the cornea and conjunctiva, active herpetic keratopathy, mycobacterial infections, fungal diseases and cup-to-disc ratio greater than 0.8. Previous hypersensitivity to the drug is an additional contraindication [22]. The most common ocular adverse events following FAc include progression of cataract and rise in IOP. Although very effective, the major concern with FAc (0.59 mg fluocinolone) was the requirement of cataract surgery in 91% enrolled phakic patients and glaucoma surgery in approximately 34% patients [18]. Pooled data from patients with uveitis treated with this previous version of FA device, the IOP was raised

by more than 10 mm Hg in more than 70% patients [27]. On the other hand, FAi demonstrates a superior safety profile with fewer ocular adverse events. Surgical intervention was required in approximately 8% of patients receiving highdose FAi (0.5 µg/day) and in 4.8% patients receiving lowdose FAi (0.2 µg/day) during a similar follow-up period for rise in IOP [26]. Two cases of endophthalmitis (incidence of 0.2%) were reported in the Phase III trials of FAi. The details of various reported ocular adverse events with FAi are noted in Table 4. The recommended dosage of FAi is one injection in the affected eye. Concurrent treatment of both eyes have not been studied and should be reserved until the ocular response to the first implant is established If there is clinical worsening, additional implant could be administered after 12 months from the previous implant. However, caution should be exercised when retreatment is planned because there are no human controlled studies available that describe potential benefit or risk [22]. The local ocular adverse events related to FAi are classified as minor or major in various clinical trials. Cataract formation and rise in IOP remain the major ocular side effects of the newer device [28]. Table 5 provides a list of various adverse events reported after the use of FAi. Safety in special populations Safety of FAi has been examined in special population groups, including pregnant and nursing patients, geriatric and pediatric age groups. It is expected that a local injection of FAi 5.2

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Table 2. Key safety and efficacy data of fluocinolone acetonide insert compared to other sustained delivery intravitreal steroid systems obtained from pivotal clinical trials involving human subjects (targeting DME). FAME A and B [26]

Retisert for DME [18]

MEAD [40]

Drug Study phase

Fluocinolone acetonide insert 3

Dexamethasone 3

Dose Number of subjects (safety)

0.2 µg/day 375 (safety analysis) 376 (efficacy analysis) 36 months 1.3

0.5 µg/day 393 (safety analysis) 395 (efficacy analysis) 36 months 1.4

Fluocinolone acetonide implant 2 (there has been no Phase III study of fluocinolone acetonide implant for DME) 0.59 mg 127

0.35 mg 347

0.7 mg 351

36 months 1

36 months 4.4

36 months 4.1

28.7

27.8

31

18.4

22.2

NA

NA

17%*

NA

NA

180

185

110*

107.9

111.6

Duration of study Number of treatments (mean) Efficacy data Visual acuity gain ‡ 15 letters (%) Visual acuity loss ‡ 15 letters (%) Mean decrease in central macular thickness (µm) Safety data Incidence of cataract (% of phakic eyes) Glaucoma surgery (%)

81.7 (n = 235) 88.7 (n = 265) 95

64.1 (n = 259) 67.9 (n = 265)

4.8

0.3

8.1

33

1.5

*Data estimated from published figures and previous publication [41]. DME: Diabetic macular edema; NA: Not available.

Table 3. Ongoing clinical studies evaluating fluocinolone acetonide insert for macular edema due to various causes*. Safety and efficacy Iluvien registry safety study of an injectable (IRISS) fluocinolone acetonide intravitreal insert

Iluvien in DME patients insufficiently responsive to available therapies (ILUMINATE)

Fluocinolone acetonide intravitreal inserts for vein occlusion in retina (FAVOR)

Purpose

To evaluate the safety and efficacy of FAi for noninfectious posterior uveitis

To assess the safety and efficacy of fluocinolone acetonide insert in subjects with macular edema secondary to RVO

Type Design

Interventional Prospective, doublemasked, randomized controlled June 2013 December 2013 120 800

To assess the safety and effect of fluocinolone acetonide insert in patients with DME considered insufficiently responsive to available therapies in a real life setting Open-label, non-interventional Prospective, observational

Start Date Estimated Enrollment Estimated July 2017 Completion ClinicalTrials. NCT01694186 gov Identifier Results Not available

To obtain safety and usage information on any patient treated with fluocinolone acetonide insert in European countries where marketing has been approved Open-label, registry Prospective, observational

December 2013 500

July 2013 20

December 2018

December 2016

October 2013

NCT01998412

NCT02080091

NCT00770770

Not Available

Not Available

Study ongoing, but not recruiting participants

*The table does not include studies evaluating fluocinolone acetonide insert for other indications. DME: Diabetic macular edema; RVO: Retinal vein occlusion.

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Interventional Prospective, double-masked, randomized controlled

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Safety evaluation of FA

Table 4. Ocular safety profile of intravitreal fluocinolone acetonide insert (FAi) at various time points in clinical trials involving human subjects.

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Adverse event/Intervention

Control group (sham) %

Phase II Study (12 month data) [23] -- FAMOUS Study Development/progression of cataract Cataract surgery Incisional glaucoma surgery Intraocular pressure lowering medications Phase III Study (36 month data) [26] -- FAME A and B Studies Development/progression of cataract 50.4 Cataract surgery 27.3 Elevated intraocular pressure 11.9 Incisional glaucoma surgery 0.5 Trabeculoplasty 0.0 Intraocular-pressure-lowering medications 14.1

Low-dose group (0.2 mg/day) %

High-dose group (0.5 mg/day) %

35 14 0.0 0.0

71.4 29 5.9 29.4

81.7 80.0 37.1* 4.8 1.3 38.4

88.7 87.2 45.5z 8.1 2.5 47.3

In either groups, most patients required £ 2 topical medications for the control of intraocular pressure. *In the low-dose group, 139 out of 374 developed elevated intraocular pressure regarded as an adverse event. z In the high-dose group, 179 out of 393 patients developed elevated intraocular pressure regarded as an adverse event.

Table 5. Various reported ocular adverse events following the low-dose (0.2 mg/day) intravitreal fluocinolone acetonide inserts (FAi) [22,28]. Adverse event Very common Cataract* Rise in intraocular pressurez Common Sub-conjunctival hemorrhage Local pain Myodesopia (vitreous floaters) Uncommon Eye irritation Vitreous detachment Conjunctivitis Corneal edema Foreign body sensation Retinal exudates Anterior chamber inflammation Retinal vascular occlusion [28] Maculopathy Optic nerve disorder

Incidence (%) 82 34 13 15 21 8 7 4 4 3 2 2 0.1 -- 1 0.1 -- 1 2

*Most subjects required cataract surgery 21 months after the injection of FAi. z The rise in intraocular pressure was between 2.5 -- 3 mm Hg and occurred from month 3 onwards.

should have a lesser impact on various organ systems because of undetectable levels in the blood [20]. There is limited data available for FAi in these special population groups; hence, precaution must be exercised at the time of prescription. Pregnancy Pregnancy is associated with systemic and ocular pathophysiological changes which can be often transient. Angiogenesis is central to physiological changes in pregnancy and 5.2.1

pathological pathways leading to ME [29]. ME due to various causes such as diabetes can aggravate during pregnancy [29,30]. FAi has been classified as a Category C drug for pregnancy [28]. There are no well-controlled studies of FAi in pregnant women. Pregnancy was an exclusion criterion in large multicenter clinical trials involving the use of FAi [23,26]. Pregnant animal studies have not been conducted for the safety analysis of FAi. Teratogenic potential of systemic corticosteroids have been well documented [31,32]. Current literature does not rule out any such potential adverse effects resulting from FAi. Nursing mothers Systemically administered corticosteroids can be excreted in human milk and potentially result in adverse effects in the infants [33]. Exogenous corticosteroids may interfere with the release of endogenous glucocorticoids and mineralocorticoids in the child. However, corticosteroids have been used extensively in pregnant women suffering from rheumatoid arthritis and systemic lupus erythematosus without evidence adverse events in the child [34]. The levels of FAi in human milk have not been evaluated. Hence, precautions must be exercised during treatment of ME in nursing mothers [22]. 5.2.2

Pediatric and geriatric use Safety of FAi has not been established in the pediatric age group. In studies involving the use of FAi, the mean age of study subjects has been above 60 years [23,26]. There have been no differences in the safety of FAi demonstrated in the aged population [28]. 5.2.3

Genotoxicity, carcinogenecity, phototoxicity and reproductive toxicity

5.3

Since the systemic levels of FA are undetectable following a single intravitreal injection, studies have not been performed

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to detect any gene defects, neoplastic disorders or reproductive toxicity. FA is stable on exposure to light; hence, no phototoxicity studies have been performed. In the absence of significant exposure of ultraviolet light to the FA in the vitreous, phototoxicity studies are not required [22].

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6.

Conclusion

Macular edema is a recurrent pathological entity responsible for decreased vision in a significant proportion of patients. Corticosteroid, especially when locally administered, is a promising therapy that targets various steps in the inflammatory pathway over a longer duration of time. Due to the prolonged nature of the condition, sustained-release drug delivery devices, with corticosteroids such as dexamethasone or fluocinolone, have the potential to bring a paradigm shift in the management of these patients. Higher efficacy, favorable pharmacokinetic profile with negligible systemic absorption, low risk of drug interactions with corticosteroids and reduced treatment burden make it a favored therapeutic approach. Long-term corticosteroid devices are associated with cataract and rise in IOP. Till date, there are only very few clinical trials that have established the safety and efficacy profile of FA sustained-release device. Current data suggests that the newer generation device, FAi, has shown improvements compared to the previous implant FAc. However, further studies are necessary to adequately elaborate the clinico-pharmacological and safety profile of FAi in ME due to various causes. 7.

Expert opinion

In the current review, various pharmacological characteristics of FAi have been summarized. FA is a medium potency corticosteroid that has been used in dermatological practice [35]. The insert FAi and the implant FAc, both contain FA, have demonstrated efficacy in the treatment of ocular inflammation and ME secondary to various retinal vascular diseases (Table 2). The goal of therapy in patients with ME is to attain high levels of drug in the posterior segment of the eye. Prior to the introduction of sustained-release FA, local therapy consisted of monthly intravitreal injections with triamcinolone acetonide or anti-VEGF agents. FAi offers a single, longterm drug delivery solution that may overcome the concerns and burdens associated with repeated injections. The pharmacokinetic and pharmacodynamic profile of FAi has been well established in the preclinical animal studies and the pivotal Phase III clinical trials. The mechanism of action of corticosteroids involves both inflammatory and antiangiogenic pathways, allowing its potential use in a wide spectrum of clinical diseases. The levels of the drug are below

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detectable levels in systemic circulation, alleviating the concerns for serious systemic adverse events from corticosteroids. It is necessary to obtain additional safety data of FAi in patients with diagnoses apart from DME, such as uveitis. One need to be vigilant that the safety data of FAi obtained from patients with other ocular diseases may be significantly different from that seen in DME patients. Such difference may be particularly relevant for ocular adverse events such as cataract development and rise in IOP. Patients with intravitreal steroid implants must be monitored carefully to assess their IOP and status of lens opacities. With newer drugs for ME in the pipeline, potential drug interactions with corticosteroids could be a possibility. With encouraging efficacy results in the two pivotal clinical trials of FAi, there has been a recent interest towards long-term treatment for ME rather than frequent monthly injections [26,36]. Therapeutic levels of the drug that prevent recurrent ME may also help to preserve photoreceptor function and health of retinal pigment epithelium [37]. Relative ease of injection as an office procedure, lack of need for explanation and smaller size of the device may make FAi an attractive therapeutic option. However, further data on repeated injections or multiple dosing are required to further understand the clinical utility of this therapy. Despite the concerns of cataract and glaucoma with corticosteroid therapies, these agents have been extensively used in ophthalmological practice through systemic, topical, periocular and intravitreal routes [38,39]. With increasing focus on improved visual outcome in patients with ME, there has been a change in the pattern of drug delivery designing. The strategy of FAi design has been to lower the drug concentration sufficiently to keep it just above the minimum inhibitory concentration and at the same time, ensure least collateral damage to other ocular structures. Further controlled clinical studies and post-marketing surveillance reports are required to fully understand how far we have reached in achieving this goal with FAi.

Declaration of interest QD Nguyen and DV Do serve on the scientific advisory boards for Genentech Inc. and Regeneron Inc. QD Nguyen also serves on the scientific advisory board of Bausch & Lomb Inc. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Expert Opin. Drug Saf. (2015) 14(7)

Safety evaluation of FA

Bibliography Papers of special note have been highlighted as either of interest () or of considerable interest () to readers. 1.

Ossewaarde-van Norel A, Rothova A. Clinical review: update on treatment of inflammatory macular edema. Ocul Immunol Inflamm 2011;19:75--83

2.

Shamsi HN, Masaud JS, Ghazi NG. Diabetic macular edema: New promising therapies. World J Diabetes 2013;4:324-38

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.

3.

4.

5.

Gulati N, Forooghian F, Lieberman R, et al. Vascular endothelial growth factor inhibition in uveitis: a systematic review. Br J Ophthalmol 2011;95:162-5 Glanville J, Patterson J, McCool R, et al. Efficacy and safety of widely used treatments for macular oedema secondary to retinal vein occlusion: a systematic review. BMC Ophthalmol 2014;14:7 Scholl S, Augustin A, Loewenstein A, et al. General pathophysiology of macular edema. Eur J Ophthalmol 2011;21(Suppl 6):S10-19

6.

Smiddy WE. Economic considerations of macular edema therapies. Ophthalmology 2011;118:1827-33

7.

van der Velden VH. Glucocorticoids: mechanisms of action and antiinflammatory potential in asthma. Mediators Inflamm 1998;7:229-37

8.

Cabrera M, Yeh S, Albini TA. Sustained-release corticosteroid options. J Ophthalmol 2014:164692

9.

10.

11.

12.

Cutino A, Green K, Kendall R, et al. Economic evaluation of a fluocinolone acetonide intravitreal implant for patients with DME based on the FAME study. Am J Manag Care 2015;21(4 Suppl):s63-72

device. Invest Ophthalmol Vis Sci 2000;41:3569-75 13.

pSivida Corp. Products (iluvien). Diabetic macular edema. Available from: http://www.psivida.com/products-iluvien. html [Last accessed 26 January 2015]

14.

Jaffe GJ, Martin D, Callanan D, et al. Fluocinolone acetonide implant (Retisert) for noninfectious posterior uveitis: thirty-four-week results of a multicenter randomized clinical study. Ophthalmology 2006;113:1020-7

15.

16.

17.

18.

.

Callanan DG, Jaffe GJ, Martin DF, et al. Treatment of posterior uveitis with a fluocinolone acetonide implant: threeyear clinical trial results. Arch Ophthalmol 2008;126:1191-201 Pavesio C, Zierhut M, Bairi K, et al. Evaluation of an intravitreal fluocinolone acetonide implant versus standard systemic therapy in noninfectious posterior uveitis. Ophthalmology 2010;117:567-75; 75 e1 Fluocinolone acetonide ophthalmicBausch & Lomb: fluocinolone acetonide Envision TD implant. Drugs R D 2005;6:116-19 Pearson PA, Comstock TL, Ip M, et al. Fluocinolone acetonide intravitreal implant for diabetic macular edema: a 3-year multicenter, randomized, controlled clinical trial. Ophthalmology 2011;118:1580-7 This study reports the 3-year efficacy and safety results of a Fluocinolone Acetonide implant in eyes with diabetic macular edema.

19.

Kane FE, Burdan J, Cutino A, et al. Iluvien: a new sustained delivery technology for posterior eye disease. Expert Opin Drug Deliv 2008;5:1039-46

Iluvien - highlights of prescribing information 2014. Available from: www. alimerasciences.com/wp-content/ uploads/2014/09/iluvien-prescribinginformation.pdf [Last accessed 10 December 2014]

20.

Arcinue CA, Ceron OM, Foster CS. A comparison between the fluocinolone acetonide (Retisert) and dexamethasone (Ozurdex) intravitreal implants in uveitis. J Ocul Pharmacol Ther 2013;29:501-7

..

Campochiaro PA, Nguyen QD, Hafiz G, et al. Aqueous levels of fluocinolone acetonide after administration of fluocinolone acetonide inserts or fluocinolone acetonide implants. Ophthalmology 2013;120:583-7 This study compares the aqueous levels of fluocinolone acetonide after administration of fluocinolone acetonide insert or fluocinolone acetonide implant in the eye.

Jaffe GJ, Yang CH, Guo H, et al. Safety and pharmacokinetics of an intraocular fluocinolone acetonide sustained delivery

21.

Driot JY, Novack GD, Rittenhouse KD, et al. Ocular pharmacokinetics of fluocinolone acetonide after Retisert intravitreal implantation in rabbits over a

Expert Opin. Drug Saf. (2015) 14(7)

1-year period. J Ocul Pharmacol Ther 2004;20:269-75 22.

MHRA. Public Assessment Report Decentralized procedure. Iluvien 190 micrograms intravitreal implant in injector. 2012. Available from: http://www.mhra.gov.uk/home/groups/ par/documents/websiteresources/ con171936.pdf [Last accessed 10 December 2014]

23.

Campochiaro PA, Hafiz G, Shah SM, et al. Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology 2010;117:1393-9; e3 The FAMOUS study compares two different doses of the fluocinolone acetonide insert and reports the aqueous levels and efficacy outcomes at month 12.

..

24.

Sanford M. Fluocinolone acetonide intravitreal implant (Iluvien(R)): in diabetic macular oedema. Drugs 2013;73:187-93

25.

Ayalasomayajula SP, Ashton P, Kompella UB. Fluocinolone inhibits VEGF expression via glucocorticoid receptor in human retinal pigment epithelial (ARPE-19) cells and TNF-alpha-induced angiogenesis in chick chorioallantoic membrane (CAM). J Ocul Pharmacol Ther 2009;25:97-103

26.

Campochiaro PA, Brown DM, Pearson A, et al. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology 2012;119:2125-32 The FAME study reports the long term efficacy and safety of two doses of fluocinolone acetonide insert in comparison with sham for the treatment of DME. Three-year results are discussed.

..

27.

Goldstein DA, Godfrey DG, Hall A, et al. Intraocular pressure in patients with uveitis treated with fluocinolone acetonide implants. Arch Ophthalmol 2007;125:1478-85

28.

Highlights of precribing information for Iluvien 2014. Alimera Sciences. Available from: http://www.alimerasciences.com/ wp-content/uploads/2014/09/iluvienprescribing-information.pdf [Last accessed 26 January 2015]

1155

M. A. Sadiq et al.

29.

Expert Opin. Drug Saf. Downloaded from informahealthcare.com by University of Otago on 07/05/15 For personal use only.

30.

Vestgaard M, Ringholm L, Laugesen CS, et al. Pregnancy-induced sightthreatening diabetic retinopathy in women with Type 1 diabetes. Diabet Med 2010;27:431-5

31.

Pratt RM, Kim CS, Grove RI. Role of glucocorticoids and epidermal growth factor in normal and abnormal palatal development. Curr Top Dev Biol 1984;19:81-101

32.

Piddington R, Herold R, Goldman AS. Further evidence for a role of arachidonic acid in glucocorticoid teratogenic action in the palate. Proc Soc Exp Biol Med 1983;174:336-42

33.

Petri M. Immunosuppressive drug use in pregnancy. Autoimmunity 2003;36:51-6

34.

Ramsey-Goldman R, Schilling E. Immunosuppressive drug use during pregnancy. Rheum Dis Clin North Am 1997;23:149-67

35.

Bleiberg J, Brodkin RH. Therapeutic efficacy of fluocinolone acetonide ointment and cream. Arch Dermatol 1964;89:561

36.

1156

vitreous implants: long-term benefit in patients with chronic diabetic macular edema. Ophthalmology 2014;121:1892-903

Pescosolido N, Campagna O, Barbato A. Diabetic retinopathy and pregnancy. Int Ophthalmol 2014;34(4):989-97

Cunha-Vaz J, Ashton P, Iezzi R, et al. Sustained delivery fluocinolone acetonide

37.

Lardenoye CW, Probst K, DeLint PJ, et al. Photoreceptor function in eyes with macular edema. Invest Ophthalmol Vis Sci 2000;41:4048-53

38.

Al Dhibi HA, Arevalo JF. Clinical trials on corticosteroids for diabetic macular edema. World J Diabetes 2013;4:295-302

39.

Ozdek S, Deren YT, Gurelik G, et al. Posterior subtenon triamcinolone, intravitreal triamcinolone and grid laser photocoagulation for the treatment of macular edema in branch retinal vein occlusion. Ophthalmic Res 2008;40:26-31

40.

Boyer DS, Yoon YH, Belfort R Jr, et al. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology 2014;121:1904-14

41.

Messenger WB, Beardsley RM, Flaxel CJ. Fluocinolone acetonide intravitreal implant for the treatment of diabetic macular edema. Drug Des Devel Ther 2013;7:425-34

Expert Opin. Drug Saf. (2015) 14(7)

Affiliation Mohammad Ali Sadiq1 MD, Aniruddha Agarwal1 MD, Mohamed K Soliman1 MD, Mostafa Hanout1 MD, Salman Sarwar1 MD, Diana V Do2 MD & Quan Dong Nguyen†3 MD MSc † Author for correspondence 1 Post Doctoral Research Fellow, University of Nebraska Medical Center, Stanley M. Truhlsen Eye Institute, Ocular Imaging Research and Reading Center (OIRRC), Omaha, NE 68198-5540, USA 2 Associate Professor, University of Nebraska Medical Center, Stanley M. Truhlsen Eye Institute, Ocular Imaging Research and Reading Center (OIRRC), Omaha, NE 68198-5540, USA 3 Professor and Chairman, University of Nebraska Medical Center, Stanley M. Truhlsen Eye Institute, Ocular Imaging Research and Reading Center (OIRRC), 985540 Nebraska Medical Center, Omaha, NE 68198-5540, USA Tel: +1 402 559 4276; Fax: +1 402 559-5514; E-mail: [email protected]

Sustained-release fluocinolone acetonide intravitreal insert for macular edema: clinical pharmacology and safety evaluation.

Inflammation plays a key role in the pathological processes leading to macular edema. Sustained release, low-dose intraocular corticosteroid delivery ...
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