Fluocinolone Acetonide (Iluvien, Yutiq)

Key points at a glance

Key points of this drug

• Fluocinolone acetonide (FA) is a sustained-release steroid implant placed in the vitreous cavity.
• Iluvien (0.19 mg) is indicated for diabetic macular edema (DME), and Yutiq (0.18 mg) for non-infectious posterior uveitis (NIU-PS).
• It releases 0.25 µg per day for 36 months, significantly reducing treatment burden by eliminating the need for frequent injections. ²⁾
• In the FAME trial (Phase III), at 24 months, visual improvement of 15 or more ETDRS letters was significantly better in the low-dose group (28.7%) compared to the sham group (16.2%).
• Main side effects are cataract (80% of phakic eyes) and increased intraocular pressure. This treatment is indicated for DME patients who did not have increased intraocular pressure with previous steroids. ⁶⁾
• Off-label use has also been reported for Irvine-Gass syndrome (post-cataract surgery CME) and serpiginous choroiditis. ²⁾⁵⁾

1. What is fluocinolone acetonide?

Fluocinolone acetonide (FA) is a type of synthetic corticosteroid. In ophthalmology, it is used as a sustained-release implant placed intravitreally.

There are currently three FDA-approved formulations. Iluvien and Yutiq are both made of non-biodegradable polyimide tubes, with the same size of 3.5 mm in length and 0.37 mm in diameter. ¹⁾ They can be administered by intravitreal injection, differing from Retisert which requires surgical implantation.

Iluvien

Content: 0.19 mg

Indication: Diabetic Macular Edema (DME)

Year of Approval: 2014 (FDA)

Administration: Intravitreal injection

Yutiq

Content: 0.18 mg

Indication: Non-infectious posterior uveitis

Year of approval: 2018 (FDA)

Administration: Intravitreal injection

Retisert

Content: 0.59 mg

Indication: Non-infectious posterior uveitis

Year of approval: 2005 (FDA)

Administration: Surgical implantation

The implant maintains an initial release rate of 0.25 µg per day and provides sustained drug delivery for 36 months. ²⁾Iluvien is indicated only for DME patients who have had prior steroid treatment without elevated intraocular pressure. ⁶⁾

Q What is the difference between Iluvien and Yutiq?

A

The drug content is nearly identical (Iluvien 0.19 mg, Yutiq 0.18 mg), and the physical structure of the device is the same. ¹⁾The approved indications differ: Iluvien is used for diabetic macular edema, while Yutiq is used for non-infectious posterior uveitis. ⁴⁾

2. Indications and Target Patients

FDA-Approved Indications

Iluvien (Diabetic Macular Edema): For patients with diabetic macular edema who have previously received steroid treatment and did not experience increased intraocular pressure. ⁶⁾ Anti-VEGF therapy is generally the first-line treatment, and FA implants are positioned as a subsequent option.

Yutiq (NIU-PS): Indicated for patients with chronic non-infectious intermediate, posterior, or panuveitis. ⁴⁾ Its usefulness has been reported in recurrent and refractory cases.

Off-Label Use

Irvine-Gass Syndrome (Pseudophakic Cystoid Macular Edema): Cystoid macular edema occurring after cataract surgery, with an incidence of 0.1–2.0%. ²⁾ FA implants are used in cases resistant to anti-inflammatory treatment.

Kiernan (2024) reported two cases of FA implant for persistent postoperative cystoid macular edema. ²⁾ In case 1, central foveal thickness (CST) improved from 668 µm to 292 µm (56.2% reduction), and visual acuity improved from 20/70 to 20/25 (15-month follow-up). In case 2, CST improved from 450 µm to 293 µm (38.4% reduction), and visual acuity improved from 20/80 to 20/25 (6 weeks).

Marques et al. (2021) reported a 36-month follow-up of 5 eyes in 3 patients, showing sustained reduction in central macular thickness (CMT). ³⁾ 80% of eyes had increased intraocular pressure, but all were manageable with eye drops.

Serpiginous choroiditis: One case intolerant to 7 years of systemic immunosuppressive therapy received Yutiq, with no recurrence reported for 20 months after administration. ⁵⁾

Recurrent bilateral NIU-PS: In a case of bilateral non-infectious posterior uveitis treated with Yutiq, best-corrected visual acuity improved from 20/80 to 20/50 in the right eye and from 20/70 to 20/40 in the left eye. ⁴⁾

Contraindications

Do not administer to the following patients.

• Active infection of the eye or surrounding area
• Glaucoma with a cup-to-disc ratio (C/D ratio) exceeding 0.8
• Hypersensitivity to any drug component
• Patients with posterior capsule defects or damage (risk of migration into the anterior chamber) ⁶⁾

Q Can Iluvien be used for all patients with diabetic macular edema?

A

Iluvien is not indicated for all types of diabetic macular edema. It is limited to patients who have not experienced an increase in intraocular pressure with prior steroid treatment. ⁶⁾ For first-line treatment of diabetic macular edema, anti-VEGF agents are typically used.

3. Pharmacological Action and Mechanism of Action

FA has the common anti-inflammatory mechanism of steroids and maintains a stable drug concentration in the vitreous as a sustained-release implant.

• Phospholipase A2 inhibition: Blocks the release of arachidonic acid, broadly suppressing the production of prostaglandins and leukotrienes. Reduces edema by blocking the upstream of the inflammatory cascade.
• Stabilization of the blood-retinal barrier: Strengthens tight junction structures and reduces vascular permeability via adenosine signaling.
• Suppression of anti-inflammatory mediators: Broadly inhibits the production of cytokines and inflammatory proteins.

FA has higher potency than dexamethasone, while allowing administration at lower doses than Retisert (0.59 mg), balancing high potency maintenance and reduced side effects. ⁴⁾

Short-acting steroids (e.g., triamcinolone) lose their effect within 90–140 days. ²⁾In contrast, the FA implant provides stable low-dose delivery for 36 months, suppressing inflammation recurrence. ²⁾

Anti-inflammatory effect

Phospholipase A2 inhibition: Blocks PG and LT production upstream

Inflammatory mediator inhibition: Suppresses broad cytokine production

Edema reduction: Cuts off the inflammatory cascade at its root

Stabilization of the blood-retinal barrier

Tight junction enhancement: Strengthens barrier structures

Decreased vascular permeability: Regulated by adenosine signaling

Sustained release: Maintains stable drug efficacy for 36 months

Advantages of sustained-release implants

Fluocinolone acetonide implant continuously releases a constant amount of drug for 36 months. This eliminates the need for frequent intravitreal injections, significantly reducing hospital visits and treatment burden. ²⁾

4. Clinical trials

FAME Trial (Phase III, Diabetic Macular Edema)

A sham-controlled, double-blind RCT involving 953 patients was conducted with a 1:2:2 allocation ratio for sham, low-dose (0.2 µg/day), and high-dose (0.5 µg/day) groups. ⁷⁾

Key results at 24 months are shown below. ⁶⁾⁷⁾

Item	Low-dose group	Sham group
Improvement of 15 letters or more	28.7%	16.2%
Cataract surgery rate	80.0%	27.3%
Glaucoma surgery rate	4.8%	0.5%

At 3 years, 75% of patients maintained effect with a single implant. ⁶⁾

PALADIN Trial (Phase IV, Diabetic Macular Edema)

An open-label trial of 95 patients (115 eyes). At 36 months of follow-up, the following results were obtained. ⁶⁾

• Foveal retinal thickness improvement: -60.69 µm (P<0.0001)
• Best-corrected visual acuity improvement: +3.61 letters (P=0.0222)
• Reduction in treatment burden: Laser treatment reduced by 55%, anti-VEGF injections by 36%, steroid injections by 78% (all P<0.0001)
• Intraocular pressure management: Incidence of IOP>30 mmHg 10.89%, glaucoma surgery rate 1.49%

In the PALADIN trial, anti-VEGF injections decreased by 36% and steroid injections by 78% before and after implant, confirming a significant reduction in treatment burden. ⁶⁾

Yutiq Phase 3 Trial (NIU-PS)

The results of the 36-month follow-up are shown below. ²⁾

• Resolution of cystoid macular edema without recurrence: 34.5% vs sham group 2.4%
• Improvement in best-corrected visual acuity of 15 or more letters: 33.3% vs 14.7%
• Rate of intraocular pressure-lowering surgery: 5.7% vs sham group 11.9%

Q How long does the effect last?

A

The implant releases the drug for 36 months. In the FAME study, 75% of patients maintained the effect with a single implant at 3 years. ⁶⁾ The PALADIN study also confirmed sustained improvement in best-corrected visual acuity at 36 months. ⁶⁾

5. Administration and Dosage

Injection Technique

Administration is performed as an outpatient intravitreal injection. Hospitalization is not required. The key steps are as follows:

• Insertion site: Insert at a point 4 mm from the corneal limbus on the inferotemporal side
• Conjunctival management: Displace the conjunctiva so that it does not overlap the puncture site
• Ideal placement: The implant should ideally be positioned inferior to the optic disc and posterior to the equator
• Position confirmation: After injection, confirm the placement of the implant using an indirect ophthalmoscope.

Dosage and Release Profile

• Iluvien: Contains 0.19 mg FA. Initial release rate 0.25 µg per day.
• Yutiq: Contains 0.18 mg FA. Similar release profile.
• Duration: 36 months.

Precautions for Administration

• Monitoring for increased intraocular pressure is essential. Before administration, confirm that there was no increase in intraocular pressure with previous steroids. ⁶⁾
• Patients with posterior capsule defects or rupture are at risk of intraocular migration. ⁶⁾
• After administration, watch for signs of endophthalmitis (eye pain, sudden vision loss, redness).
• In phakic patients, the risk of cataract progression should be explained in advance. ⁶⁾

6. Safety and Side Effects

Incidence of Major Side Effects

The incidence of major side effects is shown below. ⁶⁾

Side effect	Incidence	Management
Cataract (phakic eye)	80.0%	Cataract surgery
IOP>30 mmHg	10.89%	Eye drops
Glaucoma surgery	1.49–4.8%	Incisional surgery

Details of Each Side Effect

Cataract: In the FAME study, the cataract surgery rate in phakic eyes was 80.0% (vs. sham 27.3%), which is high. ⁶⁾ Adequate explanation to the patient is required before administration.

Elevated intraocular pressure: In the PALADIN study, IOP >30 mmHg was recorded in 10.89% of cases. ⁶⁾ Most cases are manageable with eye drops. The glaucoma surgery rate in the FAME study was 4.8% (vs. 0.5% in sham), and in the PALADIN study it was 1.49%. ⁶⁾

Implant dislocation: In patients with posterior capsule defects or zonular rupture, there is a risk of dislocation into the anterior chamber. Surgical removal is required if dislocation into the anterior chamber occurs. ⁶⁾

Implant removal: Indications for removal include uncontrolled intraocular pressure elevation, endophthalmitis, iatrogenic subretinal injection, and implant migration. ¹⁾ A non-invasive extraction method using suction via the pressure difference in the vitreous cavity by opening the valve of a 25-gauge cannula has been reported. ¹⁾

If implant removal is necessary, it can be extracted by opening the valve of a 25-gauge cannula and using the pressure difference within the vitreous cavity in a non-invasive procedure. ¹⁾

In off-label use (Irvine-Gass cases), intraocular pressure elevation was observed in 4 out of 5 eyes (80%), but all were manageable with eye drops. ³⁾

Q What is the risk of cataracts or glaucoma?

A

In phakic eyes, 80% require cataract surgery (FAME study). ⁶⁾ The glaucoma surgery rate was 4.8% in the FAME study and 1.49% in the PALADIN study. ⁶⁾ Considering these risks, treatment is limited to patients who have not experienced intraocular pressure elevation with previous steroids.

7. Latest Research and Future Prospects

For Patients: Please Read Carefully

The following information is currently under research or based on limited reports and is not standard treatment available at general hospitals. It is reference information for professionals regarding future medical developments. Please consult your doctor for actual medical care.

Ongoing and Planned Clinical Trials

NEW DAY Trial: A study directly comparing Iluvien vs. aflibercept (anti-VEGF agent) in treatment-naïve DME patients is ongoing, with results expected in 2025.

Expanding Evidence

Network meta-analysis: Yutiq has shown comparable efficacy to Ozurdex (dexamethasone implant) at 6 months and is reported to rank higher in long-term evaluations. ⁴⁾

Anti-VEGF-refractory diabetic macular edema: The use of sustained-release steroids is being considered for DME cases that do not respond adequately to anti-VEGF therapy. ⁶⁾

Reports of Off-Label Indications

Multiple case reports have shown its use in Irvine-Gass syndrome (pseudophakic cystoid macular edema), ²⁾³⁾ and it is attracting attention as a useful option in refractory and recurrent postoperative cystoid macular edema. Long-term efficacy in serpiginous choroiditis intolerant to systemic immunosuppressive therapy has also been reported in one case. ⁵⁾

Advances in Implant Removal Techniques

Development of minimally invasive techniques for removal of unnecessary or migrated implants is progressing. ¹⁾ Extraction using a 25-gauge cannula utilizing vitreous cavity pressure difference is considered a promising technique that minimizes incisions.

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8. References

1. Valikodath N, Vajzovic L. Fluocinolone acetonide implant removal from the vitreous cavity. J Vitreoretinal Dis. 2023;7(6):533-535.
2. Kiernan DF. Sustained-release low-dose fluocinolone acetonide intravitreal implant for chronic postoperative cystoid macular edema. Retinal Cases Brief Rep. 2024;18:421-427.
3. Marques JH, Abreu AC, Silva N, et al. Fluocinolone acetonide 0.19 mg implant in patients with cystoid macular edema due to Irvine-Gass syndrome. Int Med Case Rep J. 2021;14:127-132.
4. Babel AT, Chin EK, Almeida DRP. Long-acting fluocinolone acetonide intravitreal implant for recurrent bilateral non-infectious posterior uveitis. Int Med Case Rep J. 2022;15:665-669.
5. Siddiqui Y, Adams OE, Simmons MA, et al. Sustained control of serpiginous choroiditis with the fluocinolone acetonide 0.18 mg intravitreal implant. Case Rep Ophthalmol Med. 2022;2022:3962221.
6. American Academy of Ophthalmology. Diabetic Retinopathy Preferred Practice Pattern. Ophthalmology. 2024.
7. Flaxel CJ, Adelman RA, Bailey ST, et al. Diabetic retinopathy preferred practice pattern. Ophthalmology. 2024;131(1):P99-P168.