Physicians now have the option of the Food and Drug Administration (FDA)-approved sustained-release corticosteroid implants Iluvien (Alimera Sciences), which releases small doses of fluocinolone acetonide over a period of 3 years, and Ozurdex (Allergan), an extended release dose of dexamethasone that releases over 3 to 4 months.¹ The FAME Study, consisting of two 3-year, phase 3 pivotal clinical trials (Trial A and Trial B) to assess the safety and efficacy of Iluvien for diabetic macular edema (DME), showed 28.7% of patients receiving the 0.2-µg daily dose experienced ≥15-letter vision gain at 24 months, which was maintained over 36 months.² The MEAD study of Ozurdex showed 22.2% and 18.4% of patients had ≥15-letter improvement in best corrected visual acuity over 3 years with a 0.7-mg and 0.35-mg implant, respectively.³ I use both the 0.7-mg Ozurdex implant and the Iluvien implant in my treatment of DME. This article focuses on my approach to using Iluvien specifically.

The Iluvien injectable intravitreal implant contains 0.19 mg of fluocinolone acetonide. Composed of an inert, nonbiodegradable, polyimide material common in intraocular lenses, the implant is a tiny cylindrical tube 3.5 mm in length and 0.37 mm in diameter. It is injected into the vitreous using a 25-gauge proprietary insertion device that creates a self-sealing wound. The drug is then delivered through slow sustained release, coined “continuous microdosing,” over a 36-month period.⁴

MYTHS AND MISCONCEPTIONS

There are misconceptions regarding the use of Iluvien for DME, many of which may be unfounded. One misconception is that physicians will no longer need to regularly see Iluvien-treated patients. This is false. Iluvien treatment offers the patient the chance for fewer injections and fewer visits to the retina specialist, but patients will still require regular follow-up exams at least quarterly to monitor intraocular pressure (IOP). Regular follow-up visits ensure the physician’s ability to monitor the patient’s progress.

Unless pseudophakic, patients also should be monitored for cataract progression. The Iluvien clinical trials showed that roughly 80% of patients receiving the drug delivery system required cataract surgery over a 3-year period.^2,5 Physicians also may erroneously believe that patients treated with Iluvien will develop glaucoma. This is deceiving because, while patients may develop ocular hypertension, this is not glaucoma. In clinical trials,^2,5 Iluvien patients demonstrated similar IOP responses to those treated with other ophthalmic steroids, such as intravitreal triamcinolone acetonide and Ozurdex. Only 38% of Iuvien-treated patients developed elevated IOP, indicating that most treated patients did not. In comparison, 36% to 42% of patients treated with other ophthalmic steroids also required medication to manage IOP.^6,7 Elevated IOP is a drug-class side effect for all corticosteroids. Further, most of the corticosteroid-treated patients with elevated IOP could be managed successfully with topical medications, including patients treated with Iluvien. In the FDA clinical trials, 5% of Iluvien patients required IOP-lowering surgery.^2,5 This compares favorably to other studies in which 1% to 7% of patients treated with other corticosteroids required incisional IOP-lowering surgery.^6,7 Because prior treatment with a corticosteroid and absence of a clinically significant rise in IOP is now required by the Iluvien FDA label, proper patient screening can mitigate the risk of elevated IOP requiring surgical intervention when using Iluvien.

Elevated IOP is not glaucoma. Glaucoma is a disease characterized by high IOP, subsequent damage to the optic nerve, and, finally, loss of peripheral vision gradually over time. It is unlikely that patients who are being monitored closely by a physician, even with a corticosteroid-induced elevated IOP, will develop glaucoma if managed appropriately. For those who do develop glaucoma, it can be treated. The FDA label has mitigated the risk of elevated IOP with Iluvien, and consequently Iluvien could be considered one of the safer steroid options for our patients.

All treatment decisions weigh risks and benefits. Iluvien treatment is well characterized, and the known risk of elevated IOP may be justified to treat DME. At the end of the day, we are trying to preserve vision.

Another related myth is that fluocinolone acetonide implants are for late-stage patients for whom nothing else has worked. On the contrary, this implant is effective in a variety of patients, particularly those whose inflammation is incited by multiple cytokines, not just VEGF. In a subgroup analysis of the FDA phase 3 pivotal clinical trials, patients with both short- and long-term DME experienced improvement.^2,5

In my own clinical experience, patients who failed anti-VEGF therapy but did well with shorter-acting intravitreal corticosteroid injections like triamcinolone acetonide or dexamethasone have been the best candidates for Iluvien. It may be beneficial to introduce Iluvien earlier into the management of patients with DME, because the extended-release platform significantly reduces the treatment burden.

PATIENT SELECTION AND PROFILING

Ideal Iluvien patients have a proven response to a corticosteroid treatment with improvement in their DME and without a significant rise in IOP. The definition of significant rise in IOP is left to the discretion of the physician.

Other patient selection criteria include a few contraindications and warnings. Iluvien is contraindicated for glaucoma patients with a cup-to-disc ratio greater than 0.8. It is also contraindicated in patients with active or suspected ocular or periocular infections. These could include, but are not limited to, a history of a viral retinitis that might be reactivated by corticosteroids and most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases. It is also contraindicated for patients with hypersensitivity to any of the components within the product.

While not a contraindication, caution also should be taken in patients in whom the posterior capsule of the lens is absent or has a tear, though this does not apply to people who have had YAG laser capsulotomy. An opening in the posterior capsule could allow the implant to migrate into the anterior chamber.

As with any intravitreal injection, care should be taken to avoid endophthalmitis, inflammation, increased IOP, and retinal detachments. Patients also should be monitored following the injection because corticosteroids may boost the establishment of secondary ocular infections due to bacteria, fungi, or viruses. Patients with a history of ocular herpes simplex should not be exposed to corticosteroids to avoid latent reactivation of the viral infection.

After consideration of these warnings and contraindications, physicians select ideal candidates for Iluvien based on their discretion. The FDA regulates drugs and devices, but doctors practice medicine. My preference is to require patients to have prior exposure to intravitreal corticosteroids. I may accept topical exposure to products such as Pred Forte drops (prednisolone acetate ophthalmic suspension; Allergan) or Durezol drops (difluprednate ophthalmic emulsion; Alcon). However, with topical medications, is it difficult to ensure patient compliance. Therefore, I find testing for an IOP response with intravitreal corticosteroids to be the most reliable.

Patients who have a history of clinically significant IOP in response to corticosteroid therapy should be treated with caution. However, this is where the art of medicine comes in. Every physician will have a different definition for “a clinically significant rise in IOP.” It is a judgment call that requires knowledge of a patient’s cup-to-disk ratio and other risk factors for glaucoma. If a patient does have a pressure rise that requires a topical drop, this is not an absolute contraindication for eventually receiving Iluvien for DME. In the FAME A and FAME B clinical trials,^2,5 patients with an increase in IOP were generally well managed on topical drops. This is a manageable side effect.

It is important to inform patients that ideally they will only need one implant. However, we know from real-world clinical practice that diabetes is a difficult disease to treat and that there may be some breakthrough DME over time. Patients should continue to be monitored for recurrences of DME that may require “booster shots” of either an anti-VEGF agent or a corticosteroid in the future.

I do not have any requirements for a diabetes patient’s A₁c to be under control or stabilized prior to injection, because we are typically not dealing with complications from what their diabetes is at the time of DME treatment. We are usually dealing with complications of what their diabetes was 3 or more years ago. I do, however, educate patients on the benefits of long-term blood glucose control.

INCORPORATING ILUVIEN INTO YOUR PRACTICE

When a patient with DME presents to my practice, I begin by giving the patient 3 to 4 anti-VEGF injections to test for adequate response. If the patient responds well, that patient stays on the anti-VEGF agent. If there is only a partial response and I am not satisfied with the results, I will switch to a corticosteroid, typically intravitreal Ozurdex, although intravitreal Triesence (triamcinolone acetonide; Alcon) is also an option. If that patient does not develop an elevated IOP, both the patient and I are happy with the anatomical and visual response to the corticosteroid, and the patient demonstrates continued need for corticosteroid treatment, I will then recommend Iluvien.

My personal treatment protocol for DME allows ample time to provide informed consent about Iluvien to patients who may benefit from long-term delivery of a corticosteroid. This also provides my office staff sufficient time to obtain preapproval for Iluvien before the patient returns. As we already have all prior treatments leading up to the need for Iluvien in our electronic documents, we have never run into any problems obtaining preapproval, nor have we ever been required to provide additional documentation. Once the preapproval is in place, my technician will then order the drug. We do not keep Iluvien in stock; we order it for each patient as needed.

Two concerns I overcame while incorporating Iluvien into my practice were the fear that it would not be reimbursed and the fear that it might not be cost effective. These fears have been alleviated. Iluvien now has a J code. Because Iluvien injection is never an urgent or emergent procedure, there is always time to plan for an Iluvien injection at least 2 weeks in advance, thus allowing your office staff sufficient time to obtain precertification.

Iluvien has proven cost effective. It is meant for patients who respond to corticosteroids. Compared with an injection such as Ozurdex, for example, which must be administered every 3 to 4 months for most DME patients, Iluvien is one injection that lasts for 3 years. The cost of Ozurdex at the end of 3 years generally exceeds that of the Iluvien injection, making Iluvien a cost-effective treatment by comparison. This cost comparison obviously excludes any “booster” shots that might infrequently be needed during Iluvien therapy.

PEARLS FOR INJECTING ILUVIEN

I always begin with a subconjunctival lidocaine injection and let it sit for approximately 5 minutes. I then sterilize the area and deliver the injection. This is done in a similar manner to other injections, though the insertion device is a bit different. The device requires a gliding motion to push the drug implant into the eye. I stand 180° away (on the opposite side of the eye from where I am injecting) so I can better visualize the implant entering the eye. Tilting the needle anteriorly in a pseudophakic patient helps the physician to better see the implant actually enter the eye. Afterward, I view with posterior segment with indirect ophthalmoscopy to ensure proper delivery. Patients tolerate the procedure very well.

CONCLUSION

The benefits presented by sustained-release corticosteroid delivery are indisputable. The holy grail for managing many of our patients who require frequent injections is long-term drug delivery. Iluvien has solved that problem in the corticosteroid class of agents for treating DME. While risks and benefits must always be weighed, overall the long-term fluocinolone acetonide implants are a valuable option for the treatment of DME. RP

REFERENCES

1. Edelman JL. Differentiating intraocular glucocorticoids. Ophthalmologica. 2010;224(suppl 1):225-230.
2. Campochiaro PA, Brown DM, Pearson A, et al; FAME Study Group. Sustained delivery fluocinolone acetonide vitreous inserts provide benefit for at least 3 years in patients with diabetic macular edema. Ophthalmology. 2012;119(10):2125-2132.
3. Boyer DS, Yoon YH, Belfort R Jr, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014;121(10):1904-1914.
4. Campochiaro PA, Nguyen QD, Hafiz G, et al; FAMOUS Study Group. Aqueous levels of fluocinolone acetonide after administration of fluocinolone acetonide inserts or fluocinolone acetonide implants. Ophthalmology. 2013;120(3):583-587.
5. Campochiaro PA, Hafiz G, Shah SM, et al. Sustained ocular delivery of fluocinolone acetonide by an intravitreal insert. Ophthalmology. 2010;117(7):1393-1399.e3.
6. Razeghinejad MR, Katz LJ. Steroid-induced iatrogenic glaucoma. Ophthalmic Res. 2012;47(2):66-80.
7. Jonas JB, Degenring RF, Kreissig I, Akkoyun I, Kamppeter BA. Intraocular pressure elevation after intravitreal triamcinolone acetonide injection. Ophthalmology. 2005;112(4):593-598.