Continuing Education Activity

Intravitreal implants are controlled drug delivery systems that are an emerging field in treating intraocular inflammation and other posterior segment diseases needing chronic therapy. They have the advantage of targeted delivery of high drug concentrations to the posterior segment for a prolonged period. This activity reviews the various types of intravitreal implants, their indications and contraindications, the technique of implantation, the possible complications, and the role of the interprofessional team in management and follow-up.

Objectives:

• Describe the different types of intravitreal implants currently available and elaborate on their mechanism of action and possible complications.
• Review the indications for each implant and identify the situations where they might be contraindicated.
• Identify the techniques of implantation of the intravitreal implants along with the choice of anesthesia and instrumentation needed.
• Explain the role of ancillary investigations and follow-up for intravitreal implants.

Introduction

The intravitreal route is the main route of drug administration to treat diseases affecting the posterior segment of the eye. Intravitreal implants are specially designed to release drugs in a controlled manner over a longer duration. It helps to directly deliver the drug to the vitreous, thus overcoming systemic pathways and obtaining a high drug concentration in the vitreous chamber.[1]

Intravitreal implants can either be non-biodegradable (NBI) or bio-degradable (BI). NBIs are longer lasting as they can achieve near zero-order release kinetics. Since they are non-degradable, they need surgical removal or replacement. They are larger in size; hence, a larger incision is required for implantation. They are made up of ethylene vinyl acetate (EVA), polyvinyl alcohol (PVA), or polysulfone capillary fiber (PCF).

Examples of the available NBIs are Vitrasert and Retisert. BIs have the advantage of not requiring surgical removal or replacement as they degrade and disintegrate over time, thus eliminating all components from the body. They are made of polylactic acid (PLA), polyglycolic acid (PGA), PLGA, or polycaprolactones. An example of the available BI is a steroid implant containing dexamethasone called DEX Implant (Ozurdex).[2][3]

Anatomy and Physiology

The blood-ocular barrier comprises two systems: the blood-aqueous and the blood-retinal. The blood-retinal barrier is further divided into inner and outer barriers. The inner blood-retinal barrier comprises tight junctions between the retinal endothelial cells, and the outer blood-retinal barrier is the retinal pigment epithelium.

These barriers significantly restrict the extent of drugs reaching the posterior segment of the eye. Direct intravitreal injections into the vitreous help to achieve greater drug concentrations in the retina and vitreous with limited systemic side effects. However, they must be repeated frequently to maintain an effective therapeutic level of the drug since they have a short half-life. The solution to this problem is met by intravitreal implants, which help with sustained drug delivery to the posterior segment for a longer duration.[4]

Indications

The available intravitreal implants and their indications are listed:

Non-biodegradable Intravitreal Implants

1. Ganciclovir

Vitrasert (Bausch and Lomb, Rochester, USA)

Vitrasert is an intravitreal sustained-release implant consisting of an active agent, 4.5mg ganciclovir, and an inactive agent, 0.25% magnesium stearate.[2] It was the first NBI that the FDA approved in 1996 for treating cytomegalovirus retinitis. It releases ganciclovir at the rate of 1mcg/hour for a period of 5 to 8 months.[5] It is made of a discontinuous hydrophobic ethylene vinyl acetate (EVA) film surrounded by outer and inner permeable PVA layers.[3] 

The EVA helps in limiting the surface area of ganciclovir. The device works by allowing diffusion of fluid inside it, leading to the dissolution of the drug pellet, which then releases the drug into the vitreous cavity at a constant rate.[6] It’s found to control inflammation, reduce recurrences in patients with viral retinitis, and improve visual acuity.[7]

Indication: Acquired immune deficiency (AIDS) virus-associated cytomegalovirus (CMV) retinitis.[5]

Fluocinolone Acetonide

Retisert (Bausch & Lomb, Rochester, NY)

Retisert is an intravitreal NBI of a corticosteroid, fluocinolone acetonide (FA), which the FDA approved in 2005 for treating chronic non-infectious uveitis.[8][9] It consists of a small reservoir, 5*2 mm in size with 0.59 mg of FA coated with PVA and silicone laminates, and it delivers approximately 0.6 µg of drug per day into the vitreous cavity. It lasts up to 3 years. A 2.1 mg implant is also available.[10]

Indications: Chronic non-infectious posterior uveitis (NIPU) is the main indication, but it is also effective in diabetic macular edema (DME) and macular edema (ME) secondary to central retinal vein occlusion (RVO).[11][12]

Iluvein (Alimera Sciences Inc., Alpharetta, GA)

Iluvein is another intravitreal NBI of FA, cylindrically shaped with a composition similar to Retisert. It is the smallest NBI measuring 3.5 mm in length and 0.37 mm in width. One end of the cylindrical tube is coated with PVA, and the opposite end is coated with a silicone adhesive that delivers FA to the retina. It releases FA at the rate of 0.2 mcg (low dose insert) or 0.5 mcg/day (high dose insert) and lasts up to 3 years.[2]

Indication: DME - It is being evaluated in phase 2 trials for dry AMD, retinal vein occlusion, and non-infectious uveitis.[13][14]

Yutiq (EyePoint Pharmaceuticals, Inc., MA, USA)

Yutiq is another intravitreal NBI of FA which received FDA approval in 2018. It is similar to Iluvein but contains 0.18 mg FA and releases FA at the rate of 0.25 µg/day for three years. 

Indication: Chronic NIPU.[15]

Triamcinolone Acetonide

I-vation (SurModics, Eden Prairie, MN)

I-vation is a helically shaped implant containing a titanium PVA-EVA reservoir that contains 0.925 mcg of triamcinolone acetonide (TA), a steroid. The helical shape serves to anchor the implant to the sclera and increase the surface area for delivery of the drug, thus favoring enhanced drug diffusion. It measures 0.4 mm in length and 0.21 mm in width and is coated with polybutyl methacrylate and polyEVA. It lasts for up to 2 years. 

Indication: DME.[2][3]

Ranibizumab Port Delivery System (PDS) 

The PDS is a new intraocular drug delivery system for continuously delivering an anti-vascular endothelial growth factor (VEGF) antibody, ranibizumab. It is non-biodegradable, permanent, and refillable. It is made up of an ocular implant and four ancillary devices that are used for initially filling ranibizumab, for surgical implantation, for refill exchange, and for explanation. It has an extra-scleral flange that helps anchor it to the sclera, a silicon self-sealing septum that allows refilling, an implant body with the drug reservoir, and a titanium release control element that helps in titrating the ranibizumab diffusion into the vitreous. Its capacity is approximately 20 µl. It releases a minimum of 2.3 µg/day for six months.

Indication: Neovascular AMD (nAMD).[3][16]

Biodegradable Intravitreal Implants

Dexamethasone

DEX implant (Ozurdex, Allergan Inc., Irvine, CA, United States)

DEX implant is biocompatible and biodegradable. It contains 0.7 mg dexamethasone, which is released sustainably in the vitreous. It received FDA approval in June 2009 for treating retinal vein occlusion-associated macular edema and in 2010 for treating non-infectious posterior uveitis. It is a rod-shaped pellet measuring 6.5* 0.45 mm in size and contains a mixture of dexamethasone with a biodegradable PLGA polymer matrix and utilizes Allergan’s NO-VADUR technology, which degrades it to lactic and glycolic acid slowly. This allows for a prolonged release of the dexamethasone for up to 6 months.[3][14]

Indications: The main indications are RVO (central and branch) associated with ME, DME, and NIPU. It also has off-label use in Irvine Gass syndrome, nAMD, vasoproliferative retinal tumors, retinal telangiectasia, Coats’ disease, radiation maculopathy, retinitis pigmentosa, macular edema secondary to scleral buckle and pars plana vitrectomy.[17]

Verisome (Ramscor, Inc., Menlo Park, CA)

It is a long-acting intravitreal injectable drug delivery system for different drugs, including steroids, non-steroidal anti-inflammatory drugs (NSAID), and anti-VEGF. Verisome with TA provides a mean vitreous level of 1.1 mcg/ml and lasts up to 1 year. 

Indication: Verisome with TA: Chronic cystoid macular edema (CME) due to RVO, Verisome with ranibizumab: nAMD.[3] 

Table 1: Common Indications and the Appropriate Intravitreal Implants

Contraindications

Vitrasert is contraindicated in patients with ocular surface infection, in combination with intravenous cidofovir, presence of retinal tear or detachment, and allergic reactions to acyclovir or ganciclovir.[23]

Intravitreal implants with steroids are contraindicated in patients with hypersensitivity or active ocular or periocular infections (viral, mycobacterial, fungal) and glaucoma patients with a cup disk ratio >0.8. DEX implant is additionally contraindicated in patients with torn posterior capsules, in aphakic eyes, or those with anterior chamber or scleral fixated intraocular lenses due to the risk of migration of the implant into the anterior chamber.[24][25]

Ranibizumab PDS is contraindicated in patients with ocular or periocular infections, active intraocular inflammation, hypersensitive reactions to ranibizumab, patients with a recent history of stroke or myocardial infarction, and pregnancy and should be used with caution in patients with end-stage kidney disease or those on dialysis.[16][26]

Equipment

Informed consent should be taken before the procedure. The procedure can be office-based with all aseptic protocols, but a longer procedure may require an operation theatre setting.   

Standard aseptic protocols are to be followed, including hand disinfection, sterile gloves, using a sterile eyelid speculum, and topical microbicidal solution in the eye.[27]

The instruments vary depending on the type of intravitreal implantation; sterile drape, drape scissors, eyelid speculum, calipers, toothed forceps, sterile cotton buds, sterile syringes and needles, sclerotomy cannulas with infusion cannula, blade for scleral incision and suture materials may be required.

Technique or Treatment

Time out is done to confirm the eye and the correct implant and its expiration date.

• The patient should be placed in a comfortable, supine position with the head kept stable.
• The choice of anesthesia depends on the type of implant; larger implants may require local or general anesthesia. For smaller-sized implants, topical anesthesia is suitable. A few surgeons also prefer subconjunctival anesthesia.
• Povidone iodine is used to clean and sterilize the lids, lashes, and surrounding eyes.
• Topical proparacaine hydrochloride drops of 0.5% are applied for topical anesthesia.
• 5% povidone-iodine drops are also instilled in the inferior cul de sac of the conjunctiva.
• A sterile eyelid speculum is inserted in the eye.
• The location of the injection site is marked with calipers depending upon the phakic status: Phakic: 3.5 to 4 mm, Pseudophakic: 3 to 3.5 mm, and Aphakic: 3 mm.
• Superotemporal quadrant is a convenient location.
• A cotton bud dipped in proparacaine drops can provide additional anesthesia to the injection area.
• Always check the implant before insertion.
• Different implants are inserted in different ways as described:

Vitrasert and Retisert are implanted into the vitreous cavity after making a scleral incision at the pars plana and trimming prolapsed vitreous, followed by suturing it in place on the sclera.[2][7]

Iluvein is the smallest NBI that can be injected with a 25-gauge needle through the pars plana into the vitreous cavity, creating a self-sealing hole.[19] Yutiq is also inserted similarly.

I-vation implant is surgically fixed at the pars plana. The small diameter of the implant allows implantation through a <0.5mm pars plana sclerotomy. The implant has a thin cup that rests under the conjunctiva.[28]

Ranibizumab PDS has a slightly more complex method of implantation. An infusion line is first placed inferotemporally, followed by peritomy in the superotemporal quadrant. A 3.5 mm long incision in the sclera is made 4 mm posterior to the limbus, and the pars plana are ablated with the laser before making an incision. The implant is then inserted in the scleral wound, and the extrascleral flange helps anchor the sclera. The conjunctiva and tenon capsule is sutured carefully to cover the implant.[13][29]

Ozurdex is delivered intravitreally through the pars plana with a single-use applicator using a 22-gauge needle device. A tunneled injection technique is used to create an angled intrascleral injection tract to avoid a vitreous prolapse through the scleral puncture.[25]

Verisome is injected with a 30-gauge injector via the pars plana.[3]

• Following the implantation, the presence of the implant in the vitreous cavity, as well as perfusion of the optic disc, should be confirmed using an indirect ophthalmoscope after implantation.
• The speculum is removed, and topical 5% povidone-iodine drops are instilled.
• The eye is temporarily patched for an hour.

Complications

Following intravitreal implantation, complications can occur, including conjunctival hyperemia, conjunctival hemorrhage, vitreous hemorrhage, vitreous loss, hypotony, choroidal detachment, retinal detachment, accidental lens touch, intraocular inflammation, and wound dehiscence.[28]

NBI requires multiple surgeries for implantation, replacement, or removal as necessary. This can lead to an increased risk of post-surgical complications such as endophthalmitis, pseudoendophthalmitis, vitreous haze and hemorrhage, cataracts, and retinal detachment.[30]

Vitrasert can also lead to epiretinal membrane formation.[31]  Retisert has an additional risk of dissociating its main components leading to visual problems.[32][33]

BI can have an uncontrolled release of drug load during the final burst stage of the implant, which can cause complications related to drug toxicity. BI can also cloud vision, and their movement in front of the retina or anterior chamber is a possible complication.[30]

Steroid intravitreal implants are additionally associated with risks of increased intraocular pressure leading to increased IOP and glaucoma and the development or progression of cataracts. They can also migrate into the anterior chamber, which can secondarily cause damage to the corneal endothelium.[34][35] There is a greater risk of DEX implant migration into the anterior chamber in the presence of a compromised posterior capsule.[36]

Ranibizumab PDS is associated with endophthalmitis, retinal detachment, implant dislocation, septum dislodgement, vitreous hemorrhage, conjunctival erosion, retraction, and bleb formation.[16][26]

Follow-up

Follow-up of patients with intravitreal implants is important for treatment response, monitoring of side effects, and early identification of complications.

Follow-up visits depend on the disease being treated but are usually scheduled at 4 to 6 weeks to look for treatment response.

Best-corrected visual acuity should be checked at every visit.

IOP measurement by applanation tonometry is important, especially for intravitreal implants containing steroids.

Slit lamp examination is also important to look for any anterior chamber reaction and development or progression of cataracts.

In NIPU and CMV retinitis, a fundus examination should be done to look for a decrease in vitreous haze and resolution of retinitis lesions.

Ancillary investigations such as optical coherence tomography (OCT), OCT angiography (OCTA), and fundus fluorescein angiography (FFA) play a role in the follow-up.

In conditions such as DME and RVO- ME, OCT can aid in determining the response to treatment. Central subfield thickness (CST) is assessed at every visit to look for the resolution of ME. It helps in the decision-making process of re-treatment.

OCT, OCTA, and FFA can be useful in nAMD undergoing intravitreal implants to look for any signs of activity or recurrence of choroidal neovascular membranes, which will require re-treatment.

Clinical Significance

These implants have several advantages.[4] They include:

1. Bypassing the blood-retinal barrier allows higher levels of intraocular drug versus systemic administration.
2. Drug delivery is nearer to the target tissue, i.e., the retina and vitreous, thus reducing side effects on other sites in the body.
3. It provides longer-lasting drug delivery.
4. Ability to deliver drugs that cannot be administered by other routes or when compliance is a significant problem
5. Ability to remove the drug immediately in case of development of adverse effects, unlike intravitreal injections
6. Protective drugs that are not stable in vivo and would usually require frequent dosages.
7. Reduced dosage due to localized delivery, hence the need for systemic administration can be eliminated, or the dose of a systemically given drug can be significantly reduced. This makes the therapy safer due to lesser side effects and more viable for a prolonged period.[37]

Enhancing Healthcare Team Outcomes

Intravitreal implants have revolutionized the treatment of posterior segment diseases. A thorough ophthalmological examination of both the anterior and posterior segments to rule out any ocular or periocular infections before planning for intravitreal steroid implants is essential. The nurse can assist the ophthalmologist in explaining to the patient the indications of the intravitreal implant and the need for follow-up to monitor response and manage complications early. Risks and possible complications of the implant should be thoroughly explained to the patient.

The nurses should be aware of the implantation techniques and the use of intravitreal implants. The peri-injection precautions and the follow-up schedule should be explained to the patient. The patient should be explained the importance of periodic evaluation, including intraocular pressure check and optical coherence tomography. The clinic can play an active role by scheduling future visits in advance and sending timely reminders to the patient to attend the appointment. In case of complications, the physician or nurse should promptly identify those and institute treatment immediately. This interprofessional team approach will yield better patient outcomes. [Level 5]