The use of intravitreal drugs exposes the patient to complications connected to technical risk.

The injection technique is fairly standard and generally consists of a dose of 0.05 ml (for anti-VEGF) to 0.1 ml (for TA) of the agent, except for gas injection, where the dose is higher.

It is performed using a 25-, 27-, or 30-gauge needle, via the transconjunctival route 2 to 5 mm (standard average is 3-3.5-4 mm) from the limbus, depending on whether one is in the presence of a pseudophakic or phakic condition. Although there are no preferential injection quadrants, some practitioners prefer to avoid the lower quadrant, where more germs accumulate, in order to avoid the risk of intravitreal inoculation and consequent inflammation.

Injection can be either direct or performed through a small scleral tunnel incision. The aim of this second technique is to reduce the risk of leakage of the drug and/or vitreal gel into the subconjunctival space.

The conjunctiva can be moved 2 mm from the injection site, to avoid the conjunctival hole from coinciding with the scleral hole, in order to prevent direct contact with the external environment. There are a number of potential injection complications, ranging in severity from very bland to extremely serious.

The subconjunctival hemorrhage is undoubtedly the most frequent of these and although it is usually generally slight and self-limiting, it can be more substantial and a cause of concern to the patient; however, the situation normally resolves spontaneously within a few days.

The ocular surface can be interested by the intravitreal injection technique, as the needle may accidentally touch the cornea causing abrasion; this resolves spontaneously within a few hours when correct therapy is administered.

The potential complications of injection via the pars plana route include touching of the lens or intraocular lens (IOL); the former may cause local (peripheral, paracentral or central) opacity that may later develop into a cataract.

In pseudophakic patients, especially those who have undergone sulcus implantation following capsular rupture, accidental contact may cause IOL dislocation or subluxation with the risk of vitreous prolapse in the anterior chamber.

Vitreous hemorrhage is a relatively common complication of intravitreal injection and occurs in 3% to 5% of patients. Vitreous hemorrhage appears to be more commonly associated with injections performed using a 27-gauge rather than a 30-gauge needle.

Some clinicians prefer using a larger caliber needle to reduce the likelihood of needle obstruction during injection, even at the cost of creating a larger hole (risk of hypotonia and vitreous engagement).

One particular case is that of the vitrectomy patient, where the initial sclerotomy must be avoided and the injection made at a distance or in a different quadrant, to avoid partially reopening previous incisions, producing diastasis, subconjunctival leakage, loss of the remaining vitreous humor, conjunctival chemosis, and consequent hypotonia. This only applies to procedures performed a short time after the vitrectomy and from two months thereafter the only problem is likely to be a greater risk of bleeding due to conjunctival congestion in the area in which the sclerotomy was performed.

Intravitreal injection of an anti-VEGF agent is safe in terms of intraocular pressure (IOP) elevation with a return to levels under 25 mm Hg within 30 minutes from the injection. In rare cases, an increase in pressure may persist beyond this interval and it is in any case good practice to monitor IOP after intravitreal injections. Paracentesis evacuation could be taken into consideration in glaucoma patients to obtain hypotonia (Hollands, 2007).

Pegaptanib is a pegylated 28-nucleotide RNA aptamer (aptamers are synthetic oligonucleotides with binding properties similar to those of antibodies). It was the first anti-VEGF agent approved for the treatment of vascular eye disease. By blocking VEGF165, pegaptanib inhibits angiogenesis and vascular permeability.

The VISION study (VEGF Inhibition Study in Ocular Neovascularization) studies the safety and efficacy of pegaptanib. This concurrent, randomized, double-blind, controlled, doseranging study involves 1,190 patients at 117 centers worldwide; 295 receive 0.3 mg pegaptanib and 298 receive usual care with sham injections every 6 weeks. The objective of this study is to establish the safe, efficacious dose of intravitreal
pegaptanib in patients with subfoveal choroidal neovascularization (CNV) secondary to AMD.

The ocular adverse events observed in this study are:

The most common systemic adverse events are:

There is no statistically significant difference in the onset of these adverse events between patients who received pegaptanib and those who received usual care with sham injections.

Ranibizumab (Lucentis, Genentech, Inc., South San Francisco, CA) is a specific affinity-matured, recombinant, humanized anti-VEGF-A neutralizing antibody fragment (Fab). The fragment is one third the size of a full-length antibody and readily penetrates all layers of the retina after intravitreal injection. Ranibizumab is
being developed as a potential treatment for various VEGFA-mediated ocular vascular diseases and is being used in phase III trials for treatment of neovascular AMD. The one-year results from a 2-year phase III trial on the treatment of minimally classic and occult-only AMD-related choroidal neovascularization indicate that monthly injection of 0.3 or 0.5 mg ranibizumab halted the growth of the choroidal neovascularization lesion, reduced vascular leakage, and in one quarter to one third of treated patients, respectively, improved visual acuity (VA).

The ANCHOR, MARINA, and SAILOR trials studied the safety and efficacy of Ranibizumab.

The ocular adverse events showed a 1% prevalence in the ANCHOR study and a 1.5% prevalence in the MARINA study:

The analysis of systemic adverse effects of Lucentis (systemic adverse events) in both studies (ANCHOR, MARINA) has shown:

Ranibizumab (Lucentis) was approved by the US Food and Drug Administration (FDA) for intravitreal injection at a dose of 0.5 mg; the manufacturer recently issued a letter to physicians warning of the increased risk of stroke at the FDA-approved dose as compared to a lower studied dose of 0.3 mg. An interim analysis of the ongoing SAILOR study revealed a 1.2% risk of stroke in the 0.5 mg arm versus 0.3% in the 0.3 mg arm (p = .02). It is unclear whether the trend toward a higher risk of stroke in patients receiving the 0.5 mg dose of ranibizumab will persist in final analysis, however details such as causality, topography, and severity of stroke in the SAILOR study also need to be defined.

Bevacizumab (Avastin) is a recombinant humanized monoclonal IgG1 antibody that inhibits human VEGF. The drug is approved by the US Food and Drug Administration for intravenous use in combination with 5-fluorouracil-based chemotherapy for metastatic colorectal cancer. It has been administered intravitreally in VEGF-mediated diseases, such as choroidal neovascularization, central retinal vein occlusion, proliferative diabetic retinopathy, and other retinal diseases. It has not been approved by the FDA for intravitreal use and therefore it may only be used in an off-label setting. The most commonly used dose for intravitreal injection is currently 1.25 mg (0.05 ml) in the United States, although up to 2.50 mg (0.1 ml) may be used. Because such a small amount of drug from a large vial is required to treat eye disease, ophthalmologists have been obtaining the drug from compounding pharmacies that divide the vial into smaller amounts, at a lower cost.

To date, there are no randomized clinical trials demonstrating the effects of the treatment with bevacizumab for ocular vascular diseases; however, there are several case series concerning this matter.

The ocular complications of intravitreal injection of bevacizumab are: