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Bevacizumab (Avastin) Eye Injections Not Linked to Higher Risk of Blindness

FDA needn’t restrict ophthalmic use, authors say

Eye injections of bevacizumab (Avastin), used to treat retinal diseases, bring no greater risk of endophthalmitis, a potentially blinding eye infection, than injections with the much more expensive drug ranibizumab (Lucentis), both made by Genentech, according to new research from the Perelman School of Medicine at the University of Pennsylvania. The findings were published in JAMA Ophthalmology.

The study, based on insurance claims data from across the U.S., was conducted in response to reports of bevacizumab-related endophthalmitis, which led the FDA recently to propose significant restrictions on use of the drug for eye conditions.

“Our analysis of a national dataset shows that the risk for endophthalmitis is no higher with Avastin and hints that there may actually be a lower endophthalmitis risk compared to Lucentis, so the proposed FDA restrictions for Avastin might have the unintended consequence of increasing the infection risk for patients,” said senior author Brian L. VanderBeek, MD, MPH.

The findings come after years of tension between eye doctors and Genentech over bevacizumab’s ophthalmic use.

Bevacizumab is an injectable solution of monoclonal antibodies targeted at vascular endothelial growth factor (VEGF). It was the first drug designed to inhibit angiogenesis, and was approved by the FDA in 2004 for treating colorectal cancers, which typically boost angiogenesis to keep themselves well-supplied with oxygen and nutrients.

Common age- and diabetes-related retinal diseases, such as wet macular degeneration, also result in part from VEGF-driven processes, so ophthalmologists began to use bevacizumab “off label” to treat these conditions. Bevacizumab, as distributed for cancer treatment, is often repackaged by compounding pharmacies into smaller doses suitable for use in the eyes, which drives the cost of the medication down to approximately $50 per eye injection.

Genentech has also developed ranibizumab, an “eye-specific” angiogenesis-inhibiting, anti-VEGF monoclonal antibody. Ranibizumab was FDA-approved in 2006 and costs as much as $2,000 per dose, even though it is closely related to the bevacizumab antibody and multiple clinical trials have found that the two drugs have virtually the same efficacy.

To promote the use of the more-expensive ranibizumab, Genentech announced in 2007 that it would block ophthalmic use of bevacizumab by prohibiting its sales to compounding pharmacies, but the company backed away from this plan after protests from eye doctors.

Then, in 2012, a few reports in the media noted endophthalmitis outbreaks following injections of repackaged bevacizumab. Endophthalmitis is the most serious complication of anti-VEGF treatment and can lead to blindness and even loss of the eye.

The endophthalmitis outbreaks were limited to specific compounding pharmacies. Amid a general concern over potential substandard practices at compounding pharmacies nationally, the FDA announced in February 2015 that it planned to restrict the ophthalmic use of bevacizumab to the 5-day period following the repackaging of the drug by a compounding pharmacy.

“This would effectively prevent most ophthalmic use of Avastin,” VanderBeek said. “Compounding pharmacies require 14 days after repackaging just for sterility testing, and without this critical step, ophthalmologists will lack confidence in the safety of the repackaged Avastin and will be unlikely to use it.”

To get a better picture of bevacizumab’s true endophthalmitis risk, VanderBeek and his colleagues looked at the medical claims database for a large American insurance company, covering the years 2005 through 2012. The data they reviewed contained no information that identified patients.

Analyzing the 296,565 injections of bevacizumab and 87,245 injections of ranibizumab that met their inclusion criteria, the Penn researchers found 49 and 22 cases, respectively, of endophthalmitis. Thus, the rate of the complication in this dataset was very low (0.017%) for bevacizumab, and was slightly higher (0.025%) for ranibizumab.

The 35% lower rate of endophthalmitis seen in patients treated with bevacizumab was not statistically significant, but the authors say the data suggest that, on a nationwide basis, bevacizumab repackaged by compounding pharmacies does not involve a greater risk of endophthalmitis than ranibizumab packaged by its manufacturer.

The American Academy of Ophthalmology has been lobbying against the proposed new FDA regulations. “The findings from our study support their stance,” VanderBeek said.

Sources: Perelman School of Medicine; August 13, 2015; and JAMA Ophthalmology; August 13, 2015.

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