Don’t Leave the Door Open

Endophthalmitis is a nightmare for ophthalmologists; sometimes you can treat it, sometimes you lose the eye. But when you go into the eye to perform surgery – or even inject a drug – there’s always a risk that infection can occur. But even then, with precautions, the risk of endophthalmitis is miniscule. After all, the most commonly performed surgery (of all of medicine, not just ophthalmology) is cataract surgery, and people receive intravitreal injections as a matter of routine.

However, it appears that no one can fully relax. On February 21, Bloomberg published an article with a troubling first sentence: “Doctors say they’re seeing an unexplained increase in a rare, frightening side effect in patients getting Regeneron Pharmaceuticals Inc’s top-selling product, the blockbuster eye drug Eylea” (1). So what’s the story?

According to the article, the American Society of Retina Surgeons (ASRS) issued a letter to doctors in October last year asking them to be extra vigilant for endophthalmitis after administering intravitreal injections of aflibercept (Eylea), as a slight upswing in endophthalmitis rates had been noted. The society then issued another letter this January stating that the FDA had deemed a recall unnecessary and that aflibercept’s producer and distributor of the drug in the US, Regeneron, had found no manufacturing problems; the ASRS urged its members to keep the medicine refrigerated. A third letter was issued on February 15, stating that the society had received increased reports of the adverse event over the past six months, with clusters reported from practices in Ontario, Massachusetts, New Jersey, New York, Nevada, Iowa and Pennsylvania – reinforcing Regeneron’s claim that this is not due to manufacturing problems.

Despite this, endophthalmitis with Eylea is still a vanishingly rare event. Is this a case of conflating relative with absolute risk? According to the Bloomberg report, “The FDA received 71 reports last year, almost triple 2014 when the next-highest number were made. The company said it sold about 2.2 million vials of the drug last year, up from about 1 million in 2014.” The report added, “Last year, the side effect was reported in about 1 in 10,000 people who got Eylea.” So, in short: triple the absolute number of a (thankfully) incredibly rare event, when the total number of injections has more than doubled.

Still, every case of endophthalmitis is potentially blinding – what has been done to assess and address this? Regeneron is allowing doctors with an affected patient to swap out any unused vials for vials from another batch, and the ASRS noted that, though the side effect is still rare, the benefits of the drug outweigh the risks. And they agreed with Regeneron’s plan to replace vials of the drug upon request.

What might be causing the problem? The ASRS statement in the January letter, urging its members to keep the drug refrigerated, might be a clue. Bloomberg quoted Neil Bressler, Professor of Ophthalmology at the Johns Hopkins Wilmer Eye Institute, as saying: “It’s possible that the medicine, which must be constantly refrigerated from the time it leaves the factory until it is injected, has been mishandled somewhere along the line.” He went on to add: “It should be looked into and corrected if it’s real, even though it would be rare, but I don’t think there is cause for alarm at this time. The number of events is tiny, and you have to weigh that against the benefits of the treatment, which are enormous.” Whether this is the explanation or not, it’s important to keep things cool – and don’t leave the fridge door open.

Update:

On February 28th, Regeneron Pharmaceuticals issued a letter to healthcare professionals providing updated guidance amid reports of intraocular inflammation (IOI) following EYLEA injections (https://hcp.eylea.us/media/ioi.pdf), which stated:

“In order to determine the cause of this variability, Regeneron has conducted an extensive review of our manufacturing and distribution processes. This review did not identify any association of IOI rates with the EYLEA drug itself; however, an association was seen with certain batches of the syringe that were included in specific lots of final packaged EYLEA kits.” Regeneron have ceased the distribution of the impacted kits; they recommend that practitioners already in receipt of the affected kits do not use the included syringes, will “exchange affected kits as needed,” and have communicated their findings to the FDA and ASRS.

Bayer, the ex-US distributor issued a statement with the following claims:

• “Outside of the US, aflibercept is distributed in the form of a vial accompanied by a filter needle only,”
• “syringes are not provided as part of the aflibercept presentation,”
• “none of the impacted syringe lots have been distributed by Bayer in conjunction with EYLEA (aflibercept) outside the US,” and
• “the reporting rates outside US remain stable over time and there is no signal of an increased risk for IOI.”