US FDA: Tainted compounded Avastin linked to serious eye infections, blindness
This article was originally published in Scrip
The off-label ocular use of Genentech's Avastin (bevacizumab) has resulted in at least a dozen patients developing a serious eye infection, with some leading to blindness, following the intravitreal injection of a tainted compounded formulation of the drug that had been repackaged by a Florida pharmacy, US regulators said.
In an alert posted late 30 August on the US FDA's website, regulators said investigators had traced the tainted Avastin injections to a Hollywood, Florida-based pharmacy, which had split the drug from its sterile injectable 100 mg/4 mL, single-use, preservative-free vials and repackaged it into individual 1 mL single-use syringes.
The compounding pharmacy distributed the tainted Avastin to multiple eye clinics for use in treating patients, where some had developed Streptococcus endophthalmitis infections after being injected with the drug.
Avastin, which is approved for various forms of cancer, has long-been used off-label to treat neovascular (wet) age-related macular degeneration (AMD). The drug is derived from a protein similar to Genentech's Lucentis (ranibizumab), which is approved for wet AMD, along with macular oedema following retinal vein occlusion.
Lucentis, however, comes at a cost of about $2,000 per treatment, whereas the compounded Avastin sells for about $50 – the incentive for doctors to use the repackaged product.
Genentech and its parent company Roche, along with their partner Novartis, which markets the drug outside the US, have strongly objected to the off-label use of Avastin for wet AMD, insisting that it was never designed, developed or formulated for ocular uses.
"Avastin is not manufactured or approved and to date has not been proven safe for use in the eye," Genentech spokesman Terry Hurley told Scrip.
Mr Hurley noted that Avastin's current package insert warns about adverse ocular events associated with unapproved uses of the drug in the eye.
Indeed, the "Postmarketing Experience" section of Avastin's labelling points out that there have been reports of endophthalmitis, retinal detachment, increased intraocular pressure, hemorrhage, fitreous floaters, visual disturbances, ocular hyperemia, pain or discomfort and intraocular inflammation, such as iritis and vitritis, when the drug has been injected into the eye.
Mr Hurley said that compounding Avastin into smaller intravitreal doses for use in an ocular setting is associated with "uncertainty due to the risk of contamination" and subsequent infection or inflammation following the compounding procedures.
The FDA said it was collaborating with Florida health officials in an ongoing investigation of the cause of the eye infections, pointing out that the common link was the compounding pharmacy that repackaged the Avastin and the single lot of the drug used in that process.
"Health care professionals should be aware that repackaging sterile drugs without proper aseptic technique can compromise product sterility, potentially putting the patient at risk for microbial infections," the FDA said. "Health care professionals should ensure that drug products are obtained from appropriate, reliable sources and properly administered."
But the FDA's warning appears to conflict with another government agency's pursuit in demonstrating the benefits of Avastin in treating eye conditions.
In April, the US National Institutes of Health (NIH) released the results of a much-anticipated study that showed that Avastin was as effective as Lucentis in improving vision in patients with AMD (scripintelligence, 28 April 2011, 2 May 2011).
Indeed, the Comparison of AMD Treatments Trial (CATT), whose results were published online on 28 April in the New England Journal of Medicine, demonstrated that Avastin administered monthly was equivalent to Lucentis administered monthly in improving visual acuity, with 8 and 8.5 letters gained on the visual acuity charts, respectively.
Avastin administered as needed, or pro re nata (PRN), was equivalent to Lucentis PRN, with 5.9 and 6.8 letters gained, respectively. The results also showed that the PRN dosing of Lucentis was just as effective as the monthly dosing of that drug, although the comparison between Avastin as needed and monthly dosing of that drug was inconclusive.
The CATT data also showed that the mean decrease in central retinal thickness was greater in the Lucentis-monthly group than in the other groups.
The CATT investigators said the results showed that the rates of death, myocardial infarction and stroke were similar for both drugs. The proportion of patients with serious systemic adverse events, primarily hospitalizations, was higher with Avastin than with Lucentis, 24.1% vs. 19.0%.
Impact to Regeneron
The new infection concerns over Avastin may have been the trigger that sent shares of Regeneron, whose own investigational wet AMD drug Eylea (aflibercept) is awaiting FDA approval, climbing as high as $3.99, or 6.7%, on 31 August.
But the stock came down to earth as the day wore on, even closing down 43 cents at the bell, to settle at $59.03.
Investors have been jittery since 16 August when the company revealed the FDA was delaying by three months its decision on whether to permit Regeneron to market the drug in the US – an action that caught Wall Street off guard, which had expected an easy approval, given the backing of a 17 June advisory panel (scripintelligence, 17 August 2011, 20 June 2011).
Regeneron attributed the delay to the FDA classifying recent responses to questions about the chemistry, manufacturing and controls (CMC) section of the BLA as a "major amendment" to the application.
During a 17 August conference call with investors and analysts, Regeneron CEO Dr Leonard Schleifer insisted, that despite the setback, "most of our application is apparently in good shape," and that the company was not aware of any outstanding safety or efficacy issues related to the product's review.
Dr Schleifer also said he was confident the firm would win approval on or before the new 18 November Prescription Drug User Fee Act action date.
He dismissed any concerns that compounding pharmacies would be successful in splitting Eylea doses in the manner in which Avastin has been repackaged.
"It would not really be efficient, and I don't think it would be safe," Dr Schleifer said.
The reported cases of serious adverse eye events with Avastin use "talks to the inherent risks of 'cutting' a drug into smaller doses for use in the eye," said Roth Capital Partners analyst Dr Joseph Pantginis.
In a 31 August research note, he pointed out that Health Canada issued a "Dear Doctor" letter in 2008 citing at least 25 spontaneous cases of eye inflammation, endophthalmitis, blurred vision and floaters, some of which have been described as toxic anterior segment syndrome, in patients who were administered Avastin.
Even if Avastin's off-label use in the eye is unscathed by the latest infection scare, Dr Pantginis argued that Regeneron's drug still has the upper hand, since Eylea's data support every other month dosing, whereas the data for Genentech's drugs do not.
"Our physician feedback has been clear that every other month dosing would represent a significant improvement to both their practices and patient quality of life, while maintaining significant efficacy," he said.