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Ophthalmologists in Canada are hoping that an outbreak of ocular inflammation in patients being treated with bevacizumab (Avastin, Genentech) will not cause stricter regulations against its off-label intravitreal use or deter doctors from using it to treat wet age-related macular degeneration. All of the confirmed cases were linked to a specific lot of the drug that was distributed throughout Canada and other parts of the world. Health Canada currently is working with an independent laboratory to complete tests to determine the cause of the outbreak.
Lorne Bellan, MD, president of the Canadian Ophthalmological Society, and Simon Holland, MD, a Canadian cornea specialist who is acting as chairman for an investigation into the apparent outbreak, said that although the drug is not approved for use in the eye, its use in this way is so important to patients that it should not be blocked.
Bevacizumab was approved in Canada in 2005 for intravenous use in the treatment of cancer of the bowel and rectum that spread to other parts of the body. Because it is chemically related to ranibizumab (Lucentis, Genentech), however, which is approved for use in the eye but is far more expensive, many ophthalmologists successfully use bevacizumab off-label to stop visual loss or regain vision in patients with wet AMD.
"We don't want to lose use of the drug," he continued. "It's so important. The alternative is no treatment, and in this situation, that is worse than [dealing] with inflammation that can be treated."
According to Dr. Holland, about 50 confirmed cases of inflammation were reported in November among patients with wet AMD being treated off-label with bevacizumab injections. All of the cases were linked to a specific lot of the drug (lot B3002B028), which was manufactured by F. Hoffmann-La Roche Limited, based in Basel, Switzerland, and distributed throughout Canada and other parts of the world. Genentech developed the drug and retained rights to its sales and distribution in the United States.
The number of cases is in dispute. According to Genentech's Dec. 19 "Dear Healthcare Provider" letter, 36 cases of intraocular adverse events had been reported, and 32 of those were considered "serious intraocular inflammatory reactions." Of those cases, 25 had received aliquots from vials of the specific lot of bevacizumab, the letter stated.
Dr. Holland said, however, that he has confirmed reports of 50 cases, and he has unconfirmed reports of another 10 to 20 possible cases. The Canadian Ophthalmological Society's Dr. Bellan says the number is closer to 70. Roche spokeswoman Samantha Ouimet said the number of cases was 25.
Although the cases all were reported in Canada, the lot was distributed in other countries, including the United Kingdom and other parts of Europe and Australia. The lot was not distributed in the United States.
"What we were able to determine was that all of the cases in Canada happened with the unique combination of batch and shipping code," Dr. Bellan said. "No other country reported a problem with the same batch code."
Patients who received intravenous doses from that lot did not experience any problems, Ouimet said.
"All the test parameters were well within the limit for use in oncology," she said. "All microbial testing data were fully compliant. It is absolutely safe for metastatic colorectal cancer."
The fact that physicians commonly use the drug off-label puts Roche in an uncomfortable position of having to respond to a situation the company and Genentech both discourage.
"We do not in any way want to be advocating, promoting, or instructing on how people may be using this [drug] for an indication outside of oncology," Ouimet said. "We discourage it, so to engage in dialogue for its use off-label is not really appropriate for us."
Genentech similarly held the situation at arm's length.
"We don't want to interfere with a physician's prescribing choices," said Genentech spokeswoman Krysta Pellegrino, who added that the FDA was alerted to the adverse reactions reported in Canada. "All we can do is make sure it passes quality inspections for its approved use."