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Counterfeit Avastin Sparks Concerns
Despite the lower cost of off-label bevacizumab (Avastin) compared with ranibizumab (Lucentis), bevacizumab has gained the dubious distinction of being the first to be reported in a major medical journal as having been counterfeited.
The fake bevacizumab was discovered in Shanghai after 80 of 116 patients developed “florid intraocular inflammation with only minimal external erythema,” according to a letter published in the New England Journal of Medicine.1 “Both [bevacizumab and ranibizumab] are at risk of being replaced with counterfeit drugs, so vigilance is needed on the part of physicians, drug distributors and government oversight agencies,” the authors warned.
According to WHO, the report of the phony anti-VEGF drug came from a region where it is believed that up to half of medications sold are counterfeit; the FDA places the U.S. figure for counterfeit medications at below 1 percent.
But health and regulatory officials worldwide worry about new counterfeiting risks because of the globalization of drug supply chains and the greater sophistication of today’s criminals. During 2010, the Pharmaceutical Security Institute counted 2,054 counterfeiting incidents worldwide, 201 of them in North America; in 2002, only 196 cases were reported worldwide.2
The Shanghai patients received ocular injections prepared from three vials with a single batch number, according to authors Xiao-dong Sun, MD, Xun Xu, MD, and Xi Zhang, MD, who are ophthalmologists at Shanghai First People’s Hospital.
The treated patients developed intraocular inflammation, characterized by increased flare and cells in the anterior and vitreous chambers, with or without the presence of hypopyon, the authors noted. (With treatment, all patients recovered their preinjection visual acuity.)
Bevacizumab was not present in the vials or in the vitreous obtained from the 21 eyes that required vitrectomy, the NEJM authors reported, and no bacteria or fungi were found. The authors concluded that the batch of bevacizumab used in the treatment of these patients was counterfeit.
Asked for comment, a Genentech spokesman confirmed that the company had found no bevacizumab in tests of the Shanghai samples. He declined to comment on any specifics of the company’s anticounterfeiting efforts.
At the FDA, a spokeswoman said the agency currently has no evidence of counterfeiting of bevacizumab or ranibizumab or any problems with the integrity of these drugs in the U.S. supply chain.
Other safety issues. The Shanghai endophthalmitis cluster occurred at around the same time as a Florida outbreak of microbial endophthalmitis traced to repackaged intravitreal injections of bevacizumab. An FDA alert advised physicians to buy the drug only from “appropriate, reliable” sources.3
Charles Leiter, PharmD, president of Leiter’s Pharmacy, San Jose, Calif., said bevacizumab, which must be compounded for intravitreal use, should come with a clear pedigree. “I get phone calls all the time from people who want to sell me pharmaceutical ingredients for less, but I don’t buy from anybody except my regular wholesaler.”
He advised finding a compounding pharmacy that:
- Pays meticulous attention to “clean room” sterility.
- Is certified by the Pharmacy Compounding Accreditation Board (PCAB).
- Delays batch shipment until sterility and dosage have been verified in at least one sample (the United States Pharmacopeial Convention [USP] standard). Dr. Leiter advocates using independent labs to conduct the tests.
- Tests multiple samples when the lot is large and discards the entire batch if a single sample fails.
1 Sun, X. et al. N Engl J Med
Rods in Humans Imaged In Vivo
By reconfiguring the spherical mirrors in an adaptive optics scanning ophthalmoscope, researchers in New York and Wisconsin have acquired the first images in vivo of the contiguous rod photoreceptor mosaic in healthy human retinas.
Since the late 1990s, adaptive optics–equipped fundus cameras have enabled scientists to capture unprecedented retinal images, including images of individual cone photoreceptors.1 But the smaller rods proved elusive, though they outnumber cones 20-to-1.
The rods have now been imaged, thanks to a single design change that, in retrospect, was embarrassingly simple, said Alfredo Dubra, PhD, assistant professor of ophthalmology at the University of Rochester. Dr. Dubra, who led the multi-institution research team from the University of Rochester in New York and the Medical College of Wisconsin and Marquette University, both in Milwaukee, was lead author of their paper.2
“Typically, adaptive optics imaging systems have been made so that light stays mostly on a single plane,” Dr. Dubra said. “Using ideas and formulas that are over 100 years old, we realized that the performance of the adaptive optics system could be greatly improved simply by folding the optical setup in three dimensions. You just need to tilt the spherical mirrors so the light travels in two orthogonal planes. It’s amazing that we didn’t think of this 10 years ago.”
With these improved instruments, the researchers learned that the rods come into focus at a depth 10 µm to 20 µm shallower than the cones at retinal eccentricities larger than 8 degrees. This challenges the current thinking about the light-guiding properties of both cone and rod photoreceptors.
Consistent with the findings of previous histological studies, the researchers could see the absence of rods in the fovea and their emergence about 190 µm from the foveal center. Farther away from the fovea, the rods appeared to be densely packed among more sparsely distributed cones.
However, the clinical impact of being able to see the rod mosaic will not be felt until eye researchers have established what “normal” looks like, Dr. Dubra said. The researchers hope that, with the help of other scientists around the country, the required normative database will be assembled in the next five years, he added.
Ultimately, ophthalmologists may be able to track the health of individual photoreceptors in patients with retinal diseases.
1 Liang, J. et al. J Opt Soc Am A
2 Dubra, A. et al. Biomed Opt Express
Dr. Dubra reports no financial interests.
Antibiotics for Ulcers
When treating large corneal ulcers—those at least 4 mm in diameter—almost two-thirds of comprehensive ophthalmologists favor a combination of fortified antibiotics, according to an Academy survey.
Christopher J. Rapuano, MD, director of the cornea service and codirector of the refractive department at Wills Eye Institute in Philadelphia was somewhat surprised that another third of those surveyed use fluoroquinolones instead for ulcers of this size. However, he said that with certain provisos, fluoroquinolones may be a reasonable option.
Dr. Rapuano believes that a culture is typically warranted for these large ulcers, especially if foreign material might have come in contact with the eye or if a fungus or other unusual organism is suspected. Given that many comprehensive ophthalmologists are not set up to do cultures, Dr. Rapuano questioned why only a nominal percentage of them refer patients to a specialist for a 4-mm ulcer.
Moreover, frequency of drop administration and follow-up are critical with these patients. “For a 4-mm ulcer, I’ll give a drop every 5 minutes, then a drop every 15 minutes for a couple of hours, and then a drop every hour around the clock,” he said. “But you can’t start a patient on every-hour drops and say, ‘Come back in a week,’” said Dr. Rapuano, adding that it is essential to see the patient the next day. Frequent follow-up is particularly important when a significant anterior chamber reaction or a hypopyon is involved, he said.
Patient reports of improvement may precede visible progress on the exam by a day or two, Dr. Rapuano noted, and are an indication that the current treatment can continue. In the absence of noticeable improvement, however, a change in regimen or a referral to a specialist is in order.
Other factors also can influence the treatment approach. For example, Dr. Rapuano is more aggressive when treating patients with central rather than peripheral ulcers. Also, fluoroquinolones are not ideal for patients with a higher risk of methicillin-resistant staph infections. In these cases, Dr. Rapuano recommends using vancomycin. If he suspects infection with Acanthamoeba—suggested by a history of severe pain out of proportion to the clinical exam, a ring infiltrate or radial keratoneuritis—he also scrapes the eye for smears and cultures and then starts the patient on anti-Acanthamoeba treatment.
Dr. Rapuano is a consultant and lecturer for Allergan, Bausch + Lomb and Inspire/Merck and a lecturer for Alcon.
CLINICAL QUESTIONS. To better understand current practices on a number of topics, the Academy surveyed comprehensive ophthalmologists about how they would handle various clinical situations. Each month, EyeNet will feature one question—this month about corneal ulcers—and ask an expert to provide perspective on the responses. The article also will appear at www.aao.org/one with an accompanying online poll so that you can weigh in.
Hyperlipidemia & OAG
In confirming the findings of earlier studies—that diabetes and hypertension increase the risk of developing glaucoma—researchers at the University of Michigan, Ann Arbor, unearthed a surprise: Hyperlipidemia was associated with a 5 percent decreased risk of developing open-angle glaucoma (OAG).1
This longitudinal cohort study involved 2 million beneficiaries in a U.S. managed care network who received eye care between 2001 and 2007. The study focused on whether the components of metabolic syndrome—diabetes, hypertension, hyperlipidemia and obesity—affected the risk of developing glaucoma.
The study’s most important finding was the extent to which different components of metabolic syndrome were associated with OAG, said Joshua D. Stein, MD, MS, who headed the study and is assistant professor of ophthalmology at the university. The analysis found that diabetes alone increased the risk of OAG by 35 percent; hypertension, by 17 percent. Having both conditions upped the ante 48 percent. Obesity conferred a 6 percent increased risk for women but had no apparent effect on men.
Dr. Stein said, “Since these conditions often are not present in isolation, it is important to adjust for or account for other components of metabolic syndrome. The presence of one component may have a reverse impact on the relationship between other components of metabolic syndrome and glaucoma.”
1 Newman-Casey, P. A. et al. Ophthalmology