A new study has investigated the safety, sterility, and dosage consistency of Avastin, a lower-cost intravenous cancer drug that is used “off label,” via eye injection, to treat a range of retinal disorders including age-related macular degeneration, diabetic macular edema, and retinal vein occlusion.
The research concludes that a significant number of the Avastin study samples, which were prepared by pharmacists for eye injection through a process called “compounding,” (explained below) contained significant variations in dosage, as well as lower active drug levels overall compared to Avastin obtained directly from the manufacturer.
From JAMA Ophthalmology
The research, entitled Evaluation of Compounded Bevacizumab [i.e., Avastin] Prepared for Intravitreal [i.e., within the eye] Injection, was published “online first” in the September 18, 2014 edition of JAMA Ophthalmology (formerly Archives of Ophthalmology). JAMA Ophthalmology is an international peer-reviewed journal published monthly by the American Medical Association.
The authors are Nicolas A. Yannuzzi, MD; Michael A. Klufas, MD; Lucy Quach; Lauren M. Beatty; Stephen M. Kaminsky, PhD; Ronald G. Crystal, MD; Donald J. D’Amico, MD; and Szilárd Kiss, MD, who represent the Departments of Ophthalmology and Genetic Medicine at Weill Cornell Medical College, New York.
Age-Related Macular Degeneration
In wet, or exudative, macular degeneration (AMD), the choroid (a part of the eye containing blood vessels that nourish the retina) begins to sprout abnormal blood vessels that develop into a cluster under the macula (called choroidal neovascularization).
The macula is the part of the retina that provides the clearest central vision. Because these new blood vessels are abnormal, they tend to break, bleed, and leak fluid under the macula, causing it to lift up and pull away from its base. This damages the fragile photoreceptor cells, which sense and receive light, resulting in a rapid and severe loss of central vision.
Diabetic Macular Edema
Diabetic macular edema [edema = a swelling or accumulation of fluid] (DME) can occur in people with diabetes when retinal blood vessels begin to leak into the macula, the part of the eye responsible for detailed central vision. These leakages cause the macula to thicken and swell, which, in turn, creates a progressive distortion of central vision.
Although this swelling does not always lead to severe vision loss or blindness, it can cause a significant loss of central, or detail, vision, and is the primary cause of vision loss in people with diabetic retinopathy.
Retinal Vein Occlusion and Macular Edema
A retinal vein occlusion (RVO) is a blockage [i.e., “occlusion”] of the small veins that carry blood away from the retina, the light-sensitive tissue that lines the inside surface of the eye. The retina converts incoming light into nerve signals and sends them to the brain, which interprets them as visual images.
Blockage of smaller, “branching,” veins (a branch retinal vein occlusion or BRVO) in the retina often occurs when retinal arteries that have been thickened or hardened by atherosclerosis “cross over” and place pressure on a retinal vein. A branch retinal vein occlusion is sometimes referred to as “a stroke on the retina.”
Anti-Angiogenic Drugs and Anti-VEGF Treatments
Angiogenesis is a term used to describe the growth of new blood vessels and plays a crucial role in the normal development of body organs and tissue. Sometimes, however, excessive and abnormal blood vessel development can occur in diseases such as cancer (tumor growth) and AMD (retinal and macular bleeding).
Substances that stop the growth of these excessive blood vessels are called anti-angiogenic (anti=against; angio=vessel; genic=development), and anti-neovascular (anti=against; neo=new; vascular=blood vessels).
The focus of current anti-angiogenic drug treatments for retinal disease is to reduce the level of a particular protein (vascular endothelial growth factor, or VEGF) that stimulates abnormal blood vessel growth in the retina and macula; thus, these drugs are classified as anti-VEGF treatments. At present, these drugs are administered by injection directly into the eye after the surface has been numbed.
Avastin is an anti-VEGF drug that is FDA-approved since 2004 for intravenous use in colorectal cancer. It is currently used on an “off-label” basis (i.e., via eye injection) to treat retinal eye disease.
Lucentis is derived from a protein similar to Avastin, specifically for injection in the eye to block blood vessel growth in AMD. In 2005, clinical trials first established Lucentis as highly effective for the treatment of wet AMD. The FDA approved Lucentis in 2006.
Eylea was first approved by the FDA in late 2011 as an effective treatment for wet AMD. It is administered once every two months after three initial once-a-month injections.
Avastin, unlike Lucentis and Eylea, does not come prepared in single-dose ready-made vials for eye injections because the FDA has not yet approved it for that purpose. Pharmacies, therefore, must compound (i.e., remix or prepare a single dose of) Avastin for eye injections from packaging that is intended for intravenous use. This has raised concerns about Avastin sanitation and sterility issues, as well as dosage accuracy.
In a recent study, which was conducted to determine if doctors approached macular degeneration differently when treating themselves, the authors concluded that the physicians surveyed in the study would recommend different treatments for themselves than they would for a patient. The study authors also noted the following:
In published results, [the authors] speculate that economics could be a factor. They report that the annual cost is estimated to be up to $23,400 for Lucentis, up to $14,800 for Eylea (8 doses), and about $595 for Avastin.
Physicians are more likely to have extensive health insurance and the financial means to afford more expensive drugs, the researchers explain.
“In contrast, physicians may prefer treatment with [Lucentis] or [Eylea] because of the safety profile, U.S. Food and Drug Administration (FDA) approval status, and the ability to obtain the drug from sources other than a compounding pharmacy,” they write.
About the Research
Excerpted from Study Shows Inconsistent Dosages of Widely Used Eye Disease Drug: Findings Add to Public Health Debate About Pharmacy Compounding via the Weill Cornell Newsroom:
“Our evaluation showed significant differences in doses of compounded Avastin, as well as lower drug levels overall compared to Avastin that came from the manufacturer. This is troubling because the prescribed dosing regimen potentially won’t produce the desired therapeutic response, or may put a patient’s health at risk,” said co-author Dr. Szilárd Kiss. “Although there were no signs of contamination, these findings raise legitimate concerns about the quality practices of compounding pharmacies.”
Pharmacy compounding is the practice of creating customized, prescription medications to meet individual patients’ needs. At the request of a physician or other healthcare provider who is authorized to write prescriptions, a licensed pharmacist alters ingredients in drugs, such as removing allergy-causing dyes or preservatives or preparing an alternative dosage form to make it easier for patients to take their medications.
In the study, researchers obtained three Avastin samples prepared in syringes from 11 compounding pharmacies from around the United States. Two samples from each pharmacy were tested for protein concentration (to measure the average amount of drug in the syringe), while the remaining 11 samples were tested for contaminants.
The researchers compared individual doses of compounded Avastin to samples obtained directly from the drug manufacturer, Genentech — formulations identical to those compounding pharmacies buy from the company to make eye injections. They found 17 samples with significantly less drug than the respective Genentech doses (and less than what was stated on the compounding pharmacy label), as well as one syringe that was completely empty, containing absolutely no medication at all.
The researchers also compared protein concentrations of the two samples from each pharmacy. They observed significantly different drug levels between the samples in three of 10 facilities. None of the samples tested positive for bacteria or other impurities.
Co-author Dr. Donald D’Amico said, “Although, reassuringly, all of the syringes in our study were contaminant-free, the wide variations in the Avastin doses in the various samples suggest that, in clinical practice, some patients who are ‘non-responders’ may simply have been under-dosed, and other patients may have received higher doses than recommended. Clearly, greater precision is needed to provide the best care for our patients,” added Dr. D’Amico.
Compounders are licensed and regulated by their respective state boards of pharmacy, but a law passed in 2013 — the Drug Quality and Security Act — enforces new quality-control guidelines and increased federal supervision to guard against unsafe and sometimes illegal compounding practices.
More about the Study from JAMA Ophthalmology
From the article abstract:
Importance: [Avastin] acquired from compounding pharmacies for intravitreal injection may cause infectious and noninfectious inflammation. In addition to safety issues, the drug itself may have variable efficacy associated with product aliquoting [i.e., breaking it down into individual doses], handling, and distribution.
Objective: To conduct surveillance cultures, evaluate endotoxin [i.e., bacterial contamination] levels, and assess protein concentrations of [Avastin] obtained from compounding pharmacies in the United States.
Design and Setting: Prospective in-vitro study of syringes containing intravitreal preparations of [Avastin] from compounding pharmacies. This study was conducted at a university-based, good-manufacturing-practice facility and academic ophthalmology practice.
[Note: A prospective study measures a group of individuals or samples over time and follows up with them in the future.]
Results: There were no microbial contaminants or endotoxin detected in any of the samples. Of the 21 compounded samples of [Avastin] obtained from 11 pharmacies, 17 (81%) had lower protein concentrations … compared with [Avastin] acquired directly from Genentech. In 3 of 10 compounding pharmacies where more than 1 sample was available, there were statistically significant differences in the protein concentration between samples from the same compounding pharmacy.
Conclusions and Relevance: Test results from intravitreal preparations of [Avastin] acquired from compounding pharmacies were negative for microbial contaminants and endotoxin. However, there were significant variations in protein concentration that appear in general to be lower than [Avastin] acquired directly from Genentech. The clinical implications of these variable protein levels remain uncertain.
VisionAware will continue to report on Avastin compounding research as it becomes available.