The Cost of Compounding
Though ophthalmologists want to do what’s best for their patients, as in most areas of life, cost is a major factor; and there is a significant cost difference between the anti-VEGF medications.
In 2015, the American Society of Retina Specialists asked its members, “If Avastin, Lucentis and Eylea were the same cost for each patient, which drug would you use primarily for the treatment of new-onset exudative AMD?”2 Less than 10 percent indicated that they would use Avastin first, even though, in the real world, it’s actually the preferred first-line drug for 64 percent of ophthalmologists. Findings such as this show just how important cost is when choosing anti-VEGF medications.3
|After being used for a single injection in one patient, vials of Food and Drug Administration- approved anti-VEGF drugs start to pile up, physicians say.|
However, even though Avastin is cost-effective, it has a potential drawback, too: It needs to be compounded in order for it to be usable in the eye. This drawback looms large due to an outbreak of fungal meningitis from three lots of preservative-free methylprednisolone acetate compounded at the New England Compounding Center in September 2012. Further, in an article in JAMA Ophthalmology in 2013 by one of this article’s co-authors, Alan Sheyman, MD, he and his colleagues described a series of eight patients who received an intravitreal injection of compounded combined bevacizumab-triamcinolone from the same lot—who were later diagnosed with fungal endophthalmitis.4 This outbreak occurred despite the current practice of compounding pharmacies and outsourcing facilities performing microbiological testing on their compounded bevacizumab.
In addition to the obvious risk to patients in terms of complications and morbidity from using medications from compounding pharmacies and outsourcing facilities, prescribing a compounded drug may expose an ophthalmologist to liability if a patient has a negative outcome, especially if a suitable FDA-approved product is available.5 What’s more, ophthalmologists should be aware that if a claim arises, medical malpractice insurance companies may refuse coverage if a physician used non-FDA approved drugs.6 Despite the risks, some may still feel that the cost difference between bevacizumab and the FDA-approved medications is significant enough to justify compounding. However, even the Pharmacy Compounding Accreditation Board’s Principles of Compounding states, “Price differences are not a ‘significant’ difference to justify compounding.”7
In response to the fungal meningitis outbreak, the Food and Drug Administration imposed stricter regulations on compounding pharmacies, including the mandated use of patient-specific prescriptions, which requires the pharmacy to only make one compounded drug for one specific patient rather than a large lot of it. However, a recent study of one retina practice showed that these PSP’s reduced the use of Avastin by 32.7 percent. The study authors state, “Although PSP’s of compounded medications improve patient safety, a burdensome effect on the practice of medicine occurs, leading to a shift to more expensive but more convenient alternatives, namely on-label medications.”8
In some of the authors’ own practice, we have a collection of Eylea and Lucentis vials that had been used a single time on a single patient, and still contain a lot of residual medication: Each vial contains 0.2 ml of drug, while the required dosage of medication is only 0.05 ml.
Against this backdrop of the questionable safety of Avastin and its production in compounding facilities, coupled with the apparent availability of non-compounded medication remaining in these vials, we got to wondering if we could safely use those vials again. We performed the following study to find an answer.
For our study, we collected 60 Lucentis and 40 Eylea vials (a total of 100 vials) over the course of three years (2012 to 2015) after single dose/single patient use by a retina specialist (Dr. Cohen). All these vials had been stored over the course of those three years at room temperature in a bag on the shelf. Lucentis expiration dates ranged from 3/2014 to 9/2017, and Eylea dates ranged from 1/2015 to 3/2016. A third of the vials were used in 2013; a third were used in 2014 and a third were used in 2015. To administer the injections, Dr. Cohen retrieved the medicine by first removing the metal cap, wiping the rubber stopper with alcohol, removing the medicine with the 19-ga. filter needle and finally switching to a 30-ga. needle before intravitreal injection. Only the patient wore a facial mask.
We took the medication to a microbiology lab at New York University where the residual drug was removed from each vial. Under a sterile hood, we first cleaned each vial with alcohol for 10 seconds and then with Betadine for another 10 seconds. A sterile syringe with a 25-ga. needle was used to extract 0.05 ml of medication from each vial. We then plated the medication equally among blood agar and Sabouraud agar plates in an attempt to grow bacterial and fungal colonies. Then, we placed the 100 blood agar plates in an incubator at 98.6 degrees Fahrenheit for four days; we incubated the 100 Sabouraud agar plates at room temperature for three weeks. After incubation, we photographed each plate and examined it for bacterial and/or fungal growth. What we found was extremely intriguing: All 100 blood agar plates and 100 Sabouraud plates were negative—there was no bacterial or fungal growth.
In our view, even though this was a small-scale study, the lack of contamination of 100 vials of Lucentis and Eylea calls into question the FDA’s and Medicare’s policies on the use of residual medication in such vials. Drawing more medication from a single vial isn’t unprecedented: It may be surprising to know that in a survey by the Joint Commission, 6 percent of health-care practitioners admitted to sometimes or always using single dose vials for multiple patients. Also, according to a JAMA study in 2010, 28 percent of all ambulatory surgery centers admitted to using single-dose vials for multiple patients.9 Nonetheless, governmental guidelines are intended to protect patients from infections where vials become contaminated from unsafe injection practices, and we completely support the spirit of the law. The fact remains, however, that our study showed no bacterial or fungal growth in the residual medication in these 100 vials over the course of three years of storage, a strong testament to the fact that these vials can most likely be reused safely. In the coming years, we hope to see a larger-scale evaluation of the stability of these drugs over time to reinforce our findings and possibly convince the powers-that-be to eliminate risk—and waste—from the system. REVIEW
Mr. Atallah and Ms. Von Sneidern are in the pre-med program at New York University. Dr. Sheyman is a retinal specialist at Northwestern University in Chicago. Dr. Cohen is a retinal specialist at Mt. Sinai Medical Center in New York City. The authors would like to acknowledge Joel S. Mindel, MD, PhD, director of neuro-ophthalmology at Mt. Sinai School of Medicine in New York City, for his editorial review. None of the authors have a financial interest in the products discussed.
1. Bagian JP, Federico F, Barnsteiner JH, Battles JB, Beeson WH, Benjamin, Swenson D. Preventing infection from the misuse of vials. Sentinel Event Alert 2014;52:1-6.
2. Stone TW, ed. American Society of Retina Specialists 2015 Preferences and Trends Membership Survey. Chicago: American Society of Retina Specialists.
3. Thompson JT. Patient and physician convenience and the choice of intravitreal anti-vascular endothelial growth factor medications. JAMA Ophthalmol 2016;134:1:49.
4. Sheyman AT, Cohen BZ, Friedman AH, Ackert JM. An outbreak of fungal endophthalmitis after intravitreal injection of compounded combined bevacizumab and triamcinolone. JAMA Ophthalmology 2013;131:7:864.
5. Seller S, Utian WH. Pharmacy compounding primer for physicians: Prescriber beware. Drugs 2012;72:16:2043-2050.
6. Kabnick LS. Compounded sclerosants and foam: What should you know about this controversial area? Legal guidelines for use of polidocanol and sodium tetradecyl sulfate for sclerotherapy. Veith Symposium;19-23 Nov 2008;New York.
7. Pharmacy Compounding Accreditation Board: PCAB Principles of Compounding, 2012. https://secure.pcab.info/about/downloads/principles-of-compounding.pdf. Accessed February 2016.
8. Holfinger S, Miller AG, Rao LJ, Rowland DY, Hornik JH, Miller DG. Effect of regulatory requirement for patient-specific prescriptions for off-label medications on the use of intravitreal bevacizumab. JAMA Ophthalmol 2016;134:1:45-8.
9. Schaefer MK, Jhung M, Dahl M, Schillie S, Simpson C, Llata E, Perz JF. Infection control assessment of ambulatory surgical centers. JAMA 2010;303:22;2273-2279.