Compounding Pharmacies: Recent Outbreaks of Infection and Implications for the Care of Patients with Age-Related Macular Degeneration
The current management of patients with neovascular age-related macular degeneration (AMD) relies on medication delivered by serial intravitreal injections. Some of this drug supply consists of off-label bevacizumab, prepared by compounding pharmacies by the sterile transfer of drug to individual-use tuberculin syringes. Recent infectious outbreaks from compounded drugs, most notably the fungal meningitis cases linked to New England Compounding Center, illustrate the "compounded" nature of harm that can result from improperly compounded drugs.
A recent major outbreak of endophthalmitis associated with the use of compounded bevacizumab in South Florida highlights the consequences of improper compounding related to the care of patients with neovascular AMD. After 12 patients developed severe endophthalmitis following intravitreal injection of bevacizumab,1 an investigation conducted by the Food and Drug Administration (FDA) revealed Streptococcus mitus and oralis in unused, prefilled syringes of bevacizumab. Three patients who developed endophthalmitis associated with this outbreak underwent enucleation or evisceration due to the severity of infection. Flaws in sterile technique and quality control of this compounding pharmacy were documented by the FDA.2
How can patients be protected from improperly compounded bevacizumab? It is extremely important for health care providers who use compounded medications to "know" the compounding pharmacy from which they order medications. Keep a binder with copies of pharmacy licenses, inspection forms, certifications, and testing results. Good practice requires pharmacy compliance with United States Pharmacopeia (USP) <797> guidelines. In addition, consider using a facility accredited by the Pharmacy Compounding Accreditation Board (PCAB) which inspects sites independently.3
It is important to confirm that microbiologic testing is performed on all compounded medications; this testing may be performed by the compounding pharmacy or an outside lab.4 USP <71> recommends that 10% of the syringes from each lot be tested and the drug be held 2 weeks until testing confirms sterility.4 Make sure that the compounding pharmacy is not shipping drugs prior to confirming the final sterility inspection is clean and that a written report of sterility testing accompanies each shipment of medication.
How long are syringes of compounded bevacizumab "good?" The literature supports a conservative beyond use date of 3 months for compounded bevacizumab;5 however, microbiologic testing must be performed prior to release of these samples. Otherwise, a beyond use date for no greater than 14 days is used for low- risk refrigerated compounds.4 In the ophthalmologist's office, recommended practices include recording the medication lot number and using different lot numbers for bilateral injections.
Several states have recently increased regulations on compounding pharmacies such as requiring an individual prescription for each syringe of compounded medication, which makes timing medication orders and storing the supply challenging. However, consistent with USP <797>, a primary focus on medication sterility is the most critical factor to impact patient safety. When bevacizumab has been compounded using good practices, the incidence of infection is low.6 The ophthalmologist should take an active role in helping to ensure a safe supply of compounded medications.
1. Goldberg RA, Flynn HW, Jr., Isom RF, Miller D, Gonzalez S. An outbreak of streptococcus endophthalmitis after intravitreal injection of bevacizumab. Am J Ophthalmol 2012;153:204-208 e201.
2. Singleton ER. Warning Letter FLA-12-37 Infupharma, LLC. Public Health Service Food and Drug Administration, Florida Division. July 30, 2012. http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm317190.htm
3. American Academy of Ophthalmology. Verifying the source of compounded bevacizumab for intravitreal injections-February 2012. Clinical Statement: San Fransisco, CA: American Academy of Ophthalmology; 2012. http://one.aao.org/clinical-statement/verifying-source-of-compounded-bevacizumab-intravi-2
4. Yaniv AW. Implementing a pharmacy-based sterility testing program. Pharmacy Purchasing & Products 2010;7:2-4.
5. Bakri SJ, Snyder MR, Pulido JS, McCannel CA, Weiss WT, Singh RJ. Six-month stability of bevacizumab (Avastin) binding to vascular endothelial growth factor after withdrawal into a syringe and refrigeration or freezing. Retina 2006;26:519-522.
6. Moshfeghi AA, Rosenfeld PJ, Flynn HW, Jr., et al. Endophthalmitis after intravitreal vascular [corrected] endothelial growth factor antagonists: a six-year experience at a university referral center. Retina 2011;31:662-668.
About our author(s):
Colleen M. Cebulla, MD, PhD
Assistant Professor, Vitreoretinal Diseases and Ocular Oncology
Havener Eye Institute, The Department of Ophthalmology and Visual Science
The Ohio State University