More than 1,200 oncology patients in five Canadian hospitals received diluted doses of gemcitabine and cyclophosphamide for a year or longer because labels on bags of premixed IV drug solutions prepared by an outsource compounding pharmacy did not make clear that the bags were intended for single individuals only, ongoing investigations have revealed.
In its May newsletter, the London Health Sciences Centre, where 651 adults and 40 children were said to have received insufficient doses, explained how the mistake went undetected for a year. “It was not known to us that these bags from the supplier were improperly labeled. It has since been learned that these bags were overfilled, containing small amounts of extra saline liquid. This meant that the medication concentration was lower than [what was] indicated on the label. The small amount of extra liquid was very difficult to see with the naked eye and, because several people would withdraw small amounts from the bags to prepare individual doses for patients, this overfill [and dosage dilution] went undetected.”
Although the clinical effect on patients who received the lower doses of chemotherapy remained unclear, the disclosures triggered a storm of controversy and a spate of investigations into the safety of the Canadian medication supply system as well as the lack of federal or provincial oversight of compounding manufacturers that prepare drugs for institutional use.
In May, the province of Ontario, where the compounding company and four of the five hospitals are located, issued new rules intended to close the regulatory gap. The Ontario College of Pharmacists, which governs pharmacy practice registration and regulation in the province, was given clear authority to inspect all drug preparation facilities where pharmacists and technicians work, including those of compounding manufacturers.
Implications for U.S. Practice
The diluted chemo drug issue, while limited to Canada, has wider implications for pharmacists in other countries, including the United States, which is in the midst of its own broad effort to strengthen regulation of compounding pharmacies following last year’s deadly fungal meningitis outbreak originating in Massachusetts.
Michael R. Cohen, RPh, MS, ScD, the president of the Institute for Safe Medication Practices (ISMP), said the Canadian underdosing issue highlighted the need for more rigorous universal standards for preparing, labeling and administering chemotherapy and other high-alert drugs. He noted that even in U.S. hospitals, there is “an inconsistency in the way we make things in IV admixture areas” that “can lead to serious errors.”
He explained that some pharmacists just add drug to the IV bag, intending that the bag’s entire contents be administered. Others draw fluid out of the bag so that “exactly the right amount is given. But unfortunately, some of it gets hung up in the IV tubing,” and a patient might not receive the full dose. Still other pharmacists, he said, start with an empty bag and put in the exact amount, and “again [a patient] may not get the whole dose because there could be 20 mL left in the IV tubing at the end of the infusion.”
Clearly, such problems are common on both sides of the border. In April, ISMP Canada called for a national standard for labeling chemotherapy solutions with overfill volumes, in direct response to the Ontario underdosing errors.
Dr. Cohen noted that his organization had worked with its Canadian counterpart on an earlier initiative to help hospitals and ambulatory care centers worldwide evaluate the safety of their oncology drug programs. The result of the collaboration was the 2012 ISMP International Medication Safety Self Assessment (IMSSA) for Oncology. Dr. Cohen said only 50% of those who responded to the self-assessment survey reported that there was a standard way by which their hospitals prepared and labeled oncology drugs for administration.
No Patient Harm? Still Unknown
Could the chemotherapy underdosing in Canada have led to patient harm? “Not in terms of toxicities,” said Ryan Zimmerly, PharmD, an oncology pharmacist at St. Luke’s Mountain States Tumor Institute, in Fruitland, Idaho, “but potentially in terms of responses. That is something we will never know. There is some leeway as to the strength of the product you’re compounding, but in no way would 20% ever be within that window. And as a patient, knowing that you didn’t get a full dose, there would always be the question in your mind: Did that have an effect?”
Dr. Zimmerly noted that the Canadian compounding facility prepared the chemotherapy bags “in the same way you would typically see done for an individual patient.” But he added, “Never do you give standardized doses of chemotherapy. It would be rare that everybody got 2,000 mg of gemcitabine or 1,500 mg of cyclophosphamide. All of those doses are tailored based on patients’ height and weight and on organ function, whether hepatic or renal. It would be hard for me to believe that they didn’t think that those medications were being used on multiple patients, but they claim they didn’t.”
Dr. Zimmerly pointed out that “if you use a premixed bag and dilute your chemotherapy to reconstitute it and infuse it back into that bag, it’s standard that there is overfill in the bag. That’s not a concern if it’s used for a single patient, because the whole volume gets infused. But if you try to come up with an exact concentration for the bag, there is no way to do that without drawing everything out and measuring the exact volume. So if you’re going to manufacture something that’s not patient-specific, you would probably want to do that as an exact volume. You would use an empty bag and put in the exact amount of fluid that you want to have in there.”
Echoes of NECC?
Although the Canadian situation has certain similarities to the U.S. meningitis outbreak, which was tied to tainted medications manufactured by the New England Compounding Center (NECC), Dr. Cohen said there was at least one key difference. “I don’t think there are too many U.S. hospitals that would order chemotherapy bags from an outsourcer—whether multiple-dose containers or single-dose—although there may be some oncology clinics that do. It probably takes place now and then—maybe syringes, for example. But chemotherapy drugs are hard to transport. You’re always worried about leakage and breakage.”
But for hospitals that do order oncology drugs from outsourcers, there are steps that pharmacists can take to minimize the risk for errors, said Lisa Holle, PharmD, BCOP, immediate past president of the Hematology/Oncology Pharmacy Association and an assistant clinical professor at the University of Connecticut School of Pharmacy and Neag Cancer Center, in Storrs. “The best thing that a pharmacist can do is to be as responsible as possible to ensure the integrity of the supply chain,” Dr. Holle said. “So if you’re not preparing the drug in your setting, then it is important to understand the integrity of the facility where the drug is prepared and what the guidelines are for that facility.”
Dr. Holle recommended using known vendors with a reputation for quality and safety—ones that adhere to United States Pharmacopeia Chapter <797> standards and employ pharmacists trained in oncology practice. “An oncology pharmacist can be crucial to ensuring that all of the rules and regulations associated with safe manufacturing practices are followed,” she said, adding that such pharmacists should have full access to information for every patient, including diagnosis and lab values, in order to assure that doses are appropriate and compatible with other drugs the patients may be taking.
“Ideally, it would be helpful for oncology pharmacists to be involved in the whole spectrum of care.”