Results of Our Survey on Drug Storage, Stability, Compatibility, and Beyond Use Dating
ISMP would like to thank the 715 practitioners, mostly pharmacy directors and managers, staff pharmacists, clinical pharmacists, and medication safety pharmacists, who responded to our recent survey on drug storage, stability, and beyond use dating of injectable drugs. We conducted the survey to learn more about what resources pharmacists rely on to guide drug storage, stability, and beyond use dating. We were specifically interested in learning about conditions that may result in unnecessary waste of drugs during the ongoing drug shortage crisis or waste of very expensive medications given the ever rising cost associated with healthcare.
Survey background. The Centers for Medicare & Medicaid Services (CMS) standard 42 CFR §482.25(b)(3) states that “Outdated, mislabeled, or otherwise unusable drugs and biologicals must not be available for patient use.” To avoid the use of outdated drugs, CMS requires pharmacists to follow the manufacturer’s directions regarding storage, stability, and beyond use dating in the official US Food and Drug Administration (FDA)-approved prescribing information (package insert) [§482.25(a)]. The Joint Commission follows guidance from CMS on this issue, and surveyors from both agencies have cited organizations for not following the explicit directions in the manufacturer’s package insert when it comes to drug storage, stability, and beyond use dating.
Only following the manufacturer’s directions for injectable medications has proven difficult and wasteful in some situations for two primary reasons: 1) complete information on storage, stability, compatibility, and beyond use dating is often not provided in the official prescribing information, and 2) newer, evidence-based information on these matters can sometimes be found in peer reviewed journals and compendia fully endorsed by national pharmacy organizations. These compendia, which are widely used by pharmacists and drug information vendors, include the American Hospital Formulary Service (AHFS) Drug Information, Trissel’s 2 Clinical Pharmaceutics Database (electronic), Trissel’s Handbook on Injectable Drugs, and the King Guide to Parenteral Admixtures. Pharmacists should be able to use evidence-based criteria from the compendia and peer reviewed journals as long as they conform to sterility standards published in the United States Pharmacopeia (USP) Chapter <797>.
If information on storage, stability, and beyond use dating is not available in the manufacturer’s directions, CMS and The Joint Commission defer to recommendations available through nationally recognized sources. But CMS is confronted with a dilemma if the official, FDA-approved manufacturer’s directions differ from newer, evidence-based recommendations in national compendia. CMS is reviewing this matter further. We are hoping the results of our survey, as described below, provide CMS with some baseline information to support its review process.
Survey results. Before taking our survey, 16% of respondents were not aware of the CMS regulation and interpretive guidelines that require pharmacists to store drugs and biologicals in accordance with the manufacturer’s directions and State and Federal requirements. Seventeen percent of respondents were unaware that the manufacturer’s directions for some injectables differ from evidence-based information on storage, stability, and beyond use dating provided in national compendia. Some (29%) of the respondents who were not aware of the CMS regulation were also among the respondents who were not aware of the differences between the manufacturer’s directions and compendia recommendations.
Only half of all respondents said they always follow the manufacturer’s directions, when they exist, regarding drug storage, dilution, compounding, stability, and beyond use dating. Of those who always follow the manufacturer’s directions, 88% were aware of the CMS regulation requiring this, and 80% were aware that national compendia sometimes provide information on storage, stability, and beyond use dating that differs from the manufacturer’s directions.
When asked how often respondents follow recommendations in national compendia, even if it differs from the manufacturer’s directions, most reported always (21%), often (28%), or sometimes (27%). Very few (7%) said they never follow compendia recommendations if they differ from the manufacturer’s directions.
Respondents made it clear that one of the reasons they rely on compendia recommendations is that the manufacturer’s directions often provide insufficient information. Only 2% of respondents felt the manufacturer’s directions were always sufficient in determining storage, stability, compatibility, and beyond use dating after dilution when making an admixture from a single-dose vial, multiple-dose vial, or ampul.
The other prime reason for following compendia recommendations, even if they differ from the manufacturer’s directions, is that the compendia recommendations reflect the latest evidence-based practices. About a quarter of respondents reported that, upon request, manufacturers never or rarely provide newer in-house data on extended beyond use dating that differs from the package insert. Most reported that they have sometimes (38%) received this information. If the manufacturer does provide the information, it’s in writing less than half of the time. Given these circumstances, it is not surprising that practically all (98%) respondents felt that national compendia should be used to supplement the manufacturer’s directions, even when the directions conflict.
Numerous respondents also noted that a conflict of interest may exist for the drug company regarding additional drug testing or acknowledgment of external testing related to storage, stability, compatibility, and beyond use dating. They remarked that, once a drug has been approved, the company may have little incentive to conduct additional testing on its products because the results may lead to required, costly labeling (package insert) changes and a reduction in sales if the beyond use dating is extended. In communications with FDA, we’ve learned that the agency does not routinely require manufacturers to update stability and compatibility data. FDA considers this a practice-related issue.
A vast majority of respondents (97%) feel the CMS regulation and interpretive guidelines that require strict adherence to the manufacturer’s directions for storage, stability, and beyond use dating increases waste and contributes to the drug shortage crisis when evidence-based compendia information recommends a longer beyond use dating. In fact, 36% reported that following the CMS regulation often results in unnecessary waste, and 43% said it always results in waste, thus contributing to the drug shortage crisis.
Sixty-one percent of respondents said they feel compelled to discard injectable medications according to the package insert, knowing it differs from information in national compendia. These respondents collectively reported more than 100 different medications that they felt compelled to discard despite newer evidence that extends the stability and beyond use dating or alters the storage, dilution, or compatibility directions documented in the package inserts. Examples include bleomycin, cytarabine, DAPTOmycin, dacarbazine, diazepam, epoetin alfa, various insulin analogs, and various electrolytes. More than 80% of all the medications reported by respondents have been or are currently in short supply, further contributing to the alarming drug shortages in our country. Specific differences in beyond use dating or lack of information by manufacturers on stability after dilution or withdrawal from the vial for several of these medications appear in Table 1.
Respondents also told us about very expensive medications, particularly antineoplastic agents, which were discarded according to manufacturer’s directions despite newer extended beyond use dating in national compendia. Although not all of these drugs were in short supply, the unnecessary waste of very expensive drugs drives the cost of treatment higher than necessary. Bortezomib is one example. Once reconstituted, the manufacturer recommends use within 8 hours. Newer evidence suggests that 1 mg/mL solutions may be stored at room temperature for 3 days or under refrigeration for 5 days in a vial or syringe.1 Respondents reported that a single 3.5 mg vial of bortezomib costs $1,500-$2,500. With a typical dose of 1.3 mg/m2, unused portions of drug in these vials may be discarded unnecessarily.
A serious medication safety issue was also mentioned by respondents. If the manufacturer’s directions call for very short stability and beyond use dating once the drug has been diluted for infusion, some pharmacists are not mixing the drugs in the pharmacy and are instead relying on nurses in clinical areas to perform the admixture. If more liberal beyond use dating was allowed, as recommended in national compendia, nurses may not be required to prepare infusions, even if pharmacies are not open 24 hours each day. Sterility and mixing accuracy are often compromised when admixture occurs on patient care units, and an important nurse-pharmacist independent check is lost.
Conclusion. ISMP will be sharing the results of this study with CMS and The Joint Commission to help inform any future changes in the CMS policy that involves drug storage, stability, compatibility, and beyond use dating. It is understandable that CMS would rely on the expertise of FDA—the FDA-approved package inserts in this case—as the authorized source of information regarding US drugs. But since pharmacists can’t rely on drug companies to continually test new parameters for drug storage, stability, and beyond use dating, or to quickly update the package insert to reflect new findings, they do rely on up-to-date compendia to inform best practices on these matters. We hope CMS finds the study results useful as they explore the issue of allowing pharmacists to incorporate newer evidence-based information about drug storage, stability, and beyond use dating into their practice settings.
1. Andre P, Cisternino S, Chiadmi F, et al. Stability of bortezomib 1-mg/mL solution in plastic syringe and glass vial. Ann Pharmacother. 2005;39(9):1462-6