Results of ISMP's Survey on Drug Storage, Stability, Compatibility, and Beyond Use Dating

ISMP Medication Safety Alert 

In This Article

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 (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). 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.

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