Patient Safety Tip of the Week

May 5, 2015    Errors with Oral Oncology Drugs



Most reports on chemotherapy errors have focused on IV or intrathecal chemotherapy agents. But oral chemotherapy agents have been increasing in number and reports of errors relating to them are beginning to appear. Several recent articles provide important lessons to avoid such incidents.


ISMP Canada last month published an analysis of incidents involving oral chemotherapy agents that were reported to their incident database or to a national Canadian incident reporting database (ISMP Canada 2015). They analyzed 516 incidents over a 12 year period and while patient harm or death occurred in only a small minority of cases there were multiple lessons learned. They were able to identify 3 major themes: (1) lack of specialized knowledge by care providers (2) medication name mix-ups and (3) lack of safe medication handling processes. They provide case examples to illustrate each of these themes.


Chemotherapy regimens can be very complex and ISMP Canada notes that community pharmacists may not have a good understanding of chemotherapy cycles, side-effect profiles, etc. The same applies to many other non-oncologist healthcare professionals. As a result, patient education on these complex issues may be insufficient. The example they provide is a patient who was on a protocol-defined capecitabine cyclical dosing regimen who was mistakenly given capecitabine daily when admitted as an inpatient and then the prescription given the patient at discharge also erroneously called for daily capecitabine. You may recognize this problem of prescribing a drug daily rather than on a different regimen because we’ve written about very similar problems with methotrexate in the past (see our What’s New in the Patient Safety World columns for July 2010 “Methotrexate Overdose Due to Prescribing Error” and July 2011 “More Problems with Methotrexate”).


As a subtheme of the “lack of specialized knowledge” they mention that failure to include some critical information on the prescriptions may contribute. Such information might include diagnosis, patient height and weight, duration of the chemotherapy cycle, etc.


The second theme, medication name mix-ups, of course is not unique to chemotherapy agents. The ISMP Canada study notes a partial list of some of these easily mistaken drug name pairs, which may include confusion between brand names, between generic names or between brand and generic names. (Note that ISMP Canada is putting together a list of easily confused medications with TALLman lettering recommendations and ISMP in the US has recently updated its list of confused medication names.) It discusses the importance of using TALLman lettering to help avoid such errors, as well as including the indication and both brand and generic drug names on prescriptions and use of barcoding. Note that another recent article (O’Rourke 2015) identifies several factors make this particularly problematic in oncology. For example, the names of many chemotherapy agents end in “nib”.


The third theme in the ISMP Canada report is lack of safe handling procedures. Remember - many chemotherapy agents are hazardous substances and precautions must be taken to prevent exposure of healthcare workers, caretakers, etc. to these substances. Prominent warning labels should be used and standardized procedures for handling these medications are needed. The latter would include things like designating who can prepare, dispense, or administer such agents and appropriate precautions such as use of personal protective equipment and use of designated devices. An example given was failure to properly clean a tray that had been used for filling a hydroxyurea prescription before using the tray to fill another prescription. They also note use of automated packaging technologies, particularly in the long-term care setting, may inadvertently contaminate multiple medications if the packing device is exposed to hazardous chemotherapy agents.


ISMP Canada also cautions hospitals to be wary of allowing patients to use their own supply of medications when hospitalized because this may bypass many of the safety interventions put in place to prevent such incidents.


Many of these issues were identified in a classic article on medication errors related to oral chemotherapy (Weingart 2010). Weingart and colleagues identified issues with oral chemotherapy from a variety of sources. They identified over 500 such errors, including 99 actual adverse drug events. While many of the remaining events were near-misses they did provide the opportunity for patient harm and thus were helpful in identifying potential vulnerabilities. The most common complications with harm involved bone marrow suppression or compromise of treatment efficacy. The errors identified occurred in every stage of the medication use process and involved oncologists, pharmacists, nurses, patients, and patients’ families or friends. Wrong dose errors were most frequent but wrong drug errors also occurred. One particularly salient problem was supplying the wrong number of days. As noted above, chemotherapy regimens may be very complex and involve cycles and different dosing at different times so this can result in confusion for patients, pharmacists, and other healthcare workers. Actually, last year ISMP provided an example of this in an unfortunate incident where a woman being treated for a brain tumor received an overdose of lomustine (ISMP 2014). A mail order pharmacy dispensed a 3-dose supply of lomustine rather than a single dose. The patient, who had been used to taking her previous chemotherapy as a single dose, took the whole supply of lomustine as a single dose before she realized the mistake. This led to a protracted painful death with bone marrow suppression. Ironically, this was not the first such case. ISMP noted multiple prior similar errors. ISMP recommended that prescribers always specify a single dose when prescribing lomustine and specifically provide both verbal counselling and written instructions for the patient. Pharmacies and pharmacists should program alerts into their computer systems to specify “single dose only” (ISMP also suggests avoiding mail order pharmacies for such drugs since they often provide multi-month supplies and payors should only pay for single doses of such drugs) and do appropriate counselling of patients. They also note the FDA and manufacturers need to ensure that warnings appear in a much more obvious way for such drugs.


Weingart et al. also noted several cases where health literacy issues and language barriers probably played a role. The wrong drug errors were often due to look-alike sound-alike (LASA) confusion and were likely to involve chemotherapy agents being given to patients who did not have cancer. They also identified missed dose errors, errors related to confusing or ambiguous instructions, incomplete prescriptions, and others.


Importantly, the Weingart study demonstrated that the types of errors identified varied significantly by the source of the reports, i.e. reports from hospital sources differed from those from pharmacy sources, and so on.


One recent article described the team approach at Memorial Sloan-Kettering to preventing oral chemotherapy agent errors (O’Rourke 2015). Among common causes of chemotherapy errors they noted ones that may affect any medication, such as miscommunicated verbal orders, interruptions, LASA issues, use of abbreviations, packaging/labeling issues, legibility/fax issues, and drug shortages. They again highlighted the issue of taking daily doses when a different regimen was intended and provide examples, including the ones regarding methotrexate and lomustine that we discussed earlier. But they also point out that many chemotherapy agents have interactions with medications patients are taking for other medical conditions and provide a list of selected interactions. They stress a team approach and use of standardized protocols and processes. They also stress one of our frequent recommendations (“stories not statistics”), noting that the presentation of actual events is a powerful tool in educating staff about possible errors.


One particular concern with chemotherapy agents is dose calculation. Doses for some drugs are based upon the patient’s weight or body surface area (BSA), the latter requiring knowledge of the patient’s height. Any time we are dealing with dose calculations the issue of decimal points arises. In our September 9, 2008 Patient Safety Tip of the Week “Less is More…and Do You Really Need that Decimal?” we discussed whether numbers should ever follow a decimal point. They may be important in certain circumstances (eg. for a dose of 0.3 mg or 2.7 mg of a drug you would avoid rounding). However, at higher doses they become much less relevant and rounding of the dose is appropriate. For example, let’s say you performed a calculation and the result was a recommended dose of a drug is 72.2  mg. Is there really a difference if the patient gets 72 mg or 72.2 mg of most drugs? Yet ordering the latter dosage increases the risk that the decimal point may not be seen or not input into a computer or missed in a faxed order and the patient gets a 10x overdose. So we strongly recommend that in writing medication orders one specifically decides whether such fractional doses are important or merely place the patient at increased risk of an error.


Speaking of weight-based and BSA-based dose calculations, making the ECRI Institute Top 10 list for patient safety concerns for 2015 were medication errors related to pounds and kilograms (ECRI 2015). Calculations done mixing up pounds and kilograms can result in roughly a two-fold error in calculated dose. Especially for oncology drugs that have a very narrow therapeutic index and safety margin, such errors could easily result in toxicity or in lack of efficacy, depending on which direction the error is made in.


ECRI recommends doing away with scales that measure in pounds in healthcare settings and requiring all weights be input into EHR’s using only kilograms. Note that one could still erroneously enter a value in pounds in an EHR field but clinical decision support tools can at least compare a value to an expected weight and flag those falling outside that range. But it’s not failsafe. A PPSA advisory (PPSA 2009) on the importance of accurate weights in avoiding medication errors did not list chemotherapy agents among their most frequently reported medication errors but nevertheless had important recommendations. PPSA also recommends including the date of the weight. That might be particularly relevant to oncology patients who may have had significant weight change since the last recorded weight.


Both the ISMP and Memorial Sloan-Kettering experiences look to use of computerized tools to help prevent such errors. Using CPOE (computerized physician order entry) or e-prescribing systems has the advantage of automating dose calculations, thereby reducing some potential errors. They also provide easy access to standardized order sets. They also have the advantage of being able to use clinical decision support tools for generating alerts for excessive doses, etc.


Partners Healthcare and the Dana Farber Cancer Institute built a system for electronically prescribing oral chemotherapy agents (Weingart 2012). That system provided support for calculating doses based upon patient weight or body surface area and even calculations for toxicity-related dose adjustments. It also included a field for the primary cancer diagnosis, which could either be imported from other fields in the EHR or input by the ordering clinician, and another field for indicating reason for the chemotherapy agent (eg. curative, adjuvant, palliative). Clinicians could also input items such as the cycle number or a clinical trial number. The system also had the other capabilities we expect in e-prescribing systems like allergy alerts, drug-drug interaction alerts, renal dose warnings, etc. The system was well-accepted by clinicians. The reason for the chemotherapy agent was seldom entered. The primary cancer diagnosis was entered in about half the cases, perhaps because that diagnosis was often imported from other fields. There was also a free-text field where prescribers could enter things like clarifying the number of tablets of different strengths that should be taken together. Alerts were triggered in 5.9% of prescriptions but most were actually not helpful (the dose-limit for some drugs had been set below the currently used standard). Overall, 6 drugs accounted for 83% of the prescriptions, likely reflecting the patient population served by the study hospitals and practices. They learned some valuable lessons for building such systems. One was that use of the diagnosis and reason/intent field was suboptimal. Clinicians also need easier ways to indicate things like cycle number, days per cycle, nontreatment days, and instructions for combining tablets of different strength. They also learned that dose-limit alerts need to be updated regularly to keep up with current practice standards.


Another study compared non-intercepted dose errors for chemotherapy agents in paper-based vs. computer-based systems (Mattsson 2015). They found an overall risk of a prescription dose error of 1.73 per 100 prescriptions (1.60 for CPOE and 1.84 errors per 100 prescriptions, a nonsignificant difference). Fifteen different types of errors and four potential risk factors were identified. They found the computer system reduced the risk of calculation errors but introduced other errors. The Mattsson and Weingart studies highlight the potential of computerized systems to reduce errors but both show we have a long way to go in reaching that goal.


A handy monograph on preventing chemotherapy errors (Kloth 2010) has a great list of the “Do’s” and Do Not’s” of prescribing. Many of the “Do Not’s” apply to all prescribing, not just chemotherapy agents (eg. abbreviations, trailing zeros, lack of zero preceding decimals, etc.). But a few are especially important when chemotherapy drugs are used. Kloth recommends never using verbal orders for chemotherapy. Also describing “vials” should not be done since vials of chemotherapy agents come in so many sizes and concentrations. He also cautions against using outdated laboratory results for those agents that may be affected by things like renal or hepatic function. Among the “Do’s” is always writing the full name (preferably the generic name) of the drug. For doses greater than 5 mg use rounding so no digits appear after a decimal point (see above). He also emphasizes the importance of double checks. In our October 16, 2012 Patient Safety Tip of the Week “What is the Evidence on Double Checks?” we concluded that double checks remain a relatively weak safety intervention and they are prone to errors but, done correctly, the independent double check probably does provide an additional element to our defenses against errors. Particularly for high-alert medications, such as chemotherapy agents, doing independent double checks at multiple stages makes a lot of sense.




Our prior columns related to chemotherapy safety:








ISMP Canada. Analysis of Incidents Involving Oral Chemotherapy Agents. ISMP Canada Safety Bulletin 2015; 15(4): 1-4, April 22, 2015



ISMP (Institute for Safe Medication Practices). ISMP’s List of Confused Drug Names. Updated February 2015



O’Rourke K. Preventing Oral Chemo Errors: A Team Approach. Pharmacy Practice News 2015; 42: 1-4 March 2015



Weingart SN, Toro J, Spencer J, et al. Medication errors involving oral chemotherapy. Cancer 2010; 116(10): 2455-2464



ISMP (Institute for Safe Medication Practices). With oral chemotherapy, we simply must do better! ISMP Medication Safety Alert! Acute Care Edition. July 17, 2014



ECRI Institute. Top 10 Patient Safety Concerns for 2015



PPSA (Pennsylvania Patient Safety Authority). Medication Errors: Significance of Accurate Patient Weights. Pa Patient Saf Advis 2009; 6(1): 10-15



Weingart SN; Mattsson T; Zhu J; Shulman LN; Hassett M. Improving electronic oral chemotherapy prescription: can we build a safer system? Journal of oncology practice/American Society of Clinical Oncology 2012; 8(6): e168-73, 2012 Nov



Mattsson TO, Holm B, Michelsen H, et al. Non-intercepted dose errors in prescribing antineoplastic treatment: a prospective, comparative cohort study. Ann Oncol 2015; 26(5): 981-986 First published online: January 28, 2015



Kloth DD. Guide to the Prevention of Chemotherapy Medication Errors. Second Edition. New York: McMahon Publishing 2010






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