PROBLEM: Although oral chemotherapy is associated with ease of administration, an error with an oral agent can be just as deadly as an error with a parenteral formulation of chemotherapy. Just last month, Ruth Ann Collins (Figure 1), a 60-year-old woman with a history of brain cancer, died a slow and painful death after accidentally taking the equivalent of 3 cycles of oral lomustine therapy at one time (450 mg), believing the pharmacy had dispensed just a single dose (150 mg). She had previously been taking oral temozolomide (TEMODAR), which she received from the pharmacy as a single dose made up of several different strength capsules each month. However, a 3-cycle supply of lomustine (1 dose to be taken every 6 weeks pending blood tests) had been dispensed. Assuming the newly prescribed lomustine had also been dispensed as a single dose, Ruth took all the lomustine capsules provided by the pharmacy as a single dose. The overdose accelerated the deterioration of Ruth’s physical condition and likely led to her untimely death.
Prior to taking lomustine, Ruth had visited the university-based oncologist she had been seeing every 2 months since diagnosis. Ruth’s brain tumor had increased in size despite several courses of IV irinotecan (CAMPTOSAR) and oral temozolomide. The oncologist recommended trying a single dose of lomustine 150 mg, followed by a reassessment in 6 weeks to evaluate the next steps. The oncologist at the university hospital contacted Ruth’s local oncologist to discuss the recommended therapy. The local oncologist then sent a prescription for “Lomustine 100 mg, 40 mg, 10 mg” with directions to “Take as directed” to Ruth’s mail order pharmacy. He indicated on the prescription to dispense a quantity of “1 each” and authorized 12 refills. The mail order pharmacy asked a specialty pharmacy to help fill the prescription, but it could not locate a supply of the drug, possibly due to a shortage of the 100 mg capsules. The mail order pharmacy was able to procure lomustine and sent a 3-dose supply of the drug to Ruth instead of a single dose. It is uncertain why the pharmacy sent 3 doses (an 18-week supply)—even greater than the typical 3-month supply of medications most mail order pharmacies dispense. It is also uncertain if the woman’s insurance plan played a role in the decision, since sending 3 cycles of therapy at once might be less costly. Anyway, the plan for Ruth was to try a single lomustine dose and then reassess the benefit of further doses.
The mail order pharmacy dispensed three prescription bottles. One bottle contained three 100 mg capsules; the second bottle contained three 40 mg capsules; and the third bottle contained three 10 mg capsules. The labels on the bottles provided instructions for taking a dose from each bottle for a “total of 150 mg daily once per month as directed.” (See Figure 2 for the exact wording of directions on the bottle holding 40mg capsules.) But there was no additional warning statement to reinforce that the patient should take only 1 capsule from each bottle. Ruth expected the pharmacy to dispense a single dose, and she was familiar with taking several different strength capsules for a single dose when taking temozolomide previously. Thus, she took all 3 capsules from each of the 100 mg, 40mg, and 10 mg bottles. Afterwards, she became concerned because she had taken all 9 capsules and thought she may have taken an overdose. She immediately notified her husband.
Ruth’s husband called the mail order pharmacy but did not receive a satisfactory response. He then called her local oncologist, who called a poison control center. The center advised taking Ruth to an emergency department, where she received activated charcoal (about 2 hours after taking the capsules). She returned home but quickly became very ill. By week 4 after the overdose, Ruth’s body was severely bruised and swollen, she was febrile and short of breath, she had pain over her entire body, and myelosuppression was so severe she was receiving platelet infusions every other day. Ruth suffered immense physical pain and died 6 weeks after the overdose.
Ruth’s husband of 37 years reported this error to ISMP, believing he owed it to his wife to help ensure others do not suffer the same fate. Sadly, the error that led to his wife’s death has happened before. While some labeling and packaging changes (e.g., reducing the number of capsules in each manufacturer’s container) were made previously, clearly, not enough had changed to prevent his wife’s death.
ISMP has previously published at least five similar errors with lomustine in which more than 1 dose was dispensed and taken, either all at once or daily instead of every 6 weeks. The earliest error was described in 1977 in Hospital Pharmacy (vol. 12, p. 191) and recounted in the 1981 book, Medication Errors: Causes and Prevention (eds., Davis NM, Cohen M). A pharmacy had dispensed two 100 mg doses of lomustine with a label that said, “2 capsules, 100 mg.” The patient thought that meant to take both capsules together for a 100 mg dose. In a 2004 ISMP Medication Safety Alert! Acute Care newsletter (www.ismp.org/sc?id=383), ISMP published 3 lomustine errors. In one case, an oncologist ordered a single dose of lomustine for a hospitalized patient, but a pharmacist mistakenly entered the drug as a daily dose, which the patient received for 5 days. Another error originated in a community pharmacy where a pharmacist dispensed a full bottle of lomustine to the patient, which at the time contained 20 capsules. Knowing that lomustine was rarely prescribed and not wanting to discard the remaining capsules, he dispensed the entire bottle. While the directions stated to take just 4 capsules, the patient misunderstood the directions and took 4 capsules daily for 5 days. The third error led to the death of a 24-year-old woman. A poorly legible prescription for lomustine 150 mg every 6 weeks was mistaken as daily for 6 weeks, which the patient took for 21 days before she was hospitalized and died.
Dispensing more than 1 dose
The primary cause of the error that accelerated Ruth’s death was the dispensing of 3 doses of lomustine rather than a single dose. The prescribing information in the lomustine package insert notes that, “Only the appropriate number of lomustine capsules required for the administration of a single dose should be dispensed.” However, this information is buried in the package insert and is not conspicuous or near the top of the insert. In addition, the carton label of the lomustine product available in the US (NextSource Biotechnology) states, “Caution: DO NOT DISPENSE ENTIRE CONTAINER. Dispense only enough capsules for one dose.” Again, the warning is not as conspicuous as needed to ensure detection, as it is located in a dark color band at the bottom of the label (Figure 3).
The latest lomustine error clearly demonstrates that statements in the package insert and warning labels on cartons are not enough. In fact, we called three different large chain pharmacies earlier this month to ask about lomustine dispensing practices, and the pharmacists said they would dispense multiple doses of lomustine as long as the patient could pay or their insurance would cover it. This violates the US Food and Drug Administration (FDA)-approved label and package warnings from the manufacturer.
Taking more than 1 dose
While not a factor in dispensing more than a single dose of lomustine, the product’s package insert repeatedly directs pharmacists to counsel patients prior to dispensing lomustine. In practice, patient counseling occurs infrequently except in a few states where it is mandated. If it is done, counseling directives from the manufacturer may confuse patients. For example, pharmacists are directed to teach patients to take all the lomustine capsules in the container at the same time. Also, certain drug information leaflets provided to patients when dispensing lomustine contain this statement: “In order that you receive the proper dose of lomustine, there may be two or more different types of capsules in the container. This is not an error. It is important that you take all of the capsules in the container at the same time so you receive the right dose of the medicine.” A patient who is given more than a single dose of lomustine and also misunderstands the directions for use might read this information and take all the capsules at once.
SAFE PRACTICE RECOMMENDATIONS: To safely manage oral lomustine therapy, consider these recommendations.
- Specify a single dose. With lomustine prescriptions, specify dispensing just a single dose at a time. Do not prescribe more than a single-dose supply of the drug.
- Provide written instructions. Review the dosing instructions with the patient and provide written instructions if the patient will be self-administering the dose. Remind patients they should not simply assume they should take all the capsules in the bottle(s).Tell the patient to compare the prescriber’s written instructions with the pharmacy label, and to call if there are any questions before taking the dose.
- Be specific with patients. Patient counseling is critically important, and the drug should never be prescribed without talking to the patient. Warn patients that a single dose should be taken no sooner than every 6 weeks, and that they should follow the directions on the label of the prescription bottle(s) to be sure they are taking a single dose.
- Program alerts. Program warning messages such as “dispense single dose only” into order entry systems. Computers should not allow more than a single dose to be entered. Also configure the system to limit the quantity prescribed or dispensed to 300 mg or less for each prescription. Hard stops that won’t allow you to dispense the drug more than once every 6 weeks would also be helpful.
- Dispense a single dose. Provide just 1 dose of lomustine per filled prescription. If multiple doses are prescribed, call the prescriber to request dispensing a single dose.
- Combine strengths. If allowed by state regulations, place the capsules comprising a single dose in a single vial (e.g., patient medication packet that complies with all label regulations to specify the vial contents and communicate that it holds a single dose).
- Provide patient counseling. Establish a system to ensure that patients receive counseling when picking up new prescriptions and refills for lomustine (e.g., electronic stop in the sales register that requires intervention and acknowledgement by pharmacists, bag marked with a flag to alert clerical staff that counseling is required). Require the pharmacist to review the prescription label with the patient or caregiver, and use a teach-back method to confirm the patient understands the dosing schedule.
- Supply leaflets. Ensure that written drug information leaflets are given to patients and that they contain clear advice about the “single dose only” dosing schedule. Make sure information leaflets are consistent with labeled instructions.
- Enhance labels. When possible, present dosing frequency directions and warnings on patient labels and nursing medication administration records using bold font or all capital letters (e.g., CAUTION: TAKE A SINGLE DOSE ONLY ONCE EVERY 6 WEEKS). Use large print to assist elderly patients with poor eyesight.
- Fill in community pharmacies. Whenever possible, avoid filling lomustine prescriptions via mail order pharmacies or specialty pharmacies unless patient counseling can occur by phone prior to dispensing the drug.
- Reinforce education. For patients prescribed lomustine, reinforce the importance of taking a single dose. Validate the patient’s understanding of the dose
- Pay only for dispensing a single dose. Do not approve more than a single dose (i.e., a 42-day supply) or quantities that exceed 1 dose for outpatient lomustine prescriptions.
- Enhance label warnings. Make warnings to dispense only enough capsules for 1 dose more conspicuous on the carton and closer to the drug name, and also on the immediate container. Update the package insert to the new format, and move this warning closer to the beginning of the package insert in an area of prominence, near but separate from the boxed warnings.
FDA and manufacturer
- Require a Medication Guide. Require distribution of a Medication Guide to patients receiving lomustine. The Guide should highlight the single-dose dispensing requirement and the importance of talking to a pharmacist every time a lomustine dose is dispensed.