Temozolomide Adherence Packaging to Reduce Patient and Caregiver Administration Errors in Primary Brain Tumors

Katherine P. Morgan, PharmD, BCOP, CPP
The University of North Carolina Medical Center,
Pharmacy Department and The University of North
Carolina Eshelman School of Pharmacy, Division of
Practice Advancement and Clinical Education
Chapel Hill, NC

Anna Hoppert, PharmD, BCGP, CSP
The University of North Carolina Medical Center,
Pharmacy Department
Chapel Hill, NC

Lauren Meekins, PharmD, MS BCPS, CSP
The University of North Carolina Medical Center,
Pharmacy Department
Chapel Hill, NC

Introduction
Primary brain tumors are a diverse group of tumors that vary widely in histology and therefore treatment strategies. The World Health Organization (WHO) clas­sifies primary brain tumors as grade I-IV.¹ WHO grade IV, or glioblastoma, is the most common type of primary brain tumor and accounts for more than half of all malig­nant tumors in the central nervous system (CNS).1 Prognosis for glioblastoma is very poor with median survival of just over 1 year.² In addition to surgery and radiation, systemic therapy is often needed to pro­long survival in patients with primary brain tumors. A challenge when considering systemic treatment of CNS malignancies is the ability for the drugs to cross the blood brain barrier (BBB). Temozolomide is an oral alkylating agent that has good bioavailability, and due to its lipophilicity and small size, can readily cross the BBB. This makes it ideal for brain penetration.^3,4 Temozolomide also has demonstrated a favorable toxicity profile; the most common adverse effects include nausea, vomiting, fatigue and hematologic toxicities.5

Temozolomide was first identified to have activity in primary brain tumors when it was studied in relapsed anaplastic astrocyto­ma in the 1990s. It was shown to have higher objective response rates and progression free survival compared to the standard of care at the time.6 Stupp et al studied temozolomide in combination with radiotherapy for the first-line treatment of glioblastoma.7 Temozolomide 75 mg/m2 daily, including weekends, during radiation followed by six cycles temozolomide 150 mg/m2 to 200 mg/m2 on days 1 to 5, every 28 days was compared to radiotherapy alone. Radiotherapy plus temozolomide had a statistically signif­icant survival benefit over radiation alone. Temozolomide is now considered the gold standard for first line treatment of high-grade anaplastic astrocytoma and glioblastoma. In the relapsed setting, temozolomide has been studied using a variety of regimens and doses. The regimens differ by dose and schedule, in addition to the 75 mg/m2 with concomitant radiation and adjuvant temozolomide dosed 150 mg/m2-200 mg/m2 on days 1 to 5 every 28 days, salvage or metronomic regimens include 50 mg/m2 continuously, 75 mg/m2 days 1-21 every 28 days and 150 mg/m2 days 1-7 every 14 days.^8,9,10

A patient may receive a number of different temozolomide dosing schedules throughout their treatment course, based on their presentation, specifically the disease and number of relapses. Temozolomide is a prescription drug available in several capsule sizes, including 5 mg, 20 mg, 100 mg, 140 mg, 180 mg, and 250 mg; the dose is based on the patient’s body surface area.11 This allows the provider to achieve an individualized dose through a combination of these capsule sizes. The complexity of each of these regimens can be difficult for patients and their caregivers to understand, notwithstanding the regimen changes through the patient’s clinical course. An added layer of difficulty for these patients is that cognitive dysfunction is a common complication and can arise from the disease or treatment.12 Because of these factors, primary brain tumor patients are at a height­ened risk for temozolomide dosing errors.

Temozolomide patient and caregiver administration errors
A medication error is defined as “any pre­ventable event that may cause or lead to inappropriate medication use or patient harm while the medica­tion is in the control of the health care professional, patient, or consumer.”13 In a 2012 published review of the Institute for Safe Medication Practices (ISMP) and Food and Drug Administration (FDA) MedWatch database, 45 medication errors were attributed to Temozolomide over a fifteen year period.14 Of these errors, 21 (47%) were attributed to patient or caregiver administration error. Many of these errors were associated with the numerous capsules necessary to develop the patient’s personalized dose with the most common error being accidental overdose.¹⁴

Recognizing the inherent risks to patient safety in oral chemo­therapy treatments, the Center for Patient Safety at the Dana-Far­ber Cancer Institute completed a proactive risk assessment for the oral chemotherapy medication-use process. The assessment identified risk reduction strategies for all stages of the medica­tion-use process, and included four specific recommendations for the administration of temozolomide.15 These include: utilization of dosing calendars to ensure clarity on intermittent dosing schedule; providing online educational and management tools for addressing adverse effects; maintain high connectivity between the care team and patients caregivers to ensure safe home administration; and provide temozolomide in prefilled packaging.

After reviewing the risk assessment tool, our pharmacy care team (including both clinic and specialty pharmacy) confirmed the first three recommendations were already in place to minimize the risks associated with temozolomide home administration. Our organization has an integrated care delivery model wherein an embedded pharmacist engages directly with a specialty pharmacy team member who is disease-state focused. Upon prescribing of temozolomide, the pharmacy team ensures patients are provided dosing schedules and receive comprehensive education. Thereafter, follow-up phone calls are made at each subsequent month to evaluate worsening side effects and so that new adherence issues can be identified and addressed. The fourth recommendation was considered, but based on effort versus impact, we decided to hold until we evaluated the impact of the other recommendations.

As of 2019, we continued to receive reports of temozolomide ad­ministration errors from both patients and caregivers through our institution specific medication safety reporting system. Reports of both over- and under-dosing were documented. While overdosing is perceived as more severe, given the immediate concerns for toxicity, there is also concern about the clear benefits of receiving a sub-therapeutic treatment of temozolomide in primary brain tumors. Given these reports, our pharmacy team re-evaluated the utility of dispensing temozolomide in prefilled packaging; the current practice at the time was that each strength of temozolomide was dispensed in a separate amber vial.

Process improvement implementation to reduce errors
Due to the frequency of these patient-reported dosing errors identified within our institution, the specialty pharmacy worked closely with the neurology oncology clinic pharmacist to develop a procedure to dispense all temozolomide prescriptions in adherence packaging. After reviewing our patient safety reports, patients who were dispensed greater than one capsule strength of temozolomide were identified as at the largest safety risk. These patients were placed in the initial adherence packaging pilot. To comply with hazardous drug handling best practices and optimizing the dispen­sation of prescriptions, a designated filling station was developed, which contains dosing cards, a counting tray and spatula specified for hazardous drugs, and the appropriate personal protective equip­ment (PPE). During the filling process, all capsules for each dose are placed one compartment. Labels for each prescription are clearly written to include all capsule strengths needed to complete the dose and all are placed on the same dosing card.

To ensure that the process change was effective, patients were called on their last treatment day of their cycle to ensure they had no additional capsules remaining. In addition, the clinical pharma­cist continued with clinical follow-up one week, one month and monthly for at least the first six months of therapy. For patients who had to administer multiple strengths per dose of temozolo­mide, the unique packaging and expected shipped product was discussed in-depth during chemotherapy counseling to the patient and caregivers to ensure understanding.

Results
Twelve safety events were reported in our internal safety reporting system prior to implementing adherence packaging for patients with multiple strengths (Table 1). Despite success in implementing adherence packaging for this select patient population, patients tak­ing a single strength of temozolomide, either one capsule per dose or multiple capsules per dose, were still at risk for dosing errors. Though less frequent, patient and caregiver administration errors were still reported. Once the process was clearly defined and all staff were trained, all remaining temozolomide prescriptions were dispensed in adherence packaging. Since this process has been fully implemented, no temozolomide related safety reports have been submitted to the internal safety database.

Conclusion
Temozolomide is an oral alkylating agent commonly used in primary brain tumors. The complexity of the different regimens prescribed and potential cognitive dysfunction in this patient pop­ulation increases the risk of patient and caregiver administration errors. Adherence packaging for all temozolomide prescriptions proved successful in eliminating administration errors. Since imple­mentation, zero safety events have been reported related to temo­zolomide administration. However, safety events of this type may be underreported since these errors are generally patient reported and often patients are unaware of their dosing error. In addition, these errors can potentially go unidentified by the clinical team.

While the process for adherence packaging is highly manual, there are clear patient safety benefits. We would strongly recom­mend communication on the topic of adherence packaging between the clinic-based team and specialty pharmacy filling temozolomide prescriptions. This discussion should begin with completing the proactive risk assessment, followed by an effort versus impact analysis to determine your institution’s strategy to enhance safety on dispensing temozolomide.

Table 1. Safety Events Related to Temozolomide Administration Reported to Safety Database

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