Acetaminophen may be the most commonly used medication in both the inpatient and ambulatory care settings. Annually, an estimated 25–30 billion acetaminophen doses are produced in the United States, and in excess of 200 million doses of opioid– acetaminophen combination products are dispensed each year.1 Used properly, acetaminophen is a safe and effective analgesic and antipyretic agent. However, to paraphrase the sage advice of Paracelsus, a physician who practiced in the 16th century, what differentiates a poison from a remedy is the dose.2 When used excessively, acetaminophen has the potential to produce serious hepatic injury and cause death. While acetaminophen has been identified as the root cause in approximately 40% of the cases of acute liver failure in the United States, the actual number of cases is extremely low in relation to the astronomical quantity of acetaminophen used by Americans. The majority of acetaminophen-related fatalities are the consequence of acute intentional overdoses and do not result from the use of therapeutic doses or modest excursions over the maximum recommended daily dose. But the excessive chronic use of acetaminophen is not without risks; accordingly, FDA has convened several advisory committee hearings to address risk mitigation strategies, especially for acetaminophen use in the ambulatory care setting.

In the ambulatory care setting, neither the patient nor the acetaminophen dosage can be monitored, and both supratherapeutic use and overdosage are among the most common exposure calls managed by U.S. poison centers. However, in the inpatient setting, acetaminophen use, like that of any medication, can be controlled, and overexposure should conceivably be a “never event”—one that is both identifiable and preventable. Acetaminophen overexposure does nevertheless occur in hospitals, and in this issue of AJHP, important risk mitigation strategies are addressed in a White Paper from the National Council for Prescription Drug Programs (see pages e428–449).

In the White Paper, acetaminophen is used as the model to identify risk mitigation strategies for pharmaceuticals that have a low therapeutic index—a small difference between the therapeutic dose and a toxic dose. The maximum recommended daily dose of acetaminophen is 4 g administered in divided doses. Hypothetically, any cumulative daily dose that exceeds 4 g is potentially toxic. However, unlike drugs such as warfarin, unintentional minor and even repeated minor excursions in the acetaminophen daily dose, while not advised, rarely result in clinical hepatotoxicity. Nevertheless, several research publications cited in the White Paper identified the prevalence of supratherapeutic use of acetaminophen in the inpatient setting as significant and largely preventable.

The strategies elucidated in the White Paper serve as important guidelines that may be applied to any medication for which strict monitoring of dosage is critical to mitigate the risk of inadvertent overexposure in the inpatient setting. As illustrated in the White Paper, patients who receive acetaminophen are at a particularly high risk of overexposure due to its ubiquitous presence in oral, rectal, and intravenous dosage forms and, in my opinion, the relatively complacent attitude about acetaminophen held by some healthcare professionals. The guidelines recommend a number of specific pharmacist interventions directed toward making acetaminophen overexposure a never event. For example, an obvious and attainable first strategy is to reduce the number of acetaminophen-containing combination products on the formulary to minimize the risk that two or more such products will be used simultaneously. The White Paper identifies several established technologies that include databases and cumulative dose-warning and alert-override systems to notify the pharmacist and thereby optimize care by identifying the at-risk patient. Given the frequency of automated alerts for potential adverse effects, an important recommendation is to recognize the danger of alert fatigue and complacency. While the continuum of inpatient care is important, the bookends of an inpatient stay—admission and discharge—are high-risk periods because nearly 80% of medication errors occur during these transitions. One recommendation is to encourage pharmacist intervention during these two vulnerable times. The pharmacist is the gatekeeper of medication management from admission to discharge. However, if pharmacist resources are limited, admission and discharge may be the two most opportune times to prevent acetaminophen overexposure through medication reconciliation.

As emphasized in the White Paper, the integration of several simultaneous risk mitigation strategies is essential to reduce acetaminophen overexposure in the inpatient setting, but the health-system pharmacist is critical to the ultimate optimization of patient care and medication safety.


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