FDA limit on acetaminophen dosage linked to fewer hospitalizations, cases of liver failure
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Key takeaways:
- Limit in prescription and opioid products decreased yearly rate of hospitalizations (11%) and cases of acute liver failure (16%).
- Researchers did not report the same reductions involving acetaminophen alone.
A 2011 FDA mandate, which limited acetaminophen dosage to 325 mg/tablet in prescription acetaminophen and opioid products, correlated with a decrease in yearly hospitalizations and cases of acute liver failure related to toxicity.
“Anecdotally we had several patients in rapid succession with acetaminophen overdose — in the setting of taking over-the-counter flu/cold medications — requiring liver transplantation, and we wanted to understand FDA limits around dosing,” Jayme E. Locke, MD, MPH, FACS, FAST, director of the Comprehensive Transplant Institute at University of Alabama at Birmingham, told Healio. “Given the FDA mandate was restricted to prescription combination meds, we decided to see if cases of acute liver failure and hospitalizations were lower post- vs. pre-mandate.”
In an interrupted-series analysis published in JAMA, Locke and colleagues investigated the risk for hospitalization and the proportion of acute liver failure (ALF) cases related to acetaminophen and opioid toxicity before and after the FDA mandate; they derived data from the National Inpatient Sample (NIS) and the Acute Liver Failure Study Group (ALFSG).
Among 474,047,585 hospitalizations from 2007 to 2019 in NIS, 39,606 hospitalizations (median age, 42.2 years; 66.8% women) involved acetaminophen and opioid toxicity. From 1998 through 2019, there were 2,631 cases of ALF, of which 465 (median age, 39 years; 85.4% women) involved acetaminophen and opioid toxicity.
According to results, the predicted incidence of hospitalization 1 day before the FDA announcement was 12.2 cases per 100,000 hospitalizations (95% CI, 11.0-13.4), which dropped to 4.4 cases per 100,000 hospitalizations (95% CI, 4.1-4.7) by 2019.
The odds of acetaminophen and opioid toxicity-related hospitalizations increased 11% per year before the mandate (OR = 1.11; 95% CI, 1.06-1.15) and decreased by 11% per year after the mandate (OR = 0.89; 95% CI, 0.88-0.9).
Further, results showed the predicted percentage of ALF cases related to acetaminophen and opioid toxicity 1 day before the FDA announcement was 27.4% (95% CI; 23.3-31.9), which dropped to a predicted incidence of 5.3% (95% CI; 3.1-8.8) by 2019.
The proportion of ALF cases that involved acetaminophen and opioid toxicity increased to 7% per year before the announcement (OR = 1.07; 95% CI, 1.03-1.1) and decreased to 16% per year following the FDA mandate (OR = 0.84; 95% CI, 0.77-0.92).
“The FDA mandate resulted in fewer ALF cases and hospitalizations related to combination acetaminophen and opioid products,” Locke said. “We did not see the same reduction in acetaminophen alone cases, suggesting that it was the FDA mandate that had the biggest impact rather than education on the topic.”
Locke continued: “Next steps really need to focus on over-the-counter prescription products. The question remains should a similar mandate regarding acetaminophen dosing be in place for over-the-counter combination products as well. We need to be more aggressive about educating patients regarding the amount of acetaminophen in over-the-counter cold and flu medications and encourage patients not to combine these with additional doses of acetaminophen.”
Perspective
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William Carey, MD
Acetaminophen, approved by the FDA in 1955 as an over-the-counter pharmaceutical, is useful for mild to moderate pain. It was formerly sold in the U.S. in 325 mg and 500 mg pills or capsules, although there is no evidence that 500 mg is superior. The drug is also combined with many opioids to extend or amplify analgesia.
Liver failure is common in those who take massive amounts, typical in a suicide gesture or attempt. Measures have been taken in some countries to create barriers to acquisition of large amounts of acetaminophen. Less well-known is the development of liver injury from repetitive lesser doses.
In early 2011, the FDA announced new measures to reduce severe liver injury by limiting acetaminophen to 325 mg per tablet or capsule when combined with opioids. Rigorous studies to demonstrate the benefit of this public health measure are largely lacking. The current population-based study demonstrates a more than threefold reduction in the case rate (per 100,000) of admissions for liver injury from opioid-acetaminophen liver injury, and reduction in the percentage of acute liver injury cases from 27.4% to 5.3%. This absolute risk reduction of 22% is very impressive.
A public health measure with clear goals has been validated in a large study. For the health of our patients, it is best to continue to prescribe acetaminophen when clinically indicated and not to escalate dosage.
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